Short-term, nonsurgical periodontal therapy boosts interleukin-12 levels and reduces oral cancer risk.

BACKGROUND: Cytokines, including interleukin-12 (IL-12), are proteins that regulate cell survival, proliferation, differentiation, and function. IL-12 is a heterodimeric proinflammatory cytokine. It possesses tumoricidal properties and promotes M1 macrophage polarization and IFN-γ production by T helper (Th1) cells, which in turn stimulates the antitumor cytotoxic cluster of eight positive (CD8+) and natural killer cells, therefore activating an effector immune response against tumor cells. MATERIALS AND METHODS: Herein, the IL-2 levels of 60 patients with generalized chronic periodontitis (GCP) were assessed. Plaque index, gingival index, pocket probing depth, bleeding on probing percentage (BOP %), and clinical attachment loss were the clinical indicators reported. RESULTS: Patients with GCP in the pretreatment group had substantially lower mean IL-12 levels than those in the post-treatment group. Short-term, nonsurgical treatment (NST) considerably improved periodontal indices and increased IL-12 levels, thereby reducing oral cancer risk. CONCLUSION: NST is a cost-effective and accessible cancer prevention procedure for general dentists.

HDAC inhibition by Nigella sativa L. sprouts extract in hepatocellular carcinoma: an approach to study anti-cancer potential.

A wide variety of natural products have been widely used in chemoprevention therapy because they have antioxidant, anti-inflammatory, and anticancer activity. In the present study, we shed light on the 5th day germinated sprouts of N. sativa seeds and evaluated them against HDAC inhibition and antioxidant activity. The extract from the seed and sprout was extracted and characterised by LC-MS/MS, FTIR, and NMR to reveal its chemical composition, especially thymol (THY) and thymoquinone (TQ). Hepatocellular carcinoma (HCC) is a global health concern as it is a major lifestyle disease. Hence, incorporating herbal-based therapeutic compounds into everyday routines has become an attractive alternative for preventing hepatic diseases. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy for managing various carcinomas including HCC. Therefore, the 5th day of N. sativa can be used as a potential anticancer agent by inhibiting HDAC activity, as it is reported to have an important role in the management of oxidative stress. The bioactive compound of N. sativa, i.e. thymoquinone, also showed a good binding affinity with the HDAC protein (3MAX) with a stable interaction in an in silico study as compared to the standard drug (Trichostatin A) and thymol.Communicated by Ramaswamy H. Sarma.

Exploring the tumor immune microenvironment in ovarian cancer: a way-out to the therapeutic roadmap.

INTRODUCTION: Despite cancer treatment strides, mortality due to ovarian cancer remains high globally. While immunotherapy has proven effective in treating cancers with low cure rates, it has limitations. Growing evidence suggests that both tumoral and non-tumoral components of the tumor immune microenvironment (TIME) play a significant role in cancer growth. Therefore, developing novel and focused therapy for ovarian cancer is critical. Studies indicate that TIME is involved in developing ovarian cancer, particularly genome-, transcriptome-, and proteome-wide studies. As a result, TIME may present a prospective therapeutic target for ovarian cancer patients. AREAS COVERED: We examined several TIME-targeting medicines and the connection between TIME and ovarian cancer. The key protagonists and events in the TIME and therapeutic strategies that explicitly target these events in ovarian cancer are discussed. EXPERT OPINION: We highlighted various targeted therapies against TIME in ovarian cancer, including anti-angiogenesis therapies and immune checkpoint inhibitors. While these therapies are in their infancy, they have shown promise in controlling ovarian cancer progression. The use of 'omics' technology is helping in better understanding of TIME in ovarian cancer and potentially identifying new therapeutic targets. TIME-targeted strategies could account for an additional treatment strategy when treating ovarian cancer.

Natural and synthetic drugs and formulations for intravaginal HPV clearance.

BACKGROUND: Except for a few preventative Human Papillomavirus (HPV) vaccines, there is currently no cure for HPV infection. There are a number of cutting-edge strategies and potent medications or herbal formulations that can be applied topically for early clearance of HPV infection before HPV DNA gets integrated into host cell genome. This is facilitated due to cervical cancer having distinct and well-recognized long precancerous stages. OBJECTIVES: This review aims to outline every possible medication and formulation, both natural and synthetic, that can be applied topically as intravaginal application to help remove HPV infection at an early precancerous stage. RESULTS: Several anti-HPV/HPV clearance compounds and formulations for high-grade lesions are undergoing clinical trials. However, the majority of compounds are still in the early stages of development and require additional research to become viable HPV clearance candidates. Synthetic drugs may be more promising because they may have a more targeted effect; however, they may also have significant adverse effects. On the other hand, natural medications are safer to use. They are less specific, but have minimal to no adverse effects. CONCLUSIONS: This article may serve as a valuable resource of information for managing and preventing precancerous carcinogenic HPV infections. Research could be directed toward developing candidate drugs to make evidence-based decisions about advancing them to clinical trials and, eventually, to the market for potential use in the prevention and control of cervical cancer, which is almost always preventable or even curable if detected early.

Targeted Inhibition of Hsp90 in Combination with Metformin Modulates Programmed Cell Death Pathways in A549 Lung Cancer Cells.

The pathophysiology of lung cancer is dependent on the dysregulation in the apoptotic and autophagic pathways. The intricate link between apoptosis and autophagy through shared signaling pathways complicates our understanding of how lung cancer pathophysiology is regulated. As drug resistance is the primary reason behind treatment failure, it is crucial to understand how cancer cells may respond to different therapies and integrate crosstalk between apoptosis and autophagy in response to them, leading to cell death or survival. Thus, in this study, we have tried to evaluate the crosstalk between autophagy and apoptosis in A549 lung cancer cell line that could be modulated by employing a combination therapy of metformin (6 mM), an anti-diabetic drug, with gedunin (12 µM), an Hsp90 inhibitor, to provide insights into the development of new cancer therapeutics. Our results demonstrated that metformin and gedunin were cytotoxic to A549 lung cancer cells. Combination of metformin and gedunin generated ROS and promoted MMP loss and DNA damage. The combination further increased the expression of AMPKα1 and promoted the nuclear localization of AMPKα1/α2. The expression of Hsp90 was downregulated, further decreasing the expression of its clients, EGFR, PIK3CA, AKT1, and AKT3. Inhibition of the EGFR/PI3K/AKT pathway upregulated TP53 and inhibited autophagy. The combination was promoting nuclear localization of p53; however, some cytoplasmic signals were also detected. Further increase in the expression of caspase 9 and caspase 3 was observed. Thus, we concluded that the combination of metformin and gedunin upregulates apoptosis by inhibiting the EGFR/PI3K/AKT pathway and autophagy in A549 lung cancer cells.

Computational modeling of cyanobacterial phytoconstituents against toll-like receptors of skin cancer.

Melanoma is an extremely dangerous disease. The diagnosis and treatment of it may be difficult because of its diversity and complexity. More than 90% of the marine biomass (microflora and microalgae) constitutes the natural biodiversity reserves. TLR-related research developments indicate possible cancer therapeutic possibilities. In addition to its significant function in innate immunity, TLR activation is connected to the start of pyroptosis, apoptosis, or autophagy in malignance cells. For these reasons, TLR agonists are appealing candidates for the production of cancer medications. From the web databases, the ternary structures of the receptors (TLR3 and TLR4) and ligands are extracted. Sixty-nine compounds were subjected to a drug likeness filter, but only twenty-two were screened further for evaluating ADMET criteria, in which only seven compounds satisfied the pharmacological properties. These compounds are further analyzed for docking parameters against TLRs (TLR3 and TLR4) and molecular simulation investigation of the best cluster to evaluate the complex stability. Molecular docking methodology discovered that Scytonmein has a significant binding potential energy of -5.21 and -7.92 kcal/mol against TLR3 and TLR4, respectively, in comparison to the redock co-crystal structure (-3.98 and -4.30 kcal/mol, respectively). The simulation analysis demonstrates the significant stability of the Scytonemin and TLR4 complexes in terms of average RMSD and RMSF compared to the redock complex, while criteria like solvent-accessible surface area (SASA), gyration (Rg) and hydrogen bonding have further supported the significant interaction and stability of the conformations.Communicated by Ramaswamy H. Sarma.

Human Growth Hormone Fragment 176-191 Peptide Enhances the Toxicity of Doxorubicin-Loaded Chitosan Nanoparticles Against MCF-7 Breast Cancer Cells.

Introduction: Numerous drugs with potent toxicity against cancer cells are available for treating malignancies, but therapeutic efficacies are limited due to their inefficient tumor targeting and deleterious effects on non-cancerous tissue. Therefore, two improvements are mandatory for improved chemotherapy 1) novel delivery techniques that can target cancer cells to deliver anticancer drugs and 2) methods to specifically enhance drug efficacy within tumors. The loading of inert drug carriers with anticancer agents and peptides which are able to bind (target) tumor-related proteins to enhance tumor drug accumulation and local cytotoxicity is a most promising approach. Objective: To evaluate the anticancer efficacy of Chitosan nanoparticles loaded with human growth hormone hGH fragment 176-191 peptide plus the clinical chemotherapeutic doxorubicin in comparison with Chitosan loaded with doxorubicin alone. Methods: Two sets of in silico experiments were performed using molecular docking simulations to determine the influence of hGH fragment 176-191 peptide on the anticancer efficacy of doxorubicin 1) the binding affinities of hGH fragment 176-191 peptide to the breast cancer receptors, 2) the effects of hGH fragment 176-191 peptide binding on doxorubicin binding to these same receptors. Further, the influence of hGH fragment 176-191 peptide on the anticancer efficacy of doxorubicin was validated using viability assay in Human MCF-7 breast cancer cells. Results: In silico analysis suggested that addition of the hGH fragment to doxorubicin-loaded Chitosan nanoparticles can enhance doxorubicin binding to multiple breast cancer protein targets, while photon correlation spectroscopy revealed that the synthesized dual-loaded Chitosan nanoparticles possess clinically favorable particle size, polydispersity index, as well as zeta potential. Conclusion: These dual-loaded Chitosan nanoparticles demonstrated greater anti-proliferative activity against a breast cancer cell line (MCF-7) than doxorubicin-loaded Chitosan. This dual-loading strategy may enhance the anticancer potency of doxorubicin and reduce the clinical side effects associated with non-target tissue exposure.

Association between Angiotensin-Converting Enzyme- Insertion/Deletion Polymorphism and Diabetes Mellitus-2 in Saudi Population.

OBJECTIVES: The association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the development of type 2 diabetes mellitus (T2DM) has been debated vigorously but still remains controversial. Therefore, the current study was designed to determine the possible association between ACE I/D polymorphism and T2DM and hypertension (HTN) in a population of Saudi Arabian participants. METHODS: A total of 143 individuals were recruited for the study, consisting of 74 controls and 69 patients with T2DM. Genotyping was performed via polymerase chain reaction. RESULTS: The genotype frequencies for DD, ID and II in controls were 52.7%, 39.2% and 8.1%, whereas in T2D patients it was 52.2%, 40.6% and 7.2% respectively. The DD frequency was highest out of the three genotypes in both the controls and the T2DM patients. CONCLUSION: There was no significant difference found in the genotype and allele frequencies between cases and controls, suggesting that insertion/deletion polymorphism in the ACE gene may not be associated with an increased susceptibility to type 2 diabetes in our study population.

Tobacco Smoke Carcinogens Induce DNA Repair Machinery Function Loss: Protection by Carbon Nanotubes.

PURPOSE: DNA damage is a continuous process occurring within the cells caused by intrinsic and extrinsic factors, but it gets repaired regularly. If the DNA repair process is faulty, the incidences of damages/mutations can accumulate in cells resulting in cell transformation. It is hypothesized that the negative variations in DNA repair pathways in even at one point viz. genetic, translational or posttranslational stage may fairly be crucial for the beginning and development of carcinogenesis. Therefore, we investigated the potential of tobacco specific nitrosamines (TSNs) related carcinogens to interact with the enzymes involved in DNA repair mechanisms in the current study. METHODS: The derivatives of cigarettes' smoke like NNK and NNAL are very well known and recognized carcinogens. Therefore, almost 120 enzymes playing crucial role in the DNA repair process have been analysed for their reactivity with NNK and NNAL. RESULTS: The molecular docking study helped to screen out,  07 possible DNA repair enzyme targets for NNK, and 12for NNAL. Present study revealed the loss of activity of DNA repair enzymes in the presence of NNK and NNAL, and this accumulation may induce the tendency of DNA damage which can lead the transformation of exposed normal cells in to cancerous cells. This study also demonstrated the protective potential of nanoparticles like SWCNTs/MWCNTs against TSN's induced toxicity; here SWCNT against NNK (-17.16 Kcal/Mol) and MWCNT against NNK -17.01 Kcal/Mol were showing maximum binding affinities than the known biomolecular target of NNK 1UGH (Uracil-DNA glycosylase,-7.82Kcal/Mol). CONCLUSION: CNTs can be applied as chemo-preventive agents against environmental and tobacco induced carcinogens owing to their scavenging potential and warrants for in vivo and in vitro experimental validation of the results obtained from the present study.
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Investigation of Precise Molecular Mechanistic Action of Tobacco-Associated Carcinogen `NNK´ Induced Carcinogenesis: A System Biology Approach.

Cancer is the second deadliest disease listed by the WHO. One of the major causes of cancer disease is tobacco and consumption possibly due to its main component, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A plethora of studies have been conducted in the past aiming to decipher the association of NNK with other diseases. However, it is strongly linked with cancer development. Despite these studies, a clear molecular mechanism and the impact of NNK on various system-level networks is not known. In the present study, system biology tools were employed to understand the key regulatory mechanisms and the perturbations that will happen in the cellular processes due to NNK. To investigate the system level influence of the carcinogen, NNK rewired protein-protein interaction network (PPIN) was generated from 544 reported proteins drawn out from 1317 articles retrieved from PubMed. The noise was removed from PPIN by the method of modulation. Gene ontology (GO) enrichment was performed on the seed proteins extracted from various modules to find the most affected pathways by the genes/proteins. For the modulation, Molecular COmplex DEtection (MCODE) was used to generate 19 modules containing 115 seed proteins. Further, scrutiny of the targeted biomolecules was done by the graph theory and molecular docking. GO enrichment analysis revealed that mostly cell cycle regulatory proteins were affected by NNK.

Computational Outlook of Marine Compounds as Anti-Cancer Representatives Targeting BCL-2 and Survivin.

INTRODUCTION: The regulation of apoptosis via compounds originated from marine organisms signifies a new wave in the field of drug discovery. Marine organisms produce potent compounds as they hold the phenomenal diversity in chemical structures. The main focus of drug development is anticancer therapy. METHODS: Expertise on manifold activities of compounds helps in the discovery of their derivatives for preclinical and clinical experiment that promotes improved activity of compounds for cancer patients. RESULTS: These marine derived compounds stimulate apoptosis in cancer cells by targeting Bcl-2 and Survivin, highlighting the fact that instantaneous targeting of these proteins by novel derivatives results in efficacious and selective killing of cancer cells. CONCLUSION: Our study reports the identification of Aplysin and Haterumaimide J as Bcl-2 inhibitors and Cortistatin A as an inhibitor of survivin protein, from a sequential virtual screening approach.

Molecular Mechanism of Cancer Susceptibility Associated with Fok1 Single Nucleotide Polymorphism of VDR in Relation to Breast Cancer

Breast cancer is the leading cause of death among women worldwide. It is a multi-factorial disease caused by genetic and environmental factors. Vitamin D has been hypothesized to lower the risk of breast cancer via the nuclear vitamin D receptor (VDR). Genetic variants of these vitamin D metabolizing genes may alter the bioavailability of vitamin D, and hence modulate the risk of breast cancer. Materials and Methods: The distribution of Fok1 VDR gene (rs2228570) polymorphism and its association with breast cancer was analysed in a case­control study based on 125 breast cancer patients and 125 healthy females from North Indian population, using PCR-RFLP. An In silico exploration of the probable mechanism of increased risk of breast cancer was performed to investigate the role of single nucleotide polymorphisms (SNPs) in cancer susceptibility. Results: The Fok1 ff genotype was significantly associated with an increased risk of breast cancer (p=0.001; χ2=13.09; OR=16.909; %95 CI=2.20 - 130.11). In silico analysis indicated that SNPs may lead to a loss in affinity of VDR to calcitriol, and may also cause the impairment of normal interaction of liganded VDR with its heterodimeric partner, the retinoid X receptor (RXR), at protein level, thereby affecting target gene transcription. Conclusion: Breast cancer risk and pathogenesis in females can be influenced by SNPs. SNPs in VDR may cause alterations in the major molecular actions of VDR, namely ligand binding, heterodimerization and transactivation. VDRE binding and co-activator recruitment by VDR appear to be functionally inseparable events that affect vitamin D-elicited gene transcription. This indicates that breast cancer risk and pathogenesis in females may be influenced by SNPs.

Diagnostic Value of Circulating Free DNA Integrity and Global Methylation Status in Gall Bladder Carcinoma.

The current study investigates the role of circulating free DNA (cfDNA) as a liquid biopsy in diagnosis gall bladder carcinoma (GBC) utilizing levels of long DNA fragments (ALU247) derived from tumor necrosis, short apoptotic fragments (ALU115) denoting total cfDNA and cfDNA integrity denoting ratio of ALU247 and ALU115. The global methylation status of cfDNA was also estimated with the hypothesis that these parameters provide a diagnostic distinction between cancer and non-cancer subjects, with higher or altered values favoring presence of malignancy. Study group included 60 cases of GBC and 36 controls including diseased controls (cholecystitis) and healthy subjects. Median levels of ALU115, ALU247 and cfDNA integrity were significantly different in GBC at 1790.88, 673.75, 0.4718 vs. controls at 840.73, 165.03, 0.1989 ng/ml respectively. Global DNA methylation was not significantly different between GBC at 0.679% and controls at 0.695%. The sensitivity and specificity of ALU 247 in discriminating GBC from controls was highest with a sensitivity, specificity and diagnostic accuracy of 80.0%, 86.1% and 82.2% respectively. Global DNA methylation showed lowest sensitivity of 55.0% and specificity of 50.0%. Clinico-pathological parameters showing significant association with cfDNA integrity, on ROC curve analysis, showed significant diagnostic discrimination of the tumor stage, lymphovascular invasion, disease stage and grade histology. This is a first time analysis of ALU115, ALU247 and cfDNA integrity in the diagnosis of GBC and confirms that the combination of ALU247 and cfDNA integrity provides good sensitivity, specificity and diagnostic accuracy in discriminating GBC from controls as well correlates with aggressive disease parameters.

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.

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.

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.

Decoding the antineoplastic efficacy of Aplysin targeting Bcl-2: A de novo perspective.

The B-cell lymphoma-2 (Bcl-2) family proteins have been attributed to be the key regulators in programmed cell death and apoptosis with a prominent role in human cancer. Understanding the fundamental principles of cell survival and death have been the main cornerstone in cancer drug discovery for identification of novel anticancer agents. In this context the Bcl-2 family of anti-and pro-apoptotic proteins provide an excellent opportunity for development of anticancer agents, as blocking the Bcl-2 or Bcl-XL functionally promotes apoptosis in tumor cells and also sensitize them to chemo- and radiotherapies. The present study reports the identification of novel Aplysin analogs as BCL-2 inhibitors from a sequential virtual screening approach using drug-like, ADMET, docking, pharmacophore filters and molecular dynamics simulation. We identified promising Aplysin analogs that have a potential to be Bcl-2 inhibitors just like the standard drug Obatoclax. One of the compound analog 11 was identified to be a promising inhibitor of Bcl-2 in the docking, pharmacophore and simulation based models.The molecular modeling information provided here can be vital in designing of the novel Bcl-2 inhibitors.

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.