Absolute values and incidence rate of opisthorchiasis in the Russian Federation and Western Siberian region in 2014–2018.
\r\n\tA quark exhibits confinement, which means that the quarks are not observed independently but always in combination with other quarks. This makes determining the properties (mass, spin, and parity) impossible to measure directly; these traits must be inferred from the particles composed of them. There are six flavors of quarks: up, down, strange, charm, bottom, and top. The flavor of the quark determines its properties.
\r\n\tThere are three generations of quarks, based on pairs of weak positive/negative, weak isospin. The first generation quarks are up and down quarks, the second-generation quarks are strange and charm quarks, the third generation quarks are top and bottom quarks. The up and down quarks make up protons and neutrons, seen in the nucleus of ordinary matter. They are the lightest and most stable. The heavier quarks are produced in high-energy collisions and rapidly decay into up and down quarks.
\r\n\tThe baryons and mesons known at the time fell into symmetric families of multiplets (octuplets, decuplets) sharing two identical quantum numbers (spin and parity), but differing in an ordered way in others (mass, charge, baryon number and strangeness). The mathematical group to fit this complex situation-SU3, the symmetric, unitary group of dimension 3-was proposed independently by Gell-Mann and Ne'eman. The validity of SU3 was demonstrated by the experiment. A major prediction was that a particle (the omega-minus), an isotopic singlet with spin = 3/2, positive parity, mass of roughly 1,680 MeV, negative charge, baryon number +1, strangeness = -3, and stable to strong decay, should exist to complete the 3/2+ baryon decuplet. It was therefore a major triumph for the scheme when the omega-minus, a baryon with the precise mass, charge, and strangeness predicted, was discovered in 1964. All these facts introduced a quark idea fully into modern physics.
\r\n\r\n\tThis book will be a self-contained collection of scholarly papers targeting an audience of practicing researchers, academics, PhD students and other scientists. The contents of the book will be written by multiple authors and edited by experts in the field.
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"41788",title:"Is There an Infectious Agent Behind Prostate Cancer?",doi:"10.5772/54054",slug:"is-there-an-infectious-agent-behind-prostate-cancer-",body:'This CHAPTER deals with a more defined and specified issue: whether we can already identify, point our fingers toward a specific infectious agent or infectivity pathway most likely targeting and lurking behind prostate cancer (PCa). This issue became quite evident in the past 5-6 years, in view of the heated debate on the possible role of a what was considered a novel retrovirus: Xenotropic Murine Related Virus, or XMRV, in the aetiology of PCa and subsequently also of Chronic Fatigue Syndrome (CFS). Over two years ago, the same issue was discussed by the author at the International Congress on Muscle Fatigue held in Pisa in July 2010. That presentation has been now transformed in a paper, which is in press in the journal Neuro Muscolar Disease (NMD, Springer Verlag) [1]. The reader is therefore referred to that article -most likely already published by the time of this book printing- for aetiological considerations on CFS [1]. In this section, I will more extensively discuss the association of XMRV with PCa. Such an association was the first one to be discovered and this finding was the basis for also searching XMRV in CFS. In CFS, the potential association with an infective agent doesn’t appear to be trivial, since “fatigue” has been widely associated with several types of cancer in the so called Cancer Related Fatigue (CRF), also discussed more extensively in the NMD paper [1] [2].
XMRV isolation was not a sudden or isolated finding, but it rather stemmed out of approximately twenty years of research by several groups, with a leading role by the group of R. Silverman [3] [4]. This work, as well, has even older roots, since it was initiated by deciphering the antiviral response triggered by Interferon (IFN). Robert Silverman’s work was pioneering and seminal in this effort: together with Ian Kerr, he clarified the Interferon (IFN) response to viral infection, initially by characterizing the 5’-triphosporylated, 2’,5’-linked oligoadenylates or 2-5A, a second messenger in the IFN response and its synthesizing enzyme (oligo-2’,5’-A synthethase, or OAS) and finally discovering that 2-5A is the activator of an endogenous RNase activity, called RNase L [5] [3]. This is ubiquitously distributed but inactive inside cells, but it becomes strongly activated by binding 2-5A. By using radiolabelled 2-5A as probe, Silverman was able to identify and clone the gene RNASEL and to map later its location on chromosome 1q25 [5]. After approximately ten years, these studies intersected a totally different discovery path. Linkage studies on families with increased hereditary risk of prostate cancer, identified in 2002 the prostate carcinoma susceptibility gene (Hereditary Prostate Carcinoma 1, HPC-1) on chromosome 1q25, the same of RNASEL location [6]. Different alleles on this locus were associated with higher risk of PCa, such as the R462Q variant, which appeared to provide a 50% risk increase, while homozygosity doubled the risk [7]. This association between a locus behaving as a Tumor Suppressor Gene (TSG) and an Anti-Viral Response (AVR) gene is strongly suggestive of viral involvement in PCa. In the July 2010 presentation at the International Meeting on Muscle Fatigue -which was very critical of the XMRV identification- the sound evidence for viral involvement was emphasized. A logical-inference analysis showed that –most likely- a wrong viral candidate was chosen [1], Fig.1. Subsequent work has vindicated our first prediction (XMRV falsification), but additional work is required to strength the association with another candidate Virus that we propose: MFV (see later) [1]. Several studies have confirmed the RNASEL-HPC1 association [7] [8] [9] [4], but not all [10] [4] of them.
For another five years at the turn of the century, these discoveries on HPC-1 remained just suggestive of a viral involvement in PCA, for a locus –RNASEL- which behaves as a Tumor Suppressor Gene (TSG) –as already indicated by an interesting Editorial by Lengyel, in 1993 [11] and as suggested by others [12] [13]. Then Silverman with colleagues DeRisi and Ganem utilized a micro-array approach (viro-chip) [14], in order to try identifying the responsible virus [3, 15]. The first papers on XMRV appeared at the end of 2006/ beginning of 2007: they showed that XMRV was present at high frequency in patients homozygous for the R462Q allele (i.e., 8/20 or 40%) and that it is a xenotropic retrovirus with similarities with murine leukaemia viruses (MuLV) [16] [15]. Xenotropic retroviruses are endogenous viruses, which cannot infect cells of the original species, while ecotropic viruses do. Typically, endogenous murine retroviruses have been divided into two large families: ecotropic and non-ecotropic retroviruses [17] [18]. Ecotropic retroviruses -being still capable of active infection in the same species, i.e. mouse, cells- are present in only one or just a few copies (0-6) per genome. Their genetics is rather well clarified by several years of research [19]. The structure/genetics of the non-ecotropic retroviruses is more complex, also in view of the fact that they are present in a considerable (40-60) number of copies/genome. In recent years, particularly thanks to the work of J. Coffin and J. Stoye [20], non-ecotropic retroviruses have been clarified and subdivided into three subfamilies: xenotropic (XMP), not capable of replicating inside cells of the same species, polytropic (PMV), which are capable of replicating inside cells of several species including the original (mouse) and modified-polytropic (MPMV), which display altered properties in terms structure/function of the env gene [21] [17] [18]. The experiments, which distinguish among different subfamilies of non-ecotropic mouse retroviruses are: 1. infectivity/replication assays; 2. characterization of their structure by restriction enzyme and/or Southern blotting analysis; 3. complete sequencing [20, 21]. For a more detailed overview of this fascinating but rather complex scientific area, the reader is referred to two excellent review articles by J. Coffin and J. Stoye [17] [18].
XMRV was also found integrated inside mesenchimal/stromal cells -rather than in tumour cell genomes- in proximity of genes of cell cycle or hormonal control, which could provide a reasonable link to carcinogenesis [16] [4]. Indeed, such mechanisms variably defined as “promoter insertion” or “insertional mutagenesis” appear to be the most likely involved in chronically (or non-acutely) transforming Retroviruses [22] [23]. This initial report by the discoverer group was followed up a few months later by another PNAS paper, by Schlaberg et al., in which XMRV was associated to approximately 23% of cases by immuno-histochemistry (IHC), while detection of viral DNA by PCR was quite lower (6%) [24]. Beside this rather surprising finding (since the opposite would be typically expected), this report also slightly contradicted the previous ones, since 1. XMRV was directly identified in the carcinoma cells and not in surrounding mesenchimal/stromal cells, 2. there was no evidence of an association between XMRV positive cases in PCa and RNAse-L involvement by mutation/lower function, as previously described in the Urisman et al. paper [15, 24]. In that report, 40% of cases which were homozygous for the R462Q variant in RNAse-L were XMRV+ [15]. In the following months of 2010, another group from Emory University in Atalanta (GA) also reported an association between XMRV and PCa, by employing three different and complementary technologies [25]: a) a very sensitive “nested” PCR assay, b) chromosomal fluorescence hybridisation (FISH) and c) very sensitive technology for detection of neutralizing antibodies (the same group and others had previously developed this technique for detecting anti-HIV antibodies) [26] [27] [25]. Also in this report, the serologic assay was the most sensitive, detecting XMRV antibodies in 27.5 % of cases (11/40), while positivity increased in carriers of the R462Q allele (8/20 –also in this study- or 40% of cases, which were RNASEL R462Q homozygous) [25]. Finally, this report confirmed, as in the original paper by Urisman et al., the presence of XMRV in stromal/mesenchimal and not in carcinoma cells [25]. In the same year, another group from Baylor College in Houston (TX) also detected an association between XMRV and PCa in 22% of cases [28]. However, virus was strangely detected in both tumour and normal cells of affected patients and there was no correlation –as in Schlaberg et. al - with RNaseL status [28].
Together with the appearance of such positive reports, however, a series of studies presenting negative findings started to appear in the literature. Many of these negative reports came from European laboratories, although an initial negative study –often ignored- was from Johns Hopkins University (JHU) in the US [29]: see below. While the issue of XMRV detection in PCa was getting more controversial, another “XMRV-front” opened with the publication in October 2009 of a paper in Science, where Lombardi et al. reported detection of XMRV in 67% (68/101) of Chronic Fatigue Syndrome (CFS) cases [30]. While controls showed much lower detection rates, i.e. 3.7% (8/218), such value (as well as previous ones) was alarming, since it suggested that a few million people may be infected in the general “healthy” population in the US and probably elsewhere [31]. The initial Lombardi et al. paper was followed by larger numbers of negative reports, appearing in the months immediately after its publication: they will not be reviewed extensively in this chapter and the reader is referred instead to the NMD paper [1], with only one exception. In September 2010, Lo et al. published a PNAS paper describing rather frequent association between CFS and a retrovirus different from XMRV: indeed this virus appeared to be polytropic (P-MLV) instead of xenotropic (X-MLV) [32]. While some scientists applauded this novel discovery [33], the PNAS paper was accompanied by an editorial by Andrew Mason’s group, in which perplexities about these very findings were expressed [34]. Indeed, despite the relationship between the two viruses, it was extremely difficult to reconcile these findings or even to explain the discovery of XMRV as due to presence of P-MLV instead. In fact, the two viruses are clearly distinguishable by sequencing. Therefore, the idea presented at that time [33]: that the real culprit in CFS would be P-MLV and that the previous detection of XMRV should de facto be considered P-MLV detection, or that either virus could cause the same disease, was simply wrong.
The very first negative report for XMRV in PCa was from Hamburg, DE and was authored (1st) by one of the first co-authors of the original paper by Urisman: Nicole Fischer [35]. This suggests that very similar detection methods were employed in Germany: XMRV was detected only in one non-familiar PCa (of 87) and one control (of 70) sample. Neither one of these cases was homozygous for the R462Q allele [35]. An even more striking negative result was obtained by Hohn and collaborators in Berlin [36], who did not detect a single positive case among 589 PCa patients tested: this study employed a sensitive nested PCR detection, RT-PCR for gag sequences as well as serology for XMRV-specific antibodies [36]. A number of patients (76) were studied for the RNASEL allele and 12.9% scored positive [36]. Similar negative results were published in additional studies from Ireland (139 cases) [37], Holland (74 sporadic cases) [38], Mexico (55 cases) [39], USA (over 800 patients from a collaborative effort between Baylor, Johns Hopkins etc.) [40] and UK (437 patients from UK, Korea and Thailand) [41]. In the last study, a few patients scored positive: for example 2 out of 6 of Thailand’s patients were positive, potentially reaching a score of 33%. However, evidence of contamination started emerging in this British International study: some of the amplified DNA did not contain a 24 bp deletion which is a hallmark of XMRV and other evidence suggested instead presence of P-MLV (as in the previous paper by Lo et al. on CFS) [41] [32]. A few assays, specific for contamination by mouse DNA, were therefore run to confirm identity of specimens. A very sensitive assay for Intracisternal A-type particles (IAPs) and mouse mitocondrial DNA was completely concordant with XMRV presence, clearly indicating presence of contamination [41]. Therefore, this 2010 paper by Robinson should have already signalled a red-flag warning for XMRV research [41].
At the International Congress on Muscle Fatigue in 2010, I strongly criticized the association between PCa and XMRV, on the basis of such negative findings, most of which had been already published in the literature (July 2010). My analysis at the congress extended to the technology employed, thus suggesting that the viro-chip assay was –most likely- the source of error [1]. Still, data on the RNase-L association with HPC-1 were indicative of viral involvement. Contrary to the situation in PCa, in which a few independent reports confirmed XMRV presence, while they were contradicted by a limited number of studies, CFS association with this virus was essentially based upon the unique paper by Lombardi et al. in 2009, somehow overwhelmed by a plethora of negative reports [1]. However, also in CFS, the case for the likely presence of an infectious agent, most probably a virus, can be made. This is particularly clear, in view of the presence of “micro-epidemics”, often associated with CFS onset [1]. The rather strong evidence for a previous virus infection accompanied by the dramatic personal histories of CFS onset in thousands of patients could explain, but certainly NOT justify, the attachment of some patient-groups to the XMRV hypothesis, sometimes referred in the media as mass-hysteria [224]. We will later discuss whether the viral hypothesis should be completely dismissed in view of XMRV falsification or whether additional viral candidates should be investigated (see section 3).
After 2010, the majority of XMRV reports documented negative results either in PCa or in CFS cases. Yet, the heated debate could have continued much longer, with some extreme defence of the XMRV hypothesis (J. Mikovitz) and with a more balanced overview of the criticisms by R. Silverman (see for example, his excellent review in Nature Reviews of Urology, extensively discussing criticisms) [4]. Examples of debates on possible infectious agents present in human cancers are abundant in the literature: for PCa, HPVs are still extensively discussed as potential etiological agents or onset-cofactors see discussion in Sections 4.3 (3) and 4.3.1 (c). What or who was capable of rescinding the “Gordian Knot” of XMRV cancer/CFS association ? If we want to name a single scientist this is certainly John Coffin, although he extensively collaborated with other groups, especially with the group of S. Pathak. And yet, Coffin himself had written with J. Stoye in Science, accompanying one of the first papers on XMRV discovery -that of Lombardi et al. on the CFS association [30]- a positive editorial comment, which emphasized the future potential of such discovery [31].
It may be instructive in this respect to re-analyse –so to speak: after the facts- the three major editorials, which accompanied the three major discovery-articles associated with XMRV. The first is the article by Dong et al. in PNAS at the beginning of 2007 [16], therefore immediately after publication of the Urisman et al. paper (December 2006). This article really gave credibility to the XMRV hypothesis, by showing that the virus was: 1. capable of replication in human cells, once a complete copy of the provirus was cloned and reconstructed; 2. responsive to the IFN pathway, as it had been predicted in view of the RNase L mutations; 3. uses a specific receptor, XPR-1 (therefore capable of mediating entrance for both xenotropic and polytropic retroviruses) for infecting human cells; 4. in three cases analysed, XMRV was integrated in tumour cells in regions surrounding potentially interesting/important genes, in two cases next to transcription factor genes (CREB and NFAT) and in the third, next to a hormone response gene, causing inhibition of androgen receptor trans-activation (APPB2/PAT1/ARA67). The accompanying editorial, by retro-virologist Hung Fan, is certainly the most cautious and critical of the three editorials [43]. Although underlying the potential importance of these findings, Fan clearly indicated that they were generating more questions than answers and that only by answering such questions could the XMRV hypothesis be strengthened or proven [43]. In one sentence, his cautionary criticism was particularly evident: “However, another possibility is that XMRV is not causal to PC, but reflective of the reduced antiviral status of RNase L QQ individuals; another novel virus whose sequences were not detectd by the ViroChip might be the relevant agent” (bold characters are my additions) [43].
The second fundamental paper for the XMRV hypothesis was the one by Lombardi et al. (2009), in which an astonishing 67% XMRV presence was documented in Chronic Fatigue Syndrome samples [30]. The paper was already briefly described, as well as the strong critical reaction it has generated, although this section is covered in more depth in the NMD review (see [1]) [30]. Surprisingly, the accompanying editorial written by John Coffin and Jonathan Stoye, appears to emphasize the positive aspects of these findings, rather than caution the readers about potential pitfalls, such as contaminations/artefacts [31]. It is apparent that the two Editorialists, among the major experts in mouse retro-virology, believed in 2009 that XMRV had strong connection to CFS, although it should be reminded that other viral infections have been previously associated with CFS (EBV, HHSV-6, HTLV etc., see [1]) [31]. And yet Coffin’s with Pathak’s groups eventually “put the nails into the XMRV coffin one by one” [44]. Far from being a “changing party” episode, reassessment of scientific data and even of personal believes is an essential and intrinsic process of scientific endeavour. One of the greatest epistemologists of past century, Karl Popper, has identified in the process of empirical falsification one of the essential logical characters of science in western world. In his “All Life is Problem Solving” Popper suggests that our scientific theories develop as an evolutionary (almost Darwinian) process, in which it is however falsification rather than verification the discriminating instrument (Occam’s razor). Therefore, it is just natural and physiological that today in science, hypotheses and theories are continuously re-evaluated and reassessed, although in this process strong intellectual honesty and courage are also needed. Most likely, in 2009 Coffin/Stoye positively reacted and were convinced by 1. the fact that XMRV demonstrated a clear homology to MLV endogenous sequences, but different enough and with constant/homologous difference (approximately 10% throughout the viral genome) to let us believe that this was a totally new isolate. 2. The fact that all XMRV isolates detected showed strong homology among each other (less than 30 nucleotide variations in a genome of over 8000 bp.s), could be again evidence of an exogenous infecting agent (but also a contaminating virus). 3. Somehow, the general homology of XMRV with endogenous MLVs of approx. 90% may have been misleading still in 2009, since it might have suggested a mechanism of constant mutation accrual, as in phylogenetic analysis, of which the two editorialists are great experts [31]. In XMRV, however, recombination plays a major and determining role, as it was initially suggested in a PNAS editorial one year later, by Andrew Mason and colleagues (accompanying the third XMRV/MLV paper by Lo et al.) [34] [32].
Lo’s paper initially appeared (or it was presented as) confirmatory of the infection hypothesis in CFS, since a murine retroviral sequence was detected in 86.5% of cases and only 7% of controls [32] [34]. The viral sequences however were not identical or very similar to XMRV, as previously reported, and appeared to be related to endogenous Polytropic retroviruses (PMLV). This generated some scepticism, as in previous work the viral sequences had little difference from the prototype retrovirus -XMRV. In his editorial, Mason underlines some discrepancies and yet does not clearly indicate that the finding of one xenotropic and one polytropic retroviruses are incompatible [34]. In other words, a general misconception could be –and apparently was- generated: there is an endogenous-like mouse retrovirus infecting cells in prostate carcinoma and CFS. In this scenario, apparently it didn’t really matter whether it was marked with a P or with a X (for Polytropic and Xenotropic): the relevant and important point was that some type of murine endogenous-like retrovirus was infecting Homo sapiens in such disorders [34]. The paper by Ila Singh was also in line with such (mis-)interpretation [33]. On the other hand, as also pointed out in the previous editorial by Coffin and Stoye, the strength of the original XMRV hypothesis laid in the fact that all the isolates were similar to each other, although the prototype of XMRV appeared to be unique, different from any retrovirus known at that time [31]. Furthermore, Mason group’s editorial suggested that, while the issue of which retrovirus exactly is present in PCa and/or CFS was being solved, a realistic and effective strategy could have been to test already potential therapeutic approaches with antiretroviral agents [34]. Again, such attitude is logically biased by the caveat that there was no firm evidence at that time for the real involvement of a retrovirus in both human conditions: this has been completely confirmed now by XMRV falsification. In fact, the paper by Lo et al. was rather good evidence against involvement of a retrovirus in both human conditions, since it suggested that contamination could be the cause [32]. Contamination, although denied in Lo’s paper by a series of counter evidences, could explain the association with an endogenous murine polytropic retrovirus and, by extension, also with XMRV [32]. Andrew Mason group’s editorial also emphasized the fact XMRV sequences appeared to be the result of recombinatory events [34]. They observed that in XMRV, while the 5’ portion of its genome shares great homology to polytropic murine retroviruses, the 3’ end is most similar to endogenous xenotropic MLV [34].
This observation, that inescapably leads to presence of recombination, was further developed approximately one year later in a seminal article by the groups of J. Coffin and S. Pathak [45]. In this Science paper in May 2011, Paprotka et al. convincingly showed that XMRV was generated by recombination during passage of the original tumor cells in nude mice [45]. The creation of human cell line 22 Rv1 was reported in 1999 after several passages by xenotransplantation, starting from 1993. The late passages /established cell line display presence of several copies of integrated XMRV provirus as well as high titers of virus production (1010-1011 PFU/ml). However, Paprotka et al. established a few essential and undermining criticisms: 1. First of all, fully infectious XMRV could not be detected in the original tumor explant (less than 1 copy/200 cells). 2. Second, two regions of strong homology with endogenous viruses could be detected: the 5’-end (called preXMRV-2) displays strong homology to PMLV endogenous sequences, while the 3’-end region (called PreXMRV-1) is most similar to an endogenous xenotropic retrovirus (XMLV). 3. Third, highly infectious “recombinant” XMRV started to appear in xenografts passaged in nude mice since 1996, i.e., three years after initial establishment of this tumour xenografts. This strongly suggests that infectious XMRV was created or has infected these cells between 1993 and 1996. 4. Fourth, the original nude mice strains utilized in xenotransplantation experiments did contain as endogenous viruses both the endogenous xenotropic virus (pre-XMRV-1, present in 6 out of 48 tested and typical of European mouse strains) as well as the endogenous PMLV (preXMRV-2, present in 25 out of 48 tested and typical of Asian mouse strains). 5. Fifth, the overall structure of the infectious XMRV could be explained by six recombinatory events between the two viruses: preXMRV-2 and preXMRV-1. Indeed, recombination is known to frequently occur during retrovirus replication, due to a polymerase (i.e., reverse transcriptase) switching between two different templates, therefore a mechanism of “copy-choice” as compared to the classical mechanism of “cut-and-paste” typical of general recombination [45] [46]. 6. Finally, the presence of a unique XMRV structure after so many recombinatory events strongly indicates that this “creation” occurred only once, most likely during xenograft passaging into nude mice [45]. The paper by Poprotka et al. therefore concluded the “XMRV Odyssey” with a most logical and well proven explanation and XMRV-falsification [45].
Additional evidence against XMRV as an exogenous virus infecting the human species were also obtained by the group of Jay Levy, who analysed some of the same CFS samples initially studies by Lombardi et al. Since these patients, initially reported as XMRV-positive, were found devoid of this retrovirus, this finding once more strengthened the evidence for contamination in positive samples [47]. A series of subsequent papers then reported evidence for contamination [45] [44] [48] [49] [50] in: 1. PCR reagents (even Taq polymerase) employed for XMRV detection; 2. microtomes or blades for tumours sections (even one year after the initial experiment); 3. contamination of several cell lines, beside the original 22Rv1. Prostate carcinoma cells lack the APOBEK-GA3 activity and are therefore susceptible to XMRV infection, while other human cells –for example human lymphocytes- appear to be highly resistant in view of the strong mutagenic activity of APOBEK-GA3.
Together with criticism of XMRV as potential candidate for CFS, we presented data in July 2010 [1] related to a novel viral candidate for both PCa and CFS: Micro-Foci inducing Virus or MFV. While the more specific aspects related to CFS association are presented elsewhere [1], MFV properties which link this virus to PCa will be here described.
Micro-Foci inducing Virus was initially discovered in a paediatric tumor diagnoses-association generally defined as “Cancer-Cluster” (CC). A CC of neuroblastoma (NB) cases was diagnosed in Southern Louisiana in 1987-88 in the small town of Morgan City, while also the surrounding area appeared to be affected. A 12 fold increased NB incidence was recorded for a period of 18 months, while diagnoses then decreased to none [51]. This is a typical epidemiological behaviour of CCs, as it has been also recorded in other instances, such as paediatric leukaemia/lymphoma clusters [52]. Most of the tumours of this CC were conveyed to the Ochsner Foundation Research Center for further genetic analysis. The majority of them (66%) displayed elevated MYCN amplification, a well-known marker of aggressive NB. In one tumour with extremely elevated MYCN amplification (1000X the diploid value of controls), we started witnessing an elevated genetic instability in cultured tumor cells (see Fig. 1) [51]. This was accompanied by appearance of very small foci (Micro-Foci, MF) of rounded and refractile cells growing on top of the mesenchimal cells which typically grew up slowly and as monolayer in the initial tumor cultures (1ary cultures) [51] [53]. Furthermore, the initial dramatic amplification of MYCN seemed to disappear in growing primary cultures, apparently diluted out by the growth of mesenchimal flat cells (Fig. 1).
In order to find an explanation for this phenomenon, it was also noticed that the number of MFs was extremely variable, with some cultures having hundreds while others being devoid of them. An assay was therefore established by utilizing supernatants from cultures with hundreds MFs, with which we infected cells devoid of them. Since MF formation could be reproducibly transmitted even after ultra-filtration of such supernatants (through 100 μm filters), presence of a virus was hypothesized and confirmed by Electron Microscopy (EM). Transmission EM detected cytoplasmic particles of 65-73 nm for MFV (Fig. 2), while similar particles of larger size (85-92 nm) were identified in samples of paediatric lymphoma cases (MFV related Virus or MFRV), studied a few years later in Switzerland [51] [53] (Fig. 3).
Molecular cloning and partial sequencing of MFV/MFRV genome convincingly demonstrated that they share strong homology with members of the Reoviridae family, particularly Reovirus-3 (Dearing Strain) (Fig. 4).
Top-left: Southern-blotting analysis shows high level of MYCN amplification in the original NB tumour from a Cancer-Cluster in Southern Louisiana. Lanes 1-3 contain DNA extracted from the original NB tumour, while lanes 4-5 two control DNAs (patient and normal blood donor peripheral leukocytes). Amplification was evaluated as 1000X fold by dilution experiments (not shown). Top-right: Southern-blotting analysis of DNA from the original tumour (lane 2) and from tumour cells passaged in culture for 2 weeks (lane 3) and 4 weeks (lanes 4-5). Bottom left: two microfoci, composed by small, rounded neuronal cells growing on top of a monolayer of large flat mesenchimal cells with Schwann cell markers. Lower magnification (40 X). Microfocus shown at higher magnification (100X).
Electron Microscopy of MFV particles. 2A: negative staining of MFV particles (magnification = 100.000X). 2B and 2C: MFV viral “factories” in the cytoplasms of infected and transforming cells (magnifications: 15.000 and 10.000 respectively). 2D: Negative staining of MFV highest magnification (350.000X).
Electron Microscopy of MFV and MFRV particles. In 3A: MFV particles display a more localized pattern (15K X magnification), while in 3B, MFRV are spread through cell cytoplasm (5K X magnification). Fig.s 3C displays MFV at 350K X magnification (as in 2D) and Fig.s 3D-E MFRVs at 300K X and 175K magnification, respectively).
Comparison of sequences for Micron-NS –µNS- gene from MFV, a classical Reoviridae (Reovirus-3) and one isolate from Burkitt’s Lymphoma (BL). Divergence from Reo-3 is approximately 20%.
Furthermore, extensive work in vitro and in vivo has convincingly shown that MFV causes malignant transformation in vitro and tumours in animals (see Fig.s 5-8) [51] [53].
As shown in Fig. 5A normal, quasi-diploid SK-N-SH cells grow as mesenchimal cell (or Schwann-Cells) monolayers, but after MFV infection they transform (Fig. 5B) into aggressively growing NB cells. Transformed cells extensively grow in these in vitro conditions in the presence of low serum (2%), forming masses of rounded, small and packed cells (similar to MFs), which are loosely attached to the mesenchimal cell monolayer, othen floating in the medium supernatant.
Fig. 5 shows the different patterns of growth of uninfected neuroblastic SK-N-SH cells (a) and MFV-infected/transformed SK-N-SH (b). While the original SK-N-SH cells grow slowly in low serum conditions (Fig. 6), MFV-transformed cells are undistinguishable in their growth properties from cells obtained from aggressive NB tumours -for example, SK-N-BE cells (Fig. 6).
The molecular mechanism of carcinogenesis induced by MFV has been partially clarified when it became evident that normal non-tumorigenic diploid neuroblasts are rapidly destroyed by MFV infection: most monolayers are “wiped-out” in 36-72 hrs [54] [53] [55]. The only cells, which appear to sustain MFV infection without extensive apoptosis, have amplified the MYCN locus [54]. In Fig. 7, in the left panel, Southern blotting analysis (employing a MYCN specific probe) of the cell line SK-N-AS shows that the MYCN is diploid in mock-infected cells (-), but becomes highly amplified (approx. 100X) upon MFV infection and relative transformation (line 2: SK-N-AS +). A similar result was obtained with cell line VA-N-BR (3rd lane) [51]. Similar results were also obtained with cell line SK-N-SH (which is also initially diploid and non-tumorigenic in nude mice) by Q-PCR analysis. Upon MFV infection, these cells acquire a MYCN DNA level intermediate between the mock-infected cells (yellow, green lines) and cell line IMR-32 (MYCN amplification approx. 20X: black line): SH-10 cells (i.e., MFV-infected SK-N-SH) display an amplification level –by comparison- of approximately 10X (blue line).
All cells were grown in Dulbecco’s Modified MEM with the addition of 2 % Foetal Bovine Serum (FBS). NM-1 and SH-10 are two different clones of MFV- transformed SK-N-SH cells, while SK-N-BE is a a Neuroblastoma cell line established from an aggressive tumour with MYCN amplification.
The same MFV-infected/transformed SK-N-SH cells -, shown in previous page [53]- were also employed in in vivo experiments of nude mice inoculation and relative tumour growth. Inoculation of MFV-transformed SK-N-SH cells into the left flank of a nude mouse causes the appearance of large tumoral masses of NB cells (uninfected SK-N-SH cells were injected in the contra-lateral flank as control, Fig. 8).
Southern Blotting and Q-PCR analysis of genomic DNA from cells infected/transformed by MFV. Left panel: Southern blotting analysis of cell line SK-N-AS before (lane 1) and after (lane 2) MFV infection; in lane 3, cell line SK-N-VR after infection/transformation with MFV (see also text description). Right panel: Q-PCR analysis of SK-N-SH cell DNA, DNA from SH-10 (the same line infected/transformed by MFV) and DNA from IMR-32 a cell line from aggressive neuroblastoma with MYCN amplification (approximately 20X). The relative level of MYCN amplification in SH-10 cells is estimated –by comparison- in the order of 10X.
Evidence presented so far indicate that 1. in prostate carcinoma, an interferon-sensitive pathway appears to be affected. Attempts to identify an infectious agent (also on the basis of these observations), had led to identification of XMRV, a candidate virus, which has been eventually falsified by several groups (see part 1). However, as it has been emphasized in this chapter, evidence for viral involvement in PCa are rather strong and independent from the particular isolate XMRV. Indeed, as previously underlined, XMRV isolation is based upon usage of viro-chip technology and logical inference analysis predicts that this step is most error-prone [1]. In order to list and underline numerous elements indicating MFV as a strong candidate, the general IFN pathway is here considered and RNase-L as next point. Although RNase-L is also an essential part of IFN pathway, it will be discussed separately, since it is prominent in view of numerous evidence and studies performed in PCa and other pathologies. Furthermore, the fact that transgenic animals knockouts for RNASEL gene do not develop tumours at higher frequency, suggests that additional elements in the IFN pathway may also be relevant [56] [57]. Since several years ago, the IFN pathways has been extensively dissected: beside RNase-L, two additional pathways are prominent: a) the PKR signal transduction and b) the Adenosine-Deaminase of RNA (ADAR) mechanism.
Tumorigenesis in nude-mice of SK-N-SH cells infected/transformed by MFV. Injection of 107 SK-N-SH cells (right flank) or SH-10 clone (left flank) with the same number of MFV-transformed SK-N-SH cells shows the out-growth 3 weeks later of large tumoral masses in the case of MFV-infected/transformed cells (SH-10). Histological analysis confirmed the presence of human neuroblastoma cells after xenotransplantation [53].
PKR was one of the best characterized pathways in the IFN signal transduction, starting from pioneering work of Isaacs and Lindenman, who initially characterized the IFN activity [58] [59]. One of the first enzymatic activities induced by IFN and its inducers (i.e., dsRNAs) is the dsRNA dependent Protein Kinase or PKR. PKR conveys the IFN message in several ways but especially by phosphorylation of: 1. PKR itself (autocatalysis); 2. the α subunit of eIF-2a ; 3. the inhibitor of transcription factor NFkB, IkB, thus releasing such inhibition; 4. the TAT transcription factor, essential activator of HIV; 5. the NFAT protein and 6. the phosphoprotein MPP4, which binds dsRNA and is activated during the M phase of cell cycle [58] [59] [60]. Among the different activities elicited by PKR activation, the best studied and known is certainly the inhibitory effect on protein synthesis (eIF-2a) [61]. Ser-51 Phosphorylation in this case blocks initiation of protein synthesis, by inhibiting the exchange of guanine nucleotide [61] [62] [63]. There are some discussions and discrepancies on the regulation of PKR from different portions of the gene/structure: two knockout transgenic mice were generated by the groups of Karomillas/Bell [64] and Ch. Weissmann [65] [66].
The first one has been targeted in the carboxy-terminal of PKR, where is present the kinase activity, and doesn’t show impairment of antiviral response or TNF-α responses, thus indicating the redundant role of PK activity [60, 64]. To the contrary, Weissmann’s lab ko mouse and its MEFs are strongly inhibited in view of the deletion of the NH2- portion of the protein, where the dsRNA-binding domain of PKR resides [65] [66] [60]. Effectors of PKR are several types of dsRNA molecules, both artificial and natural [67]. In this respect, the genome of MFV is a strong/ideal inducer of PKR in acutely infected cells, as we have documented in both mouse and human cells. Most likely, PKR induction also contributes to the strong apoptotic effects we have documented 36-72 hours post-infection [53]. In particular, MFV-infected cells completely block protein synthesis and strongly impair rRNA production (see later) and these effects seem to be mediated by PKR and RNase-L respectively. In prostate cancer, the same pathway of PKR appears to be downstream of another essential regulator and also Tumor Suppressor function of prostate cells: PTEN [68]. Therefore, typically the deletion of PTEN (which is extremely common in prostate cancer [69]) will lead to ablation of the TSG function of PKR by phosphorylation of eIF-2a and block of protein synthesis [68] [69]. In view of the MFV/MFRV connection hypothesis, it is speculated that infection by this family of viruses will eventually cause/select for PTEN deletion, as this will inhibit cellular apoptosis, which would otherwise be inescapable [53] [55] [69].
The additional and last form of IFN response here considered is the RNA-specific Adenosine Deaminase or ADAR, which is strongly induced after viral infection [70] [71]. Although such RNA editing was initially considered a rare phenomenon, almost a curiosity of RNA regulation and fine tuning, extensive genomic sequencing by NGS and high-throughput technologies have allowed to discern considerable editing in several DNA genomic sequences by a related Deaminase activity which targets DNA, called APOBEC, as well as ADAR activity on expressed mRNAs [72] [73] [74]. It is still not clear how efficient such mechanism may be at the RNA level, since ADAR activity may protect cells but also favour virus aggression or persistence inside infected cells [70]. DNA deaminase activity as well is still poorly understood, but new phenomena discovered in human cancer cells through Next Generation Sequencing (NGS) technology suggest that genome modulation and plasticity by APOBEC could also play a major role in carcinogenesis [73] [75].
Could the ADAR activity induced by Interferon (ADAR-1) be responsible for important antiviral effects in human and other cells ? Although the question is still open and there are also examples of opposite regulation as previously mentioned –for example in Hepatitis Delta Virus (HDV) [70]-, important inhibitory effects were documented, with Measles Virus [76] [77] and with Influenza Virus in mouse cells [78]. Furthermore, a specific gene of the Adenovirus genome is responsible for counteracting the RNA-editing activity of ADAR: the VAI gene [79]. In the case of Reoviridae, little is still known but there is at least one animal model in which ADAR was induced by both artificial dsRNA and reoviridae genome (which obviously is dsRNA), although the response modality of ADAR appeared quite different [80] [81].
Among human cancer as well very little is known, particularly in the case of prostate carcinoma [82] [73]. More data have been obtained in the case of brain tumours, since ADAR is known to effect important editing in brain neurons. In at least two tumour examples, hypoediting seems to characterize cancer cells. In glioblastoma multiforme, rectification of a mutated permeable glutamate receptor to Ca++-impermeable receptor suppressed proliferation [83] [84], while in hypo-editing astrocytoma cells, re-balancing editing expression induced regression [85]. Additional work on ADAR/APOBEC in prostatic cancer and reoviridae is certainly warranted.
The clearest evidence for viral involvement in prostate carcinoma and in human cancer in general was obtained through studies of the IFN response leading to RNase-L activation. The general scheme of IFN genes activation has been clarified through years of intense studies with several models, cell lines, laboratory and transgenic animals, in vitro assays and molecular/biochemical systems [60] [86]. Without getting into too many details –and referring instead the readers to some excellent review articles on this subject [60] [86] [87] [88] - two general types of IFN molecules are known: viral IFN and immune IFN. Both IFN-α and IFN- β (as well as IFN-omega) belong to the viral form, induced by viral infection [60], while the immune form is essentially composed by IFN−γ and is induced by immune stimulation. Focusing on viral genes, this is a rather large family in humans, since 13 genes for IFN-α, 1 for IFN-β and one for IFN-omega were mapped on the short arm of human chromosome 9 [89] [90]. None of these genes contains introns, while the only IFN gene with introns is the IFN-γ form with 3, on the long arm of chromosome 12. Two types of IFN receptors, IFNAR-1 and IFNAR-2 are known on human chromosome 21: they must heterodimerize for activation by IFN-α/β [91] [92] [93]. The following signalling is today understood mostly in the JAK-STAT transduction pathway, thanks to the work of several molecular biologists, first and foremost the group of Jim Darnell at Rockefeller University [94] [95] [96]. STATs are “signal transducers and activator of transcription” molecules: at least seven of them are known, i.e. Stat-1, Stat-2, Stat-3, Stat-4, Stat-5a, Stat-5b and Sta-6. STATs are activated by members of the Janus family of Tyrosine kinases (JAKs), of which 4 members are known, i.e. Jak-1, Jak-2, Jak-3 and Tyk-2. Various combinations of Jak’s and Stat’s elements are active in transducing both viral and immune IFN signalling [87] [88]. Additional important elements are the IRFs, (IFN Regulatory Factor) family [97], which cooperate in the activation of IFN-responsive genes. These are characterized by presence of regulatory elements: ISRE or IFN-stimulated Response elements [98], usually for viral IFNs and the GAS (gamma IFN activation sites) [99]. In conjunction with Stat’s, IRFs constitute the so called ISGF (IFN stimulated gene factor’s) [100]. Having clarified this terminology, ds-RNA activation of IFN pathway does not always or only use Jak-Stat elements. The transcription factor IRF-3 (IFN response Factor 3) acts as subunit of a complex called ds-RNA activated transcription factor complex (DRAF) by sereine/threonine phosphorylation, translocation to the nucleus, association with p300/CBP and gene activation [101]. Among the activated genes, the Oligo Adenylate Synthetase gene family, or OAS, is one of the most important, because it conveys the anti-viral signal to the next and final effector: RNase-L. In humans, three OAS genes of different sizes (proteins of 40-46 kDa -OAS1-, of 69 kDa –OAS2- and of 100 kDa -OAS3-) have been mapped on the long arm of chromosome 12 (12q24.2), thus suggesting genome duplications in H. sapiens [102]. Similarly to the effectors previously considered –PKR and ADAR-, OAS proteins do contain regions for binding dsRNA, the signalling and activating effector [103] [104] [105]. However, all three effectors contain separate regions with peculiar enzymatic activities: kinase, deaminase, synthethase [60]. The exact nature of dsRNA activators is not always completely clear, but hypothesized to be formed by or to contain dsRNA elements. In the case of interest, i.e. MFV/MFRVs infection, since these belong to Reoviridae family, it is clearly fragments or segments of viral genome (dsRNA) [53] [55]. Great variation has been documented in the extent/level of OAS activation and 2-5 A production [80].
Last element, RNase-L, is activated by 2-5 A signal molecules, typically oligomers with >2 elements for optimal induction, while RNase-L must dimerize for activation [106] [107]. This endoribonuclease is typically present as monomer in a latent form, essentially in every cell (tested so far), but -after 2-5 A interaction- it homodimerizes and is activated [107], although heterodimers with RLI (RNase-L inhibitor) have been also described. As previously mentioned, RNase-L gene, called RNS4, has been mapped on the long arm of chromosome 1 (1q25), on a location corresponding to the chromosomal site for the Human Prostate Carcinoma susceptibility (HPC-1) [108], as mapped with linkage studies by Jeff Trent and others [108] [6].
In view of the coincident chromosomal location of RNASEL and HPC-1 [6] [108] and the initial speculations by Lengyel and others that this gene may behave as a bona fide Tumor Suppressor [109] [12] [13], Silverman with DeRisi and Ganem undertook the described viro-chip high-throughput search for potential viral candidates, leading to XMRV isolation [15]. As previously described and discussed in Section 1, XMRV identification has been clearly falsified as a recombination artefact arising during xenograft transplantation in nude mice [45].
In view of the coincidental chromosomal localization of HPC-1 and RNASEL, what are the evidence for RNase-L involvement after MFV/MFRV infection ? The acute phase of infection by these viruses is accompanied by a very high activation of RNase-L [53]. An assay, detecting ribosomal RNA (rRNA) degradation in infected and transforming cells was developed (U. Rovigatti, unpublished), thus confirming the extremely high levels of RNase-L induction, often leading to block of cell proliferation and apoptosis [53] [55]. In the past several years, groups in USA, France and Belgium have also documented a strong deregulation of this endoribonuclease in patients affectd by Chronic Fatigue Syndrome. Pioneering work by Suhadolnick et al at Temple Univ. initially disclosed that 2-5 A activated RNase-L is upregulated in CFS patients [110] [111] [112]. This finding was followed up by description of a lower molecular weight form (37 kDa) of the same enzyme in CFS patients by the same group [113]. The French-Belgian group of De Meirleir et al. then showed that the 37 kDa fragment is proteolytically cleaved from the original enzyme of 87 kDa, by human elastase and/or calpain [114]. The same authors also speculated that the levels of 2–5 A molecules with structures larger than dimers (trimers/tetramers) protect the 83 kD moiety from degradation [115] [116]. Presence of the 37 kD RNase-L could also explain the higher enzymatic activity (associated with the low MW form) and the ratio between the two forms was proposed as potential marker for CFS [117] [111] [118].
In conclusion, the extremely elevated levels of RNase-L in every cell type infected by MFV indicate that this could be an important parameter to be evaluated. Analysis is being performed for addressing the question of whether cells with impaired/mutated alleles of RNase-L (such as the R462Q allele) may be more resistant to the apoptogenic effect(s) of MFV/MFRV and could become better targets for carcinogenesis [53] [55] [1].
Inflammation has been estimated as being somehow responsible for 20% of human cancers: these are typically linked to infectious agents, causing chronic infections as well as by other environmental factors [119] [120] [121]. While it appears to be an essential component of carcinogenesis –being defined as “the seventh hallmark of cancer” [122]– inflammatory proceses are particularly prominent in PCa [121] [119]. Furthermore, inflammation in PCa adds an enigmatic component, which could be or become one of the best clue for deciphering its aetiology [55]. This enigmatic nature is however rather complex, as it can be distinguished by several elements:
The paradox of a rather common disease (most common cancer among men), afflicting this year over 300.000 people and killing more than 33.000 patients, only in the US [123]. For comparison, it has been observed that there is just a handful of cases described in the literature for Primary Seminal Vesicle Carcinoma, essentially in the same anatomical location [124]. This shows a peculiar and striking difference between two very close histological sites: PCa is diagnosed only in the prostate peripheral zone, rarely in the transition zone and almost never in the central zone [125]. This pattern is accompanied by typical phenomena of inflammation which is almost never of acute type (at time of diagnosis) and is characterized in the described zones by: a. chronic inflammation, b. benign prostatic hyperplasia (BPH), d. focal atrophy, e. a new type of inflammatory response defined as prostatic inflammatory atrophy (PIA) and finally developing into f. prostatic intraepithelial neoplasia (PIN) and/or g. prostatic carcinoma (PCa) [125] [126] [127] [128]. This pattern associates with an extremely common disease, the most common form of cancer in men, again suggesting a rather “common” causality [55]. As we will also consider other clues (see 2,3,4), the best explicatory mechanism is that of a common infection, in particular an infectious agent which is “endogenous” or “persitent” in H. sapiens and apparently much more frequent in certain human populations or races [129] [130] (see below)
Variation in epidemiological data for Chinese, Japanese or Arab men in comparison with the male population in Western Countries: for example, men born in South East Asia who then migrated to the US acquire a higher incidence within the first two generations [130] [131] [132]. In Shri-Lanka men, the incidence was recently assessed as 5.7 per 100.000 males, while such incidence rose up by twenty folds in immigrants to the Western Countries (for example, UK) [133]. This is again indicative of “life-style” rather than genetic factors being responsible for prostate carcinogenesis. Similar data are also present in Japanese men who migrate to the US [134]. Using similar epidemiological approaches, Hsing has recently divided different nations into three risk groups for incidence and mortality of PCa. The high risk group includes USA and several European Countries; to medium risk group belong European Nations such as UK, Italy and Spain, while Asian Countries are mostly included in the third, low risk group [130]. There is a general trend of increasing incidence, which the authors attribute to westernisation of life-style in the low-risk nations, but to TUR (trans-uretral resection) and PSA-testing in the high risk Nations [130, 134]. Interestingly, the incidence in US black males is 50-60 fold higher that that in Shanghai, China [130] [135]. The data by Julian Peto and others have confirmed these trends and the rapid changes in incidence/mortality in migrant populations (often within the first generation), thus emphasizing the concept that factors different from genetics (i.e. environmental, such as infectious agents) may be responsible [129].
The fact that inflammation, BPH and PCa typically occur in the prostate peripheral area, with almost no tumours in the central zone. This led initially LM Franks to hypothesize that in prostate cancer, the inflammatory effects are always accompanied by hyperproliferation and/or atrophy/necrosis [126]. Later, McNeal et al. have elaborated the same concept, by noticing in 1988 that in the whole gland, there is a clear-cut zonal distribution [125]. Out of 88 tumours studied, the majority (68%) arose in the peripheral gland, while 24% in the transitional zone and only 8% in the central gland zone. As mentioned, this suggests that infection through ascending urethra could be a responsible/associated factor [125] [136] [119]. Although bacteria have been initially suspected as responsible for inflammatory phenomena and as causes of carcinogenesis (Neisseria Gonorrhoeae, Clamydia Trachomatis, Trichomonas Vaginalis, and Treponema Pallidum), such intepretation has been reconsidered in post-antibiotics era, since prostatic persistant bacterial infections have dramatically dropped [137]. Still, bacteria can be often grown even from expressed fluids of asymptomatic men [138]. The possible causality by viruses is still an open question, as extensively discussed in the first section on XMRV discovery and refusal. Among viruses, several have been extensively investigated throughout the years and particularly: i.\n\t\t\t\t\t\t\tCytomegalovirus (CMV) has been investigated in view of its association with malignant transformation in vitro. Seven studies on tissues and 2 on serology do not support an association with PCa. [139] [140, 141] ii.Epsten Barr Virus (EBV) levels were shown to be not significantly different in PCa/BPH by Ab’s, PCR and IHC; [142] iii.\n\t\t\t\t\t\t\tHHV-8 was initially detected by Chang and Moore in Kaposi Sarcoma (KS) by subtractive hybridisation [143]. Initial positive results in PCa by Monini et al. [144] were later explained by infiltration with lymphocytes, most likely in HIV-1 positive (and therefore HHV-8+) patients [145, 146]. Also, the strongly positive findings by Hoffman in men from Trinidad and Tobago can be probably explained by bias of selected controls [147] [148]. iv.\n\t\t\t\t\t\t\tPolyoma Viruses have been also associated with PCa: an initial report by Monini et al. [149] was followed by an interesting paper by Das et al., since they found BKV DNA positivity more frequently in malignant tissue [150]. However, also these studies were not confirmed [151] [152]. v.\n\t\t\t\t\t\t\tHuman Papilloma Viruses (HPVs) : Extensive work has focused on these viruses throughout the years. Their relevance was also surmised from studies on women cervical/uterine cancer –pioneered by Harald zur Hausen (Nobel Prize for Medicine in 2008)- where HPVs are clearly involved in >90% of cases [153]. However: i) even Zur Hausen in reviewing this subject in his Nobel lecture dismisses the role of HPVs in PCa: in this sense, men would be some kind of “healthy carriers” of the viral carcinogen [154]; ii) Several studies have been published, some of which with positive results (for example, in an Argentinean study, 42% PCa were positive versus 0% BPH samples) [155]. However, in 24 studies from other Countries, there is no evidence of different HPV involvement between cancer specimens and controls [156]. Furthermore, the most recent meta-analysis didn’t show significant OR for PCa associated with HPV-16 (OR = 1.09) or with HPV-18 (OR = 1.08) infections [157]. Similar results were obtained by a recent review article (in press) [156]. iii) Another element which does not fit HPVs as potential carcinogens in PCa is the observation –initially made by Woodsworth [158] - that HPV infections do not elicit high inflammation or inflammation at all ([158], see also later discussion). As already mentioned, inflammation –most likely associated with a prostatic infection- is one of the Hallmarks of Cancer, particularly in this tumor type, PCa [122] [121].
Several reports (Platz; Mahmoud; Chan; Jacobs) have documented that assumption of aspirin or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) for different periods could considerably lower PCa risk [159] [160] [161] [162]. These studies have been expanded in recent years, particularly by the work of Mahmud with several Meta-Analyses [163] [164, 165] [166] [167]. A positive correlation has been detected for aspirin usage (protection) with OR in the range of 0.81- 0.83 and this is confirming what was already known from animal studies, which typically display stronger and clear-cut protective effects (also with NSAID). In the case of NSAID, the effect is less apparent, or maybe diluted out [166]. In most recent nested case-control studies, Mahmud has confirmed a modest but significant effect with all propionates, ie. Ibuprofen, Naproxen etc., but not with other NSAIDs [167]. The question is somehow connected also to the relationship between BPH and PCa, since the former has been often considered a precursor and initial inflammatory response leading to the latter [168] [169] [170]. Additional findings hower do not lend support to this hypothesis [171] [172]. Finally, a very recent study by Sutcliffe and others also does not show any effect for NSAID treatment in BPH as well as LUTS (Low Urinary Tract Symptoms) [173]. In either cases and also in view of the Mahmud meta-analyses, there may be a positive (protective) effect, but too small and/or diluted out [173].
First of all, this family of viruses infects the human population in the first years of life. By age 5, >95% of human population displays antibodies against Reoviridae and this type of viruses have been shown to be capable of persisting in infected patients and animals for several months/years [174]. Furthermore and as discussed in the next section, MFV/MFRVs display all the features of a “Stem Cell Virus” (SCV), with features of interaction in early childhood with a developing immune system [53, 175]. That a prostate cancer stem cell may be present in PCa and targeted in the first phase of carcinogenesis has been longly hypothesized and recently confirmed [176] [177] [178]. Further studies are certainly warranted in order to assess presence of MFV/MFRVs in early childhood and during ontogeny [55].
Different levels/types of MFV/MFRVs appear to be present in different human populations worldwide. However, a clear picture of the specific subtypes involved is still missing, particularly for what concerns MFV/MFRVs. This should be clarified experimentally (by viral nucleic acid and specific protein detection, presence of antibodies etc.) [174]. Furthermore, essential aspects of these viruses features are still missing as we do not have full knowledge of these viruses genome sequence/structure [53]. Patterns of infections and micro/mini-epidemics in different populations could be deduced and mirrored by what is happening with Rotaviruses (another member of Reoviridae) in the paediatric population, where dominance of one particular genotype was shown to dramatically change from year to year, at least in Central and Eastern Europe [179].
The question of inflammation in PCa leads to the search of a causing agent in both affected patients and experimental systems. This chapter has dwelled trough different aspects of this essential question. The presented appraisal of potential responsible agents clearly indicates today a lack of credible candidates among bacterial infections. Even for viral candidates, the previous discussion showed that Herpes Viruses (CMV, EBV, and HHV-8), Polyoma Viruses and Papilloma Viruses lack some of the essential features as triggering agents [157] [156]. For all these viruses, extensive detection studies were performed for years without reaching any consensus nor obtaining evidence for their presence but in a limited percentage of cases [157] [156]. Same negative result was finally obtained for a Retrovirus, XMRV, after much controversy and discussion [4] [45] [44] [48] [49] [180], while a previously retroviral candidate (HTLV-II) had been previously falsified in the case of CFS [181] [1]. It must be stressed that the essential feature discussed here is inflammation and the two most likely candidates in the previous list, i.e. Retroviruses and Papillomaviruses do not appear to induce inflammation as expected from analysis of PCa: I) Retroviruses are known to be capable of replicating inside cells, even without causing cytopathic effects or transformation for that matter [182]; II) for HPVs, the quoted work by Woodworth has clarified this point. He wrote [158]: “A hallmark of HPV infection is absence of an inflammatory response. Basal cells express low levels of HPV early proteins, they don’t undergo lysis, and they are not rapidly recognized and destroyed by resident leukocytes such as NK cells and tissue macrophages..…HPV infections can persist and remain latent for long periods and may induce tolerance to HPV antigens..”
To the contrary and as described in Section II, MFV/MFRVs are strongly apoptogenic and capable of inducing strong/very strong inflammatory responses in several experimental systems [53] [1]. In preliminary experiments, we have established primary cultures from approximately 20 cases of PCa. In the majority of cases, cultured cells displayed extensive cytopathic effects and did not survive for extensive passages, with three exceptions. While these results confirm previous descriptions by Frank, McNeal and by De Marzo’s group [125] [126] [127] [128], they also suggest that whatever factor elicited strong inflammatory mechanisms in the prostate, with cycles of hyperplasia and of necrosis, the same factor may increase its effects during in vitro culturing [55]. We are presently testing this set of PCa tumors and relative cultures (different passages) for presence of MFV/FMRVs.
Although never specifically tested, sialycilic acid and similar salts have been shown to be effective for the containment/ replication-inhibition of this family of viruses (reoviridae) [183] [184]. Any strategy or molecule capable of reducing their inflammatory responses would probably elicit similar results.
Essential aspects of PCa have been here discussed with emphasis on viral models [55] [1]. In this last section of the chapter and also in dealing with peculiar aspects of PCa carcinogenesis in connection with an infecting virus (with MFV/MFRVs as potential candidates), the issue of Cancer Stem Cells (CSC) or stemness will be discussed. The concept of Cancer Stem Cell dates back to much ground work in the past two centuries, with several pioneers such as Julius Cohnheim and Rudolf Virkow already in the 19th century: they predicted the existence of “embryonic rests” at the origin of tumor formation [185] [186]. At the beginning of XXth century, Pappenheim hypothesized the existence of embryonic stem cells, but it was only in the second half of ‘900 that experimental evidence was provided for them [187]. In Toronto, in the ‘60s and ‘70s, the research of Ernest McCulloch and James Till demonstrated that only a minute fraction of myeloma cells grew in in vitro assays in order to form colonies in semisolid media [188, 189]. The Toronto school settled the basis for further work by John Dick (see later). In the same years, similar work was carried on by Robert Bruce, showing that only 1-4% of lymphoma cells did transplant into recipients [190], and by Jim Griffin, who demonstrated low clonogenic potential for Acute Myelogenous Leukaemia cells growing in methylcellulose [191]. Three additional lines of research paved the way for the final development of CSC hypothesis. 1. Mutations or translocations were discovered in cells at birth, which became markers of leukaemia-precursor cells (i.e., TEL-AML1, MLL-AF4, AML-ETO, OTT-MAL): these cells behave as leukaemia stem cells, since they could differentiate into several lineages/compartments, while additional mutations were required for achievment of full-leukemogenesis [192] [193] [194] [52], 2. the work of Peter Fialkow clearly indicated clonal expansions of leukaemia stem cells in specific diseases such as CML, AML and Myelodisplastic Syndromes (MDS) [195] [196]. Most of this work was carried on using genetic markers such as G6PD, present on the X chromosomes: in females, one of the X is silenced by the so-called lyonization phenomenon (from Mary Lyon’s work) [197], thus allowing to distinguish the expansion of individual clones in cases of heterozygosity (for ex., A/B alleles for G6PD) [198] [199]; 3. The work of A. Hamburger and S. Salmon in Tucson, AZ, who also showed low frequency (1/10-3 to 1/10-4) of colony formation from solid tumours [200, 201]. These experiments were, however only partly convincing or reproducible (for example, in S. Salmon’s work) and further ethical questions and concern were raised by experiments of C. Sautham and A. Brunschwig who injected harvested cancer cells into the same cancer patients, again discovering that only large numbers (i.e., 106) were capable of tumor iniriation [42]. Only at the end of the 80’s and with the advent of authomated high-speed Flurescence Activated Cell Sorting (FACS) [202], the group of John Dick in Toronto was capable of convincingly and reproducibly demonstrating the existence of Leukemic Stem Cells (LSCs). This was accomplished by xenotransplantation assays, in which LSCs from AML were transplanted into Severe Combined Immunodeficient (SCID) mice, often crossed with Non-Obese Diabetic (NOD) mice, in which also the natural immune response (NK cells) is defective [203] [204]. In order to demonstrate stemness, these experiments had to prove the three essential features of stem cells, i.e. a. their capability of remaining dormant, b. their pluripotency, being capable of reproducing the full spectrum of cancer (i.e. leukaemia) phenotype; c. their capability of self-renewal by asymmetric division, thus, giving rise to both bulk tumour cells and their immature precursors [205] [206]. The paper by Bonnet and Dick in 1997 is considered the first clear-cut demonstration of the LSC concept by xenotransplantation [207]. Subsequently, the same concept (Cancer Stem Cell or CSC) was also proven in solid tumours, initially in breast cancer by Al-Hajj et al. in 2003, where the CSC was shown to be CD44+CD24-/low lineage [208]. However, additional markers were subsequently identified in breast cancer, one of the most interesting ones being Aldehyde Dehydrogenase (ALDH), which appears to affect the phenotype of cancer cells, being associated to capacity of detoxification and a more aggressive behaviour also in other types of CSC [209] [210]. ALDH however doesn’t seem to be an universal marker, as it is not, for example, associated with a more aggressive phenotype in melanoma cells [211]. Another controversial issue in recent years has concerned the frequency of Cancer Stem Cells (CSC) in different tumours. For example, a recent paper by Quintana et al. calculated that with an assay employing NOD/SCID IL2Rg mice, up to 25% of melanoma cells were tumorigenic [212]. Similar controversies are also present for the identification of prostate CSC [176] [177] [178]. In fact, two different populations of SC and prospective CSC were isolated in PCa [213] [214]. An initial paper in Nature described regeneration of the whole prostate from a single basal cell, which in addition to classical markers of prostate cell differentiation (Sca-1+, CD133+, CD44+) also displayed presence of c-KIT receptor (CD117+) [215]. However, a subsequent paper by the group of Michael Shen convincingly showed that among luminal cells, rare precursors exist which display presence of the homeobox gene NKx3-1 in absence of androgens and are therefore called castration-resistant Nkx3-1 expressing cells (CARNs) [216]. These cells can reconstitute prostate ducts after transplantation and, upon deletion of the suppressor gene PTEN, rapidly form carcinomas in vivo [216]. Finally, the group of Owen Witte has recently shown that it is also a basal cell which can initiate tumorigenesis in nude mice through cooperation of AKT, ERG and androgen receptor [217]. It is therefore possible that more than one precursor stem cell is the target of malignant transformation in prostate cancer. Furthermore, this could also fit with the described PCa carcinogenesis, in which a rather diffuse “field effect” has been known for some time [218] [219].
In initial preliminary experiments, we have shown that dilutions of MFV/MFRVs for several log.s (from 10-2 to 10-8 FFU/ml) will cause a similar number of transformants, thus indicating that the limiting factor was not the virus itself, but rather its target. Since an equal number of precursor stem cells are believed to be present in such cultures, it is hypothesized that the target is indeed a SC [1].
The Micro-Foci induced by MFV have several features of deranged stem cells, in which genetic aberrations took place, such as MYCN amplification in neuroblasts and t(8;14) / t(2;8) in paediatric lymphomas (BL-type). Even the so-called organoids or tumorspheres of PCa (prostaspheres) have similar fetures of MFs: we are now performing experiments in order to convert normal prostate tissue/cell lines into prostaspheres by MFV infection [53].
As mentioned, PCa is characterized by an initial oligoclonality, which underlines carcinogenesis through a “field-effect” (FE). Evidence of oligoclonality were also obtained by molecular biology studies (see next point). However a molecular explanation for FEs is still lacking [218] [219]: MFV/MFRVs could explain FE alterations in view of the slowly progressing infection, mostly through cell-to-cell contacts [53] [55].
In approximately 50% of PCa, peculiar translocations TMPRSS2-ERG have been detected, which join together an androgen regulated gene: the transmembrane protease serine 2 gene, TMPRSS2, with at least 26 different genes for transcription factors [220] [221, 222]. Although data on association of translocations with PCa aggressiveness are controversial, the translocation is an excellent marker of clonality (individual breakpoints): they have shown initial existence of oligoclonal disease, further evolving into monoclonality during metastatic disease [223].
We have shown in several experiments –and previously discussed in section 2- that MFV/MFRVs infection is associated or causing peculiar genetic aberrations such as MYCN amplification (I.E., Fig. 7) or t(8;14) / t(2;8) translocations in paediatric lymphoma [53]. Similarly, we hypothesize that the associated translocations induced by MFV/MFRVs in prostate cells are TMPRSS2-ERG translocations, which would confer resistance to virus-induced apoptosis [55]. Experiments are being carried out in several PCa biopsies already characterized for presence of translocations (in 25% of cases).
In this chapter, a review of general literature, as well as data previously published or unpublished by the author, was presented with the specific aim of fostering an ongoing debate on prostate cancer aetiology. This debate was particularly spurred in the past six years by the controversy arising after isolation of a new retrovirus, highly homologous to endogenous xenotropic and polytropic murine retroviruses, called XMRV [55] [1].
The first part of the chapter has focused on XMRV, its isolation and eventual falsification, also as a “parable” of scientific trajectories and behaviours in science. The most heated episodes are probably missing (but the reader could easily find them in some well-written editorials, for example the one in Science: False Positive, [224]), but the scientific rationale should be easily followed from isolation to falsification. In this first section, I underlined the difference between RNASEL – HPC-1 association and XMRV identification. While the first is rather logically strong and corroborated by several evidence and years of research, the second was essentially based on just one high-throughput technology –kind of shot-in-the-dark- experiment. It is easily biased and prone to artefacts, as it happened in this instance. However, the idea of an infecting agent in PCa is strengthened by several other elements, of which RNASEL involvement is only one (also: IFN, PKR, etc are affected; presence of inflammation, involvement of peripheral prostate, field cancerization effects, etc.).
In the second part, the candidate MFV virus was presented, in view of its affinity with PCa (IFN involvement, RNase-L strong induction, generation of inflammatory mechanisms). For RNase-L, evidence was also coming from CFS studies, again pointing toward similarities between the two conditions (and cancer related fatigue –CRF ? [2] [1]). Furthermore, MFV was isolated from a cancer-cluster (NOT through PCR enrichment) in view of its strong/powerful biological activity. This is exemplified by its very strong apoptogenic mechanisms (entire cultures wiped-out in 36-72 hours) or its capability of inducing strong genetic instability, leading to genomic aberrations, such as MYCN amplification and t(8;14) or t(2;14) [53].
Finally, in the third section, the elements of PCa carcinogenesis, where MFV/MFRVs could show more clearly its effects, were underlined: they included IFN pathways, RNASEL, inflammation and MFV capability of infecting/transforming stem-like cells [53] [55].
What are then the MFV/MFRVs properties which should be emphasized or taken home as messages? Or how we should rationalize them in this ongoing debate on PCa carcinogenesis ? As mentioned, the RNASEL – HPC-1 paradigm is logically strong and also in CFS numerous evidence point toward infections (micro-epidemics, virus-infection symptoms, IFN pathway etc.) [3] [1].
One essential property of MFV/MFRVs is its biological power, which could lead to strong and persistent infections and long-lasting inflammations in affected hosts. This could easily explain cycles of necrosis/regeneration, which we witness in BPH, PIA, PCa [53] [119].
A second important question -not addressed by this review for limited space- regards the nature of these viruses and whether they have been isolated before. In view of the persistent/ long-lasting infections they can initiate, an easy comparison/association is with EBV, which infects H. sapiens in early childhood/youth (depending from geographic areas), then remaining latent, and has been also associated with lymphomagenesis and other human cancers. Indeed, in the hospital-safari’s expeditions of Dennis Burkitt, there was a second type and non-Herpes virus (not EBV) constantly isolated [225] [226] [227] [228] [229] [230] [231] [232] (also: Jay Levy/ Thomas Bell, personal communications). All the data available today point toward a virus similar to MFV/MFRVs: in this sense and in view of our MFRVs data, these viruses could be the missing link to malignancy in BL (EBV does not cause malignancy, it just immortalizes lymphoblasts) [53] [233].
A final question, in view of the close relationship of these viruses in terms of persistence in the human population, is what justifies this proximity, which –at least for its “cousin EBV”- resembles parasitism. Several authors and M. Greaves among them, have introduced elements of “Darwinian-medicine” analysis in our interpretation of carcinogenesis [234] [235] [52] [175] [236] [237] [53] [55] [1]. The take-and-give of MFV/MFRVs with H. sapiens infections could certainly be associated to some of their properties. For example, to their strong apoptogenic effects, leading to inflammatory reactions in BPH/PIA/PCa, but also possibly to useful tissue modelling/reshaping in other instances. The described strong relationship of these viruses with stem-like cells further suggests a closer partnership of MFV/MFRVs with H. sapiens in Darwinian-medicine terms. With all possible consequences.
The goal of this work was to assess the current epidemiological and epizootological situations in the world largest focus of opisthorchiasis; to clarify the specific features in its clinical course, pathogenesis, and complications; to determine the natural, climatic, and social factors that enhance preservation of this focus; and to propose an algorithm for preventive activities.
\nThe tasks of this research are to study the epizootological situation and features of the circulation of Opisthorchis felineus in the Ob-Irtysh basin, assess the epidemiological situation of opisthorchiasis in Russia, and give recommendations on measures to prevent the disease.
\nThe concept of sustainable development [1] sets the control of unattended diseases as one of the global goals in the area of public health care; these diseases include the helminthic invasions in hyperendemic foci. The ongoing changes in all spheres of production and sale of raw materials and goods have led to serious violations of sanitary rules and norms, which deteriorate the epizootic situation for parasitic invasions in the world.
\nOpisthorchiasis, the trematodiasis caused by O. felineus Rivolta, 1884, is one of the relevant problems in both Russia (with its world largest Ob-Irtysh natural focus) and worldwide despite the implemented prevention measures. The relevance of this problem is determined by both its high incidence among adults and children, severity of the resulting pathology, and its chronic course.
\nThe socioeconomic factors, such as active migration of population, unawareness of opisthorchiasis among the newcomers to the region, poor knowledge about the rules for disinfection of local population, all-year-round consumption of fish, and homemade fish products, increase in the number of amateur fishermen and poachers, and vending of fish and fish products on unauthorized markets creates the conditions for the stable preservation of opisthorchiasis.
\nOne of the major factors that influence the level of O. felineus liver fluke invasion is a high rate of fish invasion by its metacercariae. The natural and climatic conditions that have established in the Ob-Irtysh basin support the active opisthorchiasis focus there.
\nA vast floodplain of the Ob-Irtysh basin, rich in lakes and meadows, and a developed network of first- and second-order tributaries enhance the maintenance of the Bithyniidae mollusks at a high level.
\nClose coexistence and cohabitation of the first intermediate host and cyprinid fish (second intermediate host) in the same habitats provide the implementation of liver fluke life cycle. In their abundance and species diversity, the cyprinid fish are the leader group in the Ob-Irtysh basin. A high infection rate of the prevalent fish species, which are of important commercial value, with O. felineus metacercariae is a major risk factor, influencing the incidence of this disease among local population.
\nThe liver fluke was for the first time described in 1884 by Sebastiano Rivolta, an Italian scientist. He isolated the parasite from the liver of a cat and a dog and named it the liver fluke, O. felineus, and the corresponding disease, opisthorchiasis. K.N. Vinogradov, a professor at the Tomsk University, discovered the liver fluke in the human liver in 1891. After the discovery by Vinogradov, human cases of opisthorchiasis were repeatedly recorded in 1892–1929 in Tomsk, Biysk, Novosibirsk, Tyumen oblast, Kuznetsk raion, and other localities. During WWII, a Russian soldier from Siberia died in one of the fascist concentration camps; his autopsy demonstrated 42,000 liver flukes in his liver and pancreas.
\nAs has been observed, the liver fluke is not met far and wide but rather near freshwater bodies. Brown in 1893 assumed that fish consumption is the source of liver fluke infection, which was later (1904) experimentally confirmed by M. Askanazy (Germany). In 1891, Vinogradov postulated the first intermediate host of liver fluke, which was experimentally confirmed by H. Vogel (Germany): he demonstrated that the first intermediate host was the mollusk Bithynia leachii (Sheppard, 1823).
\nThe study of opisthorchiasis commences in 1929 after publication of the information that 100 opisthorchiasis patients were admitted to the Tobolsk hospital over 6 months. This initiated organization of specialized helminthological expeditions to the Ob-Irtysh basin, headed by K.I. Skryabin. Numerous experiments have demonstrated that this region houses the largest opisthorchiasis focus. Russian helminthologists under the guidance of Skryabin paid significant attention to the study of O. felineus (1927–1929). The liver fluke larvae were for the first time discovered in the muscle of fish individuals inhabiting Siberian water bodies by N.N. Plotnikov and L.K. Zerchaninov in 1932.
\nAll these efforts allowed for discovery of a considerable incidence of opisthorchiasis among people, cats, and dogs along the Irtysh and Ob rivers up to the polar circle. In 1973, a cat was autopsied by an expedition organized by Skryabin in the north of the Tomsk oblast; eight cysts containing liver flukes were found in its liver; one of the cysts, medium in its size (similar to a walnut), contained 654 parasites.
\nThe following scientists contributed to the studies of the epidemic situation of opisthorchiasis: S.D. Titova (publications of 1946–1980), V.S. Myasoedov (publications of 1953, 1959, and 1960), M.P. Miroshnichenko (1954, 1955, and 1956), T.A. Bocharova (1971–2005), G.I. Golovko (1981–1986), and so on. The population migration to the oil and gas areas in the north of the Tomsk oblast increased the attention to this disease [3, 18, 19, 20, 21, 22, 24, 43].
\nThe liver fluke O. felineus has an intricate life cycle, which involves three hosts: the definitive host and two intermediate hosts; the life cycle comprises two free-living stages, the egg and cercaria (\nFigure 1\n).
\nLife cycle of O. felineus.
Infected domestic and wild animals that fed on fish and infected people, which are the definitive host of the liver fluke, are the sources of invasion. One trematode lays approximately 2000 eggs per day. The eggs are not viable when dry and are rapidly killed by sunlight but retain their viability for 15 months in a water body at a temperature of 4–7°C; all eggs die after 29 months [2].
\nWhen entering water with human and animal feces, the liver fluke eggs can be ingested with detritus by the first intermediate host, a Bithyniidae (genera Codiella and Opisthorchophorus) mollusk [2].
\nIn the Ob-Irtysh basin, the mollusks susceptible to the invasion inhabit only standing perennial silt water bodies. The mollusks are unable to migrate for a long distance and form local clusters. Presumably, the infection rate of mollusks depends on the population density and the distance from human dwellings [3].
\nThe infection rate of Bithyniidae mollusks in the upper reaches of Ob and Irtysh rivers within the Altai Krai is 2%, amounts to 6.1% within the Novosibirsk oblast, and varies in the range of 0.3–20.2% in the Irtysh basin in the Omsk oblast [4, 5]. The density of the mollusk population in the floodplain water bodies in the Tomsk oblast is 8100 individuals/m3; however, the prevalence of invasion is extremely low (3.7%), and the intensity is very high (on the average, 8130 ± 470 cercariae/mollusk). Coinvasions are extremely rare [6]. The infection rate of mollusks in the Tura and Pyshma river floodplains varies from 4 to 9%; the infection characteristics in the Khanty-Mansiysk Autonomous Okrug are also low, to 6.7% [7].
\nIn the mollusk gut, miracidia, free-swimming larvae, hatch from the eggs (\nFigure 1\n). A miracidium hatched from the egg enters the mollusk body cavity by passing through the gut wall to undergo a regressive metamorphosis there. It loses its larval organs (glands, epidermal plates, cilia, etc.) preserving only the germline cells and protonephridia to change into a mother sporocyst with a length up to 2 mm [2].
\nYoung sporocysts are transversely constricted to give smaller sporocysts, which propagate and form rediae. Rediae are sack-like structures with a large mouth and gut. When leaving the mother sporocyst, rediae migrate to the liver of mollusk to parthenogenetically reproduce.
\nIn the redia, tailed motile larvae—cercariae—are formed of the germ balls. The developmental stage in the mollusk takes 2–2.5 months (\nFigure 1\n) [2].
\nWith the maturation, cercariae leave the redia through the pore to migrate in the mollusk body leaving it for water, where they swim for 30–50 h. Up to 3500 cercariae can leave the mollusk during 24 h. The release of cercariae has two peaks, namely a pronounced midsummer peak and a flat spring one [2].
\nWhen encountering a cyprinid fish (ide, dace, roach, bream, Siberian roach, Caspian roach, tench, common rudd, common carp, asp, common bleak, etc.), the cercaria attaches to it; detaches its tail; loses its eyes and sensory organs; and penetrates into the muscles to form the inner and outer (a capsule of connective tissue) membranes and to transform into the next phase, metacercaria (\nFigure 1\n).
\nThe metacercariae have a size of 0.23–0.38 × 0.18–0.28 mm and are very survivable. The metacercariae become invasive 3–6 weeks after entering the fish and now are able to infect the definitive hosts—domestic and wild carnivores and omnivorous animals and humans. Metacercariae retain their viability in the fish body for 1–3 years and even to 9 years according to some data [8].
\nAs is known, only cyprinid species are suitable intermediate hosts for the metacercariae. Approximately 20 species of both aboriginal and alien cyprinid species of commercial or noncommercial value inhabit the rivers and lakes of the Ob-Irtysh basin, the most important fish species of commercial significance are the ide, bream, crucian carp, roach, and, to a lesser degree, dace [2].
\nThe rate of the fish infection by liver fluke metacercariae has been studied with different intensities in different periods. A large volume of data on the prevalence of fish infection in the Ob-Irtysh basin was accumulated in the 1990s to 2000s. Our data and the earlier results suggest high rates of infection of the ide, dace, and roach. The prevalence of ide and dace infection amounted to 20–100% and of roach, 2–80% with the intensity of infection of 1–1780 metacercariae per individual. These fish species are among the major carriers of O. felineus metacercariae and significantly contribute to the preservation of the opisthorchiasis focus. In addition, the bream and common bleak, alien species for this region, also appeared to be susceptible to the infection by liver fluke metacercariae and, correspondingly, have been involved in the maintenance and spreading of opisthorchiasis in Western Siberia [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25].
\nThe definitive hosts are infected orally by consuming the cyprinid fish muscles infected by liver fluke. The metacercarial membrane is finally destroyed in the host stomach, and the young helminth migrates along bile ducts to the liver and gall bladder to reach the sexual maturity in 20–25 days (\nFigure 1\n) [2].
\nThe intensity of invasion of definitive hosts and their role in maintaining the strength of opisthorchiasis focus are different. As is assumed, in addition to humans who account for 56.6% of the invasion, cats (15.8%), dogs (3.6%), and pigs (to 0.9%) are also significant contributors to opisthorchiasis [26]. The total prevalence of cat invasion in the opisthorchiasis focus of the Khanty-Mansiysk Autonomous Okrug in the 2000s amounted to 48.2% (males were more frequently affected than females). The prevalence of dog invasion was lower, amounting to 17.14% [27]. An analogous study in Novosibirsk demonstrated the total prevalence of cat invasion of 7.9% with the intensity of 69.9 flukes and of dog invasion of 3.4% with the intensity of 23.8 flukes. Males appeared more affected among cats and females among dogs. The invasion parameters increase with animal age [28].
\nIn addition to domestic carnivores, wild carnivores (common fox, wolf, brown bear, lynx, polecat, sable, mink, muskrat, bank vole, and others) also contribute to the liver fluke circulation in natural foci. These animals play different roles in the epizootic process in opisthorchiasis: the animals living in the floodplain and constantly “supplying” the infectious material to the biotopes of the first intermediate host are actual players of the opisthorchiasis circulation in the Ob-Irtysh basin, whereas the remaining animals are potential sources of invasion. In general, foxes and muskrats account for the largest number of invaded wild animals. The rate of invasion in the floodplain of Ob river and its tributaries reaches 77% on the background of a growth in the prevalence characteristics from the upper to lower reaches. The intensity of invasion amounts to 10–500 liver flukes per individual. The invasion of the muskrat in Western Siberia reaches 33% [29]; however, this issue requires further studies.
\nThus, a complex multihost life cycle of this parasite enhances its long-term retention in wildlife and preservation of the natural opisthorchiasis focus in the Ob-Irtysh basin.
\nOpisthorchiasis is an important social problem in Russia. Two-thirds of the world distribution range of this pathogen concentrates in this country [30]. Opisthorchiasis accounts for approximately 80% of all helminthic diseases. According to the official statistical data, up to 26,000 cases are annually recorded. The actual number of opisthorchiasis patients taking into account the correction factor is 15-fold higher [31].
\nIn total, 106,362 cases of invasion were detected in 2014–2018. The maximum number of cases was recorded in 2014 (25,545 cases) and minimum, in 2017 (18,755 cases). The incidence rate of opisthorchiasis among population in 2018 decreased by 25.3% as compared with 2014, varying from 12.79 to 17.51 per 100,000 population (\nTable 1\n).
\nRegion of Russian Federation | \n2018 | \n2017 | \n2016 | \n2015 | \n2014 | \n|||||
---|---|---|---|---|---|---|---|---|---|---|
Total\n*\n\n | \nIR\n**\n\n | \nTotal\n*\n\n | \nIR\n**\n\n | \nTotal\n*\n\n | \nIR\n**\n\n | \nTotal\n*\n\n | \nIR\n**\n\n | \nTotal\n*\n\n | \nIR\n**\n\n | \n|
Russian Federation | \n19,077 | \n12.99 | \n18,755 | \n12.79 | \n20,846 | \n14.24 | \n22,139 | \n15.15 | \n25,545 | \n17.51 | \n
Yamalo-Nenets Autonomous Okrug | \n838 | \n155.6 | \n666 | \n124.2 | \n766 | \n143.4 | \n875 | \n162.0 | \n1228 | \n226.7 | \n
Khanty-Mansiysk Autonomous Okrug | \n5046 | \n299.6 | \n4309 | \n259.2 | \n4454 | \n272.5 | \n6024 | \n374.0 | \n7370 | \n461.5 | \n
Tyumen oblast | \n1483 | \n98.9 | \n1341 | \n90.7 | \n1384 | \n95.1 | \n1518 | \n106.2 | \n1831 | \n132.2 | \n
Tomsk oblast | \n1129 | \n104.7 | \n1251 | \n116.0 | \n1336 | \n124.1 | \n1557 | \n145.5 | \n1686 | \n158.4 | \n
Novosibirsk oblast | \n3252 | \n116.6 | \n3118 | \n112.2 | \n4109 | \n148.8 | \n3930 | \n143.1 | \n3505 | \n128.3 | \n
Kemerovo oblast | \n1386 | \n51.43 | \n1704 | \n62.91 | \n1800 | \n66.23 | \n1357 | \n49.8 | \n1547 | \n56.58 | \n
Omsk oblast | \n1427 | \n72.8 | \n1450 | \n73.27 | \n1469 | \n74.24 | \n1622 | \n81.99 | \n2035 | \n103.1 | \n
Altai Krai | \n869 | \n36.7 | \n818 | \n34.3 | \n959 | \n40.2 | \n791 | \n33.09 | \n1091 | \n45.48 | \n
Absolute values and incidence rate of opisthorchiasis in the Russian Federation and Western Siberian region in 2014–2018.
Morbidity data according to Form 2 “Data on infectious and parasitic diseases” approved by Order 52 of the Russian Federal State Statistics Service of January 28, 2014.
IR is the incidence rate of disease per 100,000 population.
The natural foci of opisthorchiasis are adjacent to the Ob, Irtysh, Ural, Volga, Kama, Don, Dnepr, Severnaya Dvina, and Biryusa rivers [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42].
\nApproximately 80% of the opisthorchiasis cases are recorded in the territories adjacent to the Ob, Irtysh, and Tom river basins and their tributaries [43], housing the administrative centers of the Omsk, Novosibirsk, Tyumen, Tomsk, and Kemerovo oblasts and Khanty-Mansiysk and Yamalo-Nenets Autonomous Okrugs. Most part of the local population is affected (80–95%) [44, 45, 46]. The total incidence rate over 2014–2018 was 84,331 opisthorchiasis cases, accounting for 79.3% of the total cases in the Russian Federation.
\nThe Khanty-Mansiysk Autonomous Okrug heads the list of percentage of opisthorchiasis incidence (2.6–4.6) followed by Yamalo-Nenets Autonomous Okrug (1.2–2.3%), Novosibirsk oblast (1.1–1.5%), Tomsk oblast (1.0–1.6%), Tyumen oblast (0.9–1.3%), Omsk oblast (0.7–1.0%), Kemerovo oblast (0.5–0.7%), and Altai Krai (0.3–0.5%) [47, 48, 49, 50, 51].
\nThe incidence rate of opisthorchiasis in the analyzed regions varies, with the maximum exceeding 1.3–1.8-fold the minimal value. The highest incidence rates are recorded in the hyperendemic regions of Yamalo-Nenets (124.2–226.7) and Khanty-Mansiysk (259.2–461.5) Autonomous Okrugs, Tyumen oblast (90.7–132.2), Tomsk oblast (104.7–158.4), Novosibirsk oblast (112.2–148.8), and Omsk oblast (72.8–103.3). The Kemerovo oblast (49.8–66.23) and Altai Krai (33.09–45.48) are the regions with a high level of invasion. The incidence of opisthorchiasis in these regions severalfold exceeds the mean level for the Russian Federation with the Khanty-Mansiysk Autonomous Okrug heading the list (19–26-fold) followed by Yamalo-Nenets Autonomous Okrug (9–13-fold), Tomsk and Novosibirsk oblasts (7–10-fold), Omsk and Tyumen oblasts (5–8-fold), Kemerovo oblast (3–5-fold), and Altai Krai (2–3-fold).
\nAccording to the statistical data for 2014–2018, a decrease in the absolute characteristics and incidence rate was in general observed in all hyperendemic regions, which is explainable by inadequate diagnosing, registration, and recording of the cases as a result of decreased attention to the problem of opisthorchiasis.
\nOpisthorchiasis is mainly diagnosed among the adult population (over 90% cases in people aged 39–59); however, the level of child morbidity is rather high. Opisthorchiasis has been recorded in all age cohorts of children up to 17 years, with the age cohort of 7–14 years accounting for 60–80% of all cases recorded in children. In the Tomsk oblast, the children to 17 years old are the most affected as compared with other regions (29.7% in 2014–40.8% in 2018). In the mid-Ob river region, opisthorchiasis is detectable in children starting from 3 years (25–30%) with an increase at the age of 12–14 years (50–60%) to 100% in the adults [52]. In the child population of the city of Urai (Khanty-Mansiysk Autonomous Okrug), the most affected cohort is 7–14 (38%) and 14–17 (34%) years old versus 23 and 5% for the cohorts of 3–6 and 2–2 years [53]. An increase in the prevalence of infection among the children of 1–2 years (from 3.8 to 6.1%) is observed in the Tomsk oblast. Cases of opisthorchiasis in the children under 1 year have been recorded in Khanty-Mansiysk Autonomous Okrug (six cases in 2017).
\nIn 2008–2017, 43 cases of acute opisthorchiasis were recorded in the middle Ob basin. Among those infected, the proportion of women and men was 48.8 and 51.2%, respectively. In terms of age, the maximum number of cases of acute opisthorchiasis was recorded among people aged 20–39 years (74.4%), followed by those aged 40–49 and 50–59 years (9.3% each group), and people aged 15–19 years (7.0%).
\nThe largest number of cases of opisthorchiasis was recorded in May (20.9%) and June (32.6%), and less often opisthorchiasis was recorded in September and November (11.6% each). In other months, the infection was observed sporadically (1–2 cases). In 2008–2017, from 52.8% (2011) to 80.9% (2017) of people with recorded opisthorchiasis underwent dehelmintization (original data).
\nSince most rural population, including children, are involved in fishing, regular consumption of frozen and slightly salted freshwater fish is widespread; correspondingly, the incidence rate increases with age, and the cases of superinvasion are observable [54, 55].
\nThe morbidity patterns in the municipal entities of autonomous okrugs and oblasts are considerably different. However, the corresponding levels observed in the municipal entities of the north are higher by an order of magnitude. The significant differences in morbidity in different municipal entities of oblasts and autonomous okrugs are associated with different quality of clinical diagnostics, recording, and registration of opisthorchiasis cases rather than with the difference in diet pattern [56]. The facts that the child morbidity rate is higher than that in adults are explainable by that adult population rarer seeks medical help. Since the diet of children and adults does not significantly differ, it is likely that the adult population is highly affected with the prevalence of chronic disease courses [56].
\nThe urban population on the average accounts for 75–78% of the opisthorchiasis cases [31, 57]. However, the incidence among the rural population is higher than the urbane population. Characteristic of the urban life style is rarer consumption of freshwater fish and better adherence to good cooking practice [54].
\nOpisthorchiasis is a food-borne disease, with the pathogen transmission via eating the fish infected with the liver fluke metacercariae. The susceptibility to invasion is ubiquitous. The duodenal content induces larvae to excyst there wherefrom they migrate through the ampulla of Vater to the bile excretory ducts owing to a positive chemotaxis to bile. In 3–5 h, liver flukes (100%) are detectable in the liver, pancreas, and gall bladder (20–40%) [58, 59].
\nAfter 3–4 weeks, liver flukes turn into sexually mature maritae, producing eggs [58].
\nClinical manifestations of opisthorchiasis are manifold and depend on individual specific features of the host organism as well as infection intensity and duration [34, 60, 61]. Humans are unable to develop immunity to this pathogen; correspondingly, repeated consumption of the fish carrying metacercariae merely increases invasion [62, 63]. The counts of maritae in an individual can vary from solitary parasites to several tens and even hundreds [63].
\nThe incubation period of opisthorchiasis is on the average 2–3 weeks [58, 61]. The early (acute) and late (chronic) phases of this disease are distinguished [64]. The early phase lasts from several days to 4–8 weeks and longer [60], while the chronic phase may last for 10–20 and more years [64]. The disease may have unapparent or overt manifestations [58, 61, 65, 66].
\nCharacteristic of the subclinical case of opisthorchiasis early phase is a subfebrile temperature and insignificant eosinophilia on the background of normal leukocyte counts [58]. A subclinical course is observed in the children who have received the antigen during their embryonic development or the antibodies with mother’s milk [67, 68, 69]. This is the explanation why the manifestation of opisthorchiasis in the indigenous population of the north (Khanty and Mansi) is primary chronic with poor symptomatics and aggravation under adverse conditions, such as stress, infections, or surgery [58, 60, 61, 70, 71].
\nAn overt course of opisthorchiasis is usually observable in the patients who moved to the opisthorchiasis focus from the regions not endemic for the disease [58]. The acute phase starts abruptly and continues for 1–3 months or rarer, for 6–9 months [58, 62, 63]. A systemic allergic response determines development of inflammation in the lungs, gastrointestinal tract, musculoskeletal system, skin, and cardiovascular system [64]. The patients experience fever (from subfebrile to febrile for 1–3 weeks), eosinophilia (20–40%; sometimes, to 90%), intoxication, dyspeptic disorders (nausea, vomiting, and epigastric burning), moderate arthralgia and myalgia, and exanthems of various types [58, 60, 61, 64]; hepatocholangitic syndrome (right subcostal pain, increased liver, elevated transaminase activities, and elevated alkaline phosphatase activity) [58, 64], bronchopulmonary syndrome (hyperemic pharynx, retropharyngeal granulation, rhinitis, asthmatic bronchitis, eosinophilic infiltration in the lungs, and exudative pleurisy), and cardiovascular changes (palpitation, cardiac pain, hypotonia, and diffuse dystrophic changes in the myocardium detectable by electrocardiography) are observable [72].
\nA severe form of the acute opisthorchiasis can be represented by typhoid, hepatocholangitic, and gastroenteritic clinical variants [73]. Severe toxic and allergic responses appear as toxic epidemic necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, acute myocarditis, Quincke’s edema, or hives [60].
\nIn the absence of treatment, the acute phase transforms into a chronic one [63], which can continue for 20 years [61] and proceed either latently or with clinical manifestations [62]. A latent course is more frequent characteristic of the aboriginal population in the opisthorchiasis foci and in young people [60]. Patients have no complaints, and laboratory tests are normal. Opisthorchiasis is diagnosed in these cases only by chance during a periodic health examination or examination for other diseases [62]. In practice, this is the situation for 8% of several thousands of patients [63].
\nCharacteristics of a latent opisthorchiasis are periods of remission and exacerbation [62]. In an endemic focus, opisthorchiasis initially follows a chronic course without any acute manifestations. Clinical symptoms may appear 10–20 years after infection. Patients frequently develop the symptoms of cholangitis and cholecystitis (80–87% of the cases) [74, 75], including right subcostal pain, heaviness in the stomach, nausea, fat intolerance, dryness and bitter taste in the mouth [58], abdominal distention, frequent liquid stool [63], vomiting, eructation, hepatomegaly, and jaundice during exacerbation [73]. Part of the opisthorchiasis patients develops pancreatitis with a wave-like course (frequent alternation of remission and exacerbation periods); 45–50% of the patients experience gastritis, duodenitis, and gastric and duodenal ulcers [73, 76]. In case of gastric involvement, patients frequently develop intestinal dyspepsia and dysbacteriosis, with the absence of bifidobacteria or their decrease and an increased content of facultative opportunistic pathogenic microflora, such as Staphylococcus epidermidis and Staphylococcus aureus [74]. Patients complain of undue fatigability, petulance, sleep loss, headache, hyperhidrosis (frequently local, for example, sweaty hands), excessive salivation, pronounced dermographism, tremor (eyelids, tongue, and/or fingers), vasomotor vascular response, and subfebrile temperature [76, 77].
\nThe immunological response to antigens clinically manifests itself as an allergic syndrome, with skin itching, hives, recurrent Quincke’s edema, arthralgia, alimentary allergy, moderate eosinophilia, and specific IgE in the blood [61]. A constant presence of the liver fluke antigen wears off the immune system and decreases its ability to suppress infection [69, 78, 79].
\nChronic opisthorchiasis is a factor that is able to induce liver cancer development [63]. The early manifestations of liver cancer are an increase in the right subcostal pain and epigastria; their constant unceasing character, especially during nighttime; sensation of discomfort and heaviness; and pronounced dyspeptic disorders (anorexia, idiopathic weight loss, early satiety, abdominal distension, alternation of constipation and diarrhea, and so on). Weakness, general uneasiness, and sleep disorders rapidly worsen. The prescribed treatment of chronic opisthorchiasis fails to bring relief [80]. Hepatomegaly is characteristic of the liver cancer (the liver is dense, nodular, and painful); typical manifestations are hypochromic anemia, eosinophilia, accelerated ESR, and, in the case, of cancer, lymphopenia [80].
\nIn pancreatic cancer, patients more frequently experience weakness, vomiting, and progressive weight loss. In part of patients, vomiting is caused by impaired gastric emptying because of the tumor compression or its invasion to the duodenum. Patients lose 5–32 kg over 2–3 months [80].
\nThe main sign of pancreatic cancer is jaundice; it is persistent, increasing in its intensity, and accompanied by a high body temperature and chill. The fever and itching exhaust patients so that they lose sleep and experience growing adynamia and apathy. The liver may be increased; it has smooth surface and is less dense [80]. Characteristic of jaundice is a high concentration of bilirubin in the blood as well as increased alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase activities. Amylase activity is also increased in the liver and pancreatic cancers; thymol and sublimate tests are changed, which suggest an advanced cancer process [80].
\nPathogenesis is determined by the combined impact of parasites on the host body (mechanical, toxic, and neuroreflectory) and host body responses (immunopathological) [60, 61, 64].
\nIn the early phase, the immunopathological mechanisms with development of the immediate type allergic response are more pronounced [61, 64]. The liver fluke antigens enter the blood through mucosa and sensitize the organism (gastrointestinal tract, lungs, kidneys, liver, etc.) [60, 61]. The liver fluke metabolites induce toxic and allergic syndrome [58, 64], which are accompanied by edema, proliferation, desquamation of bile duct epithelium, and metaplasia of bile ducts with formation of goblet cells and small gland-like structures [58].
\nIn the late phase, the liver fluke metabolites induce an immune inflammation in many organs and systems [81, 82]. The immunopathological effect appears as a secondary immunodeficiency with prevalence of a delayed type allergic response; characteristics of this response are vascular involvement and regeneration of cell elements in the connective tissue with development of extensive fibroplasia [73, 83].
\nMechanical and toxic factors in the late stage become the most important [61, 64]. Young liver fluke individuals damage the bile duct walls by their spinules and the sexually mature individuals and by their oral and ventral suckers. Liver flukes consume the mucosal secretions and bile duct epithelium [45]. A mechanical stimulation of the walls of bile and pancreatic ducts interferes with the motor and secretory functions of the gastrointestinal tract [60].
\nInflammatory and proliferative processes are induced and developed in the mucosal lesions, as well as peroxidation is activated and antioxidant defense is damaged [60, 84].
\nClusters of liver flukes, their eggs, and crusts of desquamated epithelium in the ducts create a mechanical barrier for the outflow of bile and secretion, thereby enhancing the development of proliferative cholangitis and canaliculitis accompanied by different degrees of fibrosis in these organs [60].
\nFrequently, the pancreas responds to the presence of liver flukes and their metabolites by certain pathological changes. Both the exocrine and endocrine functions of the pancreas are damaged during pancreatitis [67, 85, 86].
\nPersistent hypertension develops in the duodenum, stomach, esophagus, and biliary system on the background of chronic duodenal stasis [61], creating the favorable conditions for secondary infections (Escherichia coli, staphylococci, yeast-like fungi, and others) [60].
\nThe liver fluke invasion has a negative effect in the mother-placenta-fetus system [87], increasing the probability of gestoses and miscarriage [88].
\nThe involvement of gastrointestinal tract affects digestion and absorption, leading to dysmetabolic sensitization. As a consequence, allergic skin lesions are developed, including urticarial rash in the early phase and chronic hives with exacerbation periods and remissions in the late phase [85, 86]. The urticarial rash rather frequently transforms into papular and vesicular rash. In some cases, hives can follow a hemorrhagic pattern owing to release of erythrocytes, which fall apart and form pigment spots [61, 79, 89].
\nThe host immunopathological response is the cause underlying the dystrophy and necrosis of the epithelium of biliary tract and pancreatic ducts [79, 89, 90].
\nThe sclerotic processes leading to the development of chronic hepatitis are prevalent in the late phase. Superinvasion and reinvasion lead to development of an active hepatitis as a result of an immune inflammation in the liver [61, 68, 91].
\nComplications of opisthorchiasis most frequently develop in the chronic stage. This disease belongs to the group of carcinogenic helminthiases [55, 59, 92, 93]. Liver tumors [55, 57, 94] as well as stomach, pancreas, and breast tumors most frequently develop on the background of liver fluke superinvasion [95, 96].
\nThe carcinogenesis on the background of opisthorchiasis involves multifactorial mechanisms comprising inflammatory, mechanical, and secretory-excretory processes [84, 97].
\nIn case of superinvasion, maritae provide a sustainable basis of the food substrate—permanent proliferation and differentiation of liver and pancreatic stem cells as well as the stem cells in the organs beyond their ecological niche [55].
\nAn overt inflammation determines a constant response as the regenerative cell proliferation [55, 98].
\nActivated macrophages and polymorphonuclear leukocytes produce reactive oxygen species, proteolytic enzymes, proinflammatory cytokines, and growth factors. Reactive oxygen and nitrogen species and oxysterol production play the decisive role in the disturbance of the function of proto-oncogenes, the DNA regions the abnormalities in which induce cancer transformation of liver cells [45, 66]. As a result, adjacent cells are altered, and an active regeneration of injured tissues is triggered [97, 99].
\nMaritae interfere with the bile outflow in a purely mechanical manner. The stagnant bile in the ducts interacts with free radicals to form endogenous carcinogens, which has a mutagenic effect on the DNA of cholangiocytes [100, 101]. Eggs can penetrate to the periductal tissues via the ulcerations at the sites of liver fluke sucking and cause there a granulomatous inflammation [93]. The liver fluke excretory and secretory antigens (by themselves or via the interaction with free radicals) initiate cell proliferation during a liver fluke superinvasion [57] and display direct cytotoxic and mutagenic effects [96, 98, 102, 103, 104].
\nHemozoin, a liver fluke pigment, is able to induce a carbonyl (extracellular) stress [105, 106]. A long-term injury of cholangiocytes and a mitogenic effect of growth factors are the cause underlying the complications, such as epithelial hyperplasia, periductal fibrosis, and strictures, and cysts of bile ducts followed by cholestasis, as well as lead to development of cholangiocarcinoma [80, 84, 105, 107, 108].
\nMorphologically, up to 80% of all tumors in opisthorchiasis cases are cholangiocarcinomas [109]. The risk of cholangiocarcinoma development correlates with the duration and intensity of liver fluke invasion [109, 110, 111]. The external factors enhancing cholangiocarcinoma development in opisthorchiasis cases are alcohol (demonstrated for Opisthorchis viverrini) and food nitrosamines (independent risk factor), especially in the endemic regions [98, 112, 113].
\nIn 1970–2005, 1170 patients underwent surgery because of the complications of opisthorchiasis, which accounts for 24.6% of the total opisthorchiasis cases (4756). The patients with cholangiocholecystitis (70.3%), cholecystopancreatitis (18.4%), and hepatocholecystitis (11.3%) received a conservative treatment. A repeated invasion was observable in the overwhelming majority of patients; most of the opisthorchiasis cases (75%) were of the working age with the overall age range of 21–87 years [114].
\nOpisthorchiasis is complicated by liver abscesses, ascending cholangitis, hepatitis, and gastric and duodenal ulcers [115]. Frequently met surgical complications of opisthorchiasis are opisthorchiasis pancreatitis, observed in 16% cases [115]. A dangerous complication of opisthorchiasis cysts in the liver is abscesses and their rupture followed by bile peritonitis [114].
\nThe prevention measures against opisthorchiasis comprise in the following:
\ndetection and treatment of opisthorchiasis cases in the disease focus;
dehelminthization of domestic carnivores; and
protection of water bodies from feces, proper keeping of the areas of settlements, use of sewage containers in river vessels, decontamination of sewage, and prohibition of using the content of outhouse latrines for fertilization of vegetable gardens [63].
The degree of human protection is determined by the level of their knowledge about the measures ensuring the invasion prevention and their sanitary culture [64].
\nThe personal precautions mainly reduce to good cooking practices in fish processing, which ensures fish disinfection [63]. A special attention must be paid to teaching the population to properly process fish at home [64].
\nThe disinfection is attained by thermal treatment, freezing, smoking, and salting [58].
\nThe fishes with a weight of up to 1 kg must be frozen at a temperature of −28°C for 41 h or at −35°C for 10 h. In a household refrigerator, metacercariae retain viability for over 1 month [64].
\nFish (in the case of a large individual, cut into pieces of no more than 2 cm) should be stewed for at least 20 min from the moment of boiling or fried as small flattened pieces (or minced) for 20 min in a large volume of oil. Fish pies must be kept in the oven (200°C) for at least 60 min [63].
\nFish salting requires at least 2 weeks (2 kg salt per 10 kg fish; [64]). Before cold smoking, fish is disinfected by either salting or freezing [63].
\nHot smoking requires a temperature of 70–80°C for 2–2.5 h [64].
\nThe preservation meeting the Codex Alimentarius rules also guarantees safety from the liver fluke metacercariae [58].
\nIt is always necessary to carefully wash your hands and kitchen utensils after processing raw fish [64].
\nIt is strongly recommended to avoid consumption of raw fish, weakly or shortly salted fish, or raw minced fish as well as the frozen fish as stroganina (cut into thin slices), and other local variants of raw frozen fish as well as freshly caught fish in any home-made slightly salted, smoked, or dried variants prepared without observing the described technologies and by unknown persons [63].
\nUnfortunately, insufficient attention has been recently paid to education of population, which naturally resulted in an increase in the number of opisthorchiasis cases [116].
\nThe activity of epizootic process in Western Siberia depends on the parameters of water regime in this territory. The vastness of the Western Siberian floodplains increases from south northward as well as the regular pattern, volume, and duration of spring floods; duration of summer-fall floods in the floodplains; and good water heating [57, 64]. The Western Siberian rivers are rather slow, with a long freeze-up period, preventing aeration, and winter deficiency in oxygen. Poor soil draining and excessive moistening enhance an abundance of water in the region and an increased number of floodplain water bodies, favorable for the development of Bithyniidae mollusk population [57].
\nIn addition, large-scale hydrotechnical engineering activities (construction of channels, cascade artificial water reservoirs, dead dams without byways, and littering of water bodies with household and construction waste) create favorable conditions for mollusk development [57, 64].
\nWater and soil contamination with the liver fluke eggs significantly contribute to sustainable circulation of the opisthorchiasis agent in natural biocenoses; the liver fluke eggs have been detected in 1.13 ± 0.1% of the soil samples, 15.4 ± 0.9% of wastewater and silt samples, and 1.34 ± 0.2% of water from water bodies. The intensity of wastewater and sediment seeding with liver fluke eggs was maximal and varied from 2000 to 4000 eggs/m3; this value for the soil specimens was significantly lower, 0–40 eggs/kg soil. Because of poor disinvasion efficiency, the wastewater discharged into water bodies remains uncontaminated, thereby maintaining the circulation of this pathogen in nature [57, 117].
\nA high level of population infection with opisthorchiasis is aggravated by social factors, namely, a decrease in population living standards and an increase in the share of fish and home-made fish products in the diet of the inhabitants of the cities and villages adjacent to rivers. Population buys fish in shops or unofficial markets or harvests it by themselves. In particular, 52% of opisthorchiasis cases bought the fish in unofficial markets; 34% of them were infected as a result of amateur fishing; and 14.0% received the fish shipped from a northern part of the region [57].
\nThe main risk factors of opisthorchiasis are a high infection rate of the cyprinid fish species and the eating behavior pattern, i.e., prevalence in insufficiently disinfected fish in the common diet; in addition, the cyprinid fish is typically accessible to population, as is demonstrated by all-year-round fishing. In particular, over half (58.36 ± 2.81%) of the questioned subjects were amateur fishermen, and 41.44 ± 3.33% of them have their own fishing gear (nets, dragnets, etc.). This explains why the cohort of fishermen, water transportation workers, amateur fishermen, and their family members form the risk group with the maximum infection rate in the epicenter of the Ob-Irtysh opisthorchiasis focus. In the Khanty-Mansiysk Autonomous Okrug, the opisthorchiasis rate in the most important risk groups—buoy keepers and motor fishing fleet workers with their families—amounts to 75.6 ± 2.7 and 67.8 ± 3.8%, respectively [57]. In the southern part of the focus, the infection rate of the Tobolsk fish processing plant workers was 78 ± 0.3%; of the amateur fishermen in the Tobolsk raion, 36.6 ± 3.2%; and of the persons constantly involved in fishing in the Tyumen raion, 30.8 ± 3.8 and 50.0 ± 8.1% [57].
\nA high risk of opisthorchiasis is characteristic of the socially vulnerable cohorts, which eat the fish products conditionally approved as fit for human consumption, processed and prepared without taking into account the good cooking practice [57, 118, 119, 120]. In many households, weakly salted (in particular, large batches of ungutted fish salted in barrels), undercooked, freshly frozen, and freshly harvested cyprinid fish are the common all-year-round component of their diet. Infection can take place when testing minced fish “for salt” and accidental ingestion of liver fluke larvae from hands or kitchen utensils during fish processing. Children can be infected when cooking fish broth by themselves, making a kind of barbecue, or eating fresh fish [64, 85]. A high invasion rate of the indigenous northern population in Siberia is determined by the local tradition of eating stroganina, sliced frozen raw fish [64].
\nPopulation has little knowledge about the prevention measures. Only 27.93 ± 4.25% of the adult population is aware of the thermal processing practice, and 7.74 ± 1.31% knows the proper rules for fish salting and drying [57]. As has been shown, 89.0% of the opisthorchiasis cases either neglected the good fish cooking and salting practice or do not know them at all, and 1% of the infected subjects consume raw fish (stroganina) [57].
\nThe effect of urbanization on the epidemic process is rather ambiguous [57]. One of the factors of an autogenic impact on the function of parasitic liver fluke system is the migration of population. Migration “supplies” the cohorts with a high risk of infection and poorly or completely unaware of how to prevent the invasion (who eat the improperly cooked fish) to the territories with a high risk of opisthorchiasis. An increase in population enhances the decrease in its morbidity owing to “dilution” of the aboriginal population by a large influx of uninfected newcomers, involved in shift work or expeditions [57].
\nImprovement of the sanitary knowledge owing to development of the medical network and sanitary education activities at the locations of newcomer cohorts decreases the risk for opisthorchiasis [57].
\nLow rates of dehelminthization result in an increase in the number of infection sources. Human pollution of the habitat increases the risk of infection of the population. In particular, 90% of the opisthorchiasis subjects listed for regular medical check-up in the Khanty-Mansiysk Autonomous Okrug ignored the prescribed treatment [31]. In the city of Langepas (Khanty-Mansiysk Autonomous Okrug), the incidence of opisthorchiasis increased 1.2-fold because of the problems with providing the necessary drugs, refuse of the treatment, and ignore the therapy without any particular reason [121].
\nOpisthorchiasis is an anthropozoonous natural focal biohelminthosis caused by trematodes of O. felineus. Invasion has been recorded mainly in the Ob-Irtysh basin since 1891.
\nThe main source of opisthorchiasis caused by O. felineus is a person infected with opisthorchiasis, all fish-eating mammals (dogs, cats, foxes, muskrats, etc.) can also be the final hosts. In addition to human distributing up to 56.6% of invasive material, cats (15.8%), dogs (3.6%), and pigs (up to 0.9%) are assumed to be another source of infection [26]. Intermediate and additional hosts of O. felineus inhabit water bodies, and foci of opisthorchiasis are concentrated near rivers.
\nThe first intermediate host in the focus is freshwater mollusks, subclass Prosobranchiata, family Bithyniidae, genera Codiella and Opisthorchophorus. The mollusk invasion prevalence is very low, whereas the invasion intensity is very high. One mollusk lays up to 8000 cercariae [4, 5, 6, 7].
\nThe second intermediate host is fish of the family Cyprinidae. The prevalence of invasion of fish population ranges from 20 to 100%, while the invasion intensity varies from one to several hundred metacercariae (original data).
\nRussia has the highest incidence of this helminth. Natural foci of opisthorchiasis are located near the rivers Ob, Irtysh, Urals, Volga, Kama, Don, Dnieper, Severnaya Dvina, and Biryusa [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42]. The world’s largest focus of opisthorchiasis is located in the Ob-Irtysh basin.
\nThe transmission mechanism of the infection fecal-oral route, and the transmission route is food. Infection occurs when a person eats raw or insufficiently thermally processed and freshly salted cyprinid fish, containing live larvae (metacercaria).
\nNatural susceptibility of people to opisthorchiasis is high. The population does not show durable immunity after curing. These helminths have adverse effects on human health, mainly affecting the hepatobiliary system and pancreas. Clinical manifestations of the acute phase of opisthorchiasis last from several days to 4–8 weeks or more, and the phase of chronic opisthorchiasis lasts 15–25 years or more. The duration of the incubation period (in the early phase of the disease) is 2–4 weeks (up to 6 weeks). Allergic reactions, mechanical, and neuroreflex effects of helminths play the main role in the pathogenesis of opisthorchiasis and cause biliary dyskinesia, temporary and complete cessation of bile flow, glandular proliferation in the epithelium of the biliary, and pancreatic ducts and other glandular organs. Pathological processes affect the liver (impaired secretion of enzymes and protein, reduced cholesterol synthesis, and antioxidant function of the liver), pancreas (impaired secretion of enzymes, including insulin), stomach and intestines (erosive gastritis and colitis), and skin (itching, cracks, and psoriasis). Severe complications of opisthorchiasis include biliary peritonitis, liver abscesses, liver cirrhosis, primary liver cancer (less commonly pancreas cancer), acute destructive pancreatitis, bronchial asthma, and diabetes mellitus. Due to the character of infection and a high degree of mutual adaptation of the host and the parasite, opisthorchiasis often proceeds latently (without clinical symptoms).
\nAmong people of various professions, fishermen, river fleet personnel, agricultural workers, and forest industry workers are primarily infected. In endemic areas, opisthorchiasis can be recorded at the age of 1–3 years. The infection rate attains its highest level by 25 years and keeps stable up to 50–60 years. The prevalence among the local population can reach 100% (original data).
\nThe most important prerequisites for an intensive epidemic process in these territories are natural and social factors:
abundance of rivers and lakes rich in fish and mollusks (the highest infection rate among population is recorded in territories with numerous flood meadows and former riverbeds and places where the floodplain is more developed);
hydrotechnical transformations;
intensive contamination of rivers and floodplain lakes by helminths’ eggs from permanent and temporary settlements, cities, etc. located on their banks;
prevalence of insufficiently disinfected fish in the diet and cyprinid fish consumed by the population;
specific ethnic or traditional behavior associated with food and nutrition that determines the nature of distribution and the infection rate among the population in endemic foci;
poor knowledge of preventive measures; and
infection is possible beyond these foci when exporting fish.
Simple personal preventive measures will contribute to prevention of opisthorchiasis.
\nThe optimal natural and climatic conditions together with social and economic factors create the favorable conditions for preservation of the world largest Ob-Irtysh focus of the opisthorchiasis caused by the trematode O. felineus.
\nThe work was supported by the Ministry of Education and Science of the Russian Federation (project no. 6.7525.2017/8.9), program for elevating the competitive ability of Tomsk State University, and Russian Science Foundation.
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