Cutting Edge: ATP13A2 Is an Endolysosomal Regulator of TLR9/7 Activation in Human Plasmacytoid Dendritic Cells.

ATPase cation transporting 13A2 (ATP13A2) is an endolysosomal P-type ATPase known to be a polyamine transporter, explored mostly in neurons. As endolysosomal functions are also crucial in innate immune cells, we aimed to explore the potential role of ATP13A2 in the human immunocellular compartment. We found that human plasmacytoid dendritic cells (pDCs), the professional type I IFN-producing immune cells, especially have a prominent enrichment of ATP13A2 expression in endolysosomal compartments. ATP13A2 knockdown in human pDCs interferes with cytokine induction in response to TLR9/7 activation in response to bona fide ligands. ATP13A2 plays this crucial role in TLR9/7 activation in human pDCs by regulating endolysosomal pH and mitochondrial reactive oxygen generation. This (to our knowledge) hitherto unknown regulatory mechanism in pDCs involving ATP13A2 opens up a new avenue of research, given the crucial role of pDC-derived type I IFNs in protective immunity against infections as well as in the immunopathogenesis of myriad contexts of autoreactive inflammation.

Clinical Significance of Applause Sign in Patients with Progressive Supranuclear Palsy.

Applause sign (AS) is a clinical phenomenon observed in several neurological disorders including progressive supranuclear palsy (PSP). We investigated the factors associated with AS in patients with PSP. PSP patients with AS showed greater motor impairment compared to those with negative AS. Global cognition including attention and memory were affected more in patients with positive AS. We also observed that gait variability, a known marker for unstable gait is pronounced in those who presented with positive AS. Hence, the clinician might expect a more severe disease and an unstable gait in a PSP patient presenting with AS.

Histocompatibility locus antigens regions contribute to the ethnicity bias of Epstein-Barr virus-associated nasopharyngeal carcinoma in higher-incidence populations.

Nasopharyngeal carcinoma (NPC) is one the most confusing and rare malignancy in most part of the world with significantly high occurrence in some populations of Southeast Asia, North Africa and Alaska. Apart from the dietary and environmental factors, NPC is well-associated with Epstein-Barr virus (EBV) infection in these ethnic groups. However, the internal molecular mechanism(s) for such association in specific populations is not known till date. Polymorphisms in the genes of histocompatibility locus antigens (HLA) are reported in NPC, but association of any particular polymorphism with ethnicity is not established yet. Here, we report a set of HLA polymorphisms in EBV-infected NPC samples from Northeast Indian population. These polymorphisms might play an important role for the lack of proper immune function against EBV infection and thus, eventually, for NPC generation in endemic populations like those of Northeast India.

Endogenous PTEN acts as the key determinant for mTOR inhibitor sensitivity by inducing the stress-sensitized PTEN-mediated death axis in KSHV-associated malignant cells.

As a part of viral cancer evolution, KSHV-infected human endothelial cells exert a unique transcriptional program via upregulated mTORC1 signaling. This event makes them sensitive to mTOR inhibitors. Master transcriptional regulator PTEN acts as the prime regulator of mTOR and determining factor for mTOR inhibitory drug resistance and sensitivity. PTEN is post-translationally modified in KSHV-associated cell lines and infected tissues. Our current study is an attempt to understand the functional role of upstream modulator PTEN in determining the sensitivity of mTOR inhibitors against KSHV-infected cells in an in vitro stress-responsive model. Our analysis shows that, despite phosphorylation, endogenous levels of intact PTEN in different KSHV-infected cells compared to normal and non-infected cells are quite high. Genetic overexpression of intact PTEN showed functional integrity of this gene in the infected cells in terms of induction of a synchronized cell death process via cell cycle regulation and mitochondria-mediated apoptosis. PTEN overexpression enhanced the mTOR inhibitory drug activity, the silencing of which hampers the process against KSHV-infected cells. Additionally, we have shown that endogenous PTEN acts as a stress balancer molecule inside KSHV-infected cells and can induce stress-sensitized death program post mTOR inhibitor treatment, lined up in the ATM-chk2-p53 axis. Moreover, autophagic regulation was found as a major regulator in mTOR inhibitor-induced PTEN-mediated death axis from our study. The current work critically intersected the PTEN-mediated stress balancing mechanism where autophagy has been utilized as a part of the KSHV stress management system and is specifically fitted and switched toward autophagy-mediated apoptosis directing toward a therapeutic perspective.

Characterizing gait and exploring neuro-morphometry in patients with PSP-Richardson's syndrome and vascular parkinsonism.

Gait differentiation in progressive supranuclear palsy (PSP) and vascular parkinsonism (VaP) is sometimes difficult to detect with the naked eye. Here, we compared specific gait parameters, neuro-morphometric indices, and their associations between patients with PSP Richardson's syndrome (PSP-RS) and VaP. A total of 18 PSP-RS and 13 VaP patients were recruited. Spatio-temporal gait parameters (GAITRite®) and neuroanatomical morphometry (FreeSurfer pipeline) were assessed. The groups were compared using unpaired t-tests involving 10000 random permutations after statistically controlling for total UPDRS-III and H&Y scores. Statistically significant differences between the groups were decided at < 5% Benjamini-Hochberg False Discovery Rate (FDR) for multiple-comparison related corrections. Spearman's correlations were performed to assess the significant associations (p < 0.05) between the gait parameters and morphometry indices. Among all the spatio-temporal gait parameters, PSP-RS patients displayed greater stride time, step time, swing time, and stance time variabilities compared to VaP. Morphometric analyses showed that thalamus, and caudate volumes were significantly lower, but cerebellar cortex, hippocampus, amygdala, accumbens, and putamen volumes were higher in PSP-RS than VaP. Moreover, the bilateral insula was significantly thinner in VaP than in PSP-RS. Correlation analyses support the involvement of limbic structures besides cerebellum in postural control during self-paced walking of PSP-RS patients. Our findings underline the importance of examining individual brain regions to understand the association of cortical and subcortical morphometric estimates and gait variability parameters in PSP-RS and VaP. This study suggests the involvement of the limbic system in addition to the classical neural structures for motor control and gait.

Blood-based DNA methylation in advanced Nasopharyngeal Carcinoma exhibited distinct CpG methylation signature.

The TNM staging system is currently used to detect cancer stages. Regardless, a small proportion of cancer patients recur even after therapy, suggesting more specific molecular tools are required to justify the stage-specific detection and prompt cancer diagnosis. Thus, we aimed to explore the blood-based DNA methylation signature of metastatic nasopharyngeal carcinoma (NPC) to establish a holistic methylation biomarker panel. For the identification of methylation signature, the EPIC BeadChip-based array was performed. Comparative analysis for identifying unique probes, validation, and functional studies was investigated by analyzing GEO and TCGA datasets. We observed 4093 differentially methylated probes (DMPs), 1232 hydroxymethylated probes, and 25 CpG islands. Gene expression study revealed both upregulated and downregulated genes. Correlation analysis suggested a positive (with a positive r, p ≤ 0.05) and negative (with a negative r, p ≤ 0.05) association with different cancers. TFBS analysis exhibited the binding site for many TFs. Furthermore, gene enrichment analysis indicated the involvement of those identified genes in biological pathways. However, blood-based DNA methylation data uncovered a distinct DNA methylation pattern, which might have an additive role in NPC progression by altering the TFs binding. Moreover, based on tissue-specificity, a variation of correlation between methylation and gene expression was noted in different cancers.

Genetic Variations and Altered Blood mRNA Level of Circadian Genes and BDNF as Risk Factors of Post-Stroke Cognitive Impairment Among Eastern Indians.

Post-stroke cognitive impairment (PSCI) is a clinical outcome in around 30% of post-stroke survivors. BDNF is a major gene in this regard. It is regulated by circadian rhythm. The circadian genes are correlated with stroke timings at molecular level. However, studies suggesting the role of these on susceptibility to PSCI are limited. We aim here to determine: (a) genetic risk variants in circadian clock genes, BDNF and (b) dysregulation in expression level of CLOCK, BMAL1, and BDNF that may be associated with PSCI. BDNF (rs6265G/A, rs56164415C/T), CLOCK (rs1801260T/C, rs4580704G/C), and CRY2 (rs2292912C/G) genes variants were genotyped among 119 post-stroke survivors and 292 controls from Eastern part of India. In addition, we analyzed their gene expression in Peripheral blood Mononuclear cells (PBMC) from 15 PSCI cases and 12 controls. The mRNA data for BDNF was further validated by its plasma level through ELISA (n = 38). Among the studied variants, only rs4580704/CLOCK showed an overall association with PSCI (P = 0.001) and lower Bengali Mini-Mental State Examination (BMSE) score. Its 'C' allele showed a correlation with attention deficiency. The language and memory impairments showed association with rs6265/BDNF, while the 'CC' genotype of rs2292912/CRY2 negatively influenced language and executive function. A significant decrease in gene expression for CLOCK and BDNF in PBMC (influenced by specific genotypes) of PSCI patients was observed than controls. Unlike Pro-BDNF, plasma-level mBDNF was also lower in them. Our results suggest the genetic variants in CLOCK, CRY2, and BDNF as risk factors for PSCI among eastern Indians. At the same time, a lowering expression of CLOCK and BDNF genes in PSCI patients than controls describes their transcriptional dysregulation as underlying mechanism for post-stroke cognitive decline.

Effects of non-invasive vagus nerve stimulation on clinical symptoms and molecular biomarkers in Parkinson's disease.

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson's disease (PD) patients. In a subgroup of patients, we measured selected neurotrophins, inflammatory markers and markers of oxidative stress in serum. Thirty-three PD patients with freezing of gait (FOG) were randomized to either active nVNS or sham nVNS. After baseline assessments, patients were instructed to deliver six 2 min stimulations (12 min/day) of the active nVNS/sham nVNS device for 1 month at home. Patients were then re-assessed. After a one-month washout period, they were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters (speed, stance time and step length) were observed with active nVNS. While serum tumor necrosis factor- α decreased, glutathione and brain-derived neurotrophic factor levels increased significantly (p < 0.05) after active nVNS treatment. Here we present the first evidence of the efficacy and safety of nVNS in the treatment of gait in PD patients, and propose that nVNS can be used as an adjunctive therapy in the management of PD patients, especially those suffering from FOG. Clinical trial registration: identifier ISRCTN14797144.

Synthetic antioxidants from a natural source can overtake the oncogenic stress management system and activate the stress­sensitized death of KSHV­infected cancer cells.

Synthetic and modified natural derivatives are reported as potential bioactive compounds and are being used therapeutically against various diseases in a widespread manner nowadays. Cancerous cells exhibit high levels of reactive oxygen species (ROS) internally, and thus successfully manage to sustain themselves and proliferate via antioxidative mechanisms that maintain a redox balance. On this note, various antioxidants are applied as anticancer compounds, which strategically affects the ongoing oncogenic stress management system in both a pro­ and antioxidative manner, resulting in cancer restriction, as well as sustaining cell proliferation via antioxidative mechanisms that promote cancer progression. Alike non­viral cancers, viral cancers exhibit varying levels of ROS during different stages of cancer progression. Hence, successful stress balance should be addressed, depending on the cancer cell stress response during the therapeutic management. The application of antioxidants is crucial and needs to be carefully designed in such cases; the respective underlying mechanisms are less understood. The role of antioxidants controlling the varied levels of stress response at different stages of Kaposi's sarcoma­associated herpes virus malignancy have not been fully reported. Therefore, the present study aimed to analyze the activity of certain antioxidants in KSHV­infected oncogenic cells. For this purpose, two naturally derived flavonoid­based antioxidants (theaflavin and novel curcumin derivatives) were selected and tested in different KSHV­infected cell lines. The findings presented herein demonstrate that these compounds can successfully induce the death of different KSHV­positive cells and can restrict the growth of KSHV­infected cell lines restricting viral reactivation by counteracting the oncogenic stress management system.

Novel inflammasome and oxidative modulators in Parkinson's disease: A prospective study.

INTRODUCTION: The etiopathogenesis of Parkinson's disease (PD) is not clear. Yet, it seems likely that inflammation as well as oxidative stress plays a major role in the disease pathogenesis. Based on our previous findings, we aimed to investigate prospective changes in peripheral inflammasome and oxidative modulators in relation to the progression of motor symptoms and severity of PD. METHODS: Levels of inflammatory and oxidative markers in the serum of PD patients and healthy controls were estimated by quantitative ELISA and spectrophotometric methods at the baseline and at the end of one year. RESULTS: In PD patients, serum NLRP3 inflammasome and IL-1ß levels increased significantly over a year, compared to the baseline. The average enzymatic activity of serum SOD1 was also augmented at one-year follow-up. Alongside these serummarker changes, the mean motorseverity of this patient cohort worsened over the time period. CONCLUSION: This pioneering study identified a novel association of peripheral inflammatory and oxidative markers with the progression of PD. Correlation of these serum proteins with the central pathological changes in PD and disease severity in a prospective manner might be useful not only for prognostication, but for understanding disease mechanisms and for planning future therapeutic strategies.

Is peripheral alpha synuclein a marker for gait velocity in Parkinson's disease?

BACKGROUND: The extent of gait abnormality is non-uniform across motor phenotypes of Parkinson's disease (PD). The biological basis of this heterogeneity remains intriguing. Moreover, the relationship of gait impairment with various neurodegenerative protein markers in PD is not well established. OBJECTIVES: Here, we aimed to explore the interplay between gait parameters and specific serum protein markers in PD. METHODS: A total of 62 PD patients were consecutively recruited. Blood samples and gait data were acquired from 37 and 34 patients respectively. Two-dimensional spatio-temporal gait parameters were estimated using an electronic walkway (GAITRite®, CIR Systems Inc., USA). Serum phosphorylated alpha synuclein (p-Ser129-a-syn) and total a-syn levels were measured using commercially available ELISA kit. Data was analyzed using SPSS Version 20 (IBM). RESULTS: We found that phosphorylated a-syn levels were significantly higher in PD patients with postural instability and gait difficulty compared to tremor dominant variant. Significant reduction in gait velocity was also observed with increasing levels of this pathological form of a-syn. Regression modelling showed that phosphorylated a-syn is an independent predictor of gait velocity. DISCUSSION: Our findings indicate that concentrations of peripheral p-Ser129-a-syn but not total a-syn could be a potential contributor of gait impairment in PD. Further investigation on the systemic role of phosphorylated a-syn on gait would bridge the gap between central and peripheral mechanisms underlying phenotypic variability in PD.

The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia.

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well-tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients.

Lifestyle, Epstein-Barr virus infection, and other factors could impede nasopharyngeal cancer survivorship: a five-year cross-sectional study in North Eastern India.

Nasopharyngeal Carcinoma (NPC) is one of the leading cancers in India's north-eastern (NE) region affecting a section of the population each year. A proportion of the NPC cases are observed to recur even after therapy, indicating the involvement of other factors. We aimed to explore the NPC and Epstein-Barr virus (EBV) burden in the NE region and investigate the prognostic factors for the NPC patients' poor survival and recurrence. NPC patients' information was obtained from different state hospitals between 2014 and 2019. PCR and Sanger sequencing were performed to detect EBV types. Statistical analysis, including forest plot analysis, Kaplan-Mayer survival plot, Log-rank test, cox hazard regression, and Aalen's additive regression model, were performed to determine prognostic factors for the NPC patients' lower survival and recurrence. We observed an increased incidence of NPC and EBV infection in the past five years. Step-wise statistical analyses pointed out that variable such as non-professionals (B = 1.02, HR = 2.8, 95%CI = 1.5,4.9) workers (B = 0.92, HR = 2.5, 95%CI = 1.4,4.4), kitchen cum bedroom (B = 0.61, HR = 1.8, 95%CI = 1.2,2.8), mosquito repellent (B = 0.60, HR = 1.7, 95%CI = 1.1,2.7), nasal congestion (B = 0.60, HR = 1.8, 95%CI = 1.2,2.8), lower haemoglobin level (B = 0.92, HR = 2.5, 95%CI = 1.3,4.9), tumor stage IV (B = 2.8, HR = 1.8, 95%CI = 1.6,14.3), N2 (B = 1.4, HR = 4.0, 95%CI = 1.8,9.1), N3 (B = 1.9, HR = 6.4, 95%CI = 2.8,15.3), and M+ (B = 2.02, HR = 7.5, 95%CI = 4.1,13.7) revealed significant correlation with NPC patients' poor prognosis (p < 0.05). The presence of viral factors also showed a significant association with NPC patients' decreased survival. We concluded that factors related to day-to-day life with EBV infection could be the individual predictor for NPC incidence, lower survival, and disease recurrence. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-022-00789-5.

Do peripheral immune and neurotrophic markers correlate with motor severity of Parkinson's disease?

BACKGROUND: Inflammation along with oxidative stress alters neuroplasticity which might contribute to neurodegeneration in Parkinson's disease (PD). OBJECTIVES: We aimed to explore the correlation of inflammatory-oxidative and neurotrophic changes in PD and their association with clinical staging and motor severity. METHODS: Serum oxidative markers, pro and anti-inflammatory cytokines and BDNF levels were estimated by spectrophotometric and ELISA techniques. RESULTS: Redox-Inflammatory and neurotrophic markers significantly altered in PD and strongly correlated with motor severity and stagings of PD. CONCLUSION: This study establishes a link between peripheral immune-neurotrophic markers and disease severity in PD. This can lead to novel future therapeutics.

A longitudinal quantitative analysis of gait in patients with SCA-12.

INTRODUCTION: Spinocerebellar ataxia type 12 (SCA 12) is characterized by late onset tremor, ataxia and pyramidal signs. Parkinsonism and cognitive decline may appear with time. It is considered as slowly progressive but temporal evolution of symptoms has not been reported. METHOD: We report the evolution of symptoms in three SCA12 patients followed over a range of 5-6 years. We focused on the evolution of gait abnormality as it becomes the most disabling symptom as disease advances. Two-dimensional gait parameters were studied using an electronic walkway at various time points to measure objective changes in gait. RESULT: All patients presented with tremor in the upper extremity at baseline which progressed non-uniformly over the years. Progression of gait variability measures of step length, stance time and step time were also observed. CONCLUSION: Gait characteristics such as variability may precede clinical gait abnormality and could serve as a sensitive marker for disease progression for better therapeutic intervention in disease management. Future studies with larger sample size should be undertaken to conclusively validate this observation.

Dance movement therapy in rehabilitation of Parkinson's disease - A feasibility study.

INTRODUCTION: Environmental enrichment during physical exercise was found beneficial in neurological disorders. Application of dance in a structured way could effectively enhance the environment of physical rehabilitation. Therefore, dance therapy can be an alternative exercise program with potential benefit in affect, cognition and social integration in various neurological disorders. OBJECTIVE: This pre-post experimental study without control was designed to assess the impact of dance movement therapy on cognition, quality of life and motor symptoms in PD patients. METHODS: A group of 10 mild-moderate PD patients from Movement Disorders Clinic; I-NK, participated in group sessions for a period of 2 months (twice a week). Each session involved verbal communication followed by warming up movements and concluded with target oriented physical activities, focused on physical symptoms, emotional and cognitive aspects. All the patients were assessed before and after the intervention using Unified Parkinson's Disease Rating Scale part III (UPDRS part III), Hoehn and Yahr Scale (H and Y), Parkinson's Disease Questionnaire 39 (PDQ-39) and Montreal Cognitive Assessment (MOCA). RESULTS: We observed a change in median MOCA score from 19.00 to 22.00 (p .027). PDQ 39 also showed change in median score from 59.50 to 30.00 (p .027). The change in UPDRS III (0.08) and H and Y (0.157) failed to reach significant limit. CONCLUSION: Dance Movement Therapy was found beneficial in overall cognition and quality of life in patients with mild-moderate PD. Studies with larger sample size will assess the long-term safety and effectiveness of this alternative therapy in future.

Semantic Fluency Predicts Gait Velocity in PSP.

Context: Progressive supranuclear palsy (PSP) is a large-scale network disease resulting in variable signs and symptoms including gait impairment and higher order cognitive dysfunction. Despite few studies showing the association of falls and cognitive dysfunction, the existing literature is yet to establish the exact relationship of discrete characteristics of gait with cognitive function in PSP. Aims: In this cross-sectional study, we aimed to characterize and explore the relationship of these two apparently distinct physiological phenomena in patients with PSP and across its different variants. Methods and Material: Quantitative assessment of two-dimensional gait parameters was measured using an electronic walkway (GAITRite®). Dementia Rating Scale-2 was used to assess global as well as higher order cognitive functions. Statistical Analysis Used: A regression model was used to interpret results. Results: We observed that the variability domain of gait was significantly impaired in PSP patients with severe cognitive impairment compared to that of intact cognition. Moreover, initiation/perseveration (I/P), a higher order cognitive process, and one of its specific components, i.e., complex verbal task (ß = 2.39, P < 0.001), significantly predict gait velocity in PSP [F (1, 40) = 16.102, P < 0.001]. Conclusions: Our findings indicate that the severity of cognitive functions affects gait variability, which might lead to frequent falls as observed in PSP. Furthermore, semantic fluency task of I/P function may act as a predictor of gait velocity. We suspect that higher order cognitive dysfunction through the damage of frontal lobe structure including dorsolateral prefrontal cortex or related network may influence gait in PSP.

Non-invasive vagus nerve stimulation improves clinical and molecular biomarkers of Parkinson's disease in patients with freezing of gait.

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled crossover trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson's disease (PD) patients. In a subgroup of patients, we measured selected neurotrophin levels and markers of inflammation and oxidative stress in serum, before and after the experimental intervention. Thirty-three PD patients with associated freezing of gait were randomised to either nVNS or sham. After baseline assessments, patients were instructed to deliver 6 two-minute stimulations (total 12 min/day) of the nVNS/sham device (electroCore, Inc. USA) for one month at home. Patients were then re-assessed. After a washout period of one month, the same patients were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters were observed with nVNS, including walking speed, stance time and step length, compared to sham. Similarly, overall motor function (MDS-UPDRS III) also improved significantly following nVNS stimulation. Serum Tumor Necrosis Factor (TNF)-α and glutathione levels decreased and brain-derived neurotrophic factor (BDNF) levels increased significantly (p < 0.05) after treatment with nVNS. Here we present the first double-blind sham-controlled trial evidence of the efficacy and safety of nVNS in the treatment of gait and motor function in patients with PD.

BAX -248 G>A and BCL2 -938 C>A Variant Lowers the Survival in Patients with Nasopharyngeal Carcinoma and Could be Associated with Tissue-Specific Malignancies: A Multi-Method Approach.

BACKGROUND: The association of BAX -248 G>A and BCL2 -938 C>A with different cancers created conflicts.  We studied the correlation and the effect of these polymorphisms in patients with Nasopharyngeal Carcinoma (NPC).  Methods: PCR-RFLP and Sanger sequencing were used to detect polymorphisms. Statistical analysis including forest plot and Kaplan-Meier Log-rank test was conducted to investigate the association and effect of these SNPs on the NPC patients' survival. The computational study was performed to investigate the possible regulatory role between these polymorphisms and the poor survival of NPC patients. Meta-analysis was executed to check the tissue-specific association of these polymorphisms in the context of global cancer prognosis. RESULTS: We observed an increased and significant association of BAX -248 G>A [GA:OR=5.29, 95%CI=1.67,16.67, P=0.004; GA+AA:OR=5.71, 95%CI=1.82,17.90, P =0.002; A:OR=5.33, 95%CI=1.76,16.13, P=0.003], and BCL2 -938 C>A [CA:OR=2.26, 95%CI=1.03,4.96, P=0.04; AA:OR=3.56, 95%CI=0.97,13.05, P=0.05; CA+AA:OR=3.10, 95%CI=1.51,6.35, P=0.002; A:OR=2.90, 95% CI=1.59,5.29, P=0.0005] with the risk of NPC. Also, these SNPs were strongly correlated with poor survival in NPC patients (lower estimated survival mean, lower estimated proportion surviving at 5 years with p <0.05). The computational study showed that these SNPs altered the binding affinity of transcription factors HIF1, SP1, PAX3, PAX9 and CREB towards promoter (Lower p indicates strong affinity). The meta-analysis revealed the tissue-specific association of these polymorphisms. BAX -248 G>A showed a significant correlation with carcinomas [A vs G:OR=1.60, 95%CI=1.09,2.34, P=0.01; AA vs GG:OR=2.61, 95%CI=1.68,4.06, p <0.001; AA+GA vs GG:OR=1.53,95%CI=1.04,2.25, P=0.02); AA vs GG+GA:OR=2.53, 95%CI=1.65,3.87, p <0.001], and BCL2 -938 C>A with other malignancies [A vs C:OR=1.45, 95%CI=1.26,1.66, p <0.001; AA vs CC:OR=2.07, 95%CI: 1.15,3.72, P=0.01; AA+CA vs CC:OR=1.42, 95%CI=1.18,1.72, p <0.001; AA vs CC+CA:OR=1.89, 95%CI=1.02,3.50, P=0.04]. CONCLUSIONS: BAX -248 G>A and BCL2 -938 C>A was associated with poor survival in NPC patients. It may increase cancer susceptibility through transcriptional regulation. Moreover, these SNPs' effects could be tissue-specific.
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Kaposi's sarcoma-associated herpesvirus related malignancy in India, a rare but emerging member to be considered.

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with viral malignancy, related to HIV-AIDS. With a wide geographical discrimination in its occurrence, Asian countries shows low to moderate prevalence with higher occurrence in some particular areas. India is one of the largest countries in Asia, having various geographical and cultural variations where KSHV has been considered as an unthinkable entity to cause any of its associated disease. India has been reported as a low prevalent zone for KSHV malignancy till date. Also there are no reports so far, describing the occurrence pattern of this malignancy. So this review approaches towards figuring out the tendency of prevalence pattern of this malignancy and associated risk factors found to be present in Indian population. From this study it is revealed that, KSHV related malignancy is a relatively newly reported and emerging disease in India and may exist in hidden pockets throughout India in association with tuberculosis. India shows prevalence in HIV-associated Kaposi's sarcoma in regions where socially discriminated LGBT (lesbian, gay, bisexual, and transgender) groups, unprotected sexual behavior and heterosexuality are the important risk factors for sexually transmitted viral diseases. Anti-retro viral therapy is not sufficient to combat the virus and may act adversely. On a note regarding the clinical representations of Kaposi's sarcoma, oral, mucosal, pleural and abdominal involvements are observed in worst cases and these can be considered as the main manifesting criteria for this malignancy among Indians.