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.

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.

Acceptability, feasibility and cost of point of care testing for sexually transmitted infections among South African adolescents where syndromic management is standard of care.

BACKGROUND: Young people (YP) in southern Africa are at substantial risk of HIV and sexually transmitted infections (STIs). Despite the epidemiological and biological link between STIs and HIV transmission and acquisition, infections such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) remain widely undiagnosed. Syndromic STI management is the standard of care in low- and middle-income countries (LMICs) despite a high prevalence of asymptomatic infections. We conducted an observational study to explore the acceptability, feasibility, and cost of a STI test-and-treat service for YP in Cape Town. METHODS: YP attending a mobile clinic (MC) and a youth centre clinic (YC) were offered STI screening. Urine testing for CT and NG using a 90-min molecular point-of-care (POC) test on the GeneXpert platform was conducted and treatment provided. Data were collated on demographics, sexual behaviour, presence of symptoms, uptake of same-day treatment, prevalence of CT/NG, and service acceptability. RESULTS: Three hundred sixty six participants were enrolled (median age 20, 83% female).57% (209/366) of participants tested positive for either CT (126/366, 34%) or NG (57/366, 16%) or co-infection (26/366, 7%). Clinical symptoms were a poor predictor of GeneXpert diagnosed CT or NG, with a sensitivity of 46.8% and 54.0% for CT and NG respectively. Although half of participants initially chose to receive same day results and treatment, only a third waited for results on the day. The majority of participants (91%) rated the service highly via a post-visit acceptability questionnaire. CONCLUSION: Curable STIs are highly prevalent in this population. STI screening using POC testing was feasible and acceptability was high. The study provides further impetus for moving policy beyond syndromic management of STIs in South Africa.

Cost and outcomes of routine HIV care and treatment: public and private service delivery models covering low-income earners in South Africa.

BACKGROUND: While South Africa's national HIV program is the largest in the world, it has yet to reach the UNAIDS 95-95-95 targets. To reach these targets, the expansion of the HIV treatment program may be accelerated through the use private sector delivery models. This study identified three innovative non-governmental primary health care models (private sector) providing HIV treatment, as well as two government primary health clinics (public sector) that served similar populations. We estimated the resources used, and costs and outcomes of HIV treatment across these models to provide inputs to inform decisions around how these services might best be provided through National Health Insurance (NHI). METHODS: A review of potential private sector models for HIV treatment in a primary health care setting was conducted. Models actively offering HIV treatment (i.e. in 2019) were considered for inclusion in the evaluation, subject to data availability and location. These models were augmented by government primary health clinics offering HIV services in similar locations. We conducted a cost-outcomes analysis by collecting patient-level resource usage and treatment outcomes through retrospective medical record reviews and a bottom-up micro-costing from the provider perspective (public or private payer). Patient outcomes were based on whether the patient was still in care at the end of the follow up period and viral load (VL) status, to create the following outcome categories: in care and responding (VL suppressed), in care and not responding (VL unsuppressed), in care (VL unknown) and not in care (LTFU or deceased). Data collection was conducted in 2019 and reflects services provided during the 4 years prior to that (2016-2019). RESULTS: Three hundred seventy-six patients were included across the five HIV treatment models. Across the three private sector models there were differences in the costs and outcomes of HIV treatment delivery, two of the models had results similar to the public sector primary health clinics. The nurse-led model appears to have a cost-outcome profile distinct from the others. CONCLUSION: The results show that across the private sector models studied the costs and outcomes of HIV treatment delivery vary, yet there were models that provided costs and outcomes similar to those found with public sector delivery. Offering HIV treatment under NHI through private delivery models could therefore be an option to increase access beyond the current public sector capacity.

Leveraging epigenetics to enhance the efficacy of cancer-testis antigen: a potential candidate for immunotherapy.

Ovarian cancer is the most lethal gynecological malignancy in women. The phenotype is characterized by delayed diagnosis, recurrence and drug resistance. Inherent immunogenicity potential, oncogenic function and expression of cancer-testis/germline antigen (CTA) in ovarian cancer render them a potential candidate for immunotherapy. Revolutionary clinical findings indicate that tumor antigen-mediated T-cell and dendritic cell-based immunotherapeutic approaches provide an excellent strategy for targeting tumors. Currently, dendritic cell vaccination for the treatment of B-cell lymphoma and CTA-based T-cell receptor transduced T-cell therapy involving MAGE-A4 and NY-ESO-1 are well documented and shown to be effective. This review highlighted the mechanical aspects of epigenetic drugs that can elicit a CTA-based humoral and cellular immune response and implicate T-cell and dendritic cell-based immunotherapeutic approaches.

Despite substantial advancements in prognosis and diagnostic approaches, epithelial ovarian cancer is still the most lethal gynecological malignancy worldwide. In addition to radiotherapy, chemotherapy, hormonal therapy, and surgery, immunotherapy in the clinical setting is promising. Tumor-restricted expression and strong immunogenic potential make cancer-testis/germline antigen (CTA) a potential candidate for efficient T-cell and dendritic cell-mediated cancer immunotherapy. The expression of CTAs is shown to be modulated by a specific epigenetic fine-tuning mechanism. However, the expression and role of CTA in epithelial ovarian cancer immunotherapy are poorly understood. Therefore, in the current work, the authors thoroughly highlight and explore the possible epigenetic mechanisms associated with CTA expression and their implication in T-cell and dendritic cell-based immunotherapy approaches to ovarian cancer. Understanding such a paradigm is essential to adopting a precision medicine approach for better therapeutic options.

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.

Primary healthcare seeking behaviour of low-income patients across the public and private health sectors in South Africa.

BACKGROUND: The proposed National Health Insurance (NHI) system aims to re-engineer primary healthcare (PHC) in South Africa, envisioning both private sector providers and public sector clinics as independent contracting units to the NHI Fund. In 2017, 16% of the South African population had private medical insurance and predominately utilised private providers. However, it is estimated that up to 28% of the population access private PHC services, with a meaningful segment of the low-income, uninsured population paying for these services out-of-pocket. The study objective was to characterise the health seeking behaviour of low-income, patients accessing PHC services in both the public and private sectors, patient movement between sectors, and factors influencing their facility choice. METHODS: We conducted once-off patient interviews on a random sample of 153 patients at 7 private PHC providers (primarily providing services to the low-income mostly uninsured patient population) and their matched public PHC clinic (7 facilities). RESULTS: The majority of participants were economically active (96/153, 63%), 139/153 (91%) did not have health insurance, and 104/153 (68%) earned up to $621/month. A multiple response question found affordability (67%) and convenience (60%) were ranked as the most important reasons for choosing to usually access care at public clinics (48%); whilst convenience (71%) and quality of care (59%) were key reasons for choosing the private sector (32%). There is movement between sectors: 23/76 (30%) of those interviewed at a private facility and 8/77 (10%) of those interviewed at a public facility indicated usually accessing PHC services at a mix of private and public facilities. Results indicate cycling between the private and public sectors with different factors influencing facility choice. CONCLUSIONS: It is imperative to understand the potential impact on where PHC services are accessed once affordability is mitigated through the NHI as this has implications on planning and contracting of services under the NHI.

Glioblastoma with Primitive Neuroectodermal Component Treated with Adjuvant Radiotherapy and Temozolomide: A Pooled Analysis of 23 Patients.

AIM: Glioblastoma (GBM) is one of the most aggressive neoplasms of the central nervous system with dismal survival. In recent years, different variants of GBM have been described in the literature. GBM with areas of neuroectodermal differentiation (GBM-PNET) is a relatively new entity in GBM. Presence of the neuroectodermal component increases the propensity of systemic dissemination as with other intracranial primitive neuroectodermal tumors (PNET). The optimal treatment for these patients remains a controversy, with authors reporting local radiotherapy to craniospinal irradiation and chemotherapy. We intend to analyze the pattern of care for GBM with neuroectodermal component. MATERIALS AND METHODS: We retrieved data of four patients with GBM-PNET treated in our institute; data were also retrieved from published series to derive treatment and outcome results. RESULTS: In this series, we report the outcome of a series of four patients of GBM-PNET treated with adjuvant radiotherapy and temozolomide. All but one patient underwent gross total resection of the tumor. Adjuvant hypofractionated radiation with concurrent and adjuvant temozolomide was used in all cases. The median follow-up was 12.9 months in the present series. One patient experienced local recurrence 18 months after the treatment. A review of published literature on GBM-PNET was done; studies with details of patient outcome were used for an independent analysis. Twenty-three patients were identified, and the pooled analysis revealed a median progression free and overall survival of 10 and 25, months respectively. Extent of surgery, local radiation vs. craniospinal irradiation, and age at presentation had no impact on the survival. CONCLUSION: GBM PNET is a new entity with only few cases reported so far. Clinical behavior and treatment outcome of these tumors are not different from conventional GBM. However, these patients are at higher risk of CSF dissemination. Hence, an individualized treatment approach is best suited.

South Asian Declaration-Consensus Guidelines for COVID-19 Vaccination in Cancer Patients.

We provide the South Asian Declaration, containing the consensus guidelines for coronavirus disease 2019 (COVID-19) vaccination in cancer patients.

Practical Consensus Recommendations for Optimizing Risk versus Benefit of Chemotherapy in Patients with HR Positive Her2 Negative Early Breast Cancer in India.

Breast cancer is a public health challenge globally as well as in India. Improving outcome and cure requires appropriate biomarker testing to assign risk and plan treatment. Because it is documented that significant ethnic and geographical variations in biological and genetic features exist worldwide, such biomarkers need to be validated and approved by authorities in the region where these are intended to be used. The use of western guidelines, appropriate for the Caucasian population, can lead to inappropriate overtreatment or undertreatment in Asia and India. A virtual meeting of domain experts discussed the published literature, real-world practical experience, and results of opinion poll involving 185 oncologists treating breast cancer across 58 cities of India. They arrived at a practical consensus recommendation statement to guide community oncologists in the management of hormone positive (HR-positive) Her2-negative early breast cancer (EBC). India has a majority (about 50%) of breast cancer patients who are diagnosed in the premenopausal stage (less than 50 years of age). The only currently available predictive test for HR-positive Her2-negative EBC that has been validated in Indian patients is CanAssist Breast. If this test gives a score indicative of low risk (< 15.5), adjuvant chemotherapy will not increase the chance of metastasis-free survival and should not be given. This is applicable even during the ongoing COVID-19 pandemic.

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.

A systematic review with in silico analysis on transcriptomic profile of gallbladder carcinoma.

Gallbladder cancer (GBC) is an aggressive malignancy of the biliary tract. It is asymptomatic in its early stages, and often, characterized by a poor prognosis and worse treatment response. Distribution of GBC shows both geographical as well as ethnic variations. Several studies have elucidated the differential gene expression profile between the normal gallbladder and GBCs, with varied but inconsistent results. Thus, a deep understanding of the expression profile of GBC might aid in the identification of potential biomarkers, which would further help in better disease management and appropriate therapy selection. This review summarizes studies on the transcriptomic profile of GBC with emphasis on studies pertaining to coding (mRNA) and noncoding (micro and long noncoding) RNA along with aberrant promoter methylation studies, ranging from a single gene to global gene to high throughput RNA sequencing approaches, published between 2000 to May, 2019. In addition, data mining of GBC from the available public functional genomics data repository at Gene Expression Omnibus has been done to rule out potentially important dysregulated genes in this malignancy. To the best of our knowledge, this is the first article to shed light on the RNA based gene regulatory network(s) along with bioinformatic analysis. Moreover, this review represents major research challenges and ambiguity, knowledge of which is a must for establishing molecular/ clinical biomarkers for early GBC diagnosis, management, and treatment protocols.

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.

Indian clinical practice consensus guidelines for the management of squamous cell carcinoma of head and neck.

Head and neck cancers (HNCs) are malignant tumors of the upper aerodigestive tract and are the sixth most common cancer worldwide. In India, around 30-40% of all cancers are HNCs. Even though there are global guidelines or recommendations for the management of HNCs, these may not be appropriate for Indian scenarios. In an effort to discuss current practices, latest developments and to come to a consensus to recommend management strategies for different anatomical subsites of HNCs for Indian patients, a group of experts (medical, surgical and radiation oncologists and dentists) was formed. A review of literature from medical databases was conducted to provide the best possible evidence base, which was reviewed by experts during a consensus group meeting (January, 2019) to provide recommendations.