Understanding the variant landscape, and genetic epidemiology of Multiple Endocrine Neoplasia in India.

PURPOSE: Multiple Endocrine Neoplasia (MEN) is a group of familial cancer syndromes that encompasses several types of endocrine tumors differentiated by genetic mutations in RET, MEN1 and CDKN1B genes. Accurate diagnosis of MEN subtypes can thus be performed through genetic testing. However, MEN variants remain largely understudied in Indian populations. Additionally, few dedicated resources to understand these disorders currently exist. METHODS: Using the gold-standard ACMG/AMP guidelines, we systematically classified variants reported across the three genes in the IndiGen dataset, and established the genetic epidemiology of MEN in the Indian population. We further classified ClinVar and Mastermind variants and compiled all into a database. Finally, we designed a multiplex primer panel for rapid variant identification. RESULTS: We have established the genetic prevalence of MEN as the following: 1 in 1026 individuals is likely to be afflicted with MEN linked with pathogenic RET mutations. We have further created the MAPVar database containing 3280 ACMG-classified variants freely accessible at: https://clingen.igib.res.in/MAPVar/ . Finally, our NGS primer panel covers 33 exonic regions across two pools through 38 amplicons with a total amplified region of 65 kb. CONCLUSION: Our work establishes that MEN is a prevalent disorder in India. The rare nature of Indian variants underscores the need of genomic and functional studies to establish a more comprehensive variant landscape. Additionally, our panel offers a means of cost-effective genetic testing, and the MAPVar database a ready reference to aid in a better understanding of variant pathogenicity in clinical as well as research settings.

Failure rate of isolated medial meniscus repair in the stable knee: Systematic review and meta-analysis.

PURPOSE: The present meta-analysis aims to determine the outcomes and failure rates for medial meniscus repairs in patients with stable knees. METHODS: A literature search was conducted using PubMed and Scopus with the terms '(medial meniscus OR medial meniscal) AND (repair)'. The search strategy was based on the PRISMA (Preferred Reporting Items for Systematic Meta-Analyses) protocol and included 93 articles assessed for eligibility. The search criteria were limited to studies reporting outcomes and failure rates. The exclusion criteria included languages other than English, biomechanical studies, letters to editors, non-full text, review articles, meta-analyses and case reports. RESULTS: In total, 10 studies with 595 patients were included. Degenerative tears or studies reporting meniscus repair outcomes on root repairs, revision or primary anterior cruciate ligament reconstruction, discoid menisci or ramp lesions were excluded. All studies included revision surgery and/or clinical symptoms as failure definitions. The overall medial meniscal repair failure rate was 26% with a 95% confidence interval (CI) [15%-37%]. The mean time to failure from isolated medial meniscus repair surgery was 27.7 months with 95% CI [18.5-36.9 months]. The postoperative Lysholm and IKDC scores were reported in three articles. At the final follow-up, the mean postoperative Lysholm and IKDC scores were 92.3 with 95% CI [84.5-100] and 88.6 with 95% CI [83.5-93.8], respectively. CONCLUSION: The current meta-analysis revealed an overall failure rate of 26% in the case of medial meniscus repair in a stable knee. For these reasons, the patient should be aware of the substantial risk of revision surgery (one out of four cases). Medial meniscus repair in a stable knee yielded good clinical results. LEVEL OF EVIDENCE: II.

Effect of Timing of Surgery on the Outcomes and Complications in Multi-ligament Knee Injuries: An Overview of Systematic Reviews and A Meta-analysis.

Background and Aims: Multi-ligament knee injuries (MLKI) are serious and challenging to manage. This study aimed to elucidate the impact of surgical timing on both early and long-term outcomes following an MLKI. Methods: A comprehensive search strategy was employed across PubMed, Scopus, Web of Science, and the Cochrane Library. Studies were identified using a combination of relevant keywords encompassing "multi-ligament knee injury," "knee dislocation," "reconstruction," "repair," "surgery," and "timing," and their synonyms, along with appropriate Boolean operators. Selection of articles (systematic reviews and meta-analyses) adhered to predefined inclusion and exclusion criteria. Furthermore, a meta-analysis was conducted utilizing data extracted from primary studies. Results: Early surgery for MLKI demonstrated a significant advantage over delayed surgery, reflected by significantly higher Lysholm scores (Mean Difference [MD] 3.51; 95% Confidence Interval [CI] 1.79, 5.22), IKDC objective scores (Mantel-Haenszel Odds Ratio [MH-OR] 2.95; 95% CI 1.30, 6.69), Tegner activity scores (MD 0.38; 95% CI 0.08, 0.69), and Mayer's ratings (MH-OR 5.47; 95% CI 1.27, 23.56). In addition, we found a significantly reduced risk of secondary chondral lesions (MH-OR 0.33; 95% CI 0.23, 0.48), lower instrumented anterior tibial translation in the early surgery group (MD -0.92; 95% CI -1.83, -0.01), but no significant difference was observed in the secondary meniscal tears, between the two groups. However, the early surgery group also exhibited a significantly increased risk of knee stiffness (MH-OR 2.47; 95% CI 1.22, 5.01) and a greater likelihood of requiring manipulation under anaesthesia (MH-OR 3.91; 95% CI 1.10, 13.87). Conclusion: Early surgery for MLKI improves function, and stability, and reduces further articular cartilage damage, but increases the risk of stiffness. Level of Evidence: IV. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-024-01224-1.

Pulmonary mucormycosis eroding the chest wall: challenges in the management.

Pulmonary mucormycosis is a rare, life-threatening fungal infection usually seen in immunocompromised patients. Mortality in such patients is high due to underlying immunosuppression and poor general condition of the patients. Invasion of the adjacent structures is known but, to the best of our knowledge, pulmonary mucormycosis presenting with a full thickness chest wall erosion has not been reported. We report such a case with chest wall destruction with superadded bacterial infection. The use of prosthetic materials for chest wall reconstruction was not possible due to the presence of infection. In addition, there were other intra-operative and post-operative challenges which we managed using a multidisciplinary approach. This report highlights the successful outcome of this complex situation using pre-operative optimisation, adequate surgical debridement and effective management of post-operative complications with patience and perseverance.

Drug tolerance and persistence in bacteria, fungi and cancer cells: Role of non-genetic heterogeneity.

A common feature of bacterial, fungal and cancer cell populations upon treatment is the presence of tolerant and persistent cells able to survive, and sometimes grow, even in the presence of usually inhibitory or lethal drug concentrations, driven by non-genetic differences among individual cells in a population. Here we review and compare data obtained on drug survival in bacteria, fungi and cancer cells to unravel common characteristics and cellular pathways, and to point their singularities. This comparative work also allows to cross-fertilize ideas across fields. We particularly focus on the role of gene expression variability in the emergence of cell-cell non-genetic heterogeneity because it represents a possible common basic molecular process at the origin of most persistence phenomena and could be monitored and tuned to help improve therapeutic interventions.

Reconstruction of single-cell lineage trajectories and identification of diversity in fates during the epithelial-to-mesenchymal transition.

Exploring the complexity of the epithelial-to-mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single-cell RNA sequencing is challenging due to the necessity of sacrificing cells for each measurement. In this study, we employed optimal-transport analysis to reconstruct the past trajectories of different cell fates during TGF-beta-induced EMT in the MCF10A cell line. Our analysis revealed three distinct trajectories leading to low EMT, partial EMT, and high EMT states. Cells along the partial EMT trajectory showed substantial variations in the EMT signature and exhibited pronounced stemness. Throughout this EMT trajectory, we observed a consistent downregulation of the EED and EZH2 genes. This finding was validated by recent inhibitor screens of EMT regulators and CRISPR screen studies. Moreover, we applied our analysis of early-phase differential gene expression to gene sets associated with stemness and proliferation, pinpointing ITGB4, LAMA3, and LAMB3 as genes differentially expressed in the initial stages of the partial versus high EMT trajectories. We also found that CENPF, CKS1B, and MKI67 showed significant upregulation in the high EMT trajectory. While the first group of genes aligns with findings from previous studies, our work uniquely pinpoints the precise timing of these upregulations. Finally, the identification of the latter group of genes sheds light on potential cell cycle targets for modulating EMT trajectories.

Minimal transcriptional regulation of horizontally transferred photosynthesis genes in phototrophic bacterium Gemmatimonas phototrophica.

The first phototrophic member of the bacterial phylum Gemmatimonadota, Gemmatimonas phototrophica AP64T, received all its photosynthesis genes via distant horizontal gene transfer from a purple bacterium. Here, we investigated how these acquired genes, which are tightly controlled by oxygen and light in the ancestor, are integrated into the regulatory system of its new host. G. phototrophica grew well under aerobic and semiaerobic conditions, with almost no difference in gene expression. Under aerobic conditions, the growth of G. phototrophica was optimal at 80 µmol photon m-2 s-1, while higher light intensities had an inhibitory effect. The transcriptome showed only a minimal response to the dark-light shift at optimal light intensity, while the exposure to a higher light intensity (200 µmol photon m-2 s-1) induced already stronger but still transient changes in gene expression. Interestingly, a singlet oxygen defense was not activated under any conditions tested. Our results indicate that G. phototrophica possesses neither the oxygen-dependent repression of photosynthesis genes known from purple bacteria nor the light-dependent repression described in aerobic anoxygenic phototrophs. Instead, G. phototrophica has evolved as a low-light species preferring reduced oxygen concentrations. Under these conditions, the bacterium can safely employ its photoheterotrophic metabolism without the need for complex regulatory mechanisms. IMPORTANCE: Horizontal gene transfer is one of the main mechanisms by which bacteria acquire new genes. However, it represents only the first step as the transferred genes have also to be functionally and regulatory integrated into the recipient's cellular machinery. Gemmatimonas phototrophica, a member of bacterial phylum Gemmatimonadota, acquired its photosynthesis genes via distant horizontal gene transfer from a purple bacterium. Thus, it represents a unique natural experiment, in which the entire package of photosynthesis genes was transplanted into a distant host. We show that G. phototrophica lacks the regulation of photosynthesis gene expressions in response to oxygen concentration and light intensity that are common in purple bacteria. This restricts its growth to low-light habitats with reduced oxygen. Understanding the regulation of horizontally transferred genes is important not only for microbial evolution but also for synthetic biology and the engineering of novel organisms, as these rely on the successful integration of foreign genes.

Comparative Analysis of Mouth Self-Examination Awareness Amongst Tobacco Users in Urban and Rural Populations.

BACKGROUND: Oral cavity cancer is a growing concern, especially in developing countries like India, due to risk factors such as tobacco use, alcohol consumption, nutritional deficiencies, and spicy food intake. Early detection through screening and Mouth Self-examination (MSE) can significantly improve outcomes, but limited awareness and pain in advanced stages lead to delayed detection. This study aimed to assess the knowledge and practice of MSE among tobacco users in urban and rural populations. MATERIALS AND METHODS: A comparative cross-sectional study was conducted involving tobacco users (smoking, smokeless, or both). An observational questionnaire-based approach was employed, with informed consent obtained from participants. A questionnaire in Hindi and English was used, consisting of demographic details and 13 close-ended questions. RESULTS: The analysis revealed that individuals from urban areas (71.9%) exhibited significantly higher awareness of Mouth self- examination (MSE) compared to those from rural areas (1.9%). Chi-square analysis demonstrated that urban residents exhibited significantly higher awareness, understanding, confidence, desire for information, and positive attitudes towards Mouth Self-Examination (MSE) compared to rural residents. Multivariate analysis showed that education had a consistent and substantial impact on both knowledge and practice scores. CONCLUSION: The study highlights substantial urban-rural disparities in mouth self- examination (MSE) awareness and attitudes, with urban residents demonstrating significantly higher levels. Targeted interventions and awareness campaigns are vital to bridge this gap and improve oral health practices, especially in rural areas.

Increased prevalence of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer.

Intra-tumoral phenotypic heterogeneity promotes tumor relapse and therapeutic resistance and remains an unsolved clinical challenge. Decoding the interconnections among different biological axes of plasticity is crucial to understand the molecular origins of phenotypic heterogeneity. Here, we use multi-modal transcriptomic data-bulk, single-cell, and spatial transcriptomics-from breast cancer cell lines and primary tumor samples, to identify associations between epithelial-mesenchymal transition (EMT) and luminal-basal plasticity-two key processes that enable heterogeneity. We show that luminal breast cancer strongly associates with an epithelial cell state, but basal breast cancer is associated with hybrid epithelial/mesenchymal phenotype(s) and higher phenotypic heterogeneity. Mathematical modeling of core underlying gene regulatory networks representative of the crosstalk between the luminal-basal and epithelial-mesenchymal axes elucidate mechanistic underpinnings of the observed associations from transcriptomic data. Our systems-based approach integrating multi-modal data analysis with mechanism-based modeling offers a predictive framework to characterize intra-tumor heterogeneity and identify interventions to restrict it.

Correction: Jain et al. Proteomic Approach for Comparative Analysis of the Spike Protein of SARS-CoV-2 Omicron (B.1.1.529) Variant and Other Pango Lineages. Proteomes 2022, 10, 34.

In the publication [...].

Cell-state transitions and density-dependent interactions together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity.

Cancer cell populations comprise phenotypes distributed among the epithelial-mesenchymal (E-M) spectrum. However, it remains unclear which population-level processes give rise to the observed experimental distribution and dynamical changes in E-M heterogeneity, including (1) differential growth, (2) cell-state switching, and (3) population density-dependent growth or state-transition rates. Here, we analyze the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that, while cell-state transition is necessary to reproduce experimental observations of dynamical changes in E-M fractions, including density-dependent growth interactions (cooperation or suppression) better explains the data. Further, our models predict that treatment of HCC38 cells with transforming growth factor ß (TGF-ß) signaling and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/3) inhibitors enhances the rate of mesenchymal-epithelial transition (MET) instead of lowering that of E-M transition (EMT). Overall, our study identifies the population-level processes shaping the dynamics of spontaneous E-M heterogeneity in breast cancer cells.

Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities.

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.

Variations in origin level of superior mesenteric artery, inferior mesenteric artery, and coeliac trunk in Indian population.

OBJECTIVE: The abdominal aorta is a continuation of the thoracic aorta and gives off the coeliac trunk, superior mesenteric artery, and inferior mesenteric artery. The focus of our study is to evaluate variations in the origin level in the coeliac trunk, superior mesenteric artery, inferior mesenteric artery, and aortic bifurcation in the Indian population and compare with various demographics. METHODS: The study was retrospective and the local ethics committee approval was taken before starting it. Three hundred patients who were more than 18 years of age and required contrast-enhanced CT studies were included in this. The vertebral origin level of the arteries from the abdominal aorta and aortic bifurcation level was analysed. RESULTS: The most common origin level of the coeliac trunk for both males and females was T12-L1 disc level. The most common origin level of the superior mesenteric artery was L1 upper level. The most common origin level of the inferior mesenteric artery was L3 upper level. The most common level of aortic bifurcation was L4 middle level. There was no statistical difference between the origin of any arteries in males and females in the Indian population. CONCLUSION: As per our study of the Indian population and the published literature, it is realized that there are significant variations in the origins of the coeliac trunk, superior mesenteric artery, inferior mesenteric artery, and abdominal aorta bifurcation in different populations. ADVANCES IN KNOWLEDGE: This study elaborates on potential anatomical variations in the Indian population, particularly the Mumbai city population. Also, our study compares it to different countries' data and their results in variations found in abdominal aorta branches.

Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing.

Cardiac channelopathies are a group of heritable disorders that affect the heart's electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.

Spectrum of rare and common mitochondrial DNA variations from 1029 whole genomes of self-declared healthy individuals from India.

Mitochondrial disorders are a class of heterogeneous disorders caused by genetic variations in the mitochondrial genome (mtDNA) as well as the nuclear genome. The spectrum of mtDNA variants remains unexplored in the Indian population. In the present study, we have cataloged 2689 high confidence single nucleotide variants, small insertions and deletions in mtDNA in 1029 healthy Indian individuals. We found a major proportion (76.5 %) of the variants being rare (AF<=0.005) in the studied population. Intriguingly, we found two 'confirmed' pathogenic variants (m.1555 A>G and m.14484 T>C) with a frequency of ∼1 in 250 individuals in our dataset. The high carrier frequency underscores the need for screening of the mtDNA pathogenic mutations in newborns in India. Interestingly, our analysis also revealed 202 variants in our dataset which have been 'reported' in disease cases as per the MITOMAP database. Additionally, we found the frequency of haplogroup M (52.2 %) to be the highest among all the 18 top-level haplogroups found in our dataset. In comparison to the global population datasets, 20 unique mtDNA variants are found in the Indian population. We hope the whole genome sequencing based compendium of mtDNA variants along with their allele frequencies and heteroplasmy levels in the Indian population will drive additional genome scale studies for mtDNA. Furthermore, the identification of clinically relevant variants in our dataset will aid in better clinical interpretation of the variants in mitochondrial disorders.

Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial-Mesenchymal Phenotype and Driving Malignant Progression in ER-Negative Breast Cancer.

Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial-mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state that is pivotal to the malignant transformation and tumour progression in the aggressive ER-negative subtype of breast cancer. The expression status and associated effects of miR-18a were evaluated in patient-derived breast tumour samples in combination with gene expression data from public datasets, and further validated in in vitro and in vivo breast cancer model systems. The clinical relevance of the study findings was corroborated against human breast tumour specimens (n = 446 patients). The down-regulated expression of miR-18a observed in ER-negative tumours was found to drive the enrichment of hybrid epithelial/mesenchymal (E/M) cells with luminal attributes, enhanced traits of migration, stemness, drug-resistance and immunosuppression. Further analysis of the miR-18a targets highlighted possible hypoxia-inducible factor 1-alpha (HIF-1α)-mediated signalling in these tumours. This is a foremost report that validates the dual role of miR-18a in breast cancer that is subtype-specific based on hormone receptor expression. The study also features a novel association of low miR-18a levels and subsequent enrichment of hybrid E/M cells, increased migration and stemness in a subgroup of ER-negative tumours that may be attributed to HIF-1α mediated signalling. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing miRNA signatures.

Synergistic Outcomes in Drug Delivery: Exploring Harmonious Architectures of Interpenetrating Polymer Networks.

Pharmaceutical excipients play a crucial role in determining the outcome of delivered therapeutic cargo density. By far, polymers have captured the biggest share in the excipients market. This surge in demand motivated researchers to look for newer and novel polymeric platforms. Interpenetrating polymeric networks (IPN) are a class of polymer in the same polymer blend league, where two different polymer chains penetrate; and align with each other without any sustainable covalent bond. The novel agreement between the polymer chains equips the IPN with the characteristic features of each participating polymer unit, thus making IPN superior to its predecessors. IPN has crossed a long path, especially in the pharmaceutical medicine field, from the mere coinage of the term to widespread usage, especially in drug delivery, where they increased the bioavailability and efficacy of the co-delivered drugs. The current review will highlight the major studies that have led to the current face of the IPN in various pharmaceutical domains. The present review was conducted by comprehensively reviewing published reports within the recent period using multiple keywords related to IPN and its role in drug delivery. Moving forward, continued exploration and innovation in IPN technologies promise to further enhance their applications, offering novel solutions for the challenges in drug delivery and therapeutic cargo density.

Spatial heterogeneity in tumor adhesion qualifies collective cell invasion.

Collective cell invasion (CCI), a canon of most invasive solid tumors, is an emergent property of the interactions between cancer cells and their surrounding extracellular matrix (ECM). However, tumor populations invariably consist of cells expressing variable levels of adhesive proteins that mediate such interactions, disallowing an intuitive understanding of how tumor invasiveness at a multicellular scale is influenced by spatial heterogeneity of cell-cell and cell-ECM adhesion. Here, we have used a Cellular Potts model-based multiscale computational framework that is constructed on the histopathological principles of glandular cancers. In earlier efforts on homogenous cancer cell populations, this framework revealed the relative ranges of interactions, including cell-cell and cell-ECM adhesion that drove collective, dispersed, and mixed multimodal invasion. Here, we constitute a tumor core of two separate cell subsets showing distinct intra- and inter-subset cell-cell or cell-ECM adhesion strengths. These two subsets of cells are arranged to varying extents of spatial intermingling, which we call the heterogeneity index (HI). We observe that low and high inter-subset cell adhesion favors invasion of high-HI and low-HI intermingled populations with distinct intra-subset cell-cell adhesion strengths, respectively. In addition, for explored values of cell-ECM adhesion strengths, populations with high HI values collectively invade better than those with lower HI values. We then asked how spatial invasion is regulated by progressively intermingled cellular subsets that are epithelial, i.e., showed high cell-cell but poor cell-ECM adhesion, and mesenchymal, i.e., with reversed adhesion strengths to the former. Here too, inter-subset adhesion plays an important role in contextualizing the proportionate relationship between HI and invasion. An exception to this relationship is seen for cases of heterogeneous cell-ECM adhesion where sub-maximal HI patterns with higher outer localization of cells with stronger ECM adhesion collectively invade better than their relatively higher-HI counterparts. Our simulations also reveal how adhesion heterogeneity qualifies collective invasion, when either cell-cell or cell-ECM adhesion type is varied but results in an invasive dispersion when both adhesion types are simultaneously altered.

Effectiveness of AI-powered Chatbots in responding to orthopaedic postgraduate exam questions-an observational study.

PURPOSE: This study analyses the performance and proficiency of the three Artificial Intelligence (AI) generative chatbots (ChatGPT-3.5, ChatGPT-4.0, Bard Google AI®) and in answering the Multiple Choice Questions (MCQs) of postgraduate (PG) level orthopaedic qualifying examinations. METHODS: A series of 120 mock Single Best Answer' (SBA) MCQs with four possible options named A, B, C and D as answers on various musculoskeletal (MSK) conditions covering Trauma and Orthopaedic curricula were compiled. A standardised text prompt was used to generate and feed ChatGPT (both 3.5 and 4.0 versions) and Google Bard programs, which were then statistically analysed. RESULTS: Significant differences were found between responses from Chat GPT 3.5 with Chat GPT 4.0 (Chi square = 27.2, P < 0.001) and on comparing both Chat GPT 3.5 (Chi square = 63.852, P < 0.001) with Chat GPT 4.0 (Chi square = 44.246, P < 0.001) with. Bard Google AI® had 100% efficiency and was significantly more efficient than both Chat GPT 3.5 with Chat GPT 4.0 (p < 0.0001). CONCLUSION: The results demonstrate the variable potential of the different AI generative chatbots (Chat GPT 3.5, Chat GPT 4.0 and Bard Google) in their ability to answer the MCQ of PG-level orthopaedic qualifying examinations. Bard Google AI® has shown superior performance than both ChatGPT versions, underlining the potential of such large language processing models in processing and applying orthopaedic subspecialty knowledge at a PG level.

Differential role of glucocorticoid receptor based on its cell type specific expression on tumor cells and infiltrating lymphocytes.

BACKGROUND: The glucocorticoid receptor (GR) is frequently expressed in breast cancer (BC), and its prognostic implications are contingent on estrogen receptor (ER) status. To address conflicting reports and explore therapeutic potential, a GR signature (GRsig) independent of ER status was developed. We also investigated cell type-specific GR protein expression in BC tumor epithelial cells and infiltrating lymphocytes. METHODS: GRsig was derived from Dexamethasone treated cell lines through a bioinformatic pipeline. Immunohistochemistry assessed GR protein expression. Associations between GRsig and tumor phenotypes (proliferation, cytolytic activity (CYT), immune cell distribution, and epithelial-to-mesenchymal transition (EMT) were explored in public datasets. Single-cell RNA sequencing data evaluated context-dependent GR roles, and a cell type-specific prognostic role was assessed in an independent BC cohort. RESULTS: High GRsig levels were associated with a favorable prognosis across BC subtypes. Tumor-specific high GRsig correlated with lower proliferation, increased CYT, and anti-tumorigenic immune cells. Single-cell data analysis revealed higher GRsig expression in immune cells, negatively correlating with EMT while a positive correlation was observed with EMT primarily in tumor and stromal cells. Univariate and multivariate analyses demonstrated the robust and independent predictive capability of GRsig for favorable prognosis. GR protein expression on immune cells in triple-negative tumors indicated a favorable prognosis. CONCLUSION: This study underscores the cell type-specific role of GR, where its expression on tumor cells is associated with aggressive features like EMT, while in infiltrating lymphocytes, it predicts a better prognosis, particularly within TNBC tumors. The GRsig emerges as a promising independent prognostic indicator across diverse BC subtypes.