Inhibition of leptin signaling using IONP-LPrA2 resensitizes PC cell lines to chemotherapy.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"4599",leadTitle:null,fullTitle:"Ion Exchange - Studies and Applications",title:"Ion Exchange",subtitle:"Studies and Applications",reviewType:"peer-reviewed",abstract:"This book provides broad coverage of ion exchange and its applications. 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PC is a silent disease, without reliable biomarkers that are commonly detected at an advanced stage. The deep position of the pancreas is an additional factor influencing the late detection of most symptoms of PC, when the disease is at final stages and the tumor size is large enough to interfere with the liver, gallbladder, stomach, or duodenum functions [1]. Patients have rapid disease progression, and few of them survive more than a year. Even for patients with localized disease at the time of diagnosis and undergoing curative surgical treatment, the median survival remains low, around 18 months. The overall 5-year survival rate is only 8.2% for all stages of PC [2]. Despite the advances in understanding PC biology, survival rates remain unmodified in the past years [3]. The underlying causes for PC dismal prognosis, among others, are the lack of viable methods for patient screening, late detection of specific symptoms, especially in the early stages, and few targeted therapies that remain relatively ineffective [4].
\nThe pancreas functions as an accessory gland of the digestive system and is composed anatomically and functionally of a mixed, exocrine, and endocrine component. Most of the pancreatic tissue (99%) is made up of exocrine tissue that is composed of closely packed serous acini that secrete digestive enzymes (proteases, lipases, and amylases). Some of the enzymes (e.g., trypsinogen, chymotrypsinogen, and proelastase) are secreted as inactivated precursors, to prevent pancreatic cell damage, and are activated upon release in the duodenum. Other key digestive enzymes, such as α-amylase and lipase, are present in the pancreas in their active forms. The duct cells secrete a watery, bicarbonate-rich fluid that carries the enzymes and neutralizes the acidity in the small intestine. The endocrine pancreas is composed of islets of Langerhans, clusters of about 3000 cells supported by reticulin fibers, in close contact with fenestrated capillaries. They contain three types of cells that secrete the three pancreatic hormones: α cells secrete glucagon that rises the glucose blood levels, while β cells secrete insulin that decreases the glucose blood levels and Δ cells secrete somatostatin that regulates the endocrine system and affects the neurotransmission and cell proliferation. The islet cells appear paler on hematoxylin and eosin stain (Figure 1) [5].
\nRepresentative pictures from hematoxylin and eosin staining of pancreatic tissue. (A) Pancreatic parenchyma composed in the vast majority by the exocrine pancreas composed of tightly packed acini that secrete enzymes via a duct system in the duodenum. The endocrine pancreas is composed of islets of Langerhans, which appears as clusters of pale colored cells (10×). (B) High magnification of pancreatic tissue shows exocrine tightly packed acini and endocrine islets of Langerhans. The islets appear pale due to less intracytoplasmic ribosomal content (40×).
The incidence of PC continuously raised in the past years, and it is estimated to become the second leading cause of cancer-related deaths by 2030 [6]. The highest PC incidence occurred in Northern America (7.4 per 100,000 people) and Western Europe (7.3 per 100,000 people), followed by other regions of Europe and Australia (equally about 6.5 per 100,000 people). The lowest rates (about 1.0 per 100,000 people) were observed in Middle Africa and South-Central Asia. More than half of new cases (55.5%) were registered in the more developed regions [7]. PC has been correlated to exposure to risk factors concerning lifestyle, such as obesity, or the environment [8]. The incidence of PC is higher in men than in women [9]. PC is a disease of the elderly, with most of the cases being diagnosed after the age of 55 [10]. African-Americans have the highest incidence rate of PC, that is 28-59% higher than those of other racial/ethnic groups [11].
\nMost pancreatic tumors are derived from the exocrine tissue. More than 80% of the exocrine PCs are classified as pancreatic adenocarcinomas (PAs). Microscopically, these cancers are characterized by infiltrating small glands that are lined with low-columnar, mucin-containing cells. Cell nuclei often show polymorphism, hyperchromasia, loss of polarity, and proeminent nucleoli [12]. PA shows strong desmoplastic reaction that occurs around cancer cells, which is considered a hallmark for this cancer type and may account to up to 90% of the tumor volume (Figure 2). The stroma surrounding the cancer cells is actively involved in tumor growth and dissemination. Desmoplastic stroma is composed of extracellular matrix (ECM), cancer-associated fibroblasts, stellate and inflammatory cells, and small blood vessels. Desmoplastic stroma shows high levels of cytokines and growth factors. The desmoplastic stroma creates a barrier for chemotherapeutic drug delivery. Targeted therapies against PC stromal components have so far failed to translate into significant clinical benefits [13].
\nRepresentative pictures from hematoxylin and eosin staining of PC tissue. (A) Biopsy of pancreatic adenocarcinoma. The malignant glands invade tissue eliciting a strong desmoplastic reaction. Focally intraluminal mucin may be seen (10×). (B) Higher magnification of pancreatic adenocarcinoma shows malignant irregular glands composed of cell with loss of polarity, large nuclei with high nuclear-to-cytoplasmic ratio. The nuclei show irregular shape and are hyperchromatic or vesiculated with prominent nucleoli (40×).
Pancreatic neuroendocrine tumors (PNETs), representing 1–2% of PC, are commonly called islet cell carcinomas. Functional PNET secretes biologically active hormones (insulin, glucagon, somatostatin, or vasoactive intestinal peptide), causing a clinical syndrome. Nonfunctioning PNET does not cause clinical symptoms [14]. Other types of exocrine PC include acinar cell carcinomas, adenosquamous carcinomas, colloid carcinomas, hepatoid carcinomas, intraductal papillary mucinous neoplasms and pancreatoblastomas [15].
\nThe majority of PC develops silently from pancreatic intraepithelial neoplasia (PanIN) over a long period of time that highlights the importance and the challenge for early diagnosis [16]. Survival of patients with PC depends on the tumor stage at the time of diagnosis. The American Joint Committee on Cancer staging system has defined the relationship of pancreatic tumor with surrounding tissues, lymph nodes, vessels, and distant organs [17]. The first clinical stage of PC refers to tumors that are confined within the pancreas. The second stage involves PC that is spread to the adjacent tissues, especially to the lymph nodes. In Stage 3, the disease has already spread to the blood vessels, while in Stage 4, the metastasis has occurred in distant organs. Unfortunately, at the time of diagnosis, most of the patients have already invasion of vascular, lymphatic, and perineural tissue. The most common sites for distant metastasis are the liver, lung, pleura, peritoneum, and adrenal glands. Surgery may be offered to <20% of patients with PC. An additional challenge is that surgery success rate is gravely limited by the extent of early or occult micro metastases [18].
\nThere are several factors that pose high risk for PC, such as obesity, chronic pancreatitis, diabetes, tobacco, and alcohol usage, exposure to chemicals, such as dyes and pesticides, age, and epigenetic changes. High-fat diets activate oncogenic Kras and Cox-2, causing inflammation and fibrosis in the pancreas, leading to PanINs and PC onset. Fat diet that induces pancreatic fatty infiltration could play an important role in PC. Moreover, the presence of PanINs was associated with intralobular fat accumulations [19]. The risk of PC increases with age, more than half of new cases occur in patients over 70 years old. ABO blood types and genetic variants may also influence PC risk [20]. Cigarette smoking increases the risk for PC by 75% when compared with nonsmoking individuals, and the risk persists for 10 years after smoking cessation [7]. Although several risk factors have been identified, the causes of PC are not well known. Understanding the mechanisms through which the risk factors might affect PC progression and survival is the key to develop a prevention strategy for this disease.
\nObesity is pandemic in the USA and has been associated with poor prognosis of several malignancies, including prostate, colon, breast, endometrial cancer, and PC. Both general and abdominal obesity are associated with increased PC risk. Moreover, physical inactivity has been linked with increased PC risk [7]. Obesity was linked with increased mortality from PC [21] and the promotion of stromal desmoplasia [22].
\nThe most common method for obesity detection is the determination of the body mass index (BMI) that is calculated based on the relationship between body height and weight (BMI 18.5–24.9, normal; 25.0–29.9, overweight; ≥30, obese). Obesity strongly correlates with body fat levels. Adipose tissue has a very strong endocrine function, secreting various adipokines that are involved in cancer development and progression, and insulin resistance. Leptin, IL-6, and tumor necrosis factor-alpha (TNF-α) are inflammatory factors increased in cancers, but adiponectin is protective against tumorigenesis, and its serum levels are usually decreased. Cancer patients show higher baseline levels of C-reactive protein and soluble TNFα receptor 2. Lipocalin 2 was associated with tumor invasiveness. Resistin, another proinflammatory adipokine, was increased in colon, breast, and prostate cancer. To date, many adipokines have been associated with cancer, contributing to enhanced inflammation, angiogenesis, cellular proliferation, and tumorigenesis [23].
\nOne of the main adipokines is leptin, a small protein (16 kDa), which is secreted by white, brown adipose tissue and cancer cells [24]. Leptin binding to its receptor, Ob-R, in the hypothalamus controls food intake and energy expenditure. Leptin also influences the reproductive function and is a long-term regulator of body weight. Leptin is also expressed in placenta, ovaries, skeletal muscle, stomach, and mammary epithelial cells. Leptin can inhibit bone formation. It regulates the ovulatory cycle and plays an important role in embryo implantation [25]. Obese and overweight individuals have high levels of leptin in blood but exhibit leptin resistance, failing to control food intake. Leptin blood levels in obese patients are 10 times higher (40 ng/ml) than in normal individuals (4 ng/ml). The underlying mechanism of leptin resistance in obese individuals is multifactorial that includes impairment of Ob-Rb signaling, hypothalamic neuronal wiring, leptin transport into the brain and Ob-R trafficking, endoplasmic reticulum (ER) stress, and inflammation [26]. High-leptin levels can induce cancer cell proliferation and thus can provide a link between obesity and cancer progression.
\nSeveral cancer cell types express leptin [25, 27, 28]. Both in vitro preclinical studies and patient, data suggest that leptin signaling is linked to the development of PC, breast, endometrial, colon, esophagus, stomach, thyroid gland, prostatic, hepatic, skin, brain, ovarian, lung and colon cancers, and leukemia [28, 29, 30, 31, 32]. Leptin can induce the development of nonalcoholic fatty liver disease, one of the major causes of hepatocellular carcinoma [33]. Leptin increases the proliferation of human myeloid leukemia cell lines and prostate cancer [34, 35]. In breast cancer, leptin increases the cancer cell proliferation and the expression of antiapoptosis-related proteins like Bcl-2 [36, 37]. Moreover, leptin induces the tumor angiogenesis, by promoting the expression of angiogenic factors, such as vascular endothelial-growth factor (VEGF) and fibroblast-growth factor 2 (FGF-2) [38]. Leptin has a direct effect on the proliferation of endothelial cells that were similar to VEGF [39]. Overall, leptin induces the production of inflammatory cytokines (IL-1, IL-6, and TNF-α), which can promote tumor invasion and metastasis [40].
\nThere is a correlation between increased leptin levels and PC. Overexpression of leptin promotes the growth of human PC xenografts and lymph node metastasis in mice [41]. Ob-R is expressed by pancreatic cells, but its expression is increased in PC cells. Leptin binding to Ob-R induces proliferation, migration, angiogenesis and reduces PC cell apoptosis. The receptor long isoform, Ob-Rb, is found more often in cancer cells and has full signaling capabilities, in contrast to the short isoform. Leptin and Ob-R have absolute affinity for binding. Leptin binding to Ob-R activates canonical (JAK2/STAT3, MAPK, PI-3 K/AKT1) and noncanonical signaling pathways (p38MAK, JNK, AMPK). The first leptin signaling event is the activation of JAK2, which phosphorylates Ob-R intracytoplasmic tail, leading to the phosphorylation of a tyrosine residue of STAT3 (pSTAT3). pSTAT3 forms a dimer that is translocated to the nucleus, inducing the transcription of specific genes, such as SOCS3, which acts as a potent negative feedback regulator of the JAK/STAT pathway [26]. Recently, it was reported that the central or peripheral administration of an Ob-R antagonist induced comparable changes in food intake, body weight, and hypothalamic SOCS3 expression in lean and diet-induced obesity (DIO) mice. These results suggest that endogenous Ob-R signaling may not be reduced in the context of DIO, thus challenging the established concept of leptin resistance under dietary-induced conditions [42].
\nCancer chemoresistance is a current PC challenge. Intrinsic chemoresistance occurs when chemotherapy is ineffective from the start of treatment, whereas acquired chemoresistance develops only after exposure to anticancer drugs. Although PC cells are more susceptible to Gemcitabine when compared with other anticancer agents, most patients develop resistance within weeks of treatment initiation, leading to poor survival [2]. Mechanisms of cancer chemoresistance include drug modification, reduction or inhibition of drug-induced apoptosis, overexpression of drug efflux proteins, increased expression of survival factors and deregulation of pathways, such as Notch, and expansion of cancer stem cells (CSCs), among others [43].
\nThe hierarchical model of cancer states that tumors arise from CSC or cancer-initiating cells that can reproduce all tumor cell types. CSCs have common characteristics associated to normal stem cells. CSCs are tumorigenic, show self-renewal capabilities, and can be differentiated into multiple cancer cell types. CSCs hide in the tumor niche causing relapse and metastasis. The tumor niche is composed of stromal and inflammatory cells, cytokines, ECM, and vasculature. It provides signals helping CSCs to maintain their undifferentiated state. The accumulation of ECM destroys the normal PC architecture and enhances the expression of PCSC markers [44].
\nPCSCs express various markers, including CD24+CD44+, CD133+, CD24+CD44+ESA+, ALDH+, or c-Met+. Metastatic PCSCs express CXCR4+CD133+. PCSC markers CD133 and CD44 correlated to CXCR1 expression. PCSC could be identified using Hoechst 33342 dye by flow cytometry. Hoechst-negative cells were called “side population” and were linked to chemoresistance [45]. ALDHs are a class of enzymes that oxidize aldehydes. ALDH + PCSC show clonogenic and metastatic potential that affects survival in PC. Positive PC cells for PCSC markers form tumors in mice, in contrast to negative PC cells. ALDH1 mediates resistance to Cyclophosphamide and Gemcitabine in PC. TGF-β negatively regulates ALDH1 in PC in a SMAD-dependent manner. That can be disrupted by SMAD4 mutations and deletions. Therefore, targeting PCSC could induce sensitization of PC to chemotherapeutic treatment [46].
\nChemotherapeutic agents target the bulk of the tumor but unfortunately allow the proliferation of CSC that exhibits chemoresistance. Gemcitabine kills tumor cells but increases PCSC (CD24+ and CD133+) that expresses stemness-associated genes, such as Bmi1, Sox2, and Nanog. PCSC expansion increased cell migration, chemoresistance, and tumorigenesis [47]. Drug resistant cells showed activated c-Met and increased expression of CD24, CD44, and ESA. The use of a c-Met+ cell inhibitor (Cabozantinib) abrogated Gemcitabine resistance in PC patients [48]. Administration of anti-CD44 monoclonal antibody to a human PC xenograft mouse model increased Gemcitabine sensitivity [49]. Similarly, Metformin enhanced the anti-proliferation effects of Gemcitabine by inhibiting the proliferation of CD133+ cells in PC [50].
\nAnother PCSC marker, Dclk1, was found in PanIN lesions, and PC at invasive stages [51], suggesting that PCSC may be used as diagnosis biomarkers. PCSCs show transcription factors found on embryonic stem cells (Oct-4, Sox-2, and Nanog). Increased levels of Oct-4 and Nanog correlate with early stages of carcinogenesis and worse prognosis. Oct-4 contributes to metastasis and cancer multidrug resistance. Sox-2 expression alone in PC could induce self-renewal and differentiation [24].
\nPCSC marker expression correlates with lymph node metastasis and poor survival. There are several factors that could affect PCSC maintenance and proliferation. For example, PCSC maintenance and survival are affected by miRNA34. In addition, stem cell factor (SCF) binding to its receptor, c-Kit, induces an increase in HIF-1α synthesis, which is involved in PC progression and chemoresistance [26].
\nOur data suggest that 5-FU (a common chemotherapeutic used in PC treatment) decreased PC tumorsphere formation. PC cells that expressed CD24 + CD44+, CD24 + CD44 + ESA+, and pluripotency (Oct-4, Sox-2, Nanog) markers were spared by the 5-FU treatment [30]. Therefore, the development of specific treatments against PCSC remains a challenge.
\nOverexpression of drug efflux proteins (ATP-binding cassette proteins and ABC family of proteins) increases the elimination of anticancer drugs and decreases their accumulation inside the cancer cells. ABC proteins (ABCB1, ABCC1, and ABCG2) are found in PCSC and contribute to their resistance to Gemcitabine [52]. Indeed, ABCB1 was significantly increased in CD44+ PC cells during the acquisition of resistance to Gemcitabine [53]. PC chemoresistance correlated with increased expression of CXCR4, CD133, and ABCB1 by PCSC [54]. Interestingly, ABCG2 localization and activity were not confined only to the plasma membrane, as intracellular vesicles containing ABCG2 were detected within CSC in PC, colorectal, and hepatocellular cancers. Moreover, a direct relationship between the presence of these vesicles in CSCs and the maintenance of their stem-like properties, including chemoresistance, was found. Furthermore, the vesicles accumulated ABCG2-dependent substrates, such as the fluorescent vitamin riboflavin (vitamin B2). In addition, the vesicles could accumulate ABCG2-depedent therapeutics, such as Mitoxantrone, to avoid apoptotic cell death [55]. Our data showed that PC tumorspheres treated with 5-FU were enriched in cells that overexpressed ABCC5 and ABCC11 efflux proteins [30].
\nTo gain invasive and migratory capacity, and resistance to apoptosis, cancer epithelial cells undergo EMT. The expression of transcription factors, including Snail, Slug, zinc finger E-box-binding homeobox 1 (ZEB1), and Twist, among others, induces EMT. ZEB1 deletion had a negative effect on tumor progression, invasiveness, and metastasis, reaffirming EMT’s role in PC metastasis [55]. Gemcitabine-resistant PC cells had increased Vimentin and decreased E-cadherin expression. These alterations are hallmarks of EMT.
\nOur data showed that the use of 5-FU rendered different outcomes on EMT markers in tumorspheres derived from different PC cell lines. In BxPC-3 tumorspheres, 5-FU did not change the levels of expression of EMT markers (Vimentin and N-cadherin), while in MiaPaCa-2 tumorspheres, it slightly increased the expression of N-cadherin. Moreover, 5-FU spared PC cells that were N-cadherin+ [30]. Recently, the EMT concept was challenged by studies demonstrating the existence of a hybrid epithelial/mesenchymal phenotype in cells transitioning from EMT to mesenchymal to epithelial transition (MET). Because MET has been considered crucial for metastasis seeding in distant organs, this hybrid phenotype seems to be linked to drug resistance and tumor-initiating potential. Moreover, MET could allow tumor cells to collectively migrate in clusters to form metastases in a more effective way than pure EMT single cells [55].
\nPC desmoplasia results from proliferation of cancer-associated fibroblasts and increased deposit of ECM. This process reduces elasticity of tumor tissue and increases interstitial pressure, leading to decreased perfusion of chemotherapeutic agents [56]. The proliferative pancreatic stellate cells are the primary source of many of the ECM components in PC. These cells show increased proliferation and sensitivity to mitogenic factors. Fibrous proteins (e.g., collagen) and polysaccharide chain glycosaminoglycans (e.g., hyaluronan) are ECM factors that constitute the noncellular components of PC desmoplastic tissue. A significant overproduction of ECM components can be described as the failed resolution of a healing wound, which leads to fibrosis in PC. Immune cells (macrophages, neutrophils, and regulatory T cells [Treg]) contribute to PC desmoplasia. Therapeutics reducing the contribution of the desmoplastic reaction to chemoresistance are being actively pursued as a potential therapeutic approach [57].
\nFrom the early lesions, PC cells harbor alterations in signaling pathways that remain throughout carcinogenesis. These changes not only impact tumor cells but also the surrounding stromal cells. Components of the Hedgehog (Hh) signaling pathway have essential roles in PC pathogenesis. In a global genomic analysis of PC, all tumors tested had alterations in at least one of the Hedgehog signaling genes. Hh signaling induced desmoplasia, playing a key role in chemoresistance [56]. Wnt signaling pathway is mainly involved in PC cell growth. The Wnt pathway is activated when ligands bind to the cell membrane Wnt receptor, resulting in the release of β-catenin into the cytoplasm. Increased β-catenin levels and activity have been found in PC but not in the normal pancreas [58]. Wnt pathway induces PC formation by actions not only on the tumor cells but also on the stromal compartment through increases in ECM formation [59].
\nThere are other dysregulated pathways in PC. The nuclear factor-κB (NF-κB) proteins constitute a family of transcription factors associated with mediating inflammatory responses. However, these transcription factors also control diverse genes involved in development, apoptosis, and cell proliferation. NF-κB has an important role in PC. Additionally, Notch and IL-1 induce NF-κB in PC [60]. NF-κB signaling crosstalks with other signaling pathways, oncogenic or cancer-related proteins, such as STAT3, p53, ALDH1, PI-3 K, and MAPK. A recent study that evaluated a large number of human PC samples along with a few PanIN lesions found amplification of c-Myc in 30% of the tumors [61]. c-Myc deregulation, in cooperation with other oncogenic pathways, such as Kras, is sufficient to promote tumorigenesis [62]. The complexity of the PC altered signaling pathways affects pathogenesis and could explain why there is no successful PC treatment. Relationships among tumor cells, stroma, and signaling pathway crosstalks demonstrate the importance of developing combined therapies targeting both compartments and altered signaling in PC.
\nApoptosis or programmed cell death regulates the tissue homeostasis. Chemoresistance is in part due to impairment of apoptosis in cancer cells. Antiapoptotic protein Bcl-2 is not frequently overexpressed in PC, which differs from other cancer types. In contrast, an imbalance between antiapoptotic Bcl-XL and proapoptotic Bax was found in the TGF-α murine model of PC [63]. Moreover, inhibitors of apoptosis, such as survivin, are overexpressed in PC when compared with normal pancreatic tissue. Resistant PC cells can be sensitized to death receptor–mediated apoptosis by inhibiting the NF-κB prosurvival pathway or by decreasing the expression of antiapoptotic proteins. The p53 pathway plays an important role in cancer cells avoiding the apoptosis, with mutations in p53 gene leading to increased drug resistance in PC cell lines and poor survival in PC patients [63]. Our data showed that 5-FU treatment of PC tumorspheres reduced RIP and Bcl-XL levels and increased Bax. Moreover, 5-FU increased caspase-3 activation and decreased uncleaved PARP in PC [30]. These data indicate that 5-FU actions on PC induce apoptosis through several components of the pathway. Numerous chemotherapeutic drugs target DNA synthesis in cancer cells, leading to increased apoptosis.
\nLeptin induces a wide range of prooncogenic effects. We have shown, for the first time, that leptin could be secreted by PC cells and derived tumorspheres. Moreover, leptin induced PCSC in tumorspheres [28]. In line with these data, a study of a pool analysis from PC patients showed that leptin levels and elevated Ob-R expression correlated to Oct-4 [64]. Our data demonstrated that leptin increased PC cell proliferation, tumorsphere formation, and xenograft growth in an immunocompromised mouse model. Moreover, leptin induced cell cycle progression, PCSC markers (CD24 + CD44 + ESA+, ALDH+), and ATP-binding cassette protein expression (ABCB1) in PC cells [28]. Leptin has been shown to increase the expression of miR21, while the tumor suppressors (miR200a, miR200b, and miR200c) decrease the expression of Ob-R. Furthermore, these tumor suppressors could also interact with some of the PCSC markers (c-Met, ABCB1, and CD44), which decrease their expression. Oncogenic miR21 increases the expression of ABCB1, ALDH, and CD44.
\nLeptin can directly regulate the expression of HDAC4 and HDAC5 and indirectly affect the expression of other HDAC via microRNA or PCSC markers. We have suggested that leptin can increase the expression of miR21, which in turn can increase the expression of HDAC3. Analysis of data from PC biopsies (TCGA databank) suggested that HDAC, miRNA21/200, and leptin could have complex signaling crosstalk that could be a novel therapeutic target for obese PC patients. We further determined the effects of leptin on HDAC expression in PC tumorspheres. HDAC3 and HDAC8 expression was increased by leptin. Furthermore, the Gemcitabine-induced decreased expression of HDAC2, HDAC3, and HDAC8 was reversed by leptin. Thus, we have shown that leptin through its effects on PCSC, ABCB1, and HDAC could be involved in PC chemoresistance [65]. Moreover, using another chemotherapeutic agent commonly used in PC treatment, 5-FU, we demonstrated that leptin impaired 5-FU cytotoxicity by increasing the expression and number of PCSC+, pluripotency+, and EMT+ PC cells. ABCC5 and ABCC11 expression as well as the number of positive cells for these ATP-binding cassette proteins were increased by leptin in PC tumorspheres. These leptin’s effects protected the survival of PC tumorspheres treated with 5-FU and reduced its cytotoxicity. The survival of PC tumorspheres treated with 5-FU and leptin was linked to reduced apoptosis. Leptin increased the levels of PARP, Bcl-XL, and RIP and decreased Bax. 5-FU increased caspase-3 activation, which was reduced by leptin. These data could help to unravel the multiple mechanisms through which leptin signaling contributes to drug resistance in PC [30].
\nNotch signaling controls the cell proliferation, PCSC maintenance and differentiation, apoptosis, invasion, and metastasis in cancer. Overexpression of Notch receptors (Notch1 and Notch2) was found in PCSC when compared with nonmalignant pancreatic stem cells [66]. DLL4 increase in PC cells stimulated the expression of Oct-4, Nanog, and stem cells [67]. PCSCs that express Oct-4, Sox-2, and Nanog show an increased aggressivity and chemoresistance. Notch4 overexpression was linked to PC chemoresistance to Docetaxel [68]. Expression of Notch3 and Hey1 was associated with reduced survival in PC [69]. Resistance to Gemcitabine correlated with Notch2, Notch4, and JAG1 overexpression [70]. The inhibition of Notch1 by siRNA suppressed proliferation, induced apoptosis, and reduced migration and invasion of PC cells [71].
\nNotch signaling induced EMT phenotype in Gemcitabine-resistant PC cells overexpressing Notch2, Notch4, and JAG1. Furthermore, the inhibition of Notch signaling decreased EMT markers, including Vimentin, Snail, Slug, and ZEB1, in human PC cell lines [72]. MiR200 members increased Notch activation by ZEB1 that regulates the expression of JAG1 and the mastermind-like coactivators (Maml2 and Maml3). In PC cells, miR200 expression showed an inverse correlation with JAG1 and ZEB1 levels [73]. Therefore, miR200 inhibits EMT by interacting with ZEB1/2 and the Notch pathway and represses self-renewal and differentiation in CSC. MiR200 is also involved in apoptosis [72].
\nOur data showed that leptin induced the expression of Notch family components in PC (Notch1–4, DLL4, JAG1, survivin, and Hey2), PCSC markers (CD24CD44ESA, ALDH, CD133, and Oct-4), ABCB1 (MDR1), tumorsphere formation, cell cycle progression, proliferation, and tumorigenesis. These effects were reduced by GSI [28]. Moreover, mouse and human PC and cell lines treated with adiponectin, or an adiponectin receptor agonist, AdipoRon, suppressed leptin-induced STAT3 signaling in vitro and reduced PC growth in vivo [74]. The addition of leptin to 5-FU treated tumorspheres decreased 5-FU-induced cytotoxicity and increased colony forming ability, number of cells expressing pluripotency and EMT markers, drug efflux proteins (ABCC5 and ABCC11), and Notch. Leptin also reduced the 5-FU effects on apoptosis by decreasing proapoptotic (Bax, caspase-3 activation, and PARP degradation) and increasing antiapoptotic factors (RIP and Bcl-XL). Leptin’s effects on PC tumorspheres were mainly Notch signaling dependent [30]. Therefore, the leptin-Notch axis could be a target to develop novel strategies for PC treatment.
\nTo decrease the risk of local and distant metastasis, adjuvant therapy is usually started 1–2 months after PC surgery. Although no regimen has been proven significantly more effective than others, a regimen based on 5-FU or Gemcitabine for 6 months is usually the option used to reduce PC patients’ mortality [75]. The activity of 5-FU/Leucovorin has been compared to Gemcitabine as an adjuvant therapy in the European Study Group for PC (ESPAC)-3 trial [76]. However, the study showed that median overall survival for patients treated with 5-FU/Leucovorin was 23 months when compared with 23.6 months for patients treated with Gemcitabine. The ESPAC-4 study measured the efficacy of a combination treatment with Gemcitabine plus Capecitabine when compared with monotherapy with Gemcitabine alone. The results showed a survival of 28 months in the combined therapy when compared with 25.5 months in the monotherapy group. Because the dual therapy was well tolerated, the combination of Gemcitabine and Capecitabine has been used as a standard in the clinical setting [77]. Currently, regimens with Gemcitabine plus nanoparticle albumin-bound Paclitaxel (nab-Paclitaxel) and a combination of 5-FU, Irinotecan, and Oxaliplatin (FOLFIRINOX) are evaluated in the clinical setting [78]. Gemcitabine has usually some efficacy as an adjuvant therapy, but often patients develop chemoresistance. Nab-Paclitaxel, a water-soluble compound, has enhanced distribution properties within the tumor microenvironment when compared with Paclitaxel. However, studies have shown that nab-Paclitaxel treatment neither decreased tumor stroma nor increased tumor vascular perfusion in a mouse patient-derived xenograft (PDX) tumor model [79]. The infiltration of neoplastic lesions by CD8+ T lymphocytes is associated with improved prognosis. However, a CD40 monoclonal antibody that activated CD8+ T cells in Phase I clinical trial had only a partial response [80]. FOLFIRINOX and nab-Paclitaxel plus Gemcitabine have the potential to downstage local advanced disease and to improve tumor resection rates. The use of chemoradiation therapy as an adjuvant is controversial and with minimal effects on survival in clinical trials so far [81]. New studies that incorporate modern radiation techniques and current chemotherapy regimens are still needed to determine if radiation is beneficial in PC treatment.
\nA comprehensive genetic analysis of PC showed that these tumors contain an average of 63 genetic alterations in 12 cellular signaling pathways, including Notch pathway [82]. A Phase Ib trial for PC using a combination of Demcizumab (OMP-21 M18), a monoclonal antibody against Notch ligand, DLL4, with Gemcitabine and Abraxane, showed some clinical benefits [60].An antibody against Notch2 and Notch3, Tarextumab, was tested in Phase 2 clinical trials in combination with Gemcitabine and nab-Paclitaxel in patients with metastatic PC. For these patients, the median progression-free and overall survival were 5.6 and 11.6 months, respectively. Gamma secretase inhibitors (GSIs) have been used in clinical trials in PC. For example, a GSI called RO4929097 was safely tolerated in combination with Gemcitabine and achieved clinical antitumor activity and more than 4 months of stable disease. However, the use of GSI has limitations and still represents a challenge because of the increased drug toxicity and lack of high specificity to Notch besides other substrates of γ-secretase [83].
\nDesmoplasia is a target in PC treatment. Hyaluronan, a component of the ECM of PC, is a naturally occurring nonsulfated glycosaminoglycan that was targeted using pegylated hyaluronidase (PEGPH20). In a Phase II study combining Gemcitabine, nab-Paclitaxel, and PEGPH20, there was no difference seen in the survival of PC patients that had this addition to their treatment. Also, due to the ubiquitous nature of hyaluronan, there were unexpected side effects, such as thrombosis. For the Gemcitabine, nab-Paclitaxel, and PEGPH20 study, a subset analysis was performed on the high-hyaluronan patients. In the arm receiving PEGPH20, the response rate was 45% when compared with 31% in controls, which was encouraging, and led to a Phase III clinical trial (HALO301) for patients that had high hyaluronan. In these studies, Lovenox was included for anticoagulation [84].
\nSTAT3 inhibition has been shown to decreased PC growth in mouse models. Napabucasin decreased STAT3 transcription and tumorsphere formation and showed some efficacy in PC. Napabucasin induced a median progression-free survival of >7.1 months and a median overall survival of >10.4 months in PC patients. Based on these encouraging results, it is now being evaluated in a PC Phase III study in combination with Gemcitabine and nab-Paclitaxel (NCT02993731) [85].
\nThe expression of leptin in gastroesophageal adenocarcinomas was associated with chemoresistance. Therefore, the addition of leptin antagonists to current chemotherapeutic treatment could represent a new strategy to overcome drug resistance and to improve survival of PC patients. SHLA, a leptin antagonist, increased the sensitivity of resistant gastric cancer cell line, AGS Cis5, and the esophageal adenocarcinoma, OE33, to cisplatin [86].
\nLPrA2 was designed and tested in vitro and in vivo in PC xenograft mouse models in our laboratory. LPrA2 is composed by a leptin sequence corresponding to its binding Site III of the leptin molecule. LPrA2 was conjugated to iron-oxide nanoparticles (IONP-LPrA2) to increase its bioavailability and effectiveness to block leptin signaling in cancer cells [28]. IONP-LPrA2 showed no toxicity and did not affect energy balance (body weight or food intake) or general health when it was administered to mice. IONP-LPrA2 reduced the expression of Ob-R, Notch, and PCSC markers. Furthermore, specific inhibition of leptin signaling by IONP-LPrA2 delayed tumor onset and decreased tumor growth in a PC xenograft mouse model. Our data also showed that IONP-LPrA2 could be used as an adjuvant therapy to 5-FU. In PC cells treated with 5-FU and leptin, IONP-LPrA2 reduced tumorsphere formation and cell proliferation, the number of Notch+, ABCC5/11+, and PCSC+ cells, and increased apoptosis. Thus, IONP-LPrA2 resensitized PC cells to 5-FU actions [28, 30]. In view of leptin multiple effects on PC and the involvement of Notch signaling in leptin’s effects, targeting leptin-Notch crosstalk in PC patients might be a new treatment strategy for this deadly disease (Table 1). The addition of leptin antagonists to current chemotherapeutic treatment could represent a new strategy to overcome drug resistance and to improve survival of PC patients.
\nInhibition of leptin signaling using IONP-LPrA2 resensitizes PC cell lines to chemotherapy.
PC is a lethal systemic disease that is difficult to detect and treat. This is mainly due to the fact that even patients diagnosed with early stages eventually develop metastasis. The deep abdominal position of the pancreas is an additional factor that delays the onset of specific PC symptoms. Early PC diagnosis and potential cure remain important challenges due to the lack in screening methods and specific biomarkers. PC risk factors, such as high-fat diet, obesity, tobacco, and alcohol consumption, can be modified, leading to prevention of disease occurrence and increased survival. PC desmoplastic stroma, which decreases chemotherapeutic drug delivery to the tumor, is an another current challenge to improve PC survival. Currently, combined chemotherapy strategies are used in selected patients with PC metastatic disease. The identification of novel PC targets is the key for the development of new individualized strategy for prevention and treatment. An emerging and promising area is the relationship between obesity and leptin-induced prooncogenic effects in PC, which could also affect chemoresistance and metastasis. In this respect, the use of leptin signaling antagonists as a novel sensitization adjuvant for current chemotherapeutic drugs appears as a potential new strategy to improve treatment effectiveness and patients’ survival. The use of leptin signaling antagonists could also make possible the reduction of drug dosage and the improvement of patient quality of life.
\nThis work was supported by the National Institute of Minority Health and Health Disparities (NIMHD) at the National Institutes of Health under Award Number S21MD000101 and the National Cancer Institute 5G12 MD0076021, G12 RR026250-03, NIH RR03034, and 1C06 RR18386 to Morehouse School of Medicine.
\nThe authors declare that there are no conflicts of interest in writing this chapter.
Non-pharmacological interventions (NPI) are part of the chapter on therapeutics in the health sciences. Together with pharmacotherapy, ionising or non-ionising radiation, surgery and rehabilitative medicine they comprise the procedures used to prevent and treat diseases.
\nNon-pharmacological treatments (NPT) are used for many unconventional treatments in integrative medicine.
\nThe need to use NPI is justified because it is a valid option if indicated as a preventive or curative measure. Side effects of medications are avoided, health costs are brought down and there is no significant environmental impact.
\nThe use of medicines has entailed an important change for humankind. No one doubts the benefits of antimicrobials, vaccines, anti-inflammatories, analgesics, opotherapy and specific medicines for each health problem. Modern surgery has been possible thanks to the development of anaesthetics, anticoagulants and a large number of medicines that make it possible for each intervention to be performed. Many material and human resources have been devoted to the study of numerous drugs and a powerful pharmaceutical industry (PI) has developed which occupies the highest echelons in the economy of developed countries.
\nAlthough there are many benefits provided by PI and they continue to contribute to the health of humankind, a series of problems that have arisen due to the so-called medicalization of life must be taken into account [1].
\nPrescribing is far from being totally scientific and suffers from serious shortcomings for various reasons such as commercial interests, deficiencies in clinical trials and regulatory bodies, ethics and environmental problems. Sometimes as many medicines are prescribed as the client has symptoms, whereby it invites a follow-up for possible drug interactions and side effects [2].
\nGreater prescription of medicines (polypharmacy) is associated with poorer quality of life and higher morbidity. In some developed countries, iatrogenic drugs have displaced accidents as the third or fourth leading cause of death after cardiovascular disease and cancer [3].
\nThe criteria of the prescribing physician, whether primary or specialised care, is important to avoid interactions, overdose, duplicates and other problems that may contribute to the onset of side effects. In addition, the criteria must avoid pressures from the PI and act with a cost criterion; effectiveness, safety and environmental sustainability. Due to this latter aspect, NPI should be taken into account since, in principle, they are more environmentally sustainable than medicines.
\nEvidence-based medicine (EBM) is the current benchmark when it comes to performing a healthcare intervention. Its influence also extends to the design of clinical trials and their reporting.
\nSince the onset of the 21st century, independent scientists from multinational pharmaceutical companies have denounced the inappropriate practices of the PI. Table 1 shows some of the irregular practices carried out by the PI for financial purposes, their consequences and solutions according to Ben Goldacre [4].
\nPI performance | \nConsequences | \nSolutions | \n
---|---|---|
Most clinical trials (CT) are sponsored by the PI | \nLarge percentage of positive results | \nLegislation and greater control | \n
Negative results are not published | \nThe scientific community is deprived of important information | \nIt was approved that all clinical trials had to be registered (WHO, 2004) and/or Latin American Registry of CT in progress (Latinrec) | \n
PI sometimes manipulates CT results | \nThe user of the medicine is harmed by side effects, etc. | \nGreater control of clinical trials (legislation) | \n
CT results are not always replicable | \nConcern | \nLegislation | \n
Bioethics committees and regulatory bodies are not always up to the task | \nThey evaluate efficacy, quality and safety but not the medicine’s therapeutic value | \nNeed for analysis by independent bodies | \n
Sometimes medicines for adults are prescribed at paediatric age | \nGreater chance of side effects | \nFurther information from the laboratory | \n
CT are performed with the most disadvantaged population groups (homeless, illegal immigrants, Latin Americans, etc.) | \nSelection bias and uncertainty Ethics issues | \nAdequate legislation | \n
There are conflicts of interest in the study | \nNew medicines are approved without sufficient knowledge of side effects | \nGreater control by regulatory bodies | \n
The PI distorts clinicians’ beliefs and substitutes marketing for testing | \nIncrease in pharmaceutical spending due to inappropriate medication | \nInformation transparency | \n
Criteria for approval of a new medicine are often ineffective | \nThe user and health system are harmed | \nAdequate legislation | \n
Irregular pharmaceutical industry practices (taken from Goldacre and completed by A. Ursa).
During the medical procedure, all health professionals when prescribing within the scope of their competence, must choose the best therapeutic option for their client, always bearing in mind the NPI. The reality, however, is different because the future doctor is educated in the prescription of drugs. Because the current medical paradigm requires rapid, accurate and symptomatic actions. However, the side effects of the medicines also need to be tackled. Because of this, a powerful PI has been developed with major economic interests, the medicine has been overvalued and research, development and innovation (RDI) are targeted at these interests and not at NPI [5].
\nThe PI generally spends more on marketing and marketing of medicines than on research [6].
\nAlthough it is true that the whole process that entails the launch of a new medicine on the market is lengthy and expensive, the PI often opts for a false innovation. That is how “me too” drugs arrive on the market [7], molecules similar to others in use, enantiomers, racemic mixtures, etc. The PI brings out “me too” drugs when the end of their drug patents approaches. These novelties that are not such, are usually expensive, not superior to the old drugs and are a source of major revenues for the PI [8].
\n\nTable 2 shows some methods used by researchers to obtain favourable results in clinical trials according to Sackett, Oxman, Smith, Peiró and Peralta [9].
\nMethods used by the PI to obtain favourable results in CT | \n
Contrast the effects of the drug with placebo and not with other drugs | \n
Conduct a CT against a treatment known to be inferior | \n
Compare the new drug with doses that favour the study drug over the reference drug | \n
Not apply true uncertainty criteria | \n
Perform CT too small to reveal differences from the competitor | \n
Use multiple variables in the CT and select only those that provided favourable results for publication | \n
Perform multicentre trials and select only those from sites that obtained favourable results for publication | \n
Perform subgroup analyses and select only those that are favourable for publication | \n
Present results most likely to impress. Relative risk reduction is often used instead of absolute risk | \n
Selection of the population participating in the study inappropriately | \n
Using inappropriate routes of administration of the reference drug | \n
Use surrogate instead of clinically relevant variables | \n
Delay publication and retention of data | \n
Establish the primary endpoint at the end of the study | \n
Mask side effects | \n
Highlight data favourable to the funder and not publish unfavourable data | \n
Methods used to obtain favourable results in clinical trials [9].
The PI only finances research projects most likely to yield positive results. This breaches the uncertainty principle that establishes that the patient should be included in a CT only if there is substantial uncertainty about which treatment will benefit them the most [9].
\nThe publishers that own the medical journals where the CT are published depend on the PI, since drug advertising, special issues, reprints, etc. are a source of revenue [10]. If an author publishes an unfavourable criticism against a drug or PI, he runs the risk of not receiving income for the above concepts [9].
\nThe fact that certain medicines are included in a clinical practice guide (CPG) is of major interest to the PI, since these guidelines are drawn up by experts for their use [11]. A study published in JAMA in 2002 found a high number of financial relationships between CPG experts and PI. Serious omissions were found in the declarations of conflicts of interest [9].
\nConflicts of interest and potential biases in the publication of scientific-medical research have cast doubt on the credibility of the PI [9].
\nAccording to Peter Gotzsche, from the University of Gopenhage and director of the Nordic Cochrane Centre, the PI “does not work to improve health, but to obtain the maximum benefits” and to do this “extorts, commits fraud, breaches legislation and lies” [3].
\nNon-pharmacological interventions (NPI) or non-pharmacological therapies (NPT) are defined as any non-chemical intervention, which is theoretically supported, targeted and replicable, performed on a patient or caregiver and potentially capable of obtaining a relevant benefit [12].
\nThe adoption of a healthy lifestyle is perhaps the best NPI as it will contribute to better health, more life enjoyment and reduce, except for contingencies, health costs. Thus, the ideal place to recommend NPI, as a preventive and/or curative measure is Primary Health Care, in line with the Declaration of Alma Ata of 1978 [13] and ratified 40 years later in Astaná in 2018 [14].
\nA large number of the techniques used in physiotherapy such as massage, kinesitherapy, etc., manual techniques (joint manipulations, chiropractic, etc.), various techniques used in psychotherapy, yoga, meditation, and others framed under the term non- conventional medical therapies (NCMT) such as acupuncture, moxibustion, homoeopathy, etc., belong to the NPT chapter. Many act by stimulating the body’s healing power, sometimes because they stimulate the production of biogenic amines, neuropeptides, stimulate natural defences, produce neuroprotection, etc., which contributes to homeostasis [15].
\nAlthough herbal medicine or treatment with medicinal plants forms part of the treatments used in NCMT, it is not included in this section since it deals with chemical substances. This does not mean that they should not be used but rather that it would be desirable to supplement NPT with medicinal plants of proven efficacy and safety. Homoeopathic preparations, however, do fall under the NPT heading, since after several dilutions the original substance is not observed.
\nNPT seek to relieve symptoms and improve quality of life, which is why they are widely used in the management of dementias, especially Alzheimer’s dementia, both in institutions and at home. Applied exclusively or in combination with drugs, they aim to slow down the course of the disease [16].
\nNPT should meet safety and efficacy standards [17] and for this, studies and meta-analyses have had to be performed for scientific validation, as required by evidence-based medicine according to Sackett et al. [18].
\nUnfortunately, there is not always a company or entity that finances many of these studies. Therefore, there are fewer studies published than those offered by the PI.
\nAlthough NPT are used above all in the field of Gerontology, in many other disciplines they also have both preventive and curative applications, either alone or in combination with other therapies.
\nNPT began to be applied systematically for dementia, both in institutionalised patients (nursing homes, day care centres) and in their homes. The aim was to, alleviate these processes, since there is no curative treatment [19]. NPT in the field of social and health care are called psychosocial interventions (PSI).
\nIn the 1980s, support programmes for caregivers of dementia patients, whether they were family members or individuals, needed to be performed. In recent years there has been a need to extend these programmes to professional caregivers [19].
\nSince the last century there have been several attempts to classify PSI. With regard to validating PSI in Alzheimer’s dementia, experts recommend basing their actions on systematic reviews and meta-analyses.
\nAlzheimer’s relatives’ patient associations consider the areas of intervention in terms of cognitive, functional, emotional and comprehensive aspects.
\nSome intervention programmes (IP) used in the field of Alzheimer’s disease are listed in Table 3 according to Gárate Olazábal [20].
\nIntervention programmes (IP) | \nTechniques | \nPerson who applies it | \n
---|---|---|
IP focused on behaviour | \nBehavioural training Cognitive behavioural therapy | \nPsychologist | \n
Environmental IP | \nAdaptation of physical space Adaptation of the social environment | \nClinical assistants | \n
IP focused on emotion | \nMontessori method Validation therapy Reminiscence Orientation to reality | \nPsychogeriatricians Occupational therapist Physiotherapist Nursing assistant | \n
Cognitive stimulation programme | \nArt therapy Music therapy Aromatherapy Physical exercise Light therapy | \nPsychogeriatrician Occupational therapist Physiotherapist Nursing assistant | \n
IP focused on stimulation | \nMassage Therapeutic touch | \nPhysiotherapist | \n
Other IP | \nRelaxation, acupuncture, animal therapy, etc. | \nPsychologist, doctor | \n
Intervention programmes focused on Alzheimer’s disease (taken from Gárate Olazábal and completed by A. Ursa).
These interventions can be performed either individually or in groups. Those carried out individually are more effective.
\nThe Montessori-Based Dementia Programming (MBDP) method enables adults with dementia to be given tasks initially designed solely for children. Dr. Cameron Camp and the Myers Research Institute are pioneers in the MBDP system, which began to be used in the late 1990s. It is applied at advanced stages and consists of performing scheduled activities based on activities of daily life (ADL). To achieve this, he uses cognitive rehabilitation techniques such as task division, guided repetition, progression from simple to complex, and progression from concrete to abstract. When applied properly, it improves motor skills and basic functional abilities within a reasonable period of time (included in the Barthel index) [21].
\nMany other NPI can be performed in the social health field and as a first choice, for common pathologies such as insomnia [22], anxiety and stress [23], etc.
\nSupport groups, education techniques and cognitive-behavioural training, counselling and case management, and prevention of physical and/or chemical restraints have been devised among other interventions to reduce the morbidity associated with caring for these patients [24]. This is for the caregiver, whether family or non-family, due to the major burden that falls upon them.
\nCardiovascular diseases (CVD) are the most common cause of mortality in Western countries and involve high health costs. Arteriosclerosis develops insidiously over many years and its clinical manifestations appear when the disease is advanced. The CVD burden has grown in recent decades, in parallel to an increased prevalence of risk factors such as obesity, smoking, type 2 diabetes mellitus and high blood pressure [25]. Prevention of CVD involves adopting a healthy lifestyle and intervening on biochemical modifiable factors, etc., by means of pharmacological and/or non-pharmacological treatments.
\nIn recent years, a preventive strategy has been developed in clinical practice based on what is known as cardiovascular rehabilitation (CVR), which is defined according to the World Health Organisation as “the set of activities necessary to ensure people with cardiovascular diseases, an optimal physical, mental and social condition that allows them to occupy by their own means as normal a place as possible in society” [26]. A team of professionals is required to perform CVR, it has relatively little implementation and according to cost-effectiveness studies it is favourable [27].
\nThe prevention of such common pathologies as arterial hypertension is based on dietary advice, practice of physical exercise appropriate to each situation [28], stress control, emotional management and avoiding both legal and illegal drugs.
\nMany other cardiovascular diseases can be treated as first intention with NPT or as an accompaniment to pharmacological treatment. Table 4 shows some of these pathologies, NPT and the healthcare professional who applies this.
\nPathology | \nNPT | \nProfessional who applies/supervises this | \n
---|---|---|
Hypertension | \nPhysical exercise (Briones Arteaga) | \nGeneral practitioner/specialist | \n
Acute heart failure [29] | \nVentilation, ultrafiltration, mechanical circulatory support, myocardial revascularization, etc. [29] | \nCardiologist and nursing staff | \n
Venous insufficiency of the lower limbs [30] | \nDietary advice, hydrotherapy, physical exercise (Schneider) | \nPhysician/nurse/physical therapist | \n
Primary arterial hypotension [30] | \nDietary advice, hydrotherapy, physical exercise (Schneider) | \nPhysician/nurse/physical therapist | \n
Some CVD and their non-pharmacological approach.
It would be desirable to implement cardiovascular pathology NPI in health systems to reduce the side effects of medication, polypharmacy, improve quality of life and reduce health costs.
\nChronic obstructive pulmonary disease (COPD) and asthma are common respiratory diseases and in many cases, they go undiagnosed, reduce quality of life and represent a high health cost.
\nNPT is essential in COPD patients. However, this treatment is sometimes not given adequate importance. Patients diagnosed with COPD should benefit from comprehensive care services (CCS), which are an articulated set of standardised actions aimed at meeting the COPD patient’s health needs, considering the environment and particular circumstances. Pulmonary rehabilitation (PR) is one of the essential components of non-pharmacological treatment in COPD. NPT is used as an adjunct to drug therapy [31] and has been shown to improve functionality [32].
\n\nTable 5 shows the pulmonary rehabilitation plan according to the National Heart, Lung, and Blood Institute (INCPS) [33].
\nProcedure | \nPurpose | \nResources/professionals | \n
---|---|---|
Exercise training | \nImprove muscular endurance and strength | \nTreadmill, exercise bike, weights | \n
Nutritional advice | \nEating to achieve a healthy weight | \nPeriodic supervision by the nutritionist | \n
Health education | \nKnowledge of the disease, proposals for a healthy life, recognition of flare-ups, drug management, etc. | \nSpecialist doctor/nursing team | \n
Tackling fatigue | \nAdvice on how to perform daily tasks, stress management, sleep, etc. | \nSpecialist doctor/nursing team | \n
Tips on breathing | \nImprove the quality of breathing and oxygenation | \nSpecialist doctor/nursing team | \n
Psychological advice | \nIndividual or group approach. Avoid anxiety/depression | \nPsychologist | \n
Pulmonary rehabilitation plan according to the INCPS.
Many other actions have been published for asthma (therapeutic education, massage, music therapy, etc.). However, results are not conclusive.
\nGastrointestinal tract diseases are numerous, due to different causes and many are related to an inappropriate lifestyle. In addition to the pharmacological and/or surgical, dietary and psychological treatment from which a benefit can be derived, some are susceptible to improvement with physical treatments such as different applications of hydrotherapy (washes, damp cloths plus drug substance, jets, etc.), physical exercise, relaxation techniques, etc., within the context of personalised medicine.
\n\nTable 6 shows some NPT applied in the most common digestive tract disorders (taken from Schneider and Pizzorno et al. [34, 35]).
\nCondition | \nNPT | \nEffects | \n
---|---|---|
Caries and periodontal disease | \nMechanical cleaning of teeth with dental floss | \nRemoves the bacterial plaque causing the disease | \n
Gastroesophageal reflux esophagitis (from hiatus hernia, etc.) | \nPostural when lying down (head elevated) Physical exercise | \nPrevents passage of acid from the stomach | \n
Chronic gastritis | \nCompresses, damp cloths plus drug substance, wraps, jets, etc. according to disease stage | \nReduce discomfort, improve functionality | \n
Gastrointestinal ulcer | \nFlax seed/clay plasters on abdomen, wraps and compresses for the first 4 weeks. After dry brushing of the skin, jets at alternate temperatures, etc. | \nShortens course, relieves symptoms (pain, etc.) and reduces medication | \n
Irritable bowel syndrome | \nDiet (fibre, etc.) Stress reduction (yoga, meditation) Physical exercise | \nImproves annoying symptoms (pain, etc.) | \n
Functional constipation (no organic cause) | \nDiet, physical exercise, hydration Warm sitz baths. Chamomile enema. Belly massage. Abdominal wraps, etc. | \nAdoption of a healthy lifestyle improves the frequency of defecation and avoids associated diseases (haemorrhoids, etc.) | \n
Haemorrhoids (internal and/or external) | \nDepending on scope they can benefit from a sitz bath at an alternating temperature, homoeopathy, etc. | \nReduce congestion, relieve discomfort, etc. | \n
NPT in some of the most common digestive tract diseases (taken from the book health by nature and natural medicine manual).
In the section on hepatobiliary diseases, there are many accompanying measures to pharmacological, hygienic and dietary treatments that can be performed. Given the characteristics of the book, it is not possible to elaborate in this context.
\nObesity and diabetes mellitus are among the most common of the many endocrine-metabolic disorders in Western countries. Both constitute a public health problem since they cause major morbidity and mortality, which increases the country’s health expenditure. The first measure in tackling obesity consists of adopting a healthy lifestyle that enables maintaining an optimal weight. Diet, physical exercise and medical advice should not be lacking when the body mass index is higher than 30. Individualised treatment should take precedence over guidelines or protocols. In the case of type 2 diabetes mellitus, the most common, hygienic-dietary advice needs to be strengthened as an aid to pharmacological treatment if needed [36].
\nFor dyslipidaemia, good results have been achieved with the application of cardio-healthy diets, especially for secondary dyslipidaemia [37].
\nPhysical exercise is the first indication in metabolic syndrome with the aim of reducing abdominal fat deposition and adverse cardiovascular effects. The remaining associated conditions are managed with medical advice, drug therapy, and a correct diet [38].
\nBone mineral density (BMD) gradually decreases with age and is more evident in women when menopause begins. Physical exercise in conjunction with dietary and hygiene advice has been shown to improve BMD in postmenopausal women [39].
\nRehabilitation medicine and physiotherapy as members of the health sciences are the paradigm of NPT, since a large part of their actions are based on physical procedures.
\nSome symptoms and signs that accompany many osteoarticular, neurological, psychiatric and other diseases are the usually associated inflammation and pain. Table 7 includes some procedures used in rehabilitation medicine and physiotherapy taken from Miranda Mayordomo [40].
\nTechnique/procedure | \nEffect | \nIndications | \n
---|---|---|
Kinesitherapy in its different variants | \nGain in strength and mobility | \nVarious injuries of the locomotor system, neurological, etc. | \n
Therapeutic exercise (active kinesitherapy) | \nImproved proprioception | \nIndicated in many osteoarticular processes/injuries | \n
Heat/Cold | \nAnalgesia, etc. | \nSee text below | \n
Transcutaneous electrical stimulation (TENS) | \nAnalgesia | \nMany musculoskeletal and other conditions (oncology, etc.) | \n
Cervical traction | \nAnalgesia | \nCervical spondylosis, disc prolapse, cervical injuries, torticollis, etc. | \n
Massage | \nMobilises contracted tissues, relieves pain, reduces inflammation and induration in trauma | \nSprains, muscle strain, contusion, peripheral nerve injuries, lower back pain, arthritis, peri-arthritis, bursitis, fibromyalgia, hemiplegia, paraplegia, tetraplegia, multiple sclerosis, cerebral palsy and amputation | \n
Acupuncture | \nAnalgesia | \nConditions that present with acute or chronic pain | \n
Homoeopathy | \nAnalgesia, reduces inflammation and oedema in trauma | \nSprain, painful shoulder, osteoarthritis, bursitis, epicondylitis, carpal tunnel syndrome, etc. | \n
Some physical therapies used in rehabilitation/physiotherapy (taken from Miranda Mayordomo’s book, Medical Rehabilitation and completed by A. Ursa).
The choice between heat and cold treatment is governed by principles and is sometimes applied empirically.
\nHeat provides transient relief in subacute and chronic inflammatory and traumatic disorders, such as sprains, muscle strains, fibrositis, tenosynovitis, muscle spasms, myositis, lower back pain, neck injuries, various forms of arthritis, arthralgia, neuralgia, etc. Heat increases blood flow, and helps relieve inflammation, oedema and exudates from connective tissue injuries. Heat can be applied either superficially (infrared, hot compresses, paraffin bath, hydrotherapy) or deep (ultrasound). The intensity and duration of physiological effects depend primarily on the temperature of the tissue, the rate of temperature rise, and the area treated [40].
\nCold can help relieve muscle spasms, myofascial or traumatic pain and acute inflammation (sprain, low back pain, etc). As of a certain temperature, cold induces a certain local anaesthesia (cryotherapy). Cold is usually used for a few hours after a muscle or tendon injury, up until evaluation [40].
\nHydrotherapy in rehabilitative medicine is used in many conditions. Stirred hot water stimulates blood flow and debrides burns and wounds. This treatment is performed in a Hubbar tank with water between 35.5°C and 37.7°C. Full immersion in water heated to between 37.7°C and 40°C can also help relax muscles and relieve pain. Hydrotherapy is particularly useful for range-of-motion exercises [41, 42].
\nElectrotherapy in rehabilitative medicine plays an important role in many locomotor system disorders, either exclusively or as a complement to other techniques [43].
\nThe various areas of physiotherapy, such as paediatric, respiratory, pelvic floor, neurological or sports - with their preventive, curative and rehabilitative approach – tackle numerous conditions that I do not address given the characteristics of this chapter.
\nAlthough pharmacological therapy has played an important role in psychiatric conditions since its introduction, sometimes it is difficult to comply with the therapy due to the disease itself, due to side effects or due to access to medication, either during hospitalisation or domiciliary care. Because of this, a series of non-pharmacological techniques and procedures to treat the most common neuropsychiatric pathologies have been developed. NPT in psychiatry should generally be used before drug treatment. However, the reality is usually different. Table 8 reports some of the most frequent techniques and procedures used in the most common neuropsychiatric conditions, taken from various authors.
\nCondition | \nTechnique/procedure | \nAuthor(s) | \n
---|---|---|
Anxiety | \nCognitive-behavioural therapy [44], relaxation techniques [44], yoga [44], meditation [45], contact with nature [46] | \nGalve, Ursa Herguedas | \n
Insomnia | \nCognitive-behavioural therapy, physical exercise during the day, etc. [47] [48] | \nDíez González, et al., Baides Noriega et al. | \n
Depression | \nPhysical exercise [49], phototherapy [50] | \nAlonso López et al., Tuunainen et al | \n
Cerebral palsy | \nEquestrian therapy [51] | \nJiménez de la Fuente | \n
Equestrian therapy | \nMusic therapy [52] | \nAcebes de Pablo et al | \n
Most common neuropsychiatric pathologies and non-pharmacological approach (compiled by A. Ursa).
There are NPT for neurological conditions such as migraine, multiple sclerosis, Parkinson’s disease, etc., which have been implemented in recent years. These require further studies for their validation.
\nAmong the eyeball conditions, the Bates method for improvement of vision without glasses is notable. This work was published for the first time in 1919 in the USA [53].
\nAfter several years of observation, Dr. William H. Bates (1860–1931), an American ophthalmologist, devised some exercises to restore normal vision in some eye problems and dispense with using glasses. He started from the hypothesis that the tension caused by certain visual habits were the main cause of poor eye vision. This method helps patients become aware of use of their visual organ by means of a series of eye and non-eye exercises. Table 9 shows some of these exercises according to Roselló [54].
\nTechnique | \nProcedure | \nEffect | \n
---|---|---|
Oscillations | \nRotate the trunk with the feet on tiptoes. The opposite heel lifts on every turn | \n? | \n
Palming | \nCover the eyes with the palms of the hands so that no light penetrates | \nFacilitates eye relaxation | \n
Sunning | \nLook at the sun with closed eyes, alternating light and shadow | \n? | \n
Neck rotation/flexion-extension | \nRotate the neck to both sides alternately and cervical flexion and extension | \nActivation of muscle chains | \n
Shoulder movement | \nRoll shoulders in a clockwise and anticlockwise direction | \nActivation of muscle chains | \n
Targeting exercise | \nFix vision alternately at a near (outstretched arm) and distant point | \nThe lens ligaments are exercised | \n
Eyeball rotation back and forth | \nClockwise and anticlockwise rotation | \nThe eye muscles are exercised | \n
Some Bates method exercises (taken from Roselló’s book see well without glasses).
The Bates method is indicated for all vision refractive problems such as myopia, astigmatism, hyperopia and presbyopia. It is contraindicated in the event of macular degeneration, eye infection or eyeball tumour [53].
\nIn the last few years, the Bates method has been taught on postgraduate courses at some European universities and recommended by some ophthalmologists. However, there are detractors of the method [55].
\nAlthough we cannot dispense with medicines, medical protocols and guidelines must be urgently reviewed. This is because most are based on medicines as a first line treatment option.
\nBioethics committees in clinical trials should be comprised of independent staff. Conflicts of interest in scientific publications should be more closely monitored.
\nThe acquisition of a healthy lifestyle must be promoted through Primary Healthcare, as part of a primary prevention programme.
\nNon-pharmacological treatments (NPT) are especially indicated for chronic diseases. However, many acute conditions can also benefit.
\nNumerous conditions of most bodily systems can be treated with NPT. Implementing this modality would contribute to reducing the adverse effects of medicines, bring healthcare expenditure down and lead to environmental sustainability.
\n.
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