Impact of combinatorial immunotherapies in breast cancer: a systematic review and meta-analysis.

Background: Breast cancer has the highest mortality rate among all cancers affecting females worldwide. Several new effective therapeutic strategies are being developed to minimize the number of breast cancer-related deaths and improve the quality of life of breast cancer patients. However, resistance to conventional therapies in breast cancer patients remains a challenge which could be due to several reasons, including changes in the tumor microenvironment. Attention is being diverted towards minimizing the resistance, toxicity, and improving the affordability of therapeutics for better breast cancer management. This includes personalized medicine, target-specific drug delivery systems, combinational therapies and artificial intelligence based screening and disease prediction. Nowadays, researchers and clinicians are also exploring the use of combinatorial immunotherapies in breast cancer patients, which have shown encouraging results in terms of improved survival outcomes. This study attempts to analyze the role of combinational immunotherapies in breast cancer patients, and offer insights into their effectiveness in breast cancer management. Methodology: We conducted a systematic review and meta-analysis for which we selected the randomized clinical trials (RCTs) focused on completed Phase I/II/III/IV clinical trials investigating combination immunotherapies for breast cancer. The analysis aimed to assess the efficacy of combination therapies in comparison to mono-therapies, focusing on overall survival (OS), and progression-free survival (PFS). Results: We observed that, combination immunotherapies significantly (P<0.05) improved OS as compared to single-drug therapies in the Phase I with overall Risk ratio (RR) of 16.17 (CI 2.23,117.50), Phase II with an overall RR of 19.19 (CI 11.76,31.30) and for phase III overall RR 22.27 (CI 13.60,36.37). In the case of PFS, it was significant with RR: 12.35 (CI 2.14, 71.26) in Phase I RR 6.10 (CI 4.31, 8.64) in phase II, RR 8.95 (CI 6.09, 13.16) in phase III and RR 14.82 (CI 6.49, 33.82) in Phase IV of clinical trials. Conclusion: The observed improvements in overall survival and progression-free survival suggest that combination immunotherapies could serve as a better approach to breast cancer management.

Molecular biomarkers involved in the progression of gallbladder inflammatory lesions to invasive cancer: A proteomic approach.

The progression of gallbladder inflammatory lesions to invasive cancer remains poorly understood, necessitating research on biomarkers involved in this transition. This study aims to identify and validate proteins associated with this progression, offering insights into potential diagnostic biomarkers for gallbladder cancer (GBC). Label-free liquid chromatography assisted tandem mass spectrometry (LC-MS/MS) proteomics was performed on samples from 10 cases each of GBC and inflammatory lesions, with technical duplicates. Validation was conducted through the enzyme-linked immunosorbent assay (ELISA) using 80 samples (40 GBC and 40 inflammatory lesions). Bioinformatics tools analyzed protein-protein interaction (PPI) networks and pathways. Statistical correlations with clinicopathological variables were assessed. Prognostic evaluation utilized Kaplan-Meier survival analysis and Cox regression analyses. mRNA expressions were studied using real time-polymerase chain reaction (RT-PCR). Out of 5,714 proteins analyzed, 621 were differentially expressed. Three upregulated (the S100 calcium-binding protein P [S100P], polymeric immunoglobulin receptor [PIGR], and complement C1q-binding protein [C1QBP]) and two downregulated (transgelin [TAGLN] and calponin 1 [CNN1]) proteins showed significant expression. Pathway analysis implicated involvement of proteoglycans in cancer and glycosaminoglycan metabolism. Significant correlations were observed between protein concentrations and clinicopathological variables. Prognostic factors such as tumor size, lymph node metastasis, and preoperative bilirubin levels were associated with overall survival. Protein-based assays demonstrated higher resolution compared to mRNA analysis, suggesting their utility in GBC risk stratification. S100P, PIGR, C1QBP, TAGLN, and CNN1 emerge as potential protein-based biomarkers involved in the progression from gallbladder inflammatory lesions to invasive cancer. These findings hold promise for improved diagnostic and prognostic strategies in GBC management.

Somatic mutational landscape across Indian breast cancer cases by whole exome sequencing.

Breast cancer (BC) has emerged as the most common malignancy among females. The genomic profile of BC is diverse in nature and complex due to heterogeneity among various geographically different ethnic groups. The primary objective of this study was to carry out a comprehensive mutational analysis of Indian BC cases by performing whole exome sequencing. The cohort included patients with a median age of 48 years. TTN, TP53, MUC16, SYNE1, and OBSCN were the frequently altered genes found in our cohort. The PIK3CA and KLC3 genes are driver genes implicated in various cellular functions and cargo transportation through microtubules, respectively. Except for CCDC168 and PIK3CA, several gene pairings were found to be significantly linked with co-occurrence. Irrespective of their hormonal receptor status, RTK/RAS was observed with frequently altered signaling pathways. Further analysis of the mutational signature revealed that SBS13, SBS6, and SBS29 were mainly observed in our cohort. This study supplements the discovery of diagnostic biomarkers and provides new therapeutic options for the improved management of BC.

Genomic landscape of gallbladder cancer: insights from whole exome sequencing.

BACKGROUND: Gallbladder carcinoma (GBC) is a common gastrointestinal malignancy noted for its aggressive characteristics and poor prognosis, which is mostly caused by delayed detection. However, the scarcity of information regarding somatic mutations in Indian patients with GBC has hampered the development of efficient therapeutic options. In the present study, we attempted to bridge this gap by revealing the mutational profile of GBC. MATERIALS AND METHODS: To evaluate the somatic mutation profile, whole exome sequencing (WES) was performed on 66 matched tumor and blood samples from individuals with GBC. Somatic variant calling was performed using GATK pipeline. Variants were annotated at pathogenic and oncogenic levels, using ANNOVAR, VEP tools and the OncoKB database. Mutational signature analysis, oncogenic pathway analysis and cancer driver genes identification were performed at the functional level by using the maftools package. RESULTS: Our findings focused on the eight most altered genes with pathogenic and oncogenic mutations: TP53, SMAD4, ERBB3, KRAS, ARID1A, PIK3CA, RB1, and AXIN1. Genes with pathogenic single nucleotide variations (SNVs) were enriched in oncogenic signaling pathways, particularly RTK-RAS, WNT, and TP53 pathways. Furthermore, our research related certain mutational signatures, such as cosmic 1, cosmic 6, and cosmic 18, 29, to known characteristics including patient age and tobacco smoking, providing important insights into disease etiology. CONCLUSIONS: Given the scarcity of exome-based sequencing studies focusing on the Indian population, this study represents a significant step forward in providing a framework for additional in-depth mutational analysis. Genes with substantial oncogenic and pathogenic mutations are promising candidates for developing targeted mutation panels, particularly for GBC detection.

Whole exome sequencing identifies novel variants of PIK3CA and validation of hotspot mutation by droplet digital PCR in breast cancer among Indian population.

BACKGROUND: Breast cancer (BC) is the most common malignancy with very high incidence and relatively high mortality in women. The PIK3CA gene plays a pivotal role in the pathogenicity of breast cancer. Despite this, the mutational status of all exons except exons 9 and 20 still remains unknown. METHODS: This study uses the whole exome sequencing (WES) based approach to identify somatic PIK3CA mutations in Indian BC cohorts. The resultant hotspot mutations were validated by droplet digital PCR (ddPCR). Further, molecular dynamics (MD) simulation was applied to elucidate the conformational and functional effects of hotspot position on PIK3CA protein. RESULTS: In our cohort, PIK3CA showed a 44.4% somatic mutation rate and was among the top mutated genes. The mutations of PIK3CA were confined in Exons 5, 9, 11, 18, and 20, whereas the maximum number of mutations lies within exons 9 and 20. A total of 9 variants were found in our study, of which 2 were novel mutations observed on exons 9 (p.H554L) and 11 (p.S629P). However, H1047R was the hotspot mutation at exon 20 (20%). In tumor tissues, there was a considerable difference between copy number of wild-type and H1047R mutant was detected by ddPCR. Significant structural and conformational changes were observed during MD simulation, induced due to point mutation at H1047R/L position. CONCLUSIONS: The current study provides a comprehensive view of novel as well as reported single nucleotide variants (SNVs) in PIK3CA gene associated with Indian breast cancer cases. The mutation status of H1047R/L could serve as a prognostic value in terms of selecting targeted therapy in BC.

Human papillomavirus-mediated expression of complement regulatory proteins in human cervical cancer cells.

OBJECTIVES: This study aimed to evaluate the expression pattern of complement regulatory proteins (CRPs) CD46, CD59, and CD55 in HPV-positive (HPV+) & negative (HPV-) cervical cancer cell lines in search of a reliable differential biomarker. STUDY DESIGN: We analysed the expression of CRPs in HPV 16-positive SiHa cell line, HPV 18-positive HeLa cell line, and HPV-negative cell line C33a using RT-qPCR, Western blotting, flow cytometry, and confocal microscopy. RESULTS: We observed a differential expression profile of CRPs in HPV+ and HPV- cervical cancer cell lines. The mRNA level of CD59 & CD55 showed a higher expression pattern in HPV+ cells when compared to HPV- cancer cells. However, flow cytometry-based experiments revealed that CD46 was preferentially expressed more in HPV 16-positive SiHa cells followed by HPV 18-positive HeLa cells when compared to HPV- C33a cells. Interestingly, confocal microscopy revealed a high level of CD59 expression in Hela cells and SiHa cells but low expression in HPV- C33a cells. In addition, HPV 18-positive HeLa cells expressed more CD55, which was lower in SiHa cells and very weak in C33a cells. CONCLUSION: The study demonstrates the differential expression of CRPs in both HPV+ and HPV- cervical cancer cells for the first time, and their potential to serve as an early diagnostic marker for cervical carcinogenesis.

Liquid Biopsies: Emerging role and clinical applications in solid tumours.

Late detection and lack of precision diagnostics are the major challenges in cancer prevention and management. Biomarker discovery in specific cancers, especially at the pre-invasive stage, is vital for early diagnosis, positive treatment response, and good disease prognosis. Traditional diagnostic measures require invasive procedures such as tissue excision using a needle, an endoscope, and/or surgical resection which can be unsafe, expensive, and painful. Additionally, the presence of comorbid conditions in individuals might render them ineligible for undertaking a tissue biopsy, and in some cases, it is difficult to access tumours depending on the site of occurrence. In this context, liquid biopsies are being explored for their clinical significance in solid malignancies management. These non-invasive or minimally invasive methods are being developed primarily for identification of biomarkers for early diagnosis and targeted therapeutics. In this review, we have summarised the use and importance of liquid biopsy as significant tool in diagnosis, prognosis prediction, and therapeutic development. We have also discussed the challenges that are encountered and future perspective.

Mitochondrial DNA content as a biomarker for oral carcinogenesis: correlation with clinicopathologic parameters.

BACKGROUND: Mitochondrial genome (mtDNA) exhibits greater vulnerability to mutations and/or copy number variations than nuclear counterpart (nDNA) in both normal and cancer cells due to oxidative stress generated by inflammation, viral infections, physical, mechanical, and chemical load. The study was designed to evaluate the mtDNA content in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC). Various parameters were analyzed including its variation with human papillomavirus (HPV) during oral carcinogenesis. METHODS: The present cross-sectional study comprised of two hundred patients (100 OPMDs and 100 OSCCs) and 100 healthy controls. PCR amplifications were done for mtDNA content and HPV in OPMDs and OSCC using real-time and conventional PCR respectively. RESULTS: The relative mtDNA content was assessed quantitatively and it was observed that mtDNA was greater in OSCC (7.60±0.94) followed by OPMDs (5.93±0.92) and controls (5.37±0.95). It showed a positive linear correlation with habits and increasing histopathological grades. Total HPV-positive study groups showed higher mtDNA content (7.06±1.64) than HPV-negative counterparts (6.21±1.29). CONCLUSIONS: An elevated mutant mtDNA may be attributed to increased free radicals and selective cell clonal proliferation in test groups. Moreover, sustained HPV infection enhances tumorigenesis through mitochondria mediated apoptosis. Since, mtDNA content is directly linked to oxidative DNA damage, these quantifications might serve as a surrogate measure for invasiveness in dysplastic lesions and typify their malignant potential.

Prognostic Relevance of PDL1 and CA19-9 Expression in Gallbladder Cancer vs. Inflammatory Lesions.

Chronic inflammation in the gallbladder leading to persistent epithelium damage promotes invasive cancer. The study aimed to assess the prognostic value of PDL1 and CA19-9 markers in cancer/inflammatory lesions of the gallbladder. A total of 29 cases (19 cancer and 10 inflammatory) were included. The PDL1 protein concentration level and mRNA expression were assessed in the tissues' lysates by ELISA and real-time PCR, respectively. PDL1 and CA19-9 concentration levels were compared and statistically related with clinico-pathological variables. The PDL1 protein level and its relative mRNA expression were correlated. Kaplan-Meir survival and Cox regression analyses were conducted for predicting prognosis. This study investigated the PDL1 and CA19-9 marker expression in both cancer and inflammatory cases of the gallbladder (p = 0.48 and p = 0.17 respectively). PDL1 protein expression was significantly associated with the hormonal profile of the cases (p = 0.04) at an optimum cut-off value of 13 pg/mL, while the CA19-9 marker expression was correlated with the status of liver metastasis (p = 0.0043) and size of the tumor (p = 0.004). A low PDL1 concentration was found when compared to the CA19-9 level among cancer cases (p = 0.12) and proportional in the inflammatory lesions (p = 0.63). A significant positive correlation was found between the PDL1 protein and its relative mRNA expressions in the inflammatory lesions (p = 0.029) when compared to cancer cases (p = 0.069). Our results showed that a protein-based assay for PDL1 expression would be more sensitive compared to RNA based assays for GBC risk stratifications. Overall survival was predicted with CA19-9 and PDL1 levels (p = 0.0074, p = 0.23, respectively). PDL1 and CA19-9 may act as a probable predictor of a poor prognosis in gallbladder cancer (GBC) cases.

Molecular basis of epigenetic regulation in cancer diagnosis and treatment.

The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.

Concurrent Cervical and Anal High-Risk Human Papillomavirus Infection in Women Living With HIV: An Observational Case-Control Study.

BACKGROUND: To evaluate the prevalence and correlates of concurrent uterine cervical and anal HR-HPV infections in women living with HIV (WLHIV). SETTING: A cross-sectional study was undertaken at a tertiary care hospital and linked ART center. METHODS: One hundred and forty-one WLHIV and 161 HIV-negative women were enrolled for cervical and anal cytology as well as HR-HPV testing using the HC2 method. Screen-positive women were followed-up with colposcopy/anoscopy and/or repeat cytology. Appropriate statistical tests were applied to assess the association of concurrent HR-HPV with various parameters. RESULTS: Concurrent cervical and anal HR-HPV infection was detected in 22 WLHIV (16.3%) and 5 HIV-negative women (3.1%), the difference being statistically significant ( P < 0.001 ). Among WLHIV, concurrent HR-HPV was associated with tobacco use ( P < 0.001 ), receptive anal intercourse ( P = 0.02 ), low CD4 counts ( P = 0.001 ), and negatively with ART intake ( P = 0.004 ) on bivariate analysis. Multivariate logistic regression analysis showed a positive association of concurrent HR-HPV positivity with tobacco use ( P = 0.02 ) and low nadir CD4 counts ( P = 0.03 ). CONCLUSIONS: WLHIV, especially those with CD4 counts less than 200/µL, should be offered HR-HPV screening and follow-up to detect cervical and anal lesions.

Peroxiredoxins - Urinary Surveillance Biomarkers in Urothelial Cancer.

Introduction: Urinary bladder cancer ranks the fourth most common cancer in men worldwide. Peroxiredoxins (PRDXs) are antioxidant enzymes that play an important role in cell proliferation and apoptosis. In the present study, we investigated whether PRDX 1 and 2 can be used as a urinary biomarker for surveillance of recurrence in urothelial cancer. Materials and Methods: PRDX1 and PRDX2 expression levels were examined in 119 bladder tumor specimens by immunohistochemistry and in 150 urine samples (case: 100; healthy controls: 50) using ELISA and their association with recurrence and survival of patients was evaluated. Results: Immunohistochemistry on FFPE tissue showed that both PRDX1 and PRDX2 were positive in bladder tumors and expressed in the cytoplasm and membrane of tumor cells. A significant elevation of urinary PRDX1 and PRDX2 concentration was found in bladder cancer patients and recurrent cases compared to the urine of healthy controls and primary bladder cancer patients (p<0.001 & p<0.01) respectively. However, the concentration of both proteins was not found associated with survival. Conclusion: Elevated urinary PRDX1 and PRDX2 in bladder cancer patients was found to be associated with recurrence and the estimation of urinary PRDX1 and PRDX2 during follow-up may help to extend the period between cystoscopies in patient follow-up.

High Prevalence of Cervical High-Grade Lesions and High-Risk Human Papillomavirus Infections in Women Living with HIV: A Case for Prioritizing Cervical Screening in This Vulnerable Group.

INTRODUCTION: Women living with HIV (WLHIV) are at an increased risk of developing cervical precancerous lesions and cervical human papillomavirus (HPV) infection. This study aimed at evaluating the prevalence of cervical lesions and high-risk HPV (HR-HPV) infection in WLHIV in comparison to the HIV-negative women undergoing opportunistic screening. In addition, these findings among WLHIV were correlated with the clinic-demographic factors. METHODS: A cross-sectional study was conducted among WLHIVs at a tertiary hospital and linked antiretroviral therapy (ART) center, while HIV-negative women were recruited from the health promotion clinic at our institute. With informed consent, a semi-structured questionnaire was filled on demographic and epidemiological parameters. Conventional cervical smears and samples for HPV DNA detection by HC2 high-risk HPV DNA test were collected in all participants. Cervical smears were reported using the Bethesda system 2014. Appropriate statistical analysis was performed for bivariate and multivariate logistic regression analysis for comparison between WLHIV and HIV-negative women and for correlation of abnormal cervical cytology and HR-HPV infection among WLHIVs. RESULTS: The clinic-demographic characteristics of WLHIVs and HIV-negative women were similar. On cytology, the prevalence of cervical cytological abnormalities were significantly higher (p < 0.001) among WLHIVs (14.1%) compared to HIV-negative women (3.1%). High-grade lesions were seen in 3.7% of WLHIVs, while no high-grade lesions were detected in HIV-negative women. Cervical HR-HPV infection was also significantly higher (p < 0.001) in WLHIVs (28.9%) than HIV-negative women (9.3%). Cervical precancerous lesions in WLHIVs showed positive association with current sexually transmitted infection (STI), multiple sexual partners, tobacco use, and CD4 count less than 200/µL, while cervical HPV was positively associated with current STI, tobacco use, CD4 count less than 200/µL and negatively with ART intake. On multivariate logistic regression, cervical cytological abnormalities showed a significant association with multiple sexual partners (p < 0.001), while cervical HR-HPV infection was positively associated with current STI (p = 0.01), nadir CD4 count <200/µL (p = 0.004), abnormal cervical cytology (p = 0.002) and negatively with ART intake (p = 0.03). CONCLUSION: Women living with HIV have a significantly higher prevalence of cervical precancerous lesions and HR-HPV infection compared to the general population. Considering the lack of an organized population-based cervical cancer screening program in many low-resource countries like ours, specific focus on screening this highly vulnerable population to reduce the morbidity and mortality due to cervical cancer is imperative.

Insights into the role of complement regulatory proteins in HPV mediated cervical carcinogenesis.

The persistent infection of high-risk Human papillomavirus (HR-HPV) induced cervical cancer remains a challenge in women worldwide including India. Recent advances in cancer research have paved the way for advanced cancer treatment modalities including immunotherapy by manipulating the function or number of cytotoxic T cells. It is well established that anaphylatoxins like C3a and C5a of complement system influence tumor growth by evading apoptosis leading to progression of cancer. The role of the complement system, particularly the complement regulatory proteins (CRPs) which are important determinants of immune response play a crucial role in carcinogenesis. In a tumor microenvironment (TME) assisted suppression of immune effector cells may be achieved through CRPs. However, recent advances in pharmacogenomics including drug designing and combination of these approaches have provided a holistic understanding of signaling pathways and their crosstalk, to regulate cellular communications.This review describes the role of complement system; particularly CRPs in HPV induced cervical carcinogenesis which may be used for designing anti- HPV or cervical cancer therapeutics.

Role of epigenetics in carcinogenesis: Recent advancements in anticancer therapy.

The role of epigenetics in the etiology of cancer progression is being emphasized for the past two decades to check the impact of chromatin modifiers and remodelers. Histone modifications, DNA methylation, chromatin remodeling, nucleosome positioning, regulation by non-coding RNAs and precisely microRNAs are influential epigenetic marks in the field of progressive cancer sub-types. Furthermore, constant epigenetic changes due to hyper or hypomethylation could efficiently serve as effective biomarkers of cancer diagnosis and therapeutic development. Ongoing research in the field of epigenetics has resulted in the resolutory role of various epigenetic markers and their inhibition using specific inhibitors to arrest their key cellular functions in in-vitro and pre-clinical studies. Although, the mechanism of epigenetics in cancer largely remains unexplored. Nevertheless, various advancements in the field of epigenetics have been made through transcriptome analysis and in-vitro genome targeting technologies to unravel the applicability of epigenetic markers for future cancer therapeutics and management. Therefore, this review emphasizes on recent advances in epigenetic landscapes that could be targeted/explored using novel approaches as personalized treatment modalities for cancer containment.

Molecular and genomic landscapes in secondary & therapy related acute myeloid leukemia.

Acute myeloid leukemia (AML) is a complex, aggressive myeloid neoplasm characterized by frequent somatic mutations that influence different functional categories' genes, resulting in maturational arrest and clonal expansion. AML can arise de novo (dn-AML) or can be secondary AML (s-AML) refers to a leukemic process which may arise from an antecedent hematologic disorder (AHD-AML), mostly from a myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) or can be the result of an antecedent cytotoxic chemotherapy or radiation therapy (therapy-related AML, t-AML). Clinical and biological features in secondary and therapy-related AML are distinct from de novo AML. Secondary and therapy-related AML occurs mainly in the elderly population and responds worse to therapy with higher relapse rates due to resistance to cytotoxic chemotherapy. Over the last decade, advances in molecular genetics have disclosed the sub-clonal architecture of secondary and therapy-related AML. Recent investigations have revealed that cytogenetic abnormalities and underlying genetic aberrations (mutations) are likely to be significant factors dictating prognosis and critical impacts on treatment outcome. Secondary and therapy-related AML have a poorer outcome with adverse cytogenetic abnormalities and higher recurrences of unfavorable mutations compared to de novo AML. In this review, we present an overview of the clinical features of secondary and therapy-related AML and address the function of genetic mutations implicated in the pathogenesis of secondary leukemia. Detailed knowledge of the pathogenetic mechanisms gives an overview of new prognostic markers, including targetable mutations that will presumably lead to the designing and developing novel molecular targeted therapies for secondary and therapy-related AML. Despite significant advances in knowing the genetic aspect of secondary and therapy-related AML, its influence on the disease's pathophysiology, standard treatment prospects have not significantly evolved during the past three decades. Thus, we conclude this review by summarizing the modern and developing treatment strategies in secondary and therapy-related acute myeloid leukemia.

Exosomes: A Forthcoming Era of Breast Cancer Therapeutics.

Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies.

An updated account on molecular heterogeneity of acute leukemia.

The progress in the field of personalized therapy has been the backbone for the improved mortality and morbidity figure in cancer especially with reference to acute leukemia. The same has been supported by evolving research and development in the field of genomics. The newer discoveries of mutations and the account of already discovered mutations have been playing a pivotal role to refine management strategy. Here, in this review, we are giving an account of relevant mutations and their potential role in the pathogenesis of acute leukemia. The article discusses the old and newly discovered mutations in acute myeloid/lymphoblastic leukemia. The various pathways and cross-talks between the mutations have been briefly described to develop insight towards their contributory and consequent role in the neoplastic process. The article is to sensitize the students, clinicians, and researchers towards the recent updates and development in genomics of acute leukemia.

Deciphering the impact of missense mutations on structure and dynamics of SMAD4 protein involved in pathogenesis of gall bladder cancer.

Gall bladder cancer (GBC) is the most common malignancy of biliary tract cancer associated with high mortality rate and poor prognosis due to lack of suitable biomarkers. In this study, we explored the structural and functional effects of different missense mutations occurs in SMAD4 that was associated with the development of GBC. We utilized in silico methods to predict the harmful effects of nonsynonymous missense mutations and monitored the stability of protein. We found that all mutations (D351N, G352E, R361C, R361H, E526Q) associated with SMAD4 were deleterious in nature resulting in the formation of deformed or unstable protein structure. Molecular dynamics simulation studies revealed how these mutations affect protein stability, structure, conformation and function. We observed, different mutants increase the compactness and rigidity of SMAD4 protein, alter secondary structure composition, decrease the surface area and protein-ligand interaction and affect its conformation. Findings of current work indicated that the analyzed mutations might affect the structure of protein and its caliber to interact with other molecules, which probably related to functional impairment of SMAD4 upon D351N, G352E, R361C, R361H, E526Q mutations and their involvement in cancer. Hence, the present study has significance of rational drug design and further increase our understanding of GBC development.Communicated by Ramaswamy H. Sarma.

Molecular update on biology of Wilms Tumor 1 gene and its applications in acute myeloid leukemia.

Wilms tumor gene 1 (WT1) is an important gene which is involved in growth and development of many organs. It is identified as a tumor suppressor gene in nephroblastoma. However, its role as a tumor oncogene has been highlighted by many studies in haematological as well as non haematological malignant neoplasm. The expression of WT1 on leukemic blast cells sensitised us to explore its impact on neoplastic phenomenon. WT1 is has been found both mutated as well as over expressed in different subsets of acute myeloid leukemia (AML). WT1 is a gene has been used as a biomarker for diagnosis, monitoring of minimal residual disease (MRD) and detection of relapse for molecular remission in AML. It also has potential of being a predictive molecular predictive biomarker for the treatment of leukemic cases after allogeneic transplantation. The WT1 specific expression on blast cells and its interaction with cytotoxic T cell has also been explored for its potential usage WT1 based immunotherapy. Here, we are reviewing molecular updates of WT1 gene and discuss its potential clinical applications as a predictive molecular biomarker for diagnosis, as MRD detection and as immunotherapy in AML.