Gender effect in NSCLC.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Life is structured in space but also in time. Biological rhythms have been documented in all processes involved in the malignant transformation of cells as well as in the cellular proliferation of both healthy and tumor tissues [1, 2, 3, 4, 5]. All physiological functions expressed their metabolic or specific activities according to a circadian variation [1, 2, 3, 4, 5]. This is the case not only for actively dividing tissues but also for all other tissues, such as the myocardium, central nervous system, or organs involved in the metabolization, detoxification and excretion of drugs (kidney, liver) [3, 4, 5].
Recent advances identify critical molecular events that rhythmically control drug metabolism and detoxification, cell cycle, molecular targets, deoxyribonucleic acid (DNA) repair, apoptosis, and angiogenesis [3, 4, 5]. The coordination of these processes along the 24-h period is ensured by the circadian timing system (CTS) whose hierarchical organization determines chronotherapeutic effects [3, 4, 5]. The CTS coordinates physiology and cellular functions over a 24-h period (Figures 1 and 2). This circadian physiology is generated or controlled by a central pacemaker, the suprachiasmatic nuclei (SCN) in the hypothalamus. The SCN generate circadian physiology through diffusible signals, including transforming growth factor-alpha (TGF-alpha), epidermal growth factor (EGF), prokineticin-2, cardiotrophin-like cytokine, and neuroanatomic sympathetic and parasympathetic pathways [1, 2, 3, 4, 5, 6, 7, 8].
Schematic view of the circadian timing system (CTS). The suprachiasmatic nucleus (SCN) is a biological clock located at the floor of the hypothalamus. Its period (cycle duration) is calibrated by the alternation of light (L) and darkness (D) through the rhythmic melatonin secretion by the pineal gland. The SCN controls or coordinates circadian rhythms in the body. Abbreviations: PVN, paraventricular nucleus; NPY, neuropeptide Y; TGF-alpha, transforming growth factor α; EGF, epidermal growth factor; Σ, sympathetic (after Levi et al. [3]; adapted).
Schematic representation of the molecular clock and the pathways involved into the control of relevant drug metabolism, cell cycle, DNA repair, and apoptosis in mammalian tissues. The protein dimer BMAL1-CLOCK or BMAL1-NPAS2 (a CLOCK homolog) plays an essential role in the rhythmic transcription of clock-controlled genes. After Levi et al. [3]; modified.
A dozen specific clock genes constitute the core of the molecular clock in mammals [3, 4, 5, 6]. These genes are involved in transcriptional and posttranscriptional activation and inhibition regulatory loops that result in the generation of the circadian oscillation in all physiological systems and individual mammalian cells [3, 4, 5]. In particular, the circadian locomotor output cycles kaput-brain and muscle ARNT-like protein-1 (CLOCK-BMAL1) or NPAS2-BMAL1 protein dimers play a key role in the molecular clock through the activation of transcriptional clock genes period’s (Per’s), cryptochrome (Cry’s), and Reverb’s [3, 4, 5, 9] (Figures 1 and 2).
Proper circadian regulation is essential for the well-being of the organism, and disruption of circadian rhythms is associated with pathological conditions including cancer [1, 5, 10, 11]. In mammals, the core clock genes, Per1 and Per2, are key regulators of circadian rhythms in central clock, in the hypothalamus, and in peripheral tissues [9, 10, 11, 12, 13]. Recent findings revealed molecular links between Per genes and cellular components that control fundamental cellular processes such as cell division and DNA damage [9, 10, 11, 12, 13]. New data also shed light on mechanisms by which circadian oscillators operate in peripheral organs to influence tissue-dependent metabolic and hormonal pathways [4, 5]. Circadian cycles are linked to basic cellular functions, as well as to tissue-specific processes through the control of gene expression and protein interactions. By controlling global networks such as chromatin remolding and protein families, which themselves regulate a broad range of cellular functions, circadian regulation impinges upon almost all major physiological pathways including immunological ones [4, 5].
In 2002, we performed an overview of accessible experimental and clinical data allowing to believe in possible improvement in NSCLC management through chronobiological considerations. Here we will update our previous review with experimental and clinical recent contributions considering only circadian rhythmicity [14].
It is to be emphasized that we were unable to find any study on that subject using new biological alternatives such as targeted therapies or immunotherapy approaches.
Studies performed by Hashimoto et al. on a murine model with circadian-varying lung tumor induction through timed single- or split-dose irradiation have already been reviewed [14, 15].
Cancer development associated to circadian disturbances both in damaged (target) and undamaged tissues and systems [1, 3, 4, 5] has been described some years ago. Experimentally, the importance of deregulation of circadian rhythms before the development of liver cancer in rats exposed to diethyl-nitrosamine, a carcinogen that can also induce lung tumors, was reported by Filipsky et al. [16].
Molecular insights illustrate how dysregulation of circadian rhythms might influence the susceptibility to cancer development and provide further support for the emerging role of circadian genes in tumor suppression [12]. Silencing of tumor suppressor genes, such as the Per1—clock core gene, resulting from epigenetic alterations may occur early in lung cancer tumorigenesis [9, 17].
These observations allow considering Per1 gene as a potential target for chemoprevention.
Epidemiologic studies in human beings have evidenced a probable relationship between altered circadian rhythms and tumorigenesis. A high incidence of cancer has been observed in long-term shift workers such as flight attendants, nurses, or industrial workers [18, 19, 20]. Recent studies have also suggested that alterations of sleep quality were susceptible to enhance the risk of various cancers including lung cancers [21, 22]. Disruption of melatonin circadian rhythms (peak at night after dim-lighting) could partially explain such observations [23]. However, a large epidemiologic on thousands of Chinese female textile workers apparently failed to confirm an increased risk of lung carcinoma [24].
On the other hand, sport practice and regular physical activity, which are known to facilitate and maintain circadian general activities, may have an inverse effect, thus minimizing the risk of developing a lung cancer [25].
Hashimoto et al. recently reported that DNA synthesis activity in the normal lung was low but higher during the night [15]. Also a large number of experimental animal studies document circadian rhythm in cell proliferation in spontaneous or transplanted tumors, growing in ascitic fluid or solid phases [1, 2]. Precisely, Burns et al. studied alterations of DNA synthesis rhythmicity in selected organs of mice (i.e., bone marrow) bearing a transplanted Lewis lung carcinoma (LLC) [26].
Colombo et al. [27] reported day/night differences of spontaneous apoptosis in two different murine tumors, one of these being a lung one, in addition to circadian rhythms of division, peaks of apoptosis matching with mitoses valleys [27].
In human, circadian rhythmicity of cell proliferation has been reported for squamous cell carcinomas of the lung, as those of the skin and cervix [1, 2, 14, 28]. Various mechanisms responsible for the deregulation of the cell cycle and enhanced susceptibility to oncogenesis through activation of cell proliferation and cancer promotion have been identified. For example, in NSCLC, overexpression of cyclin D1, and mutation of p16 leading to a shortened and accelerated G1-phase and permanent phosphorylation (and inactivation) of pRb are known; in addition, mutations of p53 (with further impaired apoptosis) or pRb have been observed both in NSCLC and SCLC [29].
Tissues such as the liver, pituitary, and kidney but also the lung exhibit robust circadian rhythmicity in cultures [3, 4, 5]. Circadian timers are important for lung functions; for example, there is a well-documented link between diurnal variations in lung physiology (i.e., airway narrowing and inflammation) and nocturnal asthma [30]. Gibbs et al. have studied the cellular localization of core clock genes in both mouse and human organotypic lung slices [30]; they also established the effects of glucocorticoids on pulmonary clock [30]. They were able to demonstrate a marked circadian rhythm in PER2 expression that is responsive to glucocorticoids. Immunohistochemical techniques were used to localize specific expression of core clock proteins and glucocorticoid receptor on the epithelial cells lining the bronchioles (Clara cells and type II pneumocyte cells) in both mouse and human lung tissues [30]. Selective ablation of Clara cells resulted in the loss of circadian rhythm in lung slices, demonstrating these cells to be critical for maintaining coherent circadian oscillations in the lung tissue. The coexpression of glucocorticoid receptor and core clock components establishes them as a likely interface between humoral suprachiasmatic nucleus output and circadian lung physiology [30].
Clock genes or proteins PER1 and PER2 have been linked to DNA damage response pathways in a series of studies, involving among others Lewis lung carcinoma (LLC) cells [3, 6, 9, 11, 12, 13]. Overexpression of either PER1 or PER2 in cancer cells inhibits their neoplastic growth both in vitro and in vivo and increases their apoptotic rate [13]. Also high expression of circadian gene mPer2 is able to diminish radiosensitivity of LLC and EMT6 cells with decreased expression of bax and p53 and increased expression of c-myc and bcl-2 [12, 13, 31]. This type of observations illustrates that the circadian system is involved in the protection and restoration of tumor cells, i.e., those of LC, against environmental detriments, such as gamma irradiation [13]. The gene, mPer2, might be considered as an inhibitor of tumor radiotherapy effects [32].
Downregulation of Per1 or Per2 enhanced tumor growth (i.e., of LLC cells) in vitro [12, 13, 31, 33]. Thus Per1 and Per2 exert their tumor suppressor functions in a circadian time-dependent manner [9, 31, 32, 33]. Also downregulation of Per1 or Per2 increases tumor growth only at given specific times of the day [12]. These optimal times may be shifted in tumors that have mutant period genes [12].
Overexpression of Per1 makes human cancer cells sensitive to DNA damage-included apoptosis; in contrast, inhibition of Per1 in similarly treated cells blunted apoptosis [9]. The apoptotic phenotype was associated with altered expression of key cell cycle regulators. In addition, Per1 interacted with the checkpoint proteins ATM and Chk2. Ectopic expression of Per1 in human NSCLC cell lines led to significant growth reduction [6, 9]. Per1 m-RNA expression was high in the normal lung and downregulated in a large panel of tumor samples from NSCLC patient samples as well as in lung cancer cell lines [3, 4, 5, 6, 8, 11]. In addition, Gery et al. showed that ectopic or forced expression of Per1 in NSCLC cell lines led to growth inhibition, G2M cell cycle arrest, apoptosis, and reduced clonogenic potential [6, 17]. The influence of Per1 on cell cycle and apoptosis seems to be p53-status independent [5, 13].
Timeless (TIM) a homolog of a drosophila circadian rhythm gene has circadian properties in exploration in mammals [34]. Precisely its expression is enhanced in lung cancer cell lines where its knockdown was related to the induction of apoptosis, suppression of proliferation, and clonogenic growth [34]. In surgically resected specimens from 88 consecutive patients, high TIM protein levels as gauged by immunohistochemistry (IHC) correlated with poor overall survival [34, 35].
Taken together those results support clearly the hypothesis that circadian rhythm disruption plays an important role in lung tumorigenesis, as well as a link between circadian epigenetic regulation and cancer development.
Hori et al. working on experimental Sato lung tumor were able to correlate biological time of greatest tumor growth and highest tissue blood flow (during dark span) [36]. This finding strongly suggests that tumor tissue blood flow has a determining influence on tumor proliferative activity and that tumor growth is influenced by circadian variation in tumor tissue blood flow [36].
These results were confirmed by Blumenthal et al. who also showed that the blood flow rhythm may differ between tumor and normal tissues, thus creating a window of opportunity when tumors could be targeted with a therapeutic agent such as vascular endothelial growth factor (VEGF) inhibitors [37].
The molecular mechanism regulating circadian expression of VEGF in tumor cells (Lewis lung carcinoma cells among others) has been investigated by Koyanagi et al. [38]. They found that the expression of VEGF in hypoxic tumor cells was affected by the circadian organization of molecular clockwork. The core circadian oscillator is composed of an autoregulatory transcription-translation feedback loop in which clock and BMAL1 are positive regulators and period (Per) and cryptochrome (Cry) genes whose expression in the implanted tumor cells showed also a circadian oscillation act as negative ones. The levels of VEGF m-ribonucleic acid (RNA) in tumor cells implanted in mice rose substantially in response to hypoxia, but the levels fluctuated rhythmically in a circadian fashion. These findings support the notion that monitoring of circadian rhythm in VEGF production may be useful for choosing the most appropriate time of day (i.e., when VEGF production is increased) for administrating antiangiogenic agents [38].
In order to identify possible mechanisms underlying tumor progression related to circadian disrhythmicity, Yasumina et al. injected epidermoid HeLa cells in nude mice exposed to a 24-h light cycle (L/L) or to a “normal” 12-h light/dark cycle (L/D) [39]. A significant increase in tumor volume in the L/L group compared with the L/D group was observed. In addition, tumor microvessels and stroma were strongly increased in L/L mice but were not associated to an increase in the production of VEGF. DNA microarray analysis showed enhanced expression of WNT10A (wingless gene 10A). WNT10A could stimulate growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio-/stromagenesis [39]. Thus, WNT10A may be a novel angio-/stromagenic growth factor. These findings also suggest that circadian disruption induces the progression of malignant tumors via a WNT signaling pathway in models involving tumor cells similar to that encountered in human NSCLC [39].
Binding parameters and constant dissociation of EGFR circadian variations, peaking late in dark span, were related to DNA synthesis activity variations in actively dividing mouse tissues [40]. EGFR by itself was found to be capable of phase shifting the prominent circadian rhythm of DNA synthesis, i.e., in the esophagus [40, 41]. Phosphorylation of the cyclic monophosphate (cAMP) response element-binding protein (CREB) and SER-133-phospho-CREB (PCREB) is a transcriptional factor that may regulate circadian cell rhythmicity [41]. Concentrations of EGF (and nerve growth factor (NGF)) were monitored in mouse saliva [42]; both growth factors exhibited identical diurnal variations, peaking between 12:00 and 20:00 h. Otherwise, the effect of EGF injections on cell kinetics of mouse tongue epithelium appeared to be time-dependent [41, 42].
Of interest, some studies were also performed in humans. Salivary (on the contrary to urinary or plasmatic) EGF level followed an apparent diurnal rhythm related to feed [43]. It was markedly reduced in the case of oral inflammation or head and neck cancer; in those situations, the capacity of oral mucosal defense could therefore be impaired [43].
EGFR is present in the majority of tumor cells in head and neck cancer [43]. Though circadian rhythmicities in cell proliferation and clock genes have been demonstrated in oral mucosal [45] and in related cancers [1, 2], so far, no study has dealt with the search for circadian variability in EGFR expression in squamous cell carcinomas. However, a circadian rhythm in plasmatic EGF level (with an acrophase around 14:20, a peak-to-trough interval of 26% and a superimposed 12-h frequency) has been reported in metastatic breast cancer patients [45].
As stated earlier, the circadian axis comprises a central clock (SCN; paraventricular areas) and a downstream network of hypothalamic relay station that modulates arousal, feeding, and sleeping behavior among others [4, 46] (Figure 2).
Communication between the clock and these hypothalamic signaling centers is mediated in part by diffusible substances that include ligands of the EGFR [4, 5, 6, 7, 8, 44, 46] (Figures 1 and 2). A significant functional role for EGFR in the suprachiasmatic nucleus is suggested by recent findings showing that epidermal growth factor receptor and its ligand TGF-α are highly expressed in the suprachiasmatic nucleus. Also EGFR activation induces behavioral and physiological effects, strengthening the notion that EGFR can modulate suprachiasmatic nucleus neural function and behavior [4, 5, 6, 7, 8, 44, 46]. Furthermore, Vadigepalli et al. confirmed that gene expression response to EGFR is circadian time dependent [8]; this response includes several genes encoding different neuropeptide receptors, ion channels, and kinases. In order to hypothesize the transcription factors underlying the EGFR response, different circadian time-dependent gene expression groups were analyzed for enriched transcriptional regulatory elements in the promoters. Results indicate that several transcription factors such as Elk 1 and cAMP-responsive element-binding protein/activating transcription factor family, known to be “input points” to the core clock network, are playing a role. Taken together, these results indicate that EGFR has a circadian time-dependent neuromodulatory function in the suprachiasmatic nucleus [7, 8].
Diurnal variation in immune and inflammatory function is evident in the physiology and pathology of animals and humans [47, 48].
Studies highlight the extent to which the molecular clock, most notably the core clock proteins BMAL1, CLOCK, and REV-ERBα, controls fundamental aspects of the immune response [47, 48, 49]. Examples include the BMAL1-CLOCK heterodimer-regulating Toll-like receptor 9 (TLR9) expression and repressing expression of the inflammatory monocyte chemokine ligand (CCL2) as well as REV-ERBα suppressing the induction of interleukin-6 (IL-6) [49].
Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. The loss of circadian gating was coincidental with suppressed REV-ERBα expression. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin and identifies REV-ERBα as the key link between the clock and immune function. REV-ERBα may therefore represent a unique therapeutic target in human inflammatory disease [49].
Also mechanistically, Bmal1 deficiency in macrophages increases pyruvate kinase M2 (PKM2) expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 (programmed cell death-ligand 1) in a STAT1-dependent manner (signal transducer and activator of transcription 1). Consequently, targeted ablation of PKM2 in myeloid cells or administration of anti-PD-L1-neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1-deficient mice [47, 48, 49].
Circadian variation in pharmacokinetics (PK) has been observed in rodents for all the drugs routinely administered to LC patients, i.e., pyrimidine derivatives, anthracyclines, vinca-alkaloïds (vinorelbine), topoisomerase inhibitors, taxanes, platinum derivatives, gemcitabine, other antimetabolites, etc. [1, 3, 4, 5]. These chrono-PK were expressed though circadian-varying metabolization, detoxification, excretion, and also maximal concentration (CMax) or area under the curve (AUC) [1, 3, 4, 5].
Chronotolerance has been observed in rodent studies long time ago for any chemotherapy agents routinely used for NSCLC patients [1, 2, 3, 4, 5]. As a recent example, best tolerance and chronoefficacy of gemcitabine alone or in combination with cisplatin were observed with best antitumor efficacy when both drugs were given around their least toxic time schedule, respectively, 11 and 15 hours after light onset (HALO) in animal facility [50]. In an older study, Flentje et al. had also documented the circadian chronoefficacy of cyclophosphamide (CPA) in LLC [51].
Chronotolerance to an experimental radioimmunotherapy with 131 I-anti-carcinoembryonic antigen (CEA) IgG was reported [52]. A 30% increase in maximum tolerated dose was possible when the drug was given at the trough of the bone marrow division activity (around 9 HALO) [52].
Clock, as a member of histone acetyltransferases, controls acetylation of histone 4 required for repair of DNA double-strand breaks thanks to several repair genes such as excision repair cross-complementing group 1 (ERCC1) or activator protein 1 (AP1) [6]. Expression of histone acetyltransferase genes is associated with cisplatin resistance [6, 53]. Histone acetyltransferase inhibition (i.e., by vorinostat) may increase carboplatin and paclitaxel activity in NSCLC cells [54]. The acetyl-CoA-binding motive is found in clock and shows sequence similarity with MYST members, i.e., Tip 60. Tip 60 which is overexpressed in human epidermoid cisplatin-resistant cancer cells [53] exerts a control regulation on several genes implicated in DNA repair (i.e., ERCC1 and AP1) [53].
Furthermore, the promoter region of the Tip 60 gene contains several E-boxes, and its expression is regulated by the E-box-binding circadian transcription factor clock! Thus, clock and Tip 60 regulate not only transcription but also DNA repair, through periodic (diurnal) histone acetylation in cell populations that can be found in human NSCLC [53].
Finally, of interest, diurnal-varying pharmacokinetics of erlotinib (a largely used tyrosine kinase inhibitor (TKI) for treating human NSCLC) has been reported both in xenograft-bearing nude mice [55] and in Lewis tumor-bearing mice. [56]. Circadian rhythm plays a critical role in the pharmacokinetics of erlotinib in mice, and the mechanisms may be attributed to gene expression rhythms of drug-metabolizing enzymes in liver tissues [56]. The inhibitory effect of erlotinib on phosphorylation of EGFR, AKT (type of serine/threonine protein kinase, also called protein kinase B), and mitogen-activated protein kinase (MAPK) varies with its administration time. The results indicate that the antitumor effect of erlotinib is more potent when the drug is administered when the activities of EGFR and its downstream factors increase [55, 56].
In human as well, pharmacokinetics of some major drugs used in NSCLC have been reported to be circadian varying [1, 2, 3, 4, 5, 28, 44]. Circadian variation of plasma 5-fluorouracil (5 FU) concentration has been repeatedly observed when the drug is infused for a few days at a constant rate [57, 58]. This was reported when the drug was given either as a single agent or with a platinum derivative [58]. Similarly, plasmatic concentration of vindesine, a semisynthetic vinca-alkaloïd derived from vinblastine, exhibit circadian variation with peak between 9 am and 3 pm, when infused at a constant rate for 48 h [59]. Also the fixation of platinum ion to plasma proteins was shown to be circadian varying with an acrophase during late afternoon [60]. More recent assessment of circadian variability of cisplatin pharmacokinetics confirmed that cisplatin clearance was 1.38- and 1. 22-fold higher for total and unbound drug with administration at 06:00 pm vs. 06:00 am [61].
Host chronotolerance to anticancer drugs used in NSCLC patients has also been observed in clinical practice. Pyrimidine derivatives such as 5 FU are less toxic when infused during nighttime sleep [1, 3, 4, 5, 57, 58]. Also platinum derivatives such as cisplatin, carboplatin, and oxaliplatin are better tolerated between 3 and 6 pm while anthracyclines are less toxic in the morning [1, 3, 4, 5, 57, 58]. The first reported chronotherapy randomized trial, based on diurnal cell kinetics, treating mostly NSCLC patients, compared a 40-h sequential chemotherapy beginning either at 10 am or at 10 pm [28]. In this study, patients who received the sequential chronotherapy from 10 am experienced significantly greater granulocyte toxicity [14, 28].
Focan et al. also reported on host chronotolerance of 124 chemotherapy-naïve advanced NSCLC patients, receiving randomly etoposide for 3 days either at 6 am (group A) or 6 pm (group B) and cisplatin at day 4 at 6 pm [62]. A lesser degree of hematological toxicity was documented in group A, while cisplatin was better tolerated in group B [62]. Similar results were reported by Krakowski et al. [63].
Focan et al. also performed a randomized phase I–II trial comparing as first-line treatment, a complex sequential chronotherapy with 5 FU, folinic acid (FOL), and carboplatin with 24-h sinusoidal variation of drug delivery [64] (Figure 3). The reference schedule (peaks of 5 FU and FOL at 4 am, peak of carboplatin at 4 pm vs. two other schedules peaking, respectively, at + or – 8 hours, repetition for 5 days every 3 weeks) appeared to be the least toxic one with an overall excellent clinical tolerance [14, 64] (Figure 4). Toxicity data were reviewed in order to detect a possible gender effect as had been observed in metastatic colorectal cancer [3, 4, 5, 65]. Despite of no significant difference in treatment adaptation or dose intensity between men and women, overall increased serious toxicities were recorded in women versus men. Severe leukopenia and mucositis occurred more than twice as frequently in women than in men (grade 3–4 leukopenia per course, 7.7 vs. 3.2%; grade 3–4 mucositis, 6.6 vs. 1.2%) [14].
Programs of ambulatory chronotherapy with 5 FU, folinic acid (leucovorin-LV), and carboplatin (CBDCA). The reference schedule is compared to two others with varying peaks (−8 h; +8 h). Daily delivery is automatically repeated by a chrono-programmable pump (Melodie) five times every 21 days (FFC5_16).
Tolerability of chronomodulated 5 FU-LV-CBDCA infusion (grades 3–4 toxicities; in green, leucocytes; in red, granulocytes; in yellow, mucositis). Reference schedule was clearly the least toxic one (p < 0.007–0.025).
According to the results of the phase I–II trial described above [64], a phase II study was further performed on 68 advanced NSCLC previously untreated patients with the best circadian schedule [3, 14]. An excellent therapeutic index with a maximum of 17%, grades II–IV toxicities were observed and a gender effect was confirmed (Table 1) [3, 14].
Gender effect in NSCLC.
Further analyses in advanced colorectal cancers have shown that the pattern of chronotolerance in men was rather sinusoidal with an optimal time corresponding to the reference modality; conversely in women the pattern was damped with optimal peaks of delivery possibly located 6 h later than in men [66]. The male subgroup showed a mean clearance (CL) value twice larger than the value observed in the female subgroup [66]. On the other hand, one has also to remind that the distribution of genes with circadian-varying expression was quite different in men and women in oral mucosa [44].
A number of groups studied tumor-marker (CEA-carcinoembryonic antigen, alpha-fetoprotein, and others) rhythms but with similar disappointing results [1, 2, 67]. If in controls, a clear group circadian rhythmicity with an afternoon peak around 03:00 pm was evident, in cancer patients, individual variability or absence of rhythm were evidenced [1, 67].
Hormonal, hematological, and rest-activity cycles perhaps might constitute more promising markers of the host’s internal circadian time structure. The most prominent hormonal circadian rhythms are cortisol (peak time occurs early in the morning in diurnally active persons) and melatonin (peak time occurs during the first half of the dark period in diurnally active people) [3, 4, 5, 67]. Important alterations of the normal circadian profile of these rhythms have been described in lung and other cancer patients with low performance status and high tumor burden [67].
Bartsch and colleagues [68] reported peculiarities in the cortisol and melatonin circadian rhythms in LC patients. Experimental data suggest interactions between interleukin-2 (IL-2; antitumor immune response is an IL-2-dependent phenomenon) and the pineal gland, which also may play a role in the control of immunity and cancer growth [69, 70]. The melatonin rhythm was evaluated in a group of LC patients receiving subcutaneous IL-2 treatment [70]. Prior to IL-2 therapy, none of the patients showed a normal 24-h rhythm of melatonin; IL-2 administration induced a normalization of the melatonin circadian rhythm with a nighttime peak in the majority of cases [70]. This observation suggests that abnormal pineal function in some lung cancer patients might arise in part from altered endogenous IL-2 production [70]. On the other hand, IL-2 administration induced a rise in cortisol with maintenance of 24-h rhythmicity [70].
Melatonin, tryptophan, and 6-sulfatoxymelatonin circadian profiles in blood and urine were compared in 30 advanced NSCLC cancer versus 63 healthy volunteers [66, 71]. All three molecule concentrations were significantly lower in cancer patients with a significant inverse correlation between melatonin and tryptophan levels [71].
Circadian rhythmicity in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) was studied in control subjects and LC patients [72]. GH stimulates IGF-1 production in the liver and other tissues, while IGF-1 can promote cell cycle progression and apoptosis inhibition. GH and IGF-1 also stimulate lymphopoiesis and immune function [72, 73].
In LC patients, a progressive increase in GH and a steady decline of IGF-1 serum levels with loss of circadian rhythmicity were observed. This loss of diurnal rhythms could play a role in carcinogenesis and tumor growth regulation [71, 72, 73, 74, 75]. All profiles of time-related neuroendocrine-immune system components seemed to be the advancing stage of disease [71, 72, 73, 74, 75, 76].
Mazzocoli et al. assessed altered time neuroendocrine-immune system function in lung cancer patients [75]. Circadian rhythmicity with night acrophases was validated in the control group for hormone serum level (melatonin, TRH, TSH, GH,) and for lymphocyte subset variation (CD3-, CD4-, HLA DR-, CD20-, and CD25-expressing cells). Cortisol, CD6, CD8 bright, CD8 dim, CD16, TcR-delta-1, and delta-TcS1 presented circadian rhythmicity with acrophase in the morning/at noon. In LC patients cortisol, TRH, TSH, and GH serum level and all lymphocyte subsets (except for CD4) showed some altered circadian rhythmicity. Mesor of cortisol, TRH, GH, IL-2, and CD16 was increased, whereas that of TSH, IGF-1, CD8, CD8 bright, TcR-delta-1, and delta-TcS1 was decreased [75]. Peak times however are related similar to those of control subjects [75]. The melatonin/cortisol mean nocturnal level ratio was also decreased in LC patients [75, 76]. Taken together, these results suggested that lung cancer is associated with alteration in the proportions and 24-h profiles of various lymphocyte subsets; this may be related to disease stage and probably altered immune function [73, 74, 75, 76].
Lissoni et al. also observed in NSCLC treated by chemotherapy (+/− melatonin) that lymphopenia and altered cortisol rhythmicity were associated with worsened quality of life (QOL), loss of psychosexual identity, and lower spiritual and faith scores [77, 78].
The persistence of a circadian time structure like that of control normal subjects seems to be an independent prognostic factor, at least in advanced breast or colon cancers [10, 18, 79, 80]. As stated earlier, the strongest circadian rhythms are those of cortisol (with the clinical interest being the morning-afternoon gradient) and melatonin (with a nighttime peak) [2, 4]. Noninvasive easy-to-repeat assessment techniques have been validated for the determination of the 24-h time structure: titrations of cortisol and melatonin in the saliva and 6-hydroxymelatonin sulfate in the urine [81]. Nocturnal urinary 6-sulfatoxymelatonin is also correlated with the proliferation of cell nuclear antigen (PCNA) in lung tumors [68]. Thus, its determination might constitute a noninvasive tool to estimate circadian tumor cell proliferation in lung or other tissues.
Cortisol diurnal rhythm and slope have been related to survival in metastatic breast cancer patients by Sephton et al. [18]. Similarly, the same authors together with Chinese counterparts could also link the quality of persistent diurnal cortisol rhythm to the prognosis (survival) in LC patients [19, 20].
Assessment of the rest-activity circadian cycle by actometry measurements also seems an easy way to estimate the general circadian profile of individuals [1, 4, 5, 82, 83, 84]. In advanced colorectal cancer, it was demonstrated in two studies that patients retaining a prominent rest-activity circadian rhythm will enjoy better quality of life and sleep, less fatigue, less depression, and improved survival [82, 83, 84]. Such evaluations were proposed to lung cancer patients and validated [82, 83, 84]. Focan et al. evaluated rest-activity rhythms in 28 advanced NSCLC before chronotherapy [83]. Better general physical activity and circadian rhythmicity were recorded in those patients receiving also corticosteroids [83]. Hrushesky and his group also studied circadian function in NSCLC patients by actigraphic recordings [82, 84]. They tried to correlate the rest-activity rhythms with sleep disturbances, quality of life (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30)) and mood (anxiety; depression—HADS—hospital anxiety and depression scale) [82, 84]. All patients suffered from severe disturbances of daily sleep-activity cycles, but each patient also maintained some degree of circadian organization. QOL measurements were correlated with circadian destructors, fatigue prominent during daytime, and altered moods [82, 84].
Before initiation of their radiotherapy, a high percentage (30–50%) of 185 patients experienced significant disturbances in sleep-wake circadian rhythmicity; these perturbations occurred in both sleep initiation and maintenance [85].
Recent clinical observations have shown that elevated levels of TGF-alpha are associated with fatigue, flattened circadian rhythms, loss of appetite, and depression in patients with metastatic cancer [46]. These data support the hypothesis that a symptom cluster of fatigue, appetite loss, and sleep disruption commonly seen in cancer patients may be related to EGFR ligands released either by the cancer itself or by the host in response to the stress of cancer and suggest that further examination of their role in the production of symptom clustering is warranted [46]. Those observations also suggest to consider the central clock as a possible target for restoration of normal circadian rhythmicity in cancer patients!
During the last decade, the management of NSCLC has evolved [86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97]. Platinum-based chemotherapy remains the standard front-line in treatment of advanced unresectable NSCLC in which cisplatin or carboplatin are combined with another chemotherapeutic agent such as taxanes, pemetrexed, or gemcitabine [87]. However the results in terms of response rate, progression-free survival, and median overall survival remained stable over time [86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97].
Thus, progresses confirmed by phase III trials came from targeted and immunotherapeutic biological approaches. Targeted therapies against EGFR mutations and anaplastic lymphoma kinase (ALK) gene rearrangement have improved the survival in a small proportion of patients whose tumors were expressing these molecular abnormalities [88, 89, 90, 91].
Also the recent development and success of immune checkpoint inhibition of programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) for treating metastatic cancers seemed to open a new pavement for fruitful research [86, 92, 93, 94, 95, 96, 97].
Unfortunately to the best of our knowledge, despite precise theoretical observations depicted related to circadian expression, on targets of TKI inhibitors, EGFR blockers, antiangiogenic agents, and immune active-agents (lymphoid system; PD1; PDL1), by now no study has been launched to take into account any chronobiological considerations!
As a matter of fact, in NSCLC, only a few studies deal with considerations on temporal dimension for drug delivery.
Studies from Focan et al. have already been mentioned and reviewed elsewhere [14]. In the first pioneered study [14, 28], a significant better tumor outcome was observed in the group treated at the better dosing time, thus from 10 am for a 40-h sequential schedule [14]. In the second phase III trial using etoposide and cisplatin, despite varying toxicities, there were no differences in overall drug dose intensities nor in tumor outcome gauged by the frequency of tumor responses as well as survival [62]. On the contrary, Krakowski et al. observed an increased dose intensity of drugs when given at their best circadian schedule [63].
According to the results of the phase I-II trial described [59] that had confirmed diurnal tolerance of a complex infusion regimen including 5FU, Fol, and carboplatin for 5 days every 3 weeks, a phase II study was further performed on 68 advanced NSCLC previously untreated patients with the best circadian schedule [3, 14]. Tumor evolution remained within the frame of the literature, but patients enjoyed an improved therapeutic index [3, 14].
Lissoni et al. successively performed small randomized trials (with 20–40 patients per group) in advanced NSCLC patients [67, 68, 77, 78]. They observed progressive improvement of tumor outcome (response rate; 1-year survival, etc.) and quality of life through the association with standard cisplatin-based chemotherapy, melatonin, and sometimes interleukin-2 (IL2) [67, 68, 77, 78]. They have reviewed their results on 370 cases suffering from NSCL and gastrointestinal tract cancers [78]. They confirmed a higher rate of tumor responses and better long-term survival in patients who had received melatonin [78]. These observations were linked to positive circadian effects in cancer-relevant psycho-neuroendocrine and immune pathways [77, 78]. According to these authors, a high degree of faith may positively influence the efficacy of chemotherapy and the clinical evolution of NSCLC by improving the lymphocyte-mediated antitumor immune response and probably general host circadian rhythmicity [78].
Hrushesky’s group performed also a randomized blinded trial on 84 advanced NSCLC patients receiving chemotherapy with etoposide and cisplatin together with melatonin or placebo (personal communication). Those patients receiving melatonin during the evening enjoyed higher response rates (29 vs. 8–11%) and longer survival in multivariate analysis (personal communication).
Two meta-analyses appeared to confirm survival benefits associated with melatonin therapy in cancer patients [98, 99]. One analysis has focused upon 8 trials that used a dosage of 20 mg of melatonin, while the second one reviewed 21 clinical trials on solid tumors using various doses of melatonin [98, 99]. Both analyses report that the administration of melatonin reduces the relative risk of death at 1 year by an average of 37%, doubles the frequency of complete response, and reduces the prevalence and/or severity of chemotherapy-induced nausea/vomiting, hypotension, and hematological toxicity. Thus some authors consider melatonin as a probable effective treatment for human NSCLC [100]!
Despite advances in research and a better understanding of the molecular pathways of NSCLC, few effective therapeutic options are available for most patients with NSCLC without druggable targets, especially for patients with squamous cell NSCLC [86, 87, 88, 89, 90, 91].
Chrono-PKs of erlotinib have been investigated in rodents [55, 56]. On the other hand, Iurisci et al. observed an improvement of circadian rest-activity rhythms together with a relief of symptoms in a limited trial on advanced NSCLC patients [101].
Nevertheless, no trial taking into account temporal dimension has been launched at present time.
Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte antigen-4 or anti-programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) have induced durable response rates across a broad range of solid tumors. In NSCLC, pembrolizumab and similar antibodies have replaced chemotherapy as first-line treatment for patients with PD-L1 tumor proportion score (TPS) of at least 50% [92, 93, 94, 95, 96, 97], while pembrolizumab plus platinum and pemetrexed for those with nonsquamous histology irrespective of PD-L1 expression [92, 93, 94, 95, 96, 97].
As discussed in previous chapters, it is conceivable to consider the temporal (diurnal) dimension when administering either targeted or immunologic treatments to lung cancer patients, but, to the best of our knowledge, no study on that subject has been launched to date. We could regret this lack of interest, while dissection of molecular pathways of the circadian clock system has been awarded in 2017 with a Nobel Prize!
In a single non-randomized limited study, gamma knife radiosurgery for brain metastases of NSCLC was delivered either in the morning (10.00 am to 12:30 pm, 58 cases) or in the afternoon (12:30 pm to 3:00 pm, 39 cases) [102]. Patients treated in the morning enjoyed better tumor local control at 3 months (97 vs. 67%), longer survival (9.5 months vs. 5 months), and a lower rate of central nervous system (CNS)-related cause of death. Those results, which may be related to circadian susceptibility of target cancer cells (? more cells in G2-M phase; more apoptosis in the morning?), prompted the activation of a prospective randomized RTOG study whose results have not yet been published.
With another methodology, Badiyan et al. [103] reevaluated the impact of daytime on tumor outcomes after stereotactic radiosurgery (SRS), in 437 patients NSCLC treated for CNS metastases. They confirmed a cut point of 11:41 am for providing the highest predictive value for overall survival [103].
In this review, we have tried to gather pertinent animal and human data supporting the need to take into account temporal dimensions (i.e., circadian) for prevention and treatment of human NSCLC. The importance of biological rhythmicity was evidenced regarding carcinogenesis, molecular biology and genetics, cells kinetics, apoptosis, DNA repair mechanisms, platinum resistance, etc. These observations are fully applicable to human NSCLC.
Some randomized clinical trials for human LC have confirmed chronotolerance and probably chronoefficacy of combined chemotherapy. Furthermore, theoretical considerations allow to propose the application of chronobiological concepts to improve the management of human NSCLC either by working on the host circadian rhythmicity and on circadian variation of targets expression, such EGFR and VEGF receptors, or on the new molecular targets or pathways also circadian varying in their expression (e.g., ERCC1, DNA repair, Tip 60, etc.).
Similarly circadian variations in multiple immunological pathways warrant further interest. These considerations would bring hope to improve overall tumor outcome by optimizing “classical” therapeutic index of chemotherapies but also circadian host rhythmicity by acting on the central clock (i.e., by TKI administration) and/or molecular machinery (receptors, various enzymatic pathways, DNA metabolism and repair, immunology pathways, etc.).
Also the potential role of melatonin as resynchronizing agent and as a potentially active agent warrants further evaluations.
Eventually the increased toxicity of chemotherapy in women is intriguing, peculiarly when host circadian rhythmicity seemed to be implicated.
The authors gratefully thank Prof Dr. Francis Levi from Warwick University (UK) for constructive discussions all along the process of this work and for reviews on some chapters. Muriel Focan (Chief Officer Bank of New York, Brussels, Belgium), for reviewing English formulation, and Audrey Stultiens (Clinical Research, Oncology Department, CHC-Liège), for actualizing figures, are also warmly acknowledged.
The authors have no conflict of interest to declare.
To Jeffrey C. Hall, Michael Rosbash, and Michael W. Young who received jointly the Nobel Prize in Physiology or Medicine 2017 “for their discoveries of molecular mechanisms controlling the circadian rhythm.”
In recent times, potential energy, environment, and economic interests have stimulated motorized industry to develop and enhance efficient, clean, and sustainable vehicle, particularly, for city transportation. This new invention should not contingent on oil as a sole of energy source. Additionally, reducing engine size, replacing mechanical components by electrical devices, transferring request information electronically instead of mechanically, and designing integrated control systems are considered other targets that automotive manufactures are aiming to attain in producing new means of transportation. At that juncture, the automotive industry introduced electrical vehicle (EV), which is driven by alternative energy sources that provide magnificent means for efficient, clean, and environmentally urban transportation.
The trend technology toward electronic components and circuits coming from their technical merits not only reduces the weight of vehicles but also has the potential for a large number of integrated functions and features. Some of these new electronically operated systems are taken place under the concept of x-by-wire, which involves brake-by-wire, throttle-by-wire, and steer-by-wire. These electrical vehicle subsystems yet still undergo considerable challenging issues that need intensive study and investigation in order to find out appropriate design and powerful operated system.
This chapter presents x-by-wire technology implementation in electric vehicle. BBW is a new brake technology in which mechanical and hydraulic components of traditional brake systems are replaced by electric circuits and devices to carry out the function of braking in a vehicle by wire-transmitted information. The advantages of electronic devices such as reducing vehicle weight and increasing brake performance are considered the main purpose trends of the automotive industry toward this new brake technology. Another application known as n EPAS system is a driver-assisted feedback system designed to boost the driver input torque to a desired output torque causing the steering action to be undertaken at much lower steering efforts. Particle swarm optimization (PSO) algorithm is implemented as tuning mechanism for fractional-order PID (FOPID) controller. The aim of this controller is to track the assist current generated by lookup table. The results show the performance and efficiency of using PSO algorithm for FOPID tuning.
The motivation of this study is to enhance the safety aspects for the vehicle while attaining any desired speed. To achieve that, an optimal brake force at different road types and conditions and for different brake commands must be obtained within a reasonable time and without vehicle sliding.
The proposed design of BBW used in this study is schematically illustrated in Figure 1, which includes one wheel of vehicle model as seen inside the dotted box. According to the figure, the suggested principle of work of BBW is adopted which is demonstrated as follows:
Proposed BBW architecture for one-wheel brake model.
Primarily, reducing (or halting) vehicle speed comes as a result of pressing down on the brake pedal by the driver. The braking pedal of BBW is usually equipped with several electronic sensors that provide redundant information about braking request. Thus, when a brake force applies to the brake pedal, three possible sensors are usually utilized to measure required braking force: (1) pedal displacement sensor (measures pedal displacement as a result of applying force on the pedal) [3], (2) force sensor (measures applied force on brake pedal), and (3) pressure sensor (measures applied pressure to brake pedal) [5]. In addition to that, the brake pedal of BBW may not necessarily be as the general brake device, rather than it could be a hand-adjacent device placed at the steering wheel that enables driver to apply brakes with hand movement as suggested in [5]. However, since the focus of this study is to design control strategy for braking action, it is assumed that braking request is already measured and available in the form of voltage source as adopted by Mingfei’s design [1]. Therefore, the chosen voltage source of this study exists within a range of 0–5 V in which 0 V relates to released brake pedal and 5 V relates to fully pressed pedal. This voltage range is formulated in such a way that brake pedal input, which is in the form of voltage source, matches the desired vehicle speed by using 1D lookup table as shown in Figure 2. This lookup table enables a range of inputs that correspond to [0–5] Volts which in turn this range corresponds to the vehicle speed range [0–100] Km/h; for example, if the input brake pedal corresponds to 2.5 V, the relative required vehicle speed will be 50 Km/h as illustrated in Figure 2(b). Nonetheless, the relative values of vehicle speed are changeable according to initial vehicle speed (vehicle speed before braking action), whereas voltage range remains constant all the time and has the capability to correspond to any given vehicle speed by updating vehicle initial speed. For instance, if the initial vehicle speed is set to 50 Km/h, the voltage range [0–5] V will correspond to the vehicle speed [0–50] Km/h as explained in Figure 2(b).
Lookup table of the input brake force. (a) Tool box. (b) Vehicle speed-voltage source.
Upon determining the required brake request, the braking command is then sent to the control unit (CU) via wires as shown in Figure 1. The CU located at the wheel after that determines exactly the control signal that must be transmitted to the brake actuator unite in order to slow down or stop the vehicle. Nevertheless, the control signal of the CU is considered the input for the electrical actuator (permanent magnetic DC motor) where this signal takes the form of the desired braking torque. Consequently, electronic actuator of the brake unit operates based on the desired braking torque which in turn decreases (or stops) vehicle speed according to the desired speed.
The control unit, however, is updated through feedback control strategies where wheel speed is considered the input to the feedback control system according to applied control strategy. Moreover, the interaction between brake pedal, control unit, electronic actuator, and wheel as well as vehicle speed is completely accomplished by wires. In view of that, vehicle brake system is designed and structured.
The suggested control brake system employs fuzzy-PID controller to obtain the desired vehicle speed based on tuning of traditional PID controller. The applied control algorithm must be able to function to any required vehicle speed that is determined by the driver. The proposed control system design applied to handle this task is schematically illustrated in Figure 3.
BBW control system design.
As depicted in Figure 3, the system input (brake pedal force) is determined by the driver in the form of voltage signal ranging from 0 V (refers to release pedal) to 5 V (refers to fully pressed pedal). Upon determining the required vehicle speed by lookup table, the speed signal is then sent to the control unit which is based on either PID or fuzzy-PID controllers. The implemented control algorithm then determines the desired voltage source that must be transmitted to electrical actuator in order to generate required braking torque. The wheel speed after that is decreased by applying brake torque causing modification in overall system dynamics which in turn leads to vehicle speed deceleration.
The error signal transmitted into control algorithm, however, is determined by the difference between input signal (desired vehicle speed) and feedback signal (wheel speed) which is given by the following relationship:
The control strategy used to deliver the desired vehicle speed is based on maintaining peak slip ratio within the maximum adhesion characteristic range [0.02–0.35]. Locating peak slip ratio within the maximum friction characteristic initiated from applying ideal and accurate brake torque is capable of deriving proper and acceptable vehicle-wheel speed relationship.
The control objective of both controllers is to decrease vehicle velocity to the desired vehicle speed (5 Km/h) while maintaining slip ratio within its maximum range [0.02, 0.35]. Besides, the control algorithms are designed to operate braking action on dry asphalt road type, whereas other road types and conditions (such as wet asphalt, wet and dry cobblestone, and concrete) are applied to examine and investigate whether the controllers can handle characteristic variations of the system or not.
a) PID controller design
A cascade-form PID controller is designed based on manual tuning method, where the three terms of PID controller (proportional, integral, and derivative) are employed. Accordingly, the overall controller output is considered the sum of the contributions of the individual PID terms which is further expressed in Eq. (1), where
b) Fuzzy-PID controller design
Although PID manual tuning method provides stable output response, PID controller does not achieve the desired control specifications since the dynamics of the system has nonlinear and variant parameters which in turn degrade system performance. Therefore, fuzzy logic controller has been introduced to PID controller in order to improve the response as well as to enhance system performance based on fuzzy-PID tuning. In fact, fuzzy-PID controller is considered as a link between traditional control which has well-established theory and intelligent control that conquers traditional control problems like nonlinearity.
Fuzzy-PID scheme, in addition, can employ different structures and forms based on the input to the fuzzy controller on the one hand and on the arrangement of PID parameters and their locations with respect to fuzzy controller on the other hand. Nonetheless, these different structures are possible in the context of knowledge description and explanation, whereas they should be examined with respect to their functional behavior. The proposed structure of this study is schematically illustrated in Figure 4, which generates incremental and absolute fuzzy-PID signal based on direct action to tune PID parameters through fuzzy inference.
Fuzzy-PID controller (MATLAB Simulink scheme).
As shown in Figure 4, the error and rate change of error are considered as the time-varying inputs to the fuzzy logic controller (linguistic inputs), whereas tuned (proportional, integral, and derivative) gains are the output of the controller (linguistic outputs). Regarding linguistic inputs, there are other choices (such as integral of error) that could also be used as input variables, yet the selection variables make good intuitive sense, particularly as the input error is naturally engaged in the control problem of regulating process output around specific set point. The controller input variable however must have proper information available to provide good decision to derive vehicle speed into the desired speed to achieve high-performance operation based on fuzzy-PID tuning. On the other hand, the linguistic output variables are expressed as tuned (proportional, integral, and derivative) gains where the output values of these tuned gains are implemented to tune the conventional PID controller as shown in Figure 4.
The adopted linguistic values and their corresponding abbreviations in conjunction with their linguistic variables are summarized in Table 1.
Linguistic variables | Linguistic values | Linguistic value abbreviation | |
---|---|---|---|
Input | Error | Positive, zero, and negative | P, Z, and N, respectively |
Rate change of error | |||
Output | Proportional gain | Positive, zero, and negative | P, Z, and N, respectively |
Integral gain | Zero, positive small, and positive large | Z, PS, and PL, respectively | |
Derivative gain | Zero, positive small, and positive large | Z, PS, and PL, respectively |
Linguistic variables alongside their linguistic values and abbreviations.
This table provides a language to express the control decision-making process in the context of established input–output framework. For example, the statement “error is negative” can be referred to the situation where the vehicle speed curve exists above the desired speed and needs more braking force. In contrast, the statement “error is positive” can be referred to the situation where the vehicle speed curve exists below the required speed curve and needs to decrease applying torque to obtain the desired vehicle speed.
Upon determining linguistic quantification, the rule base of the control system is set to capture expert’s knowledge on how to tune the system and describe applied control strategy. Since there are two input variables and three output variables, the possible rules can at most reach to
Error | ||||
---|---|---|---|---|
Change in error | N | Z | P | |
N | N | N | Z | |
Z | N | Z | P | |
P | Z | P | P |
Fuzzy rule base for proportional gain.
Error | ||||
---|---|---|---|---|
Change in error | N | Z | P | |
N | Z | Z | PS | |
Z | Z | PS | PL | |
P | PS | PL | PL |
Fuzzy rule base for integral and derivative gains.
The meaning of the above linguistic description is quantified via membership function, whereas triangular shape is considered in this study for all inputs as well as all outputs for its simplicity, linear grade distribution, and fairly limited availability of the relevant information about the linguistic terms. In due course, the selected membership functions and their associated universe of discourse as well as linguistic values of this study are revealed in Figure 5. The designed membership functions are overlapped, and the height of the intersection of each two successive fuzzy sets is ½.
Membership functions and their corresponding values. (a) Membership functions and their values for error input et. (b) Membership functions and their values for change of error ∆et. (c) Membership functions and their values for proportional gain. (d) Membership functions and their values for integral gain. (e) Membership functions and their values for derivative gain.
Since a clear picture on the linguistic variables, rule base, and membership functions have been explained, we move to the important issue of how the exact fuzzy controller works. In doing so, the first component of fuzzy controller is fuzzification process which is the act of acquiring the value of the input variable and defining numeric magnitudes for the membership function that are set for that variable. After that, the inference mechanism takes the action through two steps:
Matching the premise associated with all the rules to the controller inputs to determine which rules apply to the current condition. In other words, each rule in the rule base has different premise membership functions on the one hand and function of error and change in error on the other hand; therefore, the quantification of the certainty that each rule base applies to the current condition can be obtained upon providing specific values for the error and change in error.
Determining the conclusion (what the control action to take) that should be applied by using selected rules to relate to the current situation. This conclusion is classified with a fuzzy set that signifies the certainty that the input to the plant should undertake various values.
Therefore, as long as the input to the inference process (set of rules) is on, its corresponding output operates which is in the form of implied fuzzy sets. However, these implied fuzzy sets are then converted to crisp values (numeric values) by combining their effects to give the most certain controller outputs. The defuzzification process is obtained by bisector method which divides the area by a vertical line into two equal subregion areas. In addition, the mean of maximum and the largest of maximum are also applied to the system for the purpose of validity in which both of them provide close output result.
The vehicle model and controller algorithms are examined in MATLAB software. For the results of investigation and analysis, the initial vehicle-wheel speeds are set to 100 Km/h, whereas the desired vehicle speed is set to 5 Km/h. The reason of choosing 5 Km/h as the desired vehicle speed instead of zero Km/h is because slip ratio magnitude goes to infinity as vehicle speed approaches zero which in turn leads to inappropriate output behavior. On the other hand, selecting the desired low speed helps to examine maximum slip ratio that controls algorithm derives; hence, the ability to evaluate control performance and output response of the system will be more effective and visible.
The output responses of fuzzy-PID controller for dry asphalt road type are presented in Figure 6, whereas Figure 6(a) demonstrates the output responses of vehicle-wheel, and Figure 6(b) shows the output responses of slip ratio. Yet, the output responses of traditional PID controller are imposed in the same figure (Figure 6) to illustrate the comparison between traditional PID controller and fuzzy-PID controller.
Output responses of fuzzy-PID controller for dry asphalt road type. (a) vehicle-wheel speed. (b) Slip ratio.
As shown in Figure 6(a), both controllers could derive stable output response smoothly. However, the output performance of the fuzzy-PID controller is much better than conventional PID controller since PID controller derives large steady-state error on the one hand and takes long time (approximately 15 seconds) to approach the desired vehicle speed (5 Km/h) on the other hand. In contrast, fuzzy-PID controller overcomes these problems being provided better output performance with zero steady-state error. As a result, fuzzy-PID controller could obtain the required vehicle speed within approximately 9 seconds which in turn assists to reduce stopping vehicle time 60% as compared to PID controller and more importantly the ability of fuzzy-PID controller to eliminate steady-state error to zero. Therefore, fuzzy-PID controller shows superior and outstanding controller.
On the other side, the output response of slip ratio associated with vehicle-wheel speed as shown in Figure 6(b) reveals smooth output response particularly before attaining the desired output speed. As depicted from the figure, the maximum slip ratio is the same for both controllers which approximately equals to 0.027. Though the maximum slip ratio magnitude seems a small value, the main cause for vehicle-wheel deceleration is considered since friction force between road surface and wheel surface principally depends on the slip ratio magnitude even though if the slip ratio possesses very small magnitude that may reach to mili-slip ratio.
This fact is clearly observed from Figure 6(b), especially within the time interval [2, 4] seconds, where the slip ratio of fuzzy-PID controller output response (blue line) has larger magnitude than PID output response (red line) by mili-values. This slight divergence that fuzzy-PID created, by trivial increases in slip ratio magnitude, leads to dramatically improve and enhance output response by decreasing vehicle stopping time 60% as compared to conventional PID controller.
As shown in the table, the slip ratio increases as the adhesion characteristic decreases. For instance, the maximum adhesion characteristic of dry asphalt is about 1.18 which is considered a large value; hence, its magnitude-derived slip ratio is small (0.027 for PID controller and 0.028 for fuzzy-PID controller). In contrast, the wet cobblestone adhesion characteristic has a small value (0.34), and therefore its derived slip ratio has a large value (0.26 for PID controller and 0.33 for fuzzy-PID controller).
The other significant notice that can be observed from Table 4 is the maximum slip ratio of fuzzy-PID controller which is slightly larger than the one derived by PID controller, meanwhile fuzzy-PID performance is considered superior and much better than PID performance as demonstrated above. Accordingly, the slip ratio magnitude is considered extremely important in braking operation even though if it possesses very small value since braking process depends on the road-wheel surfaces. Nonetheless, a certain magnitude range of slip ratio is permissible where if its magnitude exceeds that range, the operating system may undergo unwanted behavior (wheel locks up or losses the control) particularly if it goes to a large value (more than 0.5).
Road-type controller-type | Max. adhesion char. | PID | Fuzzy-PID |
---|---|---|---|
Asphalt (dry) | 1.18 | 0.027 | 0.028 |
Asphalt (wet) | 0.8 | 0.035 | 0.035 |
Concrete | 1.1 | 0.028 | 0.029 |
Cobblestone (dry) | 1 | 0.085 | 0.087 |
Cobblestone (wet) | 0.34 | 0.26 | 0.33 |
Maximum derived slip ratios for PID and fuzzy-PID controllers.
It is also concluded that the mathematical derivation and its investigation of the brake system model are accurate and valid particularly because the examination and exploration of the output results are entirely identical to the analysis and investigation of each system’s variable as demonstrated in Section 3. Besides, the suggested feedback control signal which is based on wheel speed was able to deliver detailed and thorough information about the status of braking system which assists to update system’s variable effectively.
EPAS presents the continuing future of power-assisted steering technology for passenger vehicles and has already been started to appear in high-volume, lead-vehicle applications; more flexible than traditional hydraulic power-assisted steering (HPAS) system, the fact of EPAS is to supply steering assistance to the driver utilizing an electrically controlled electric motor. EPAS is a classic exemplary case of a smart actuator operating under feedback control. It can provide necessary assist torque in different car speeds and different driver torques [6]. It has been reported in [6] that among electric power-assisted steering (EPAS) system available for passenger cars, EPAS systems provide the best fuel consumption [7, 8, 9]. The plot shown in Figure 7 indicates that EPAS systems have the lowest fuel consumption in comparison to hydraulic power-assisted steering (HPAS) system with savings in excess of 3.0% in average and up to 3.5% in city driving [6].
Typical EPAS fuel consumption saving.
According to the steering torque, automobile speed as well as road conditions, the system can provide the real-time assistant torque through assist motor to help driver steering and make steering easier and gentle, which guarantees that the driver has the best steering feel in the variety of operating conditions. At present, the design for the assist motor control have mainly two methods: the first one is motor current loop control based on classical control theory and the other one is the state-space model
The aim of this study in EPAS is to control the electric motor to supply the appropriate assist torque to decrease the driver’s steering effort in various speeds. The EPAS control must ensure the generation of the desired assist torque, a stable system with a large amount of assistance. The most important issue is electric motor tracking precisely the target current. To develop the electric motor current tracking performance, particle swarm optimization (PSO) algorithm is applied as tuning mechanism for fractional-order PID (FOPID) controller.
The EPAS includes a torque sensor, which senses the action of the driver along with the action of the automobile; an ECU, which performs calculations on assisting force based on signals from the torque sensor; a motor, which creates turning power based on the output from ECU; and a reduction gear, which increases the turning force from the motor and transfers it to the steering system and pinion and rack (Figure 8).
EAPS dynamic model.
The parameters associated with the rack model are
Parameters | Symbols | Value | Units |
---|---|---|---|
Driving wheel moment of Inertia | 0.04 | ||
Driving wheel damping | 0.362 | ||
Pinion radius | 0.0078 | ||
Rack and wheel assembly mass | 32 | ||
Viscous rack damping | 650.5 | ||
Motor gear ratio | 16.5 | ||
Motor stiffness | 125 | ||
Motor inductance | 0.0015 | ||
Motor resistance | 0.15 | ||
Motor torque constant | 0.02 | ||
Motor EMF constant | 0.02 | ||
Motor moment of Inertia | 0.000452 | ||
Motor damping | 0.003339 | ||
Steering column stiffness | 115 | ||
Tire spring rate | 91,061 |
The function of ECU is to collect the torque sensor and the vehicle speed signal, select a suitable motor target current by an assist characteristic curve, execute a control by comparing with the feedback actual current, and then drive the DC motor.
Fractional-order PID (FOPID) controller denoted by
where
Fractional-order PID controller.
where μ and λ are an arbitrary real numbers. Taking μ = 1 and λ = 1, a classical PID controller is obtained. Thus, FOPID controller generalizes the classical PID controller and expands it from point to plane as shown in Figure 10. This expansion provides us much more flexibility in designing PID controller and gives an opportunity to better adjust the dynamics of control system. This increases the robustness of the system and makes it more stable. However, with increase in parameters to be tuned, the optimization problem associated with the system becomes more difficult [17]. For achieving a certain performance, it is desired to develop a systematic algorithm for the FOPID optimization as shown in Figure 11.
Control strategy.
(a) Classical PID controller and (b) FOPID controller.
Figure 12 shows an open-loop response of system, as depicted in the figure below, that motor current cannot follow the step unit. The close-loop unit step response of EPAS system using classical PID controller and PSO-FOPID are shown in Figure 13.
Unit step response of EPAS open-loop system.
Unit step response of EPAS system using classical PID and optimal FOPID.
Figure 14 shows three signals (i) motor current tracking of the look-up table, (ii) driving wheel input torque and (iii) the electric motor output current. The vehicle speed is 20km/h while the driver input torque is represented as a sine wave of 9 N.m amplitude.When the input torque of driving wheel
Driver torque and motor current in 20 km/h.
In this study, a design of fuzzy-PID controller for BBW system is presented. In addition to that, a design structure for BBW is proposed which helps to elaborate a principle of work of the suggested BBW system. The braking mechanism and operation of BBW system are grasped and realized by obtaining mathematical derivation of the brake system based on quarter car model. Two controller algorithms based on PID and fuzzy-PID controllers are then implemented to check the validity of mathematical derivation on the one side and to operate braking mechanism of BBW on the other side. The simulation result which is conducted on different road types and conditions shows that fuzzy-PID controller is a superior and outstanding controller as compared to PID controller, where the fuzzy-PID controller assists to reduce stopping vehicle time 60% and the most important thing is the ability of fuzzy-PID controller to improve the system performance by eliminating steady-state error to zero. Besides, the result analysis and investigation demonstrate that larger adhesion characteristics lead to produce larger brake force which in turn assists to reduce vehicle stopping time.
For EPAS system, FOPID (fractional-order PID) controller has been presented, and it was tuned to control the motor current. All simulations for the whole EPAS system are implemented by MATLAB/Simulink software showing a comparison of classical PID and optimal PID tracking performance. PSO algorithm has been implemented to find optimal values of FOPID parameters. From the simulation results, it fulfills the control objectives and achieves good assistant in different speeds.
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She performed research in perioperative autotransfusion and obtained the degree of PhD in 1993 publishing Peri-operative autotransfusion by means of a blood cell separator.\nBlood transfusion had her special interest being the president of the Haemovigilance Chamber TRIP and performing several tasks in local and national blood bank and anticoagulant-blood transfusion guidelines committees. Currently, she is working as an associate professor and up till recently was the dean at the Albert Schweitzer Hospital Dordrecht. She performed (inter)national tasks as vice-president of the Concilium Anaesthesia and related committees. \nShe performed research in several fields, with over 100 publications in (inter)national journals and numerous papers on scientific conferences. \nShe received several awards and is a member of Honour of the Dutch Society of Anaesthesia.",institutionString:null,institution:{name:"Albert Schweitzer Hospital",country:{name:"Gabon"}}},{id:"83089",title:"Prof.",name:"Aaron",middleName:null,surname:"Ojule",slug:"aaron-ojule",fullName:"Aaron Ojule",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Port Harcourt",country:{name:"Nigeria"}}},{id:"295748",title:"Mr.",name:"Abayomi",middleName:null,surname:"Modupe",slug:"abayomi-modupe",fullName:"Abayomi Modupe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"Landmark University",country:{name:"Nigeria"}}},{id:"94191",title:"Prof.",name:"Abbas",middleName:null,surname:"Moustafa",slug:"abbas-moustafa",fullName:"Abbas Moustafa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94191/images/96_n.jpg",biography:"Prof. Moustafa got his doctoral degree in earthquake engineering and structural safety from Indian Institute of Science in 2002. He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. His research interest includes earthquake engineering, seismic design, nonlinear dynamics, random vibration, structural reliability, structural health monitoring and uncertainty modeling.",institutionString:null,institution:{name:"Minia University",country:{name:"Egypt"}}},{id:"84562",title:"Dr.",name:"Abbyssinia",middleName:null,surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Fort Hare",country:{name:"South Africa"}}},{id:"202206",title:"Associate Prof.",name:"Abd Elmoniem",middleName:"Ahmed",surname:"Elzain",slug:"abd-elmoniem-elzain",fullName:"Abd Elmoniem Elzain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kassala University",country:{name:"Sudan"}}},{id:"98127",title:"Dr.",name:"Abdallah",middleName:null,surname:"Handoura",slug:"abdallah-handoura",fullName:"Abdallah Handoura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Supérieure des Télécommunications",country:{name:"Morocco"}}},{id:"91404",title:"Prof.",name:"Abdecharif",middleName:null,surname:"Boumaza",slug:"abdecharif-boumaza",fullName:"Abdecharif Boumaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Abbès Laghrour University of Khenchela",country:{name:"Algeria"}}},{id:"105795",title:"Prof.",name:"Abdel Ghani",middleName:null,surname:"Aissaoui",slug:"abdel-ghani-aissaoui",fullName:"Abdel Ghani Aissaoui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105795/images/system/105795.jpeg",biography:"Abdel Ghani AISSAOUI is a Full Professor of electrical engineering at University of Bechar (ALGERIA). He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n12-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n13-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n14- Abdel Karim M. El Hemaly. 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