Nuclear lamin A/C phosphorylation by loss of androgen receptor leads to cancer-associated fibroblast activation.

Alterations in nuclear structure and function are hallmarks of cancer cells. Little is known about these changes in Cancer-Associated Fibroblasts (CAFs), crucial components of the tumor microenvironment. Loss of the androgen receptor (AR) in human dermal fibroblasts (HDFs), which triggers early steps of CAF activation, leads to nuclear membrane changes and micronuclei formation, independent of cellular senescence. Similar changes occur in established CAFs and are reversed by restoring AR activity. AR associates with nuclear lamin A/C, and its loss causes lamin A/C nucleoplasmic redistribution. AR serves as a bridge between lamin A/C and the protein phosphatase PPP1. Loss of AR decreases lamin-PPP1 association and increases lamin A/C phosphorylation at Ser 301, a characteristic of CAFs. Phosphorylated lamin A/C at Ser 301 binds to the regulatory region of CAF effector genes of the myofibroblast subtype. Expression of a lamin A/C Ser301 phosphomimetic mutant alone can transform normal fibroblasts into tumor-promoting CAFs.

Corrigendum to: "Endoscopic duodenal mucosal resurfacing improves glycaemic and hepatic indices in type 2 diabetes: 6-month multicentre results" [JHEP Reports 5 (2019) 101041].

[This corrects the article DOI: 10.1016/j.jhepr.2019.10.006.].

Drug use survey to identify significant drug-drug interactions and assess clinical importance in the outpatient setting of a tertiary care hospital.

OBJECTIVES: Drug-drug interactions (DDIs) are a common problem in pharmacotherapy, particularly in situations where multiple disorders must be treated at the same time. We conducted a drug use survey in the general medicine outpatient department of a tertiary care hospital with the objective of assessing the potential for DDI in individual prescriptions for adult patients. MATERIALS AND METHODS: Drugs prescribed in the current physician-patient encounter were considered in conjunction with medicines already being received by the patient as well as those discontinued in the past 1 month. Free online DDI checkers (available at https://www.drugs.com/drug_interactions.html and https://reference.medscape.com/) were used to identify potential DDI and categorize them into mild, moderate, and severe categories. We did not consider food, alcohol, or smoking-related interactions. RESULTS: A total of 153 prescriptions, having two or more drugs, were collected, and they accounted for 1052 prescribed drugs. Among them, 613 (58.27%) were prescribed in index visits, and the rest 438 (41.63%) were preexisting medication. The number of drugs prescribed in index visits ranged from 1 to 9 (mean ± standard deviation [SD] 4.0 ± 1.86; median 4). Potential DDIs were identified in 103 (67.32%) instances. The total number of interactions identified was 412. Of these, 19.66% had minor, 77.67% moderate, and 7.19% major clinical implications. Potential DDI count in each prescription was found from 0 to 13 in number (mean ± SD 2.7 ± 3.12; median 2.0). This number correlated strongly with the number of drugs being received by individual subjects (Rho 0.744; P < 0.001). CONCLUSIONS: Potential DDIs are a reality in day to day prescribing practice. Substantial proportion of these DDIs may have significant clinical implications. Prescribers need to be sensitized to this issue. Combining human expertise with technological solutions such as automated drug interaction alerts can help rectify the situation. Similar surveys are needed on a periodic basis to improve medication safety for patients.

Tracking Missing Deaths: An Exploratory Study on the Mortality Impact of COVID-19 in Kozhikode City, India.

BACKGROUND: The debate over the extent of the mortality impact of COVID-19 in India is still unsettled. OBJECTIVES: This article contributes to the debate, seeking to explore the true mortality impact of the pandemic, by answering four interrelated questions. First, is there any discrepancy between recorded and actual death count? Second, if so, how large it is? Third, what is the extent of misclassification of COVID-19 mortality, and fourth, what is the magnitude of deaths that could be indirectly linked to COVID-19? MATERIALS AND METHODS: To answer the questions, we explored three sources of data-all-cause mortality data from the civil registration system, records maintained at the burial grounds/cemeteries and crematoriums, and a household survey. The data collection period was between August 2021 and November 2021. The instrument used for data collection of verbal autopsies was built on the instrument proposed by the World Health Organization for adult mortality. RESULTS: The results revealed that deaths due to various causes including COVID-19 increased considerably at some points in 2020-2021 compared to the base year 2019 in the study setting. Notably, 5.5% of the noninstitutional deaths were unreported at the time of the survey and many deaths were plausibly misclassified, leading to undercounting of COVID-19 deaths. Overall, about half of our sampled deaths (48%) had either direct or indirect attribution to the pandemic. CONCLUSION: The extent of undercounting of pandemic-related deaths is likely to be either similar or worse in other states. To get reliable state and national estimates, policymakers should conduct a large-scale study.

Neutral or Detrimental Effects of TREM2 Agonist Antibodies in Preclinical Models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.

A Study of Prevalence of Renal Function Abnormalities and Their Association with the Individual Components of Metabolic Syndrome.

INTRODUCTION: Metabolic syndrome (MetS) is one of the most important emerging pandemics of the 21st century and is associated with renal dysfunction in a significant number of subjects, the association of which is shown to be of greater significance in the South Asian population. AIMS AND OBJECTIVES: The prevalence of renal dysfunction in patients with MetS is the primary outcome. The secondary outcome is to assess the strength and significance of the association between the individual components of MetS and the presence of renal dysfunction. MATERIALS AND METHODS: This is a hospital-based cross-sectional observational study conducted for 2 years in a tertiary care hospital in India. A total of 100 diagnosed subjects of MetS were taken as cases and underwent relevant blood tests. Data were collected and analyzed in a Statistical Package for the Social Sciences (SPSS) v29 sheet. RESULTS: Over a period of 18 months, 100 subjects with MetS were documented, among which 66% had albuminuria, with microalbuminuria being 24% and the rest being macroalbuminuria. Among the same subjects, 30% had an estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73m2. Waist circumference (WC) [measured by the National Institutes of Health (NIH) protocol] had the strongest association with increased albuminuria (r = 0.540; p-value < 0.001) as well as reduced eGFR (r = 0.460; p-value < 0.001). CONCLUSION: All the components of MetS, for example, increased WC, hypertension, increased fasting glucose, raised triglyceride (TG), and low high-density lipoprotein (HDL), have statistically significant correlations with increased urine albumin-to-creatinine ratio (ACR) and decreased eGFR, signifying glomerular injury and renal dysfunction, respectively.

Stress hyperglycemia exacerbates inflammatory brain injury after stroke.

Post-stroke hyperglycemia occurs in 30% - 60% of ischemic stroke patients as part of the systemic stress response, but neither clinical evidence nor pre-clinical studies indicate whether post-stroke hyperglycemia affects stroke outcome. Here we investigated this issue using a mouse model of permanent ischemia. Mice were maintained either normoglycemic or hyperglycemic during the interval of 17 - 48 hours after ischemia onset. Post-stroke hyperglycemia was found to increase infarct volume, blood-brain barrier disruption, and hemorrhage formation, and to impair motor recovery. Post-stroke hyperglycemia also increased superoxide formation by peri-infarct microglia/macrophages. In contrast, post-stroke hyperglycemia did not increase superoxide formation or exacerbate motor impairment in p47 phox-/- mice, which cannot form an active superoxide-producing NADPH oxidase-2 complex. These results suggest that hyperglycemia occurring hours-to-days after ischemia can increase oxidative stress in peri-infarct tissues by fueling NADPH oxidase activity in reactive microglia/macrophages, and by this mechanism contribute to worsened functional outcome.

Predicting multi-label emojis, emotions, and sentiments in code-mixed texts using an emojifying sentiments framework.

In the era of social media, the use of emojis and code-mixed language has become essential in online communication. However, selecting the appropriate emoji that matches a particular sentiment or emotion in the code-mixed text can be difficult. This paper presents a novel task of predicting multiple emojis in English-Hindi code-mixed sentences and proposes a new dataset called SENTIMOJI, which extends the SemEval 2020 Task 9 SentiMix dataset. Our approach is based on exploiting the relationship between emotion, sentiment, and emojis to build an end-to-end framework. We replace the self-attention sublayers in the transformer encoder with simple linear transformations and use the RMS-layer norm instead of the normal layer norm. Moreover, we employ Gated Linear Unit and Fully Connected layers to predict emojis and identify the emotion and sentiment of a tweet. Our experimental results on the SENTIMOJI dataset demonstrate that the proposed multi-task framework outperforms the single-task framework. We also show that emojis are strongly linked to sentiment and emotion and that identifying sentiment and emotion can aid in accurately predicting the most suitable emoji. Our work contributes to the field of natural language processing and can help in the development of more effective tools for sentiment analysis and emotion recognition in code-mixed languages. The codes and data will be available at https://www.iitp.ac.in/~ai-nlp-ml/resources.html#SENTIMOJI to facilitate research.

ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation.

There are significant commonalities among several pathologies involving fibroblasts, ranging from auto-immune diseases to fibrosis and cancer. Early steps in cancer development and progression are closely linked to fibroblast senescence and transformation into tumor-promoting cancer-associated fibroblasts (CAFs), suppressed by the androgen receptor (AR). Here, we identify ANKRD1 as a mesenchymal-specific transcriptional coregulator under direct AR negative control in human dermal fibroblasts (HDFs) and a key driver of CAF conversion, independent of cellular senescence. ANKRD1 expression in CAFs is associated with poor survival in HNSCC, lung, and cervical SCC patients, and controls a specific gene expression program of myofibroblast CAFs (my-CAFs). ANKRD1 binds to the regulatory region of my-CAF effector genes in concert with AP-1 transcription factors, and promotes c-JUN and FOS association. Targeting ANKRD1 disrupts AP-1 complex formation, reverses CAF activation, and blocks the pro-tumorigenic properties of CAFs in an orthotopic skin cancer model. ANKRD1 thus represents a target for fibroblast-directed therapy in cancer and potentially beyond.

Cross-sectional study on the psychosocial factors, the severity of depression, and coping strategies among patients attempting suicide.

Background: With around 10-20 million individuals attempting suicide each year, suicide attempts have been considered a significant public health issue. A significant fraction of it is caused by depression. Life events and other psychosocial stressors were frequently linked to both depression and suicidal behavior. Coping strategies are cognitive, emotional, and behavioral approaches used to lessen and cope with the negative impacts of stressful situations. Aim: This study aimed to find the psychosocial factors, the severity of depression, and coping strategies among patients attempting suicide. Materials and Methods: Study design: This study was a hospital-based descriptive cross-sectional study. A total of 120 consecutive cases were selected using Patient Health Questionnaire 2 (PHQ-2) scales and assessed for severity of depression and coping strategies using the Hamilton Depression Rating Scale (HAM-D) and Coping Orientation to Problem Experienced Inventory (Brief-COPE) scales, respectively. Pearson's Chi-square or Fisher's exact test and independent-samples t-test have been performed to see the association between categorical and continuous variables. The Pearson correlation coefficient has been used to see the relationship between two continuous variables. Results: Most of the cases (33.3%) were found to be severely depressed. Among all the cases, the majority, that is, 90.8%, were using avoidant-type coping strategies and only 9.2% were using approach-type coping strategies. A significant positive correlation between the avoidant-type coping strategy and depression and a negative correlation between the approach-type coping strategy and depression was found. Conclusion: Patients with depression attempting suicide were found to utilize avoidant-type coping strategies to cope with life stresses. Hence, it is crucial to place greater emphasis on assessing coping strategies and focus on teaching approach-oriented coping strategies as a means to prevent suicidal attempts.