Pattern recognition in the landscape of seemingly random chimeric transcripts.

The molecular and functional diversity generated by chimeric transcripts (CTs) that are derived from two genes is indicated to contribute to tumor cell survival. Several gaps yet exist. The present research is a systematic study of the spectrum of CTs identified in RNA sequencing datasets of 160 ovarian cancer samples in the The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov). Structural annotation revealed complexities emerging from chromosomal localization of partner genes, differential splicing and inclusion of regulatory, untranslated regions. Identification of phenotype-specific associations further resolved a dynamically modulated mesenchymal signature during transformation. On an evolutionary background, protein-coding CTs were indicated to be highly conserved, while non-coding CTs may have evolved more recently. We also realized that the current premise postulating structural alterations or neighbouring gene readthrough generating CTs is not valid in instances wherein the parental genes are genomically distanced. In addressing this lacuna, we identified the essentiality of specific spatiotemporal arrangements mediated gene proximities in 3D space for the generation of CTs. All these features together suggest non-random mechanisms towards increasing the molecular diversity in a cell through chimera formation either in parallel or with cross-talks with the indigenous regulatory network.

Military chaplains and mental health clinicians: Overlapping roles and collaborative opportunities.

Military chaplains and mental health clinicians have unique professional roles and functions within the Department of Defense. However, they also have intersecting roles in delivering care to service members with mental health issues. Although diagnosis and treatment of clinical disorders is the primary focus of mental health clinicians, military chaplains are often the first contact made by service members seeking help for mental health concerns, due in part to issues of greater accessibility, ensured confidentiality, and less stigma. There is growing recognition of the importance of spirituality in the well-being and readiness of service members, as many mental health issues have a spiritual dimension. As a result, chaplains and mental health clinicians often address many of the same issues, albeit with different approaches. This review examines overlap in the work of chaplains and mental health clinicians and contrasts their complementary treatment approaches. These overlapping issues and complementary approaches highlight the potential for greater collaboration between these two professional groups, which could be beneficial for the care of service members. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

RBM47 is a Critical Regulator of Mouse Embryonic Stem Cell Differentiation.

RNA-binding proteins (RBPs) are pivotal for regulating gene expression as they are involved in each step of RNA metabolism. Several RBPs are essential for viable growth and development in mammals. RNA-binding motif 47 (RBM47) is an RRM-containing RBP whose role in mammalian embryonic development is poorly understood yet deemed to be essential since its loss in mouse embryos leads to perinatal lethality. In this study, we attempted to elucidate the significance of RBM47 in cell-fate decisions of mouse embryonic stem cells (mESCs). Downregulation of Rbm47 did not affect mESC maintenance and the cell cycle but perturbed the expression of primitive endoderm (PrE) markers and increased GATA4 + PrE-like cells. However, the PrE misregulation could be reversed by either overexpressing Rbm47 or treating the knockdown mESCs with the inhibitors of FGFR or MEK, suggesting an implication of RBM47 in regulating FGF-ERK signaling. Rbm47 knockdown affected the multi-lineage differentiation potential of mESCs as it regressed teratoma in NSG mice and led to a skewed expression of differentiation markers in serum-induced monolayer differentiation. Further, lineage-specific differentiation revealed that Rbm47 is essential for proper differentiation of mESCs towards neuroectodermal and endodermal fate. Taken together, we assign a hitherto unknown role(s) to RBM47 in a subtle regulation of mESC differentiation.

Behavioural interventions for tobacco cessation in India: A systematic review and meta-analysis.

Tobacco consumption is an area of public health concern in India. One of the unmet needs of many low-resource countries is to provide cost-effective tobacco cessation interventions for reducing tobacco-related mortality. This article reviews studies on non-pharmacological interventions for tobacco cessation in India. A systematic review by PICO (population, intervention, comparison, outcome) of behavioural intervention-based tobacco cessation studies that met the inclusion criteria, with a minimum 1-month follow-up, reporting outcomes in terms of frequencies or percentages published between 2010 and 2020 was performed. Following the review stages, 16 studies comprising 9,613 participants were included in the review. A pooled estimate was derived using both fixed-effects and random-effects models. The intervention showed good overall efficacy for any tobacco user (relative risk [RR] = 1.73 [95% confidence interval [CI]: 1.58-1.90) (fixed-effect model)] and (RR = 2.02 [95% CI: 1.64-2.48] [random-effects model]). Behavioural intervention studies targeted towards only smokers (RR of 1.81 [95% CI: 1.55-2.11] and 1.96 [95% CI: 1.52-2.53]) and combined smoking and smokeless tobacco users (RR of 1.69 [95% CI: 1.50-1.90] and 2.12 [95% CI: 1.49-3.01]) were equally efficacious. The review provides the effectiveness of behavioural interventions in quitting tobacco among users of both smoking and smokeless forms of tobacco. The review findings are of particular significance to inform health policy decisions on the integration of cost-effective brief behavioural intervention into existing health care services in resource-constrained countries.

Tobacco Cessation Program among Cab Drivers in Mumbai, India: An Interventional Study.

Background: Tobacco epidemic is one of the biggest public health threats, killing nearly seven million people annually. With implementation of smoke-free public places legislation, cabs in India are smoke free. However, large majority of cab drivers are addicted to tobacco. Aims: The objectives were to measure cab drivers' knowledge, attitude, and practices about tobacco pre and post intervention, educate them regarding hazards of tobacco and need for smoke-free cabs, perform oral cancer screening, and provide assistance to quit tobacco. Subjects and Methods: This interventional study among cab drivers was conducted in Mumbai during 2015-2018. Different cab unions in Mumbai were contacted and 400 cab drivers were enrolled and interviewed. They were offered health education, oral cancer screening, and tobacco cessation assistance at regular intervals for 1 year. Results: About 63.8% of cab drivers used tobacco, mainly in smokeless forms. Almost 94.1% intended to quit, 66.3% had made previous quit attempts, and 69.8% expressed the need of assistance for quitting. One hundred and twelve cab drivers were diagnosed with oral precancers and one with oral carcinoma. About 49.4% of cab drivers quit tobacco and 46.7% reduced tobacco consumption at the end of 1 year. According to multivariate logistic regression analysis, Muslim cab drivers were less likely to quit tobacco as compared to Hindus. Conclusion: Adherence to smoke-free laws plays a significant role in reducing exposure of cab drivers to secondhand smoke. This program demonstrates the successful implementation of tobacco cessation program that could be replicated among other workforces.

Single-cell sequencing: A cutting edge tool in molecular medical research.

The rapid development of advanced high throughput technologies and introduction of high resolution "omics" data through analysis of biological molecules has revamped medical research. Single-cell sequencing in recent years, is in fact revolutionising the field by providing a deeper, spatio-temporal analyses of individual cells within tissues and their relevance to disease. Like conventional sequencing, the single-cell approach deciphers the sequence of nucleotides in a given Deoxyribose Nucleic Acid (DNA), Ribose Nucleic Acid (RNA), Micro Ribose Nucleic Acid (miRNA), epigenetically modified DNA or chromatin DNA; however, the unit of analyses is changed to single cells rather than the entire tissue. Further, a large number of single cells analysed from a single tissue generate a unique holistic perception capturing all kinds of perturbations across different cells in the tissue that increases the precision of data. Inherently, execution of the technique generates a large amount of data, which is required to be processed in a specific manner followed by customised bioinformatic analysis to produce meaningful results. The most crucial role of single-cell sequencing technique is in elucidating the inter-cell genetic, epigenetic, transcriptomic and proteomic heterogeneity in health and disease. The current review presents a brief overview of this cutting-edge technology and its applications in medical research.

A Multistep Tumor Growth Model of High Grade Serous Ovarian Carcinoma Identifies Hypoxia Associated Signatures.

High-grade serous ovarian carcinoma (HGSC) is associated with late-stage disease presentation and poor prognosis, with limited understanding of early transformation events. Our study presents a comprehensive analysis of tumor progression and organ-specific metastatic dissemination to identify hypoxia-associated molecular, cellular, and histological alterations during HGSC tumor growth. H&E staining and subsequent histological assessment of tumor volume-based categories revealed recapitulation of numerous clinical features, including the prevalence of >0.0625≤0.5cm3 volume tumors and metastatic spread by orthotopic xenografts. The constant evolution of the tissue architecture concerning increased hyaluronic acid deposition, tumor vasculature, necrosis, altered proliferative potential, and gland forming ability of the tumor cells was identified. Flow cytometry and label chase-based molecular profiling across the tumor regenerative hierarchy identified the hypoxia-vasculogenic niche and the hybrid epithelial-mesenchymal tumor-cell state as determinants of self-renewal capabilities of progenitors and cancer stem cells (CSCs). A regulatory network and mathematical model based on tumor histology and molecular signatures predicted hypoxia-inducible factor 1-alpha (HIF1A) as a central node connecting epithelial-mesenchymal transition, metabolic and necrotic pathways in HGSC tumors. Thus, our findings provide a temporal resolution of hypoxia-associated events that sculpt HGSC tumor growth, and an in-depth understanding of it may aid in the early detection and treatment of HGSC.

NSG-70, a new glioblastoma cell line with mixed proneural-mesenchymal features, associates NOTCH1-WNT5A signaling with stem cell maintenance and angiogenesis.

BACKGROUND: Glioblastoma initiation and progression is believed to be driven by Glioma stem cells (GSCs). Activation of NOTCH1 and WNT, and more recently, non-canonical WNT5A signaling, has been demonstrated to regulate self-renewal and differentiation of the GSCs crucially. High expression levels of NOTCH1 and WNT in GBM tumors contribute to the sustenance of GSCs and mediate characteristic phenotypic plasticity, which is reflected by the different subtypes and tremendous intra-tumor heterogeneity. However, the coregulation of NOTCH1 and WNT5A is not well understood. Here, we studied the role of these molecules in regulating the characteristics of different GSC subtypes. METHODS: We established a novel GSC-enriched cell model, referred to as NSG-70, from a patient with recurrent GBM. NSG-70 cells harbor a unique cytogenetic feature, viz. isochromosome 9q. At the same time, its expression profiles indicate that it is a mixed lineage comprising proneural and mesenchymal subtypes. We examined the relevance of NOTCH1 and WNT5A signaling and their coordinated action in GBM using these cells and other patient-derived models representing different GSC subtypes. RESULTS: Our data revealed that the downregulation of NOTCH1 resulted in the suppression of stem cell and mesenchymal markers and significantly reduced the levels of WNT5A. NOTCH1 knockdown also led to a notable reduction in the vasculogenic mimicry of GSCs. Interestingly, knockdown of WNT5A exhibited similar effects and drove quiescent GSC towards proliferation. In a complementary manner, ectopic expression of WNT5A or rhWNT5A treatment rescued the effects of NOTCH1 knockdown. CONCLUSION: The resistance of GSCs towards conventional therapies in part due to subtype interconversion demands therapies targeting specific GSC subtype. Our study suggests the need for a combinatorial approach that could effectively target the NOTCH1-WNT5A signaling axis toward eliminating GSCs.

A monoclonal antibody against annexin A2 targets stem and progenitor cell fractions in tumors.

The involvement of cancer stem cells (CSCs) in driving tumor dormancy and drug resistance is well established. Most therapeutic regimens however are ineffective in targeting these regenerative populations. We report the development and evaluation of a monoclonal antibody, mAb150, which targets the metastasis associated antigen, Annexin A2 (AnxA2) through recognition of a N-terminal epitope. Treatment with mAb150 potentiated re-entry of CSCs into the cell cycle that perturbed tumor dormancy and facilitated targeting of CSCs as was validated by in vitro and in vivo assays. Epigenetic potentiation further improved mAb150 efficacy in achieving total tumor regression by targeting regenerative populations to achieve tumor regression, specifically in high-grade serous ovarian adenocarcinoma.

Screening for breast cancer: Cost-effective solutions for low- & middle-income countries.

Low- and middle-income countries (LMICs) have limited financial resources and proportionately smaller portions allocated for health budget. With competing health priorities, treatment of the diagnosed cases and establishment of treatment facilities are the main concerns in LMICs. Infectious diseases, reducing infant, child and maternal mortality may seem crucial as compared to early cancer detection. LMICs that are committed to providing comprehensive cancer care, will need to judiciously choose the screening tool depending on specifics of how the tool is expected to perform in the population and the cost-effectiveness with respect to the number of lives expected to be saved. Increasing awareness about breast health in general and common cancers and non communicable diseases (NCDs), in particular, may lead to symptomatic women approaching the healthcare facilities at an earlier stage. When the limited available resources are mobilized towards cancer screening, increasing awareness would lead to greater acceptability of the programme. The reach of the programme to achieve good population coverage, the establishment of the diagnostic referral linkages and the availability and accessibility of treatment facilities, will all decide the outcome of the screening programme.

A case report of extensive cerebral venous sinus thrombosis: a sequela of COVID-19?

Coronavirus disease 2019 (COVID-19) is an infectious respiratory disease that is often the trigger for thrombotic complications. Cerebral venous sinus thrombosis (CVST) represents a small percentage of strokes, frequently proving to be a diagnostic challenge. We report a 31-year-old lady presenting with a persistent headache, 18 weeks after a mild COVID-19 illness. On her second visit, CT venography revealed extensive CVST. She was commenced on low-molecular-weight heparin, and was monitored closely in the neuro-medical intensive care unit. She was discharged 2 weeks later, with no residual neurological deficit, and commenced on a direct oral anticoagulant in the community. CVST should be considered in patients presenting with a refractory headache, with greater suspicion if previously infected with SARS-CoV-2.

RNA binding motif 47 (RBM47): emerging roles in vertebrate development, RNA editing and cancer.

RNA-binding proteins (RBPs) are critical players in the post-transcriptional regulation of gene expression and are associated with each event in RNA metabolism. The term 'RNA-binding motif' (RBM) is assigned to novel RBPs with one or more RNA recognition motif (RRM) domains that are mainly involved in the nuclear processing of RNAs. RBM47 is a novel RBP conserved in vertebrates with three RRM domains whose contributions to various aspects of cellular functions are as yet emerging. Loss of RBM47 function affects head morphogenesis in zebrafish embryos and leads to perinatal lethality in mouse embryos, thereby assigning it to be an essential gene in early development of vertebrates. Its function as an essential cofactor for APOBEC1 in C to U RNA editing of several targets through substitution for A1CF in the A1CF-APOBEC1 editosome, established a new paradigm in the field. Recent advances in the understanding of its involvement in cancer progression assigned RBM47 to be a tumor suppressor that acts by inhibiting EMT and Wnt/[Formula: see text]-catenin signaling through post-transcriptional regulation. RBM47 is also required to maintain immune homeostasis, which adds another facet to its regulatory role in cellular functions. Here, we review the emerging roles of RBM47 in various biological contexts and discuss the current gaps in our knowledge alongside future perspectives for the field.

Evaluating the Performance of Hybrid Capture 2 Test as a Primary Screening Test from Studies Conducted in Low and Middle-Income Country Settings- Special Focus India.

Among the screening tests for cervical cancer, advantages of screening with second generation molecular Hybrid Capture 2 (HC2) test is the high sensitivity and negative predictive value that makes it easy to implement as a cervical cancer screening policy necessitating less screening rounds. High income countries are now implementing HC2 test in their national cervical cancer screening program. Since the acceptance of any screening test depends on the sensitivity of the test, the current study was carried out to evaluate the sensitivity of HC2 test reported from Low- and Middle-income countries (LMIC) which share major burden of cervical cancer globally and to establish if HC2 test could be used as a primary screening test in India. MATERIALS AND METHODS: The population based cross sectional studies from LMICs which evaluated HC2 test as a primary screening modality to diagnose Cervical intraepithelial neoplasm grade 2 and above (CIN2+) lesions were included. RESULTS: A total of 18 studies from LMIC involving 1,13,086 women were reviewed for sensitivity of HC2 as a primary screening test. The overall average sensitivity and specificity to diagnose CIN2+ lesions were 79.84% (95% CI-71.01,86.73) and 85.63% (95% CI- 84.37,86.92) respectively. India demonstrated an average sensitivity and specificity of 65% (95% CI 57,77) and 93% (95% CI- 92,94) respectively. CONCLUSION: Results from LMIC demonstrate a comparably low sensitivity of HC2 test to diagnose CIN2+ lesions as compared to that reported from High income countries. Sensitivity of HC2 was substantially low for India. The current study discusses issues of HC2 assay and the role of untreated Reproductive tract infections as probable causes for low sensitivity of the test. This needs further research in an attempt to improve the sensitivity of the test in an era of self-sampling and low-cost HPV test on horizon to improve the coverage for cervical cancer.
.

Determinants of Compliance to Population-Based Oral Cancer Screening Program among low Socioeconomic Women in Mumbai, India.

BACKGROUND: The use of tobacco, especially smokeless variety, is common and culturally accepted among Indian women. Hence, oral cavity cancers rank as the fourth most common cancers among Indian women. OBJECTIVES: The objectives of this study were to study factors determining compliance of women for oral cancer screening in a population-based program in Mumbai and to create awareness among women regarding ill effects of tobacco and importance of oral cancer screening. MATERIALS AND METHODS: This is a community-based organized service program for awareness and screening of oral cavity cancers among women residing in low socioeconomic areas of Mumbai, India. Screening was conducted by oral visual inspection by trained primary health workers (PHWs). Univariate and multivariate logistic regression analyses were conducted to identify predictors of participation in oral cancer screening. RESULTS: 138,383 population was surveyed, out of which 13,492 eligible women were enlisted for oral cancer screening. Among these, 12,495 were contacted and 11,895 (95.12%) women participated in a cancer awareness program and 11,768 (94.18%) participated in oral cancer screening. According to results of multivariate logistic regression analysis, women belonging to Hindu religion 94.57%, with mother tongue Marathi 94.76%, and with family history of cancer 95.84% complied significantly higher to oral cancer screening as compared to other women. CONCLUSION: This program has assisted in identifying predictors of compliance to oral cavity screening. Furthermore, it demonstrates that good compliance can be achieved through multiple household visits, personal invitation during camps, organizing well-planned Health Education Program, and the use of simple, low-cost visual inspection test performed by trained PHWs.

Pilot approach to analyzing patient and citizen involvement in health technology assessment in four diverse low- and middle-income countries.

BACKGROUND: In low- and middle-income countries (LMICs) striving to achieve universal health coverage, the involvement of different stakeholders in formal or informal ways in health technology assessment (HTA) must be culturally and socially relevant and acceptable. Challenges may be different from those seen in high-income countries. In this article, we aimed to pilot a questionnaire for uncovering the context-related aspects of patient and citizen involvement (PCI) in LMICs, collecting experiences encountered with PCI, and identifying opportunities for patients and citizens toward contributing to local decision- and policy-making processes related to health technologies. METHODS: Through a collaborative, international multi-stakeholder initiative, a questionnaire was developed for describing each LMIC's healthcare system context and the emergence of opportunities for PCI relating to HTA. The questionnaire was piloted in the first set of countries (Brazil, Indonesia, Nigeria, and South Africa). RESULTS: The questionnaire was successfully applied across four diverse LMICs, which are at different stages of using HTA to inform decision making. Only in Brazil, formal ways of PCI have been defined. In the other countries, there is informal influence that is contingent upon the engagement level of patient and citizen advocacy groups (PCAGs), usually strongest in areas such as HIV/AIDS, TB, oncology, or rare diseases. CONCLUSIONS: The questionnaire can be used to analyze the options for patients and citizens to participate in HTA or healthcare decision making. It will be rolled out to more LMICs to describe the requirements and opportunities for PCI in the context of LMICs and to identify possible routes and methodologies for devising a more systematic and formalized PCI in LMICs.

Hybrid control approaches for hands-free high level human-computer interface-a review.

For more than a decade, more number of human-machine interfaces had been developed by various combination of user inputs such as speech, hand and head gestures, eye gaze and body movements, etc. And many research issues have been addressed, including facial expression recognition, human emotion analysis, speech recognition/synthesis, human-computer interaction, virtual reality and augmented reality interaction, etc. As a result, the development of a hybrid approach becomes a central issue for hands-free high-level human computer, to help elderly and disabled people. They characterise the user's preferred communication style and support user's ability to flexibly combine modes or to switch from one input mode to another that may be better suited to a particular task or setting. This review discusses the various hybrid control approaches of hands-free high level human-computer interface.

Evidence based appropriate triage strategies for implementing high risk HPV as primary technology in cervical cancer screening.

Primary cervical cancer screening by HPV testing for high risk human papillomavirus (hrHPV) is expected to replace cytology-based programs in many parts of the world. Its high sensitivity and negative predictive value permit longer screening intervals up to beyond five years. However, low positive predictive value can lead to unnecessary referrals and overtreatment since most hrHPV infections are transient and will not develop disease. Therefore risk stratification is needed to effectively triage and identify women among the hrHPV positives, who are at an increased risk of cervical (pre)cancer who need further diagnostic evaluation to decide on further management. Several triage strategies like HPV16/18 genotyping, p16/Ki67 dual staining and DNA methylation markers (CADM1, MAL and miR-124-2) have been evaluated to determine suitable triage options. Triage with p16/Ki-67 dual-stain provided better long-term risk stratification than cytology with significant reduction in cumulative 5 years CIN3+ risk in p16/Ki-67 negative women. DNA methylation assays have shown higher specificity than cytology and higher sensitivity than HPV16/18 genotyping with added advantages of reproducibility and application on self-collected samples. Based on current evidence, Pap cytology with or without additional HPV16/18 genotyping remains the most recommended triage strategies for primary HPV screening. Other strategies will need more longitudinal studies to provide evidence of risk reduction in test negative results. WHO recommends Visual Inspection with Acetic Acid (VIA) for triaging HPV-positive women in LMIC settings. An optimal triage strategy that can be integrated with primary HPV screening should be able to segregate and reassure the large majority of women who are at very low risk of cervical cancer.

Functional balance between Tcf21-Slug defines cellular plasticity and migratory modalities in high grade serous ovarian cancer cell lines.

Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis that can be initiated by single cell epithelial to mesenchymal transition (EMT) or cooperative cell migration (CCM). Our study identifies novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma (HGSC). Differential expression and subcellular localization associate Tcf21, Slug with epithelial, mesenchymal phenotypes, respectively; however, gene manipulation approaches identify their association with additional intermediate phenotypic states, implying the existence of a multistep epithelial-mesenchymal transition program. Live imaging further associated distinct migratory modalities with the Tcf21/Slug status of cell systems and discerned proliferative/passive CCM, active CCM and EMT modes of migration. Tcf21-Slug balance identified across a phenotypic spectrum in HGSC cell lines, associated with microenvironment-induced transitions and the emergence of an epithelial phenotype following drug exposure. Phenotypic transitions and associated functionalities following drug exposure were affirmed to ensue from occupancy of Slug promoter E-box sequences by Tcf21. Our study effectively provides a framework for understanding the relevance of ovarian cancer plasticity as a function of two transcription factors.

Optimizing high risk HPV-based primary screening for cervical cancer in low- and middle-income countries: opportunities and challenges.

Disparities in the incidence and mortality due to cervical cancer between developed and developing countries continue to persist due to suboptimal health care systems in low- to middle-income countries (LMICs) that are unable to implement organized programs for screening which lack the technical, infrastructure and financial resources for adequate coverage and access to quality assured cervical cancer screening services that further reduce their effectiveness. The challenges in introducing quality cytology screening in LMICs led to the evaluation of alternative screening approaches such as visual inspection with acetic acid (VIA) and human papillomavirus (HPV) testing-based screening. Large-scale clinical trials have generated sufficient evidence of efficacy of HPV-based screening for the introduction as the primary technology in cervical cancer screening. Being more objective, automated with better sensitivity than cytology requiring fewer rounds of screening and opportunity for self-sampling, HPV testing is thus poised to be more cost-effective in providing opportunity for wider coverage, making it ideal for incorporating into primary screening programs of LMIC settings that could help reduce regional disparities. But its optimal implementation in public health programmatic settings in LMIC still faces barriers due to high operating cost and logistic challenges. This review summarizes and presents evidence for HPV primary screening leading to higher program efficiency in cervical cancer screening programs. Policy measures and strategies to overcome the resource limitations and weaknesses in health care service delivery in low resource settings need to be assessed and streamlined to leverage the initial high program costs with that of the long term potential benefits for HPV DNA testing to reach its full potential in reducing cervical cancer incidence and mortality.