Organochlorine pesticides disrupt T helper cell regulation and reduce IL-2 and IFN-γ favoring infection and production of autoantibodies among pemphigus patients.

The list of environmental factors that trigger autoimmune diseases in genetically susceptible individuals has grown in the recent years and is far from complete. The possible intervention of the environment in triggering these diseases is ever more perceived by the clinicians. This study investigated the effect of environmental factors like organochlorine pesticides (OCPs) on proportions of different T lymphocyte subsets and their cytokine secretion in-vitro among pemphigus patients, before and after specific immunosuppressive therapy. Higher levels of OCPs like ß-HCH (isoform of hexachlorohexane), α-endosulfan (a form of endosulfan) and p,p΄-DDE (a metabolite of o,p'-dichlorodiphenyltrichloroethane) were observed in the blood of pemphigus patients as compared to healthy controls. HCH and DDT exposure caused specific reduction in CD8+CD45RA+ and CD4+CD25+ T lymphocyte subpopulations in these patient PBMCs. A strong reduction in Th1 (IL-2 and IFN-γ) cytokines upon exposure to these OCPs in-vitro was also observed. These findings indicate that HCH and DDT have a significant impact on Th1 lymphocytes. Impaired production of these cytokines might favor infections and production of autoantibodies. We therefore speculate that the systemic absorption of the pesticide after the topical contact may be one of the factors triggering the immunological mechanism among pemphigus patients.

Combined effect of ipilimumab and nivolumab improves oncology endpoints in metastatic melanoma patients.

Metastatic melanoma has less frequency, but considered as the most dreaded cancer. The combination of nivolumab & ipilimumab is proving their mettle in treating metastatic melanoma. The patients when administered with the combination of nivolumab & ipilimumab have shown improved median progression free survival, objective response rate and overall survival rate compared with nivolumab and ipilimumab monotherapy. The combination shrinks the tumor cells by attacking different checkpoints viz. CTLA-4 and PD-L1, respectively. The combination treatment reveals reduced disease progression and suggests nivolumab's non-cross resistant nature. The median progression free survival in "nivolumab plus ipilimumab" group has shown an increase of 66.7% and 296.6% in comparison to nivolumab and ipilimumab monotherapy. The other parameter viz. objective response rate improvement is equivalent to almost 14% and 38.6% when compared to nivolumab and ipilimumab monotherapy, respectively.

Microbes in gynecologic cancers: Causes or consequences and therapeutic potential.

Gynecologic cancers, starting in the reproductive organs of females, include cancer of cervix, endometrium, ovary commonly and vagina and vulva rarely. The changes in the composition of microbiome in gut and vagina affect immune and metabolic signaling of the host cells resulting in chronic inflammation, angiogenesis, cellular proliferation, genome instability, epithelial barrier breach and metabolic dysregulation that may lead to the onset or aggravated progression of gynecologic cancers. While microbiome in gynecologic cancers is just at horizon, certain significant microbiome signature associations have been found. Cervical cancer is accompanied with high loads of human papillomavirus, Fusobacteria and Sneathia species; endometrial cancer is reported to have presence of Atopobium vaginae and Porphyromonas species and significantly elevated levels of Proteobacteria and Firmicutes phylum bacteria, with Chlamydia trachomatis, Lactobacillus and Mycobacterium reported in ovarian cancer. Balancing microbiome composition in gynecologic cancers has the potential to be used as a therapeutic target. For example, the Lactobacillus species may play an important role in blocking adhesions of incursive pathogens to vaginal epithelium by lowering the pH, producing bacteriocins and employing competitive exclusions. The optimum or personalized balance of the microbiota can be maintained using pre- and probiotics, and fecal microbiota transplantations loaded with specific bacteria. Current evidence strongly suggest that a healthy microbiome can train and trigger the body's immune response to attack various gynecologic cancers. Furthermore, microbiome modulations can potentially contribute to improvements in immuno-oncology therapies.

AA genotype of cyclin D1 G870A polymorphism increases breast cancer risk: Findings of a case-control study and meta-analysis.

BACKGROUND: Cyclin D1 (CCND1) polymorphisms, a regulator of the cell cycle progress from G1 to the S phase, may lead to uncontrolled cell proliferation and lack of apoptosis. G870A, a common single-nucleotide polymorphism in CCND1 influences breast cancer risk. However, the association between G870A polymorphism and breast cancer risk is ambiguous so far. MATERIALS AND METHODS: In this case-control study, we analyzed the role of G870A polymorphism with breast cancer risk in Indian women. A meta-analysis of 18 studies was also performed to elucidate this association by increasing statistical power. RESULTS: In our case-control study, significant risk association of the CCND1 G870A AA genotype with breast cancer in total cohort (odds ratio [OR], 2.98; 95% confidence interval [CI], 1.64-5.42; P value, 4.96e-04) and premenopausal women (OR, 3.31; 95% CI, 1.54-7.08; P value, .003) was found. The results of the meta-analysis showed that AA genotype of the CCND1 G870A polymorphism significantly increases breast cancer risk in total pooled data (AA vs GG+GA: OR = 1.20; 95% CI = 1.03 to 1.39; P value, 0.016*) and Caucasian (AA vs GG+GA: OR = 1.22; 95% CI = 0.99 to 1.51; P value, .056*) but not in Asian population. Further, a significant protective association with breast cancer was also found in the GA vs AA comparison model in pooled data (OR = 0.73; 95% CI = 0.58 to 0.92; P value, .007*) as well as in Caucasian subgroup (OR = 0.62; 95% CI = 0.49 to 0.94; P value, .022*). CONCLUSION: CCND1 G870A AA genotype was found associated with breast cancer risk. Future association studies considering the environmental impact on gene expression are required to validate/explore this association.

A trial sequential meta-analysis of TNF-α -308G>A (rs800629) gene polymorphism and susceptibility to colorectal cancer.

PURPOSE: Tumor necrosis factor-α (TNF-α), secreted by the activated macrophages, may participate in the onset and progression of colorectal cancer (CRC). The association of TNF-α -308 G>A (rs1800629) single-nucleotide polymorphism (SNP) with CRC risk has been investigated by many studies but the results are inconclusive. A trial sequential meta-analysis was performed for precise estimation of the relationship between TNF-α -308 G>A gene polymorphism with CRC risk. METHODS: Medline (PubMed), EMBASE (Excerpta-Medica) and Google Scholar were mined for relevant articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the significance of association. RESULTS: The pooled analysis indicated no risk associated with TNF-α -308 G>A SNP and overall CRC risk in five genetic comparison models, i.e. allelic (A vs. G: P = 0.524; OR = 1.074, 95% CI = 0.863-1.335), homozygous (AA vs. GG: P = 0.489; OR = 1.227, 95% CI = 0.688-2.188), heterozygous (AG vs. GG: P = 0.811; OR = 1.024, 95% CI = 0.843-1.244), dominant (AA+AG vs. GG: P = 0.630; OR = 1.055, 95% CI = 0.849-1.311) and recessive (AA vs. AG+GG: P = 0.549; OR = 1.181, 95% CI = 0.686-2.033). Subgroup analysis revealed that TNF-α -308 G>A SNP is associated with reduced risk of CRC in Asian ethnicity. The study showed no publication bias. CONCLUSIONS: No association of TNF-α -308 G>A SNP with overall CRC risk was found. This SNP is likely to be protective against CRC in Asian population when compared with Caucasian population. Larger prospective-epidemiological studies are warranted to elucidate the roles of TNF-α -308 G>A SNP in the etiology of CRC and to endorse the present findings.

Niacin deficiency modulates genes involved in cancer: Are smokers at higher risk?

The role of niacin's metabolite, nicotinamide adenine dinucleotide (NAD), in DNA repair via base-excision repair pathway is well documented. We evaluated if niacin deficiency results in genetic instability in normal human fetal lung fibroblasts (MRC-5), and further, does it leads to enhanced accumulation of cigarette smoke-induced genetic damage? MRC-5 cells were grown discretely in niacin-proficient/deficient media, and exposed to nicotine-derived nitrosamine ketone (NNK, a cigarette smoke carcinogen). Niacin deficiency abated the NAD polymerization, augmented the spontaneous induction of micronuclei (MN) and chromosomal aberrations (CA) and raised the expression of 10 genes and suppressed 12 genes involved in different biological functions. NNK exposure resulted in genetic damage as measured by the induction of MN and CA in cells grown in niacin-proficient medium, but the damage became practically marked when niacin-deficient cells were exposed to NNK. NNK exposure raised the expression of 16 genes and suppressed the expression of 56 genes in cells grown in niacin-proficient medium. NNK exposure to niacin-deficient cells raised the expression of eight genes including genes crucial in promoting cancer such as FGFR3 and DUSP1 and suppressed the expression of 33 genes, including genes crucial in preventing the onset and progression of cancer like RASSF2, JUP, and IL24, in comparison with the cells grown in niacin-proficient medium. Overall, niacin deficiency interferes with the DNA damage repair process induced by chemical carcinogens like NNK, and niacin-deficient population are at the higher risk of genetic instability caused by cigarette smoke carcinogen NNK.

In silico CD4+, CD8+ & humoral immunity associated antigenic epitope prediction and HLA distribution analysis of HTLV-I.

PURPOSE: The linkage of human T-cell leukemia virus type 1 (HTLV-1) to fatal diseases is a well known fact for many years. However, there has been no significant progress in the field of the treatment that can lead to the development of a successful vaccine. Furthermore, there are no means of assessing the risk of disease and its prognosis in the infected people. METHODS: The current study has taken the cognizance of the importance of host's immune response in reducing the risk of infectious diseases to carry out immunoinformatics driven epitope screening strategy of vaccine candidates against HTLV-1. In this study, a genetic variability and HLA distribution analysis among the documented HTLV-1 genotypes I, II, III, IV, V & VI was performed to ensure the coverage of the vast majority of population, where vaccine would be employed. The meticulous screening of effective dominant immunogens was done with the help of ABCPred and Immune Epitope Database. RESULTS: The results showed that the identified epitopes might be protective immunogens with high conservancy and potential of inducing both protective neutralizing antibodies and T-cell responses. The peptides "PSQLPPTAPPLLPHSNLDHI", "PCPNLVAYSSYHATY", and "YHATYSLYLF", were 100% conserved among different isolates from far and wide separated countries, suggesting negligible antigenic drift in HTLV-1. CONCLUSIONS: Overall, the mentioned epitopes are soluble, non-toxic suitable candidates for the development of vaccine against HTLV-1 and warrant further investigation and experimental validation.

Impact of p53 arg72pro SNP on Breast Cancer Risk in North Indian Population.

BACKGROUND: Genetic changes in p53 gene contribute to breast cancer susceptibility. OBJECTIVE AND METHODS: A case-control study and a meta-analysis were performed to investigate the role of p53 codon72 SNP with breast cancer susceptibility in Indian women. RESULTS: p53 heterozygous arginine variant was associated with decreased risk of breast cancer in total cohort. In meta-analysis, Allelic and GG vs. CC genetic comparison model were found to be associated with breast cancer risk. Moreover, recessive comparison model indicated a protective correlation with breast cancer occurrence. CONCLUSION: The findings of our case-control study and meta-analysis suggest a significant association between p53 Arg72Pro polymorphism and an increased risk of breast cancer in Indian population.

Meta-analysis reveals no correlation of caveolin-1 G14713A (G>A) gene polymorphism with increased cancer risk in Taiwanese population.

OBJECTIVES: The role of caveolin-1 (CAV1)(G>A, rs3807987) polymorphism is still dubious in cancer causation in Taiwanese population. The present study is an effort to assess the above relation for precise conclusion. METHODS: EMBASE and PubMed (MEDLINE) databases were explored for the pertinent case-control studies reporting the connection of CAV1 G14713A polymorphism to the vulnerability to cancer. A cumulative analysis using meta-analytic approach was accomplished and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for all the polymorphs. RESULTS: Overall, 2549 subjects and 3161 controls were analyzed from six selected studies. Our study showed no confirmation of noteworthy risk between CAV1 G14713A polymorphism and susceptibility to cancer in any of the polymorph, for instance, allele (A vs. G: P = 0.165; OR = 1.252, 95% CI = 0.911-1.721), homozygous (AA vs. GG: P = 0.252; OR = 1.328, 95% CI = 0.817-2.157), heterozygous (AG vs. GG: P = 0.091; OR = 1.356, 95% CI = 0.952-1.930), dominant (AA vs. GG + AG: P = 0.345; OR = 1.191, 95% CI = 0.829-1.709), and recessive (AA + AG vs. GG: P = 0.125; OR = 1.344, 95% CI = 0.921-1.961). CONCLUSIONS: We conclude that CAV1 G14713A polymorphism does not contribute as an independent predisposing risk factor for developing cancer in Taiwanese population.

Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors.

Metastatic melanoma is a least common form of cancer as it accounts only for 1% of all cancer cases. But, it is most deadly in nature and is haunting mankind for long emotionally as well as economically. The sites for the onset of the disease are pigment-producing cells of the skin, mucosa, eye etc. It has the potential to spread other sites like subcutaneous tissue, lymph nodes, lungs, liver, bone and brain. The United States Food & Drug Administration has approved various drug molecules from time to time. The molecules (Dabrafenib-BRAF inhibitor and Trametinib-MEK inhibitor) have proved their credentials alone and in combination as well. These molecules have demonstrated good results for various end points like median progression free survival, overall survival, objective response etc. The median progression free survival for patients using dabrafenib and trametinib were 5.1 and 4.8 months, respectively (administered singly). It has increased to 11.4 months in the combination treatment "dabrafenib + trametinib", which is approximately 104% and 138% greater than dabrafenib and trametinib treated groups alone. Similarly, the overall survival rate and objective response rate for the patients administered with "dabrafenib + trametinib" have been increased by 72% 64%, respectively. All these increments in these parameters were for a short period of time as the molecules were unable to withstand the pressure of resistance developed in the patients. So, the current review suggests the use of BRAF and MEK inhibitors as intermittent therapy along with heat shock protein 90 (HSP90) molecules.

Impact of LMP7 (rs2071543) gene polymorphism in increasing cancer risk: evidence from a meta-analysis and trial sequential analysis.

Genetic variant LMP7 (low molecular weight polypeptide 7) -145 C > A may influence the function of immune surveillance of an individual and lead to cancer development. Various studies have investigated the relevance of LMP7 -145 C > A gene polymorphism with cancer risk; but, their results are conflicting and inconsistent. To obtain a comprehensive conclusion, a meta-analysis was performed by including eight eligible published studies retrieved from PubMed (Medline), EMBASE and Google Scholar web search until December 2016. Individuals with AA genotype (AA vs CC: p = 0.001; OR = 2.602, 95% CI = 1.780 to 3.803) of LMP7 -145 C > A were found to have 2 folds higher risk of cancer than those with CC genotype. The recessive genetic model (AA vs AC + CC) also indicated that individuals with AA genotype have 2 folds higher cancer risk than AC and CC genotypes (p = 0.001; OR = 2.216, 95% CI = 1.525 to 3.221). Also, significant increased cancer risk was observed in Asians but not in Caucasians. No publication bias was observed during the analysis. Trial sequential analysis also strengthened our current findings. These results suggest that genetic variant LMP7-145 C > A has significant role in increasing cancer risk in overall and Asian population, and could be useful as a prognostic marker for early cancer predisposition.

Impact of TNF -308 G>A (rs1800629) gene polymorphism in modulation of leprosy risk: a reappraise meta-analysis of 14 case-control studies.

PURPOSE: Earlier studies have shown that tumor necrosis factor (TNF) -308 G>A (rs1800629) gene polymorphism is implicated in the susceptibility to leprosy, but results were inconsistent. METHODS: A meta-analysis of 14 studies involving 3327 leprosy cases and 3203 controls was performed to appraise the association of TNF -308 G>A polymorphism with leprosy using MEDLINE (PUBMED), EMBASE, and Google Scholar web databases. RESULTS: Overall, no significant association was observed in allelic (A vs. G: P=0.068; OR = 0.836, 95% CI = 0.689-1.013), homozygous (AA vs. GG: P=0.394; OR = 0.810, 95% CI = 0.499-1.315), heterozygous (GA vs. GG: P=0.059; OR = 0.780, 95% CI = 0.603-1.010), dominant (AA + GA vs. GG: P=0.067; OR = 0.797, 95% CI = 0.625-1.016), and recessive (AA vs. GG + GA: P=0.594; OR = 0.877, 95% CI = 0.542- 1.420) genetic models. Subgroup analysis showed no association in Asians. Whereas, reduced risk was found in allelic contrast (A vs. G: P=0.014; OR = 0.832, 95% CI = 0.718-0.963) and dominant models (AA + GA vs. GG: P=0.004; OR = 0.790, 95% CI = 0.673-0.928) of the mixed population. CONCLUSIONS: TNF -308 G>A polymorphism is not associated with leprosy risk in the overall population. However, subgroup analysis demonstrated protective effect of the said polymorphism in leprosy risk in the Latin American population, but showed no association in the Asians.

Pembrolizumab's non-cross resistance mechanism of action successfully overthrown ipilimumab.

The incidences of melanomas are increasing by leaps and bounds across the globe despite early detection and intervention. The numbers of patients dying from metastatic melanoma have been continually increased over the past thirty years. It has been considered as one of the most therapy-resistant malignancies due to the cross-resistant mechanism developed by the metastatic cells. With time, many new therapies came and they failed miserably. Ipilimumab, a monoclonal antibody that works to activate the immune system by targeting CTLA-4 proved to be a boon for advance melanoma very recently. But it could not stand firmly against the resistant metastatic skin cancer cells. Now, the new skin cancer drug named pembrolizumab proved as a new miraculous molecule. It's a humanized monoclonal antibody that blocks a biological pathway called programmed cell death-1 (PD-1), which melanoma cells activate to suppress the immune system. This antibody has surpassed ipilimumab at all the stages of clinical trials because of its non-cross resistant mechanism to malignant cells. The present review critically analyses the reasons of efficacy success of pembrolizumab over ipilizumab shown at various stages of clinical trials.

Differential pharmacology and clinical utility of sonidegib in advanced basal cell carcinoma.

Patients suffering from advanced basal cell carcinoma (BCC) have very limited treatment options. Sonidegib selectively inhibits the growth of Hedgehog pathway-dependent tumors and can treat locally advanced BCC patients who are not candidates for surgery or radiation therapy. The BOLT clinical trials were conducted to evaluate the efficacy/potency of sonidegib in the treatment of advanced BCC or metastatic BCC. The patients were randomized in 1:2 ratios to receive 200 or 800 mg oral sonidegib daily, stratified by disease, histological subtype and geographical region. The primary efficacy analyses showed that 18 patients in the 200 mg group and 35 patients in the 800 mg group show an objective response (Central Review Committee) that corresponds to 43% (95% confidence interval [CI]: 28-59) and 38% (95% CI: 28-48) in their respective categories. Disease control was found in 93% (39 patients) and 80% (74 patients) of the patients administered 200 and 800 mg sonidegib, respectively. The adverse events were assessed by the Central Review Committee as well as the investigator review team as per the guidelines of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The most frequently found adverse events reported in BOLT trials were muscle spasms, alopecia, dysgeusia (taste disturbance), nausea, elevated blood creatine kinase and fatigue. Comparatively, the patients administered 200 mg sonidegib showed fewer adverse events than those in the 800 mg sonidegib category. Thus, the benefit of using the 200 mg dose of sonidegib outweighs the associated risks and it can be inferred that it would be judicious to choose doses of lesser strength.

Fast and efficient detection of tuberculosis antigens using liposome encapsulated secretory proteins of Mycobacterium tuberculosis.

PURPOSE: A rapid and efficient diagnostic test was developed for the detection of Mycobacterium tuberculosis antigens in serum samples of active tuberculosis (TB) and extrapulmonary TB patients via a liposomal agglutination-based method. METHODS: A rapid card test has been developed to facilitate the recognition of high-affinity binding rabbit raised purified culture filtrate protein antibodies coupled on the surface of activated liposomal preparation. In the presence of TB antigens, the polyclonal antibodies bound to the liposomal particles demonstrate a visible agglutination reaction. RESULTS: The developed assay was simple, rapid, reliable, sensitive, and specific as a diagnostic test for the detection of antigens in serum samples of clinically confirmed cases of TB within 4-5 minutes' duration. The test was evaluated at different hospitals, medical colleges, and pathology centers, and involved 1483 participants. This investigation was conducted to detect the presence of these antigens during the period of active growth of the microorganism in serum samples for pulmonary TB and processed tissue biopsy for other extrapulmonary TB. Results obtained using this test were compared with acid-fast bacilli smear and culture results. CONCLUSION: Our study demonstrated that the newly developed liposome tuberculosis antigen card test detected antigens in our study population with approximately 97.48% sensitivity and 95.79% specificity. This is the first study to report the liposomal encapsulation of culture filtrate proteins from M. tuberculosis for diagnostic application.

Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis.

The association of interleukin-6 (IL-6)-174G > C (rs1800795) single nucleotide polymorphism (SNP) with the risk of acquiring rheumatoid arthritis (RA) is a relevant issue because of conflicting and consensus lacking reports published in literature. We investigated IL-6-174G > C promoter polymorphism in 34 RA patients, attending a tertiary care hospital in north India. We also performed a meta-analysis, of the previously published studies reporting this genetic relationship, in overall population, and independently in Asian and Caucasian ethnicities to further elucidate this association. A total of 13 studies, including the current one, involving 3291 RA cases and 3812 controls were analyzed. Out of the 13 studies, 6 were from Asian, 6 from Caucasian and 1 from a mixed population. Our case-control study showed significant association of IL-6-174G > C SNP with increased RA risk: allelic (OR = 3.750, 95% CI = 1.800-7.813, p < 0.001); dominant (OR = 2.800, 95% CI = 1.167-6.721, p = 0.021); and recessive (OR = 36.72, 95% CI = 2.004-672.7, p = 0.015). The meta-analysis revealed the increased RA risk associated with IL-6-174G > C SNP in overall population: allelic (OR = 1.650, 95% CI = 1.169-2.329, p = 0.004); homozygous (OR = 1.380, 95% CI = 0.906-2.101, p = 0.133); heterozygous (OR = 1.559, 95% CI = 1.001-2.428, p = 0.049); dominant (OR = 1.663, 95% CI = 1.078-2.567, p = 0.022); and recessive (OR = 1.366, 95% CI = 0.964-1.935, p = 0.079). Subgroup analysis also showed this polymorphism to be associated with increased RA risk in Asian population: allelic (OR = 3.724, 95% CI = 1.361-10.190, p = 0.010); dominant (OR = 3.823, 95% CI = 1.320-11.074, p = 0.013); and recessive (OR = 4.357, 95% CI = 1.634-11.623, p = 0.003), but not in Caucasian population. This meta-analysis shows that IL-6-174G > C SNP is significantly associated with increased RA risk in overall, and specifically in Asian population.

Improving Production of Tacrolimus In Streptomyces Tacrolimicus (ATCC 55098) Through Development of Novel Mutant by Dual Mutagenesis

ABSTRACT Tacrolimus is a polyketide macrolide produced by Streptomyces species which is widely used as anti-fibrotic agent and potent immunosuppressant. In this article dual mutagenesis approach using mutagens (NTG+EMS+UV) was used to develop a mutant strain of Streptomyces tacrolimicus (ATCC 55098) for higher tacrolimus production and this strain showed higher tacrolimus production at 82.5 mg/l. Interestingly; addition of L-Lysine (0.2 g/l) into the production medium further enhanced the tacrolimus production to ~102 mg/l at 7-L fed-batch bioreactor. To the best of our knowledge this is the first report mentioning efficient strain development for higher production of tacrolimus using dual mutagenesis. The obtained data presents an impressive model for higher production of tacrolimus and enhanced our understanding regarding improvement in production capacity of tacrolimus in Streptomyces tacrolimicus.

TNF-α -308 G > A (rs1800629) Polymorphism is Associated with Celiac Disease: A Meta-analysis of 11 Case-Control Studies.

Celiac disease (CD) remains one of the most significant autoimmune diseases worldwide. The pathogenesis of CD is not clearly understood and is probably attributed to genomic variations and host genetic make-up. Case-control and cohort studies of the association between the TNF-α -308 G > A (rs1800629) polymorphism and CD susceptibility have yielded inconsistent results. In this study, PubMed, EMBASE, and Google Scholar web-databases were searched for pertinent reports showing association of TNF-α -308 G > A gene with CD risk. A total of eleven reports involving 1774 controls and 1147 CD cases were included. Significant associations in four genetic models, viz. variant allele (A vs. G: p = 0.001; OR = 2.051, 95% CI = 1.452-2.895), variant homozygous (AA vs. GG: p = 0.001; OR = 6.626, 95% CI = 3.569-12.300), recessive (AA vs. GG + AG: p = 0.001; OR = 4.766, 95% CI = 3.177-7.152) and dominant (AA + AG vs. GG: p = 0.008; OR = 1.910, 95% CI = 1.181-3.088) were found in comparison with wild type homozygous GG genotype. However, heterozygous genetic model did not show any association. Sensitivity analysis revealed stable and statistically robust results. Our results suggest that TNF-α -308 G > A gene polymorphism significantly contributes to CD susceptibility.

Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies.

Vismodegib, itraconazole and sonidegib as hedgehog pathway inhibitors and their relative competencies in the treatment of basal cell carcinomas.

The advent of more sophisticated studies published has clarified the understating of the root cause of various skin cancers or basal cell carcinomas (BCCs). The remarkable role is played by the comprehensive work done on unraveling the mechanism controlling the function of hedgehog (Hh) pathway. The defective Hh pathway has been found as the major cause for BCCs as activated Hh signaling within primary cilia plays a key role in the pathogenesis of BCCs. The BCC accounts for up to 40% of all cancers in the US, with growing incidences in other countries as well. Thus, it is considered to be utmost important by the researchers all over the world developing drugs for the treatment of skin cancers targeting Hh pathway. Fewer drugs like vismodegib, itraconazole and sonidegib have shown promising results inhibiting the awry function of Hh pathway resulting in treatment of different forms of skin cancers. These drugs have shown positive results but failed to prove their potential as expected. Vismodegib and sonidegib are better but fail in case of resistant tumors. This review article describes the mechanism of actions of these Hh pathway inhibitors and provides the rationale for their effectiveness/non-effectiveness for the treatment of metastatic or locally advanced BCC.