Increased cancer risk in HIV-infected individuals occupationally exposed to chemicals: Depression of p53 as the key driver.

The growing exposure to occupational chemicals and the spread of human immunodeficiency virus (HIV) infection are major global health issues. However, there is little data on the carcinogenic risk profile of HIV-infected individuals who have been occupationally exposed to chemical mixtures. This study therefore investigated the levels of cancer risk biomarkers in HIV-infected individuals exposed to occupational chemicals, exploring the relationship between apoptotic regulatory and oxidative response markers as a measure of cancer risk. Study participants (mean age 38.35±0.72 years) were divided into four groups according to their HIV status and occupational chemical exposure: 62 HIV-positive exposed (HPE), 66 HIV-positive unexposed (HPU), 60 HIV-negative exposed (HNE), and 60 HIV-negative unexposed (HNU). Serum p53, ß-cell lymphoma-2 (bcl2), 8-hydroxydeoxyguanosine (8-OHdG), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured using standard methods. Clusters of differentiation 4 (CD4+) T-lymphocytes were enumerated using flow cytometry. Serum p53 and bcl2 levels in HPE (0.91±0.11ng/ml and 122.37±15.77ng/ml) were significantly lower than HNU (1.49±0.15ng/ml and 225.52±33.67ng/ml) (p < 0.05), respectively. Wildtype p53 and bcl2 were positively and significantly correlated with 8-OHdG (r = 0.35, p<0.001; r = 0.36, p<0.001) and SOD (r = 0.38, p<0.001; r = 0.39, p<0.001). After controlling for gender, age, BMI, and cigarette smoking, both HIV status and SOD activity were significantly associated with wildtype p53 and bcl2 (p < 0.05). Malondialdehyde was significantly higher in the HPE (0.72 ± 0.01 mg/ml) than in the HNE (0.68 ± 0.01 mg/ml) and HNU (0.67 ± 0.01 mg/ml) groups (p < 0.05). The HPE group showed significantly lower CD4 counts than the HNE and HNU groups. Individuals who are HIV-infected and occupationally exposed to chemicals have a constellation of depressed immunity, elevated oxidative stress, and loss of tumour suppressive functions, which together intensify cancer risk, providing valuable scientific and public health bases for preventive measures in this vulnerable population.

Deeper Insight in Metastatic Cancer Progression; Epithelial-to- Mesenchymal Transition and Genomic Instability: Implications on Treatment Resistance.

Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance, but the actual mechanism that underlies this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulate chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of the EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interactions that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs, work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

Emerging Metabolomics Biomarkers of Polycystic Ovarian Syndrome; Targeting the Master Metabolic Disrupters for Diagnosis and Treatment.

BACKGROUND AND OBJECTIVE: Metabolomics is a powerful exploratory tool for discovering new diagnostic molecules or biomarkers due to its ability to highlight several interactions between different biochemical molecules and pathways in composition in health and disease thereby advancing our understanding, to provide evidence based diagnosis and treatment of such a complex disease including polycystic ovarian syndrome (PCOS). The aim of this study was to review available literature on the use of metabolomic approach and to critically evaluate and draw a synthesis to highlight novel biochemical markers for clinical application in PCOS. METHOD: Studies that applied metabolomic approach to investigate PCOS and those meeting selection criteria were searched and, critically evaluated. RESULT: Here we highlighted the metabolic reactions and perturbation of some metabolic pathways present in patients with polycystic ovarian syndrome and normal subjects that can allow better understanding of the disorder and help developing a new generation diagnostic and treatment algorithm. CONCLUSION: A number of disease-related metabolites have been discussed which have extraordinary potential for a clinical utility as diagnostic and treatment monitoring biomarkers.

A New Perspective of Lysosomal Cation Channel-Dependent Homeostasis in Alzheimer's Disease.

Studies have reported typically biophysical lysosomal cation channels including TPCs. Their plausible biological roles are being elucidated by pharmacological, genetic and conventional patch clamp procedures. The best characterized so far among these channels is the ML1 isoform of TRP. The reported TRPs and TPCs are bypass for cation fluxes and are strategic for homeostasis of ionic milieu of the acidic organelles they confine to. Ca(2+) homeostasis and adequate acidic pHL are critically influential for the regulation of a plethora of biological functions these intracellular cation channels perform. In lysosomal ion channel biology, we review: ML1 and TPC2 in Ca(2+) signaling, ML1 and TPC2 in pH(L) regulation. Using Aß42 and tau proteins found along clathrin endolysosomal internalization pathway (Fig. 3), we proffer a mechanism of abnormal pH(L) and ML1/TPC2-dependent cation homeostasis in AD.

Metabolic Basis of Polycystic Ovarian Syndrome; Indications for Biochemical Screening.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous condition with wide range of phenotype the cause of this disorder is unknown, however, increased ovarian androgen production including increased theca cell responsiveness to gonadotropin stimulation, increased pituitary secretion of luteinizing hormone, and hyperinsulinemia have been suggested. Some known risk factors are ethnicity and environmental factors including lifestyle and bodyweight. METHOD: Relevant English language studies from January 1995 to September 2015 were identified, reviewed, synthesized and discussed extensively. RESULT: various forms of PCOS, and the underlying mechanisms; and highlights biochemical, morphological and metabolic hallmarks of PCOS, including trends and emerging phenotypes; and presents a simplified synthesis that integrates current understanding of biochemical and metabolic endocrinology of PCOS are summarized. As no generally accepted criteria exist for its diagnosis, some existing diagnostic criteria that cut across different geographical regions are also highlighted. CONCLUSION: Indeed, emerging evidence points that the severity of menstrual problems could serve as a predictor of the like-hood of insulin resistance in women of reproductive age, suggesting the need for routine metabolic screening and early intervention in PCOS.

Innate and adoptive immune cells contribute to natural resistance to systemic metastasis of B16 melanoma.

The greatest hurdle in cancer treatment is the metastasis of primary tumors to distant organs. Our knowledge on how different immune cells, in the absence of exogenous stimulation, prevent tumor metastasis in distant organs is poorly understood. Using a highly metastatic murine lung B16 melanoma cell line BL6-10, we employed naive mice that genetically lack CD4(+) or CD8(+) T cells, or are depleted of dendritic cells (DCs) or natural killer (NK) cells to understand the relative importance of these cells in metastasis prevention. Irrespective of the presence of naïve CD4(+) T, CD8(+) T, DCs, or NK cells, lungs, which act as primary site of predilection for B16 melanoma, readily developed numerous lung BL6-10 melanoma colonies. However, their absence led to B16 melanoma metastasis in variable proportions to distant organs, particularly livers, kidneys, adrenals, ovaries, and hearts. NK cells mediate prevention of BL6-10 metastasis to various organs, especially to livers. Mechanistically, CD40L signaling, a critical factor required for DC licensing and CD8(+) cytotoxic T lymphocyte (CTL) responses, was required for CD4(+) T cell-mediated prevention of systemic BL6-10 metastasis. These results suggest that the composition and functions of different immune cells in distant tissue microenvironments (distant organs other than primary sites of predilection) robustly mediate natural resistance against melanoma metastasis. Thus, harnessing these immune cells' responses in immunotherapeutics would considerably limit organ metastasis.

Anion Gap Toxicity in Alloxan Induced Type 2 Diabetic Rats Treated with Antidiabetic Noncytotoxic Bioactive Compounds of Ethanolic Extract of Moringa oleifera.

Moringa oleifera (MO) is used for a number of therapeutic purposes. This raises the question of safety and possible toxicity. The objective of the study was to ascertain the safety and possible metabolic toxicity in comparison with metformin, a known drug associated with acidosis. Animals confirmed with diabetes were grouped into 2 groups. The control group only received oral dose of PBS while the test group was treated with ethanolic extract of MO orally twice daily for 5-6 days. Data showed that the extract significantly lowered glucose level to normal values and did not cause any significant cytotoxicity compared to the control group (P = 0.0698); there was no gain in weight between the MO treated and the control groups (P > 0.8115). However, data showed that treatment with an ethanolic extract of MO caused a decrease in bicarbonate (P < 0.0001), and more than twofold increase in anion gap (P < 0.0001); metformin treatment also decreased bicarbonate (P < 0.0001) and resulted in a threefold increase in anion gap (P < 0.0001). Conclusively, these data show that while MO appears to have antidiabetic and noncytotoxic properties, it is associated with statistically significant anion gap acidosis in alloxan induced type 2 diabetic rats.

Exposure of Prostate to Lipopolysaccharide and Hypoxia Potentiates Neoplastic Behavior and Risk for Prostate Carcinogenesis In Vivo.

A number of studies showed that men from tropical countries have higher burden of prostate cancer similar to data from USA. We developed a translational model to examine whether exposure to microbial inflammation-inducing molecule lipopolysacchride LPS was associated with prostatic cell transformation to more proliferative phenotype as indicated by PSA secretion. Immunocompetent adult mice were divided into two groups; the first group received a local prostate inoculation with E. coli, while the second group received inoculation with sterile solution of saline as vehicle. At the end of 6 days, the PSA values were measured and compared. In the second experiment, two groups of animals were involved. The test group received two drops of the hydrogen peroxide orally for six to seven days to induce hypoxia, while the control group received normal saline. Blood samples were evaluated for serum level of PSA. Result showed a 2-fold increase in level of PSA compared to the control mice in the E. coli inoculated-LPS exposed animals. In addition, exposure of the animals to hypoxic stress resulted in 3.5 fold increase in the serum PSA compared to the control group, which was found to be statistically significant (P < 0.0001). In conclusion, our data shows that chronic prostatic infection and exposure to inflammatory stimulus, especially LPS, may alter the phenotype of prostate epithelial cells for increased PSA secretion, a known cancer-like behavior; this is mediated by compromised redox state and oxidative stress injury. We propose that exposure of the prostate epithelial cells to lipopolysaccharide (LPS) promotes chronic inflammation and risk of neoplastic behavior of the prostate in vivo; this may explain the high rate of prostate cancer in tropics.

Infection, inflammation and prostate carcinogenesis.

Several reports have shown that the incidence of prostate cancer is on the increase and that more men would be diagnosed of prostate cancer in the next decades. Many approaches are being applied towards reducing the cases of prostate cancer, especially in the very rich countries. However, these have not been effective due to the poor current understanding of the pathophysiology of prostate carcinogenesis. The current work presents a review of how chronic infection and inflammation may contribute to prostate carcinogenesis.