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Deenaz Zaidi,1,2 Hien Q Huynh,1 Matthew W Carroll,1 Shairaz Baksh,1,3,4 Eytan Wine1,2,5 1Department of Pediatrics, 2Department of Medicine, Centre of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR), 3Department of Biochemistry, 4Department of Oncology, Cancer Institute of Northern Alberta (CRINA), 5Department of Physiology, University of Alberta, Edmonton, AB, Canada Purpose: A significant feature of pediatric inflammatory bowel diseases (IBD), which include Crohn disease (CD), and ulcerative colitis (UC), is failure to suppress inflammation. The inability to regulate inflammation renders a major challenge toward establishing effective treatments in IBD. Nuclear factor kappa-light-chain-enhancer of activated B-cells-induced inflammation is inhibited by A20 through interactions with TAX1BP1 (Tax1-binding protein 1) and A20-binding inhibitor of NF-κβ activation (ABIN)-1 (A20 binding and inhibitor of NF-κβ) and upon phosphorylation by inhibitor of nuclear factor kappa-β kinase subunit beta (IKKβ), which stabilizes it. We hypothesized that dysregulation of A20 is an important factor in uncontrolled inflammation in pediatric IBD.Patients and methods: Gene expression of A20, IKKβ, ABIN-1, TAX1BP1, A20 protein, cytokine levels, and A20 phosphorylation was analyzed in the terminal ileum (TI) of 39 patients (14 non-IBD, 15 CD, and 10 UC). A20 expression and protein in T-84 cells and ex vivo biopsies of patients were measured after treatment with Escherichia coli strains or tumor necrosis factor (TNF)-α.Results: TNF-α levels and A20 expression were increased in the TI of CD patients. A20 protein levels and ABIN-1 expression were low, TAX1BP1 expression was high, and IKKβ was unchanged. A20 expression positively correlated with biopsy TNF-α levels and inflammatory markers in CD patients. A20 phosphorylation appeared lower in CD patients. A20 expression in TI biopsies from CD patients and T84 cells was triggered with E. coli, strain LF82, while A20 protein levels remained unchanged.Conclusion: We describe a potential mechanism related to failure of A20 to suppress inflammation in CD, characterized by high A20 expression and low A20 protein levels. The dysregulation of A20 is potentially due to alterations in ABIN-1, and infection with E. coli strain LF82 could affect the function and stability of A20. Our study signifies an important finding in A20 regulation in IBD, which prevents it from suppressing inflammation. Keywords: A20, ABIN-1, inflammation, NF-κβ, TAX1BP1, E. coli

This study investigates cognitive assessment disparities between literate and illiterate individuals through a comprehensive analysis of the Modified MMSE (MACE) and the HMSE. Using a sample of older adults, the research examines correlations in scores across various cognitive domains, revealing significant associations among literate subjects but nonsignificant correlations among illiterate individuals. Item differences between MACE and HMSE introduce biases in illiterate subjects' scoring profiles, rendering them more vulnerable to higher positivity on MACE than HMSE. The ranking and weighted percentage data highlight variations in subtest difficulty. Despite the small sample size, qualitative comparisons underscore the need for culturally and linguistically sensitive cognitive assessments tailored to diverse educational backgrounds. The study's implications for clinical practice and recommendations for future research are discussed, emphasizing the importance of nuanced interpretations in cognitive assessment. [ABSTRACT FROM AUTHOR]

This paper brings out the socio-economic condition of the exodus employees in Tamil Nadu. We analyse the income patterns, remittance structure, their consumption and nature of work especially in leather industries. Generally, Tamilnadu is boasting of good number of leather industries. It enables to improve the production of leather goods of very high quality. A large number of employees from northern states of India are travelling to Tamil Nadu for earning their lively hood. We came to know that large number of exodus labour arrive to Tamil Nadu through the informal networks which guide them in getting jobs in leather goods manufacturing industries. poor economic conditions in their native places and high wage rate and better employment opportunities in Tamil Nadu have been identified as few of the main reasons of their migration. Even after their migration, due to unsatisfied income level, the dwelling status of the exodus labourers are not much satisfactory, these exodus employees don't have good standard of living along with unhygienic sanitation. There are various reasons for the exodus labour to arrive in Tamil nadu. This paper tries to point out those factors and the post migration situation of these exodus labourers. [ABSTRACT FROM AUTHOR]

Abstract Background The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC) is associated with frequent treatment failures (~90% in metastatic cases), and these tumors frequently contain PTEN abnormalities. Results Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. Conclusion Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories.

RASSF1A is a recently identified 3p21.3 tumour suppressor gene frequently inactivated in a wide range of sporadic human cancers including non-small cell lung cancer (NSCLC) and neuroblastoma (NB). Little is known about the function of RASSF1A although preliminary data suggests that it may have multiple functions. To gain insights into RASSF1A function we have characterized the expression profile of RASSF1A expressing derivatives of the lung cancer cell line A549. Interrogation of a cDNA microarray containing over 6000 probes identified 66 genes showing at least a 2-fold change in expression. Among these were many genes with relevance to tumourigenesis. We confirmed the microarray results at the RNA level for 22 genes, the majority of these were also confirmed in silicon in other NSCLC cell lines. Furthermore we confirmed 10 genes at the RNA level in two NB cell lines indicating that these target genes have relevance in non-lung cell backgrounds. Protein analysis of 6 genes (Cyclin B3, TGM2, CBH2, DAPK1, TXN and CTSL) showed the changes induced by RASSF1A at the RNA level correlated with changes in protein expression in both NSCLC and NB cell lines. Induction of TGM2, CDH2 and DAPK1 by transient transfection of RASSF1A adds further support for the candidacy of these genes as true targets. We have identified and confirmed several novel targets for RASSF1A tumor suppressor gene and this should help towards understanding mechanisms that contribute to RASSF1A biological activity. [ABSTRACT FROM AUTHOR]

Ischemic stroke induces a debilitating neurological insult, where inflammatory processes contribute greatly to the expansion and growth of the injury. Receptor-interacting protein kinase 2 (RIPK2) is most well-known for its role as the obligate kinase for NOD1/2 pattern recognition receptor signaling and is implicated in the pathology of various inflammatory conditions. Compared to a sham-operated control, ischemic stroke resulted in a dramatic increase in the active, phosphorylated form of RIPK2, indicating that RIPK2 may be implicated in the response to stroke injury. Here, we assessed the effects of pharmacological inhibition of RIPK2 to improve post-stroke outcomes in mice subjected to experimental ischemic stroke. We found that treatment at the onset of reperfusion with a RIPK2 inhibitor, which inhibits the phosphorylation and activation of RIPK2, resulted in marked improvements in post-stroke behavioral outcomes compared to the vehicle-administered group assessed 24 h after stroke. RIPK2 inhibitor-treated mice exhibited dramatic reductions in infarct volume, concurrent with reduced damage to the blood-brain barrier, as evidenced by reduced levels of active matrix metalloproteinase-9 (MMP-9) and leakage of blood-borne albumin in the ipsilateral cortex. To explore the protective mechanism of RIPK2 inhibition, we next pretreated mice with RIPK2 inhibitor or vehicle and examined transcriptomic alterations occurring in the ischemic brain 6 h after stroke. We observed a dramatic reduction in neuroinflammatory markers in the ipsilateral cortex of the inhibitor-treated group while also attaining a comprehensive view of the vast transcriptomic alterations occurring in the brain with inhibitor treatment through bulk RNA-sequencing of the injured cortex. Overall, we provide significant novel evidence that RIPK2 may represent a viable target for post-stroke pharmacotherapy and potentially other neuroinflammatory conditions., Competing Interests: Declaration of competing interest Dr. Shairaz Baksh is the president and CEO of BioImmuno Designs, Inc., and is affiliated with Bio-Stream Diagnostics, Inc. The rest of the authors declare no competing financial interests., (Copyright © 2023. Published by Elsevier Inc.)

Overcoming the limited bioavailability and extensive metabolism of effective in vitro drugs remains a challenge that limits the translation of promising drugs into clinical trials. Resveratrol, despite its well-reported therapeutic benefits, is not metabolically stable and thus has not been utilized as an effective clinical drug. This is because it needs to be consumed in large amounts to overcome the burdens of bioavailability and conversion into less effective metabolites. Herein, we summarize the more relevant approaches to modify resveratrol, aiming to increase its biological and therapeutic efficacy. We discuss combination therapies, derivatization, and the use of resveratrol nanoparticles. Interestingly, the combination of resveratrol with established chemotherapeutic drugs has shown promising therapeutic effects on colon cancer (with oxaliplatin), liver cancer (with cisplatin, 5-FU), and gastric cancer (with doxorubicin). On the other hand, derivatizing resveratrol, including hydroxylation, amination, amidation, imidation, methoxylation, prenylation, halogenation, glycosylation, and oligomerization, differentially modifies its bioavailability and could be used for preferential therapeutic outcomes. Moreover, the encapsulation of resveratrol allows its trapping within different forms of shells for targeted therapy. Depending on the nanoparticle used, it can enhance its solubility and absorption, increasing its bioavailability and efficacy. These include polymers, metals, solid lipids, and other nanoparticles that have shown promising preclinical results, adding more "hype" to the research on resveratrol. This review provides a platform to compare the different approaches to allow directed research into better treatment options with resveratrol.

Importance: Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development., Competing Interests: See Acknowledgments for conflicts of interest.

Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.

Background: Post-COVID conditions (PCC) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about early treatment, inflammation, and PCC., Methods: Among 883 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of CCP vs. control plasma with available biospecimens and symptom data, the association between early COVID treatment, cytokine levels and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14 and day 90 using a multiplexed sandwich immuosassay (Mesoscale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between COVID treatment, cytokine levels and PCC were examined using multivariate logistic regression models., Results: One-third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and loss of smell (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis including diabetes, body mass index, race, and vaccine status, female sex (adjusted odds ratio[AOR]=2.70[1.93-3.81]), older age (AOR=1.32[1.17-1.50]), and elevated baseline levels of IL-6 (AOR=1.59[1.02-2.47]) were associated with development of PCC.There was a trend for decreased PCC in those with early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment., Conclusion: Increased IL-6 levels were associated with the development of PCC and there was a trend for decreased PCC with early CCP treatment in this predominately unvaccinated population. Future treatment studies should evaluate the effect of early treatment and anti-IL-6 therapies on PCC development., Competing Interests: Conflicts of Interest: Kelly Gebo- Consults for the Aspen Institute, Teach for America, served as a non-paid member of scientific advisory board for Pfizer and writes COVID management guidelines for UpToDate which are out of scope of paper. Sonya L. Heath- Nothing to disclose Yuriko Fukuta- Nothing to disclose Xianming Zhu- Nothing to disclose Sheriza Baksh- Nothing to disclose Alison G. Abraham- Consultant for Implementation Group Inc, Hirslanden Klinik, Zurich CH, & ELSEVIER, Feben Habtehyimer- Nothing to disclose David Shade- Nothing to disclose Jessica Ruff- Nothing to disclose Malathi Ram- Nothing to disclose Oliver Laeyendecker- Nothing to disclose Reinaldo E. Fernandez- Nothing to disclose Eshan U. Patel- Nothing to disclose Owen R. Baker- Nothing to disclose Shmuel Shoham- Served on a CCP guideline panel Edward R. Cachay- has received unrestricted research grants from Gilead and Merck paid to the Regents of the University of California. He also participated in an advisory board to Theratechnologies for an unrelated topic. Judith S. Currier- Consulted for Merck and Company in 2021, currently not on any guidelines panel Jonathan M. Gerber- Nothing to disclose Thomas J. Gniadek- Currently employed by Fenwal, Inc., a Fresenius Kabi Company. Barry Meisenberg- Nothing to disclose Donald N. Forthal- nothing to disclose Laura L. Hammitt- research funding to my institution from AstraZeneca, CDC, Merck, NIH, and Pfizer. Moises A. Huaman- M.A.H. reports contracts from Gilead Sciences Inc, Insmed Inc, AN2 Therapeutics, Inc to the University of Cincinnati, outside the submitted work. Adam Levine- Nothing to disclose Giselle S. Mosnaim- Received research grant support from Teva, Alk-Abello, and Genentech and currently receives research grant support from Novartis, GlaxoSmithKline, and Sanofi-Regeneron. Serves as Immediate Past President of the American Academy of Allergy Asthma and Immunology and Co-Chair of the Continuous Assessment Program Examination for the American Board of Allergy and Immunology Bela Patel- Part of COVID trials and PAH trials, no disclosures relevant to CP James H. Paxton- Research funding from MindRhythm, Inc Jay S. Raval- Consultant and Advisor with Sanofi Genzyme; Board of Directors Member with the American Society for Apheresis, no overlap with CP Catherine G. Sutcliffe- Nothing to disclose Shweta Anjan- Nothing to disclose Seble Kassaye- Helped to produce educational materials related to HIV with Integritas Communications, LLC and Vindico Medical Education, LLC Janis E. Blair- Nothing to disclose Karen Lane- nothing to disclose Nichol A. McBee- Nothing to disclose Amy L. Gawad- Nothing to disclose Piyali Das- Nothing to disclose Sabra L. Klein- Nothing to disclose Andrew Pekosz- Nothing to disclose Arturo Casadevall- Serve on the scientific advisory board of SAB Therapeutics Evan M. Bloch- EMB reports personal fees and non-financial support from Terumo BCT, Abbott Laboratories, Tegus and UptoDate, outside of the submitted work. EMB is a member of the United States Food and Drug Administration (FDA) Blood Products Advisory Committee. Served on a CCP guideline panel Daniel Hanley- Dr. Hanley reports personal fees from Neurelis, Neurotrope, and medicolegal consulting. Aaron A.R. Tobian- Served on a CCP guideline panel David J. Sullivan- Founder and Board member with stock options (macrolide for malaria) DJS reports AliquantumRx, Hemex Health malaria diagnostics consulting and royalties for malaria diagnostic test control standards to Alere- all outside of submitted work