Decoding dysregulated genes, molecular pathways and microRNAs involved in cervical cancer.

BACKGROUND: The present study aimed to identify dysregulated genes, molecular pathways, and regulatory mechanisms in human papillomavirus (HPV)-associated cervical cancers. We have investigated the disease-associated genes along with the Gene Ontology, survival prognosis, transcription factors and the microRNA (miRNA) that are involved in cervical carcinogenesis, enabling a deeper comprehension of cervical cancer linked to HPV. METHODS: We used 10 publicly accessible Gene Expression Omnibus (GEO) datasets to examine the patterns of gene expression in cervical cancer. Differentially expressed genes (DEGs), which showed a clear distinction between cervical cancer and healthy tissue samples, were analyzed using the GEO2R tool. Additional bioinformatic techniques were used to carry out pathway analysis and functional enrichment, as well as to analyze the connection between altered gene expression and HPV infection. RESULTS: In total, 48 DEGs were identified to be differentially expressed in cervical cancer tissues in comparison to healthy tissues. Among DEGs, CCND1, CCNA2 and SPP1 were the key dysregulated genes involved in HPV-associated cervical cancer. The five common miRNAs that were identified against these genes are miR-7-5p, miR-16-5p, miR-124-3p, miR-10b-5p and miR-27a-3p. The hub-DEGs targeted by miRNA hsa-miR-27a-3p are controlled by the common transcription factor SP1. CONCLUSIONS: The present study has identified DEGs involved in HPV-associated cervical cancer progression and the various molecular pathways and transcription factors regulating them. These findings have led to a better understanding of cervical cancer resulting in the development and identification of possible therapeutic and intervention targets, respectively.

Modifying lignin composition and xylan O-acetylation induces changes in cell wall composition, extractability, and digestibility.

BACKGROUND: Lignin and xylan are important determinants of cell wall structure and lignocellulosic biomass digestibility. Genetic manipulations that individually modify either lignin or xylan structure improve polysaccharide digestibility. However, the effects of their simultaneous modifications have not been explored in a similar context. Here, both individual and combinatorial modification in xylan and lignin was studied by analysing the effect on plant cell wall properties, biotic stress responses and integrity sensing. RESULTS: Arabidopsis plant co-harbouring mutation in FERULATE 5-HYDROXYLASE (F5H) and overexpressing Aspergillus niger acetyl xylan esterase (35S:AnAXE1) were generated and displayed normal growth attributes with intact xylem architecture. This fah1-2/35S:AnAXE1 cross was named as hyper G lignin and hypoacetylated (HrGHypAc) line. The HrGHypAc plants showed increased crystalline cellulose content with enhanced digestibility after chemical and enzymatic pre-treatment. Moreover, both parents and HrGHypAc without and after pre-treating with glucuronyl esterase and alpha glucuronidase exhibited an increase in xylose release after xylanase digestion as compared to wild type. The de-pectinated fraction in HrGHypAc displayed elevated levels of xylan and cellulose. Furthermore, the transcriptomic analysis revealed differential expression in cell wall biosynthetic, transcription factors and wall-associated kinases genes implying the role of lignin and xylan modification on cellular regulatory processes. CONCLUSIONS: Simultaneous modification in xylan and lignin enhances cellulose content with improved saccharification efficiency. These modifications loosen cell wall complexity and hence resulted in enhanced xylose and xylobiose release with or without pretreatment after xylanase digestion in both parent and HrGHypAc. This study also revealed that the disruption of xylan and lignin structure is possible without compromising either growth and development or defense responses against Pseudomonas syringae infection.

From unstructured accident reports to a hybrid decision support system for occupational risk management: The consensus converging approach.

INTRODUCTION: Workplace accidents in the petroleum industry can cause catastrophic damage to people, property, and the environment. Earlier studies in this domain indicate that the majority of the accident report information is available in unstructured text format. Conventional techniques for the analysis of accident data are time-consuming and heavily dependent on experts' subject knowledge, experience, and judgment. There is a need to develop a machine learning-based decision support system to analyze the vast amounts of unstructured text data that are frequently overlooked due to a lack of appropriate methodology. METHOD: To address this gap in the literature, we propose a hybrid methodology that uses improved text-mining techniques combined with an un-bias group decision-making framework to combine the output of objective weights (based on text mining) and subjective weights (based on expert opinion) of risk factors to prioritize them. Based on the contextual word embedding models and term frequencies, we extracted five important clusters of risk factors comprising more than 32 risk sub-factors. A heterogeneous group of experts and employees in the petroleum industry were contacted to obtain their opinions on the extracted risk factors, and the best-worst method was used to convert their opinions to weights. CONCLUSIONS AND PRACTICAL APPLICATIONS: The applicability of our proposed framework was tested on the data compiled from the accident data released by the petroleum industries in India. Our framework can be extended to accident data from any industry, to reduce analysis time and improve the accuracy in classifying and prioritizing risk factors.

Unveiling Novel Drug Targets and Emerging Therapies for Rheumatoid Arthritis: A Comprehensive Review.

Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disease, that causes joint damage, deformities, and decreased functionality. In addition, RA can also impact organs like the skin, lungs, eyes, and blood vessels. This autoimmune condition arises when the immune system erroneously targets the joint synovial membrane, resulting in synovitis, pannus formation, and cartilage damage. RA treatment is often holistic, integrating medication, physical therapy, and lifestyle modifications. Its main objective is to achieve remission or low disease activity by utilizing a "treat-to-target" approach that optimizes drug usage and dose adjustments based on clinical response and disease activity markers. The primary RA treatment uses disease-modifying antirheumatic drugs (DMARDs) that help to interrupt the inflammatory process. When there is an inadequate response, a combination of biologicals and DMARDs is recommended. Biological therapies target inflammatory pathways and have shown promising results in managing RA symptoms. Close monitoring for adverse effects and disease progression is critical to ensure optimal treatment outcomes. A deeper understanding of the pathways and mechanisms will allow new treatment strategies that minimize adverse effects and maintain quality of life. This review discusses the potential targets that can be used for designing and implementing precision medicine in RA treatment, spotlighting the latest breakthroughs in biologics, JAK inhibitors, IL-6 receptor antagonists, TNF blockers, and disease-modifying noncoding RNAs.

Recent advances in CAR T-cell engineering using synthetic biology: Paving the way for next-generation cancer treatment.

This book chapter highlights a comprehensive exploration of the transformative innovations in the field of cancer immunotherapy. CAR (Chimeric Antigen Receptor) T-cell therapy represents a groundbreaking approach to treat cancer by reprogramming a patient immune cells to recognize and destroy cancer cells. This chapter underscores the critical role of synthetic biology in enhancing the safety and effectiveness of CAR T-cell therapies. It begins by emphasizing the growing importance of personalized medicine in cancer treatment, emphasizing the shift from one-size-fits-all approaches to patient-specific solutions. Synthetic biology, a multidisciplinary field, has been instrumental in customizing CAR T-cell therapies, allowing for fine-tuned precision and minimizing unwanted side effects. The chapter highlights recent advances in gene editing, synthetic gene circuits, and molecular engineering, showcasing how these technologies are optimizing CAR T-cell function. In summary, this book chapter sheds light on the remarkable progress made in the development of CAR T-cell therapies using synthetic biology, providing hope for cancer patients and hinting at a future where highly personalized and effective cancer treatments are the norm.

TEX13B is essential for metabolic reprogramming during germ cell differentiation.

STUDY QUESTION: What is the functional significance of Tex13b in male germ cell development and differentiation? SUMMARY ANSWER: Tex13b regulates male germ cell differentiation by metabolic reprogramming during spermatogenesis. WHAT IS KNOWN ALREADY: Studies in mice and humans suggest that TEX13B is a transcription factor and is exclusively expressed in germ cells. STUDY DESIGN, SIZE, DURATION: We sequenced the coding regions of TEX13B in 628 infertile men and 427 ethnically matched fertile control men. Further, to identify the molecular function of Tex13b, we created a Tex13b knockout and conditional overexpression system in GC-1spg (hereafter, GC-1) cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our recent exome sequencing study identified novel candidate genes for male infertility. TEX13B was found to be one of the potential candidates, hence we explored the role of TEX13B in male infertility within a large infertile case-control cohort. We performed functional analyses of Tex13b in a GC-1 cell line using CRISPR-Cas9. We differentially labelled the cell proteins by stable isotope labelling of amino acids in cell culture (SILAC) and performed mass spectrometry-based whole-cell proteomics to identify the differential protein regulation in knockout cells compared to wild-type cells. We found that Tex13b knockout leads to downregulation of the OXPHOS complexes and upregulation of glycolysis genes, which was further validated by western blotting. These results were further confirmed by respirometry analysis in Tex13b knockout cells. Further, we also performed a conditional overexpression of TEX13B in GC-1 cells and studied the expression of OXPHOS complex proteins by western blotting. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a rare variant, rs775429506 (p.Gly237Glu), exclusively in two non-obstructive-azoospermia (NOA) men, that may genetically predispose these men for infertility. Further, we demonstrated that Tex13b functions in the transcription regulation of OXPHOS complexes. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: We examined the function of Tex13b in GC-1 in vitro by knocking out and conditional overexpression, for understanding the function of Tex13b in germ cells. Unfortunately, this could not be replicated in either an animal model or in patient-derived tissue due to the non-availability of an animal model or patient's testis biopsies. WIDER IMPLICATIONS OF THE FINDINGS: This study identified that Tex13b plays an important role in male germ cell development and differentiation. The findings of this study would be useful for screening infertile males with spermatogenic failure and counselling them before the implementation of assisted reproduction technique(s). STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Council of Scientific and Industrial Research (CSIR) under the network project (BSC0101 and MLP0113) and SERB, the Department of Science and Technology, Government of India (J C Bose Fellowship: JCB/2019/000027). The authors do not have any competing interest.

Investigating the Influence of ANTXR2 Gene Mutations on Protective Antigen Binding for Heightened Anthrax Resistance.

Bacillus anthracis is the bacterium responsible for causing the zoonotic disease called anthrax. The disease presents itself in different forms like gastrointestinal, inhalation, and cutaneous. Bacterial spores are tremendously adaptable, can persist for extended periods and occasionally endanger human health. The Anthrax Toxin Receptor-2 (ANTXR2) gene acts as membrane receptor and facilitates the entry of the anthrax toxin into host cells. Additionally, mutations in the ANTXR2 gene have been linked to various autoimmune diseases, including Hyaline Fibromatosis Syndrome (HFS), Ankylosing Spondylitis (AS), Juvenile Hyaline Fibromatosis (JHF), and Infantile Systemic Hyalinosis (ISH). This study delves into the genetic landscape of ANTXR2, aiming to comprehend its associations with diverse disorders, elucidate the impacts of its mutations, and pinpoint minimal non-pathogenic mutations capable of reducing the binding affinity of the ANTXR2 gene with the protective antigen. Recognizing the pivotal role of single-nucleotide polymorphisms (SNPs) in shaping genetic diversity, we conducted computational analyses to discern highly deleterious and tolerated non-synonymous SNPs (nsSNPs) in the ANTXR2 gene. The Mutpred2 server determined that the Arg465Trp alteration in the ANTXR2 gene leads to altered DNA binding (p = 0.22) with a probability of a deleterious mutation of 0.808; notably, among the identified deleterious SNPs, rs368288611 (Arg465Trp) stands out due to its significant impact on altering the DNA-binding ability of ANTXR2. We propose these SNPs as potential candidates for hypertension linked to the ANTXR2 gene, which is implicated in blood pressure regulation. Noteworthy among the tolerated substitutions is rs200536829 (Ala33Ser), recognized as less pathogenic; this highlights its potential as a valuable biomarker, potentially reducing side effects on the host while also reducing binding with the protective antigen protein. Investigating these SNPs holds the potential to correlate with several autoimmune disorders and mitigate the impact of anthrax disease in humans.

Perceived Stress, Blood Biomarkers, and Cognitive Functioning in Older Adults.

INTRODUCTION: There is a substantial gap in knowledge regarding how perceived stress may influence the relationship between serum-measured biomarkers for Alzheimer's disease and cognitive decline. METHODS: This study consists of 1118 older adult participants from the Chicago Health and Aging Project (CHAP) (60% Black participants and 63% female participants). Linear mixed effects regression models were conducted to examine the role of perceived stress in the association between three blood biomarkers: total tau (t-tau), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) on global cognitive decline. Stratified analysis by stress level was also conducted to evaluate the associations between each blood biomarker and baseline cognitive function and decline. All models adjusted for age, race, sex, education, time, and their interactions with time. RESULTS: The interaction of stress, NfL concentration, and time was statistically significant on global cognition ( ß = -0.064 [SE = 0.028], p = .023) and on episodic memory ( ß = -0.097 [SE = 0.036], p = .007). CONCLUSIONS: Greater stress level worsens the association between high NfL concentration and cognitive decline. Stress management interventions may be helpful to reduce the rate of cognitive decline in individuals with high concentrations of NfL.

Guillain-Barre syndrome following COVID-19 vaccination: a study of 70 case reports.

Background and objective: Guillain-Barre syndrome (GBS) has been found to have some interesting association with vaccinations. This paper mainly focuses on exploring different associations between COVID-19 vaccination and GBS. Methods: Electronic databases such as PubMed, Google Scholar, Cochrane, and Embase were searched using MESH terms for case reports published till 1 August 2023 from which 70 case reports were documented involving 103 individuals from 23 different countries. Result and discussion: The case reports were from a wide range of individuals aged from 13 to 87 years with an average age of 53±20 interquartile range years along with male predominance. The average time between receiving the vaccine and the onset of symptoms was 13.08±2.14 days. Prominent clinical features included back pain, facial diplegia, weakness, and paraesthesia whereas the main diagnostic studies were cerebrospinal fluid (CSF) analysis and electromagnetic studies. The principal diagnostic clue was albumin-cytological dissociation in CSF while being negative for anti-ganglioside antibodies or SARS-CoV-2. Available treatment options consisted of intravenous immunoglobulin and Plasmapheresis. Patients with comorbidities such as diabetes mellitus, hypertension, dyslipidemia, permanent atrial fibrillation, hypothyroidism, Hashimoto's thyroiditis, Chronic Obstructive Pulmonary Disease, asthma, osteoporosis, migraine, rheumatoid arthritis, osteoarthritis, ulcerative colitis, coeliac disease, seizures, bipolar disorder, endometriosis, multiple sclerosis, bell's palsy, squamous cell carcinoma, prostate cancer were included in our study. Conclusion: Overall, this review evaluated innovative and clinically relevant associations between COVID-19 vaccination and GBS. Understanding of this uncommon potential side effect of COVID-19 vaccination is crucial for prompt diagnosis and appropriate treatment. Importantly, GBS should not be considered a contraindication to vaccination. This underscores the importance of ongoing research to enhance the safety and efficacy of COVID-19 vaccination efforts.

Statin Initiation and Risk of Incident Alzheimer Disease and Cognitive Decline in Genetically Susceptible Older Adults.

BACKGROUND AND OBJECTIVES: The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. METHODS: This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. RESULTS: The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (ß = 0.021, 95% CI 0.007-0.034) and episodic memory (ß = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. DISCUSSION: Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele.

WITHDRAWN: Exploring The Diverse Therapeutic Potentials of Synthetic Analogues of Keto-terpenoids (+) Carvone: A Future Scaffold

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Dietary fats and the APOE-e4 risk allele in relation to cognitive decline: a longitudinal investigation in a biracial population sample.

BACKGROUND: APOE-e4 is the strongest genetic risk factor for Alzheimer's disease. However, the influence of APOE-e4 on dietary fat intake and cognition has not been investigated. OBJECTIVE: We aim to examine the association of types of dietary fat and their association to cognitive decline among those with and without the APOE-e4 allele. METHODS: The study included 3,360 Chicago Health and Aging Project (CHAP) participants from four Southside Chicago communities. Global cognition was assessed using a composite score of episodic memory, perceptual speed, MMSE, and diet using a 144-item food frequency questionnaire. APOE genotype was assessed by the hME Sequenom mass-array platform. Longitudinal mixed-effect regression models were used to examine the association of dietary fat and the APOE-e4 allele with cognitive decline, adjusted for age, sex, education, smoking status, and calorie intake. RESULTS: The present study involved 3,360 participants with a mean age of 74 at baseline, 62% African Americans, 63% females, and a mean follow-up of 7.8 years. Among participants with the APOE-e4 risk allele, higher intakes of total and saturated fat (SFA) were associated with a faster decline in global cognition. Among individuals with the APOE-e4 risk allele, a 5% increase in calories from SFA was associated with a 21% faster decline (ß = -0.0197, P = 0.0038). In contrast, a higher intake of long-chain n-3 polyunsaturated fatty acids (LC-n3 PUFA) was associated with a slower rate of decline in global cognition among APOE-e4 carriers. Specifically, for every 1% energy increment from LC-n3 PUFA, the annual rate of global cognitive decline was slower by 0.024 standardized unit (SD 0.010, P = 0.023), about 30.4% slower annual cognitive decline. Higher SFA or other types of dietary fat were not associated with cognitive decline among APOE-e4 non-carriers. CONCLUSIONS: Our study found a significant association between SFA and faster cognitive decline, LC-n3 PUFA and slower cognitive decline among those with the APOE-e4 allele. Our findings suggested that higher intake of SFA might contribute faster cognitive decline in combination with APOE-e4 whereas LC-n3 PUFA might compensate the adverse effects of APOE-e4. The interaction between intakes of different types of dietary fat and APOE-e4 on cognitive function warrants further research.

Extracellular Vesicles in Malaria: Shedding Light on Pathogenic Depths.

Malaria, a life-threatening infectious disease caused by Plasmodium falciparum, remains a significant global health challenge, particularly in tropical and subtropical regions. The epidemiological data for 2021 revealed a staggering toll, with 247 million reported cases and 619,000 fatalities attributed to the disease. This formidable global health challenge continues to perplex researchers seeking a comprehensive understanding of its pathogenesis. Recent investigations have unveiled the pivotal role of extracellular vesicles (EVs) in this intricate landscape. These tiny, membrane-bound vesicles, secreted by diverse cells, emerge as pivotal communicators in malaria's pathogenic orchestra. This Review delves into the multifaceted roles of EVs in malaria pathogenesis, elucidating their impact on disease progression and immune modulation. Insights into EV involvement offer potential therapeutic and diagnostic strategies. Integrating this information identifies targets to mitigate malaria's global impact. Moreover, this Review explores the potential of EVs as diagnostic biomarkers and therapeutic targets in malaria. By deciphering the intricate dialogue facilitated by these vesicles, new avenues for intervention and novel strategies for disease management may emerge.

Healthy Lifestyle and Cognition in Older Adults With Common Neuropathologies of Dementia.

Importance: A healthy lifestyle is associated with better cognitive functioning in older adults, but whether this association is independent of the accumulation of dementia-related pathologies in the brain is uncertain. Objective: To determine the role of postmortem brain pathology, including ß-amyloid load, phosphorylated tau tangles, cerebrovascular pathology, and other brain pathologies, in the association between lifestyle and cognition proximate to death. Design, Setting, and Participants: This cohort study used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study with autopsy data from 1997 to 2022 and up to 24 years of follow-up. Participants included 754 deceased individuals with data on lifestyle factors, cognitive testing proximate to death, and a complete neuropathologic evaluation at the time of these analyses. Data were analyzed from January 2023 to June 2023. Exposures: A healthy lifestyle score was developed based on self-reported factors, including noncurrent smoking, at least 150 minutes of physical activity per week, limiting alcohol consumption, a Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet score higher than 7.5, and a late-life cognitive activity score higher than 3.2. The lifestyle score ranges from 0 to 5, with higher scores reflecting a healthier lifestyle. Main Outcomes and Measures: The global cognitive score was derived from a battery of nineteen standardized tests. Brain pathology measures included ß-amyloid load, phosphorylated tau tangles, global Alzheimer disease pathology, vascular brain pathologies, Lewy body, hippocampal sclerosis, and TAR DNA-binding protein 43. Results: Of 586 included decedents, 415 (70.8%) were female, 171 (29.2%) were male, and the mean (SD) age at death was 90.9 (6.0) years. Higher lifestyle score was associated with better global cognitive functioning proximate to death. In the multivariable-adjusted model, a 1-point increase in lifestyle score was associated with 0.216 (SE = 0.036, P < .001) units higher in global cognitive scores. Neither the strength nor the significance of the association changed substantially when common dementia-related brain pathologies were included in the multivariable-adjusted models. The ß estimate after controlling for the ß-amyloid load was 0.191 (SE = 0.035; P < .001). A higher lifestyle score was associated with lower ß-amyloid load in the brain (ß = -0.120; SE = 0.041; P = .003), and 11.6% of the lifestyle-cognition association was estimated through ß-amyloid load. Conclusions and Relevance: This study found that in older adults, a healthy lifestyle may provide a cognitive reserve to maintain cognitive abilities independently of common neuropathologies of dementia.

Fcgr2b and Fcgr3 are the major genetic factors for cartilage antibody-induced arthritis, overriding the effect of Hc encoding complement C5.

Like rheumatoid arthritis (RA) in humans, collagen-induced arthritis (CIA) in mice is associated with not only MHC class II genetic polymorphism but also, to some extent, with other loci including genes encoding Fc gamma receptors (FCGRs) and complement C5. In this study, we used a cartilage antibody-induced arthritis (CAIA) model in which arthritis develops within a 12-h timeframe, to determine the relative importance of FCGRs and C5 (Hc). In CAIA, inhibiting or deleting FCGR3 substantially hindered arthritis development, underscoring the crucial role of this receptor. Blocking FCGR3 also reduced the levels of FCGR4, and vice versa. When employing an IgG1 arthritogenic cocktail that exclusively interacts with FCGR2B and FCGR3, joint inflammation was promptly initiated in Fcgr2b-- mice but not in Fcgr3-- mice, suggesting that FCGR3 is sufficient for CAIA development. Regarding complement activation, Fcgr2b++.Hc** mice with C5 mutated were fully resistant to CAIA, whereas Fcgr2b--.Hc** mice developed arthritis rapidly. We conclude that FCGR3 is essential and sufficient for CAIA development, particularly when induced by IgG1 antibodies. The human ortholog of mouse FCGR3, FCGR2A, may be associated with RA pathogenesis. FCGR2B deficiency allows for rapid arthritis progression and overrides the resistance conferred by C5 deficiency.

Gut-brain axis interplay via STAT3 pathway: Implications of Helicobacter pylori derived secretome on inflammation and Alzheimer's disease.

Helicobacter pylori is a pathogenic bacterium that causes gastritis and gastric carcinoma. Besides gastric complications its potential link with gut-brain axis disruption and neurological disorders has also been reported. The current study investigated the plausible role and its associated molecular mechanism underlying H. pylori mediated gut-brain axis disruption and neuroinflammation leading to neurological modalities like Alzheimer's disease (AD). We have chosen the antimicrobial resistant and susceptible H. pylori strains on the basis of broth dilution method. We have observed the increased inflammatory response exerted by H. pylori strains in the gastric as well as in the neuronal compartment after treatment with Helicobacter pylori derived condition media (HPCM). Further, elevated expression of STAT1, STAT3, and AD-associated proteins- APP and APOE4 was monitored in HPCM-treated neuronal and neuron-astrocyte co-cultured cells. Excessive ROS generation has been found in these cells. The HPCM treatment to LN229 causes astrogliosis, evidenced by increased glial fibrillary acidic protein. Our results indicate the association of STAT3 as an important regulator in the H. pylori-mediated pathogenesis in neuronal cells. Notably, the inhibition of STAT3 by its specific inhibitor, BP-1-102, reduced the expression of pSTAT3 and AD markers in neuronal compartment induced by HPCM. Thus, our study demonstrates that H. pylori infection exacerbates inflammation in AGS cells and modulates the activity of STAT3 regulatory molecules. H. pylori secretome could affect neurological compartments by promoting STAT3 activation and inducing the expression of AD-associated signature markers. Further, pSTAT-3 inhibition mitigates the H. pylori associated neuroinflammation and amyloid pathology.

Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models.

B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor TP53, supporting the need for further drug development. Del17p has been associated with reduced copy number and gene expression of RNA polymerase II subunit alpha (POLR2A) in other tumor types. We therefore studied the possibility that HDP-101, an anti-BCMA antibody drug conjugate (ADC) with the POLR2A poison α-amanitin could be an attractive agent in myeloma, especially with del17p. HDP-101 reduced viability in myeloma cell lines representing different molecular disease subtypes, and overcame adhesion-mediated and both conventional and novel drug resistance. After confirming that del17p is associated with reduced POLR2A levels in publicly available myeloma patient databases, we engineered TP53 wild-type cells with a TP53 knockout (KO), POLR2A knockdown (KD), or both, the latter to mimic del17p. HDP-101 showed potent anti-myeloma activity against all tested cell lines, and exerted enhanced efficacy against POLR2A KD and dual TP53 KO/POLR2A KD cells. Mechanistic studies showed HDP-101 up-regulated the unfolded protein response, activated apoptosis, and induced immunogenic cell death. Notably, HDP-101 impacted CD138-positive but not-negative primary cells, showed potent efficacy against aldehyde dehydrogenase-positive clonogenic cells, and eradicated myeloma in an in vivo cell line-derived xenograft (CDX). Interestingly, in the CDX model, prior treatment with HDP-101 precluded subsequent engraftment on tumor cell line rechallenge in a manner that appeared to be dependent in part on natural killer cells and macrophages. Finally, HDP-101 was superior to the BCMA-targeted ADC belantamab mafodotin against cell lines and primary myeloma cells in vitro, and in an in vivo CDX. Together, the data support the rationale for translation of HDP-101 to the clinic, where it is now undergoing Phase I trials, and suggest that it could emerge as a more potent ADC for myeloma with especially interesting activity against the high-risk del17p myeloma subtype.

Depressive Symptoms, Glial Fibrillary Acid Protein Concentrations, and Cognitive Decline in a Cohort Study.

BACKGROUND: Little is known about how depressive symptoms and glial fibrillary acid protein (GFAP) concentrations taken together may influence cognitive functioning. Understanding this relationship may inform strategies for screening and early intervention to decrease the rate of cognitive decline. METHODS: This study sample includes 1 169 participants from the Chicago Health and Aging Project (CHAP), consisting of 60% Black participants and 40% White participants, and 63% female participants and 37% male participants. CHAP is a population-based cohort study of older adults with a mean age of 77 years. Linear mixed-effects regression models tested the main effects of depressive symptoms and GFAP concentrations and their interactions on baseline cognitive function and cognitive decline over time. Models included adjustments for age, race, sex, education, chronic medical conditions, body mass index, smoking status, alcohol use, and their interactions with time. RESULTS: The interaction of depressive symptomology and GFAP (ß = -0.105 [standard error = 0.038], p = .006) on global cognitive function was statistically significant. Participants with depressive symptoms including and above the cutoff and high log of GFAP concentrations had more cognitive decline over time, followed by participants with depressive symptoms below the cutoff and high log of GFAP concentrations, depressive symptom scores including and above the cutoff and low log of GFAP concentrations, and depressive symptom scores below the cutoff and low log of GFAP concentrations. CONCLUSIONS: Depressive symptoms have an additive effect on the association between the log of GFAP and baseline global cognitive function.

Blockade of phosphodiesterase 5 by sildenafil reduces tumor growth and potentiates tumor-killing ability of cisplatin in vivo against T cell lymphoma: Implication of modulated apoptosis, reactive oxygen species homeostasis, glucose metabolism, and pH regulation.

In the past years, PDE5 has emerged as a promising therapeutic target for many cancers due to its highly upregulated expression. Interestingly, a recent in vitro study by our group has shown the antitumor and chemopotentiating action of sildenafil against T cell lymphoma. Our study showed that lower doses of sildenafil (50 µM) and cisplatin (0.5 µg/mL) exhibited 4% and 23% cytotoxicity against HuT78 cells, respectively, which was dramatically increased up to 50% when treated with both. Hence, the present study was designed to evaluate the antitumor and chemo-potentiating action of sildenafil in a murine model of T cell lymphoma (popularly called as Dalton's lymphoma [DL]). In the present study, DL-bearing mice were administered with vehicle (PBS), sildenafil (5 mg/kg bw), cisplatin (5 mg/kg bw), and sildenafil and cisplatin followed by evaluation of their impact on tumor growth by analyzing various parameters. The apoptosis was assessed by Wright-Giemsa, annexin-V, and DAPI staining. Reactive oxygen species (ROS) level was examined through DCFDA staining. The expression of genes and proteins were estimated by RT-PCR and Western blotting, respectively. The experimental findings of the study demonstrate for the first time that sildenafil inhibits tumor growth and potentiates tumor inhibitory ability of cisplatin by altering apoptosis, glycolysis, ROS homeostasis, and pH regulation in T cell lymphoma-carrying host. In addition, our investigation also showed amelioration of tumor-induced liver and kidney damage by sildenafil. Overall, the experimental data of our study strongly advocate the use and repurposing of SDF in designing promising chemotherapeutic regimens against malignancies of T cells.

Temporal Patterns of Change in Physical and Cognitive Performance.

BACKGROUND: This study examined the relation between declines in physical and cognitive performance in older people. METHODS: A population-based cohort of 7 483 adults (average age 72 years) were interviewed. Physical performance was assessed with 3 standardized tests and a combination of 4 cognitive tests was used to assess cognitive function. Rate of change in physical and cognitive performance was determined for each interval between interviews. In mixed effects linear regression models adjusted for age, sex, race, and study time, and change in each factor was used to predict change in the other factor. We examined time associations by using changes in the predictor measured at 1, 2, or 3 intervals before the outcome change. RESULTS: Decline in cognitive function was most strongly predicted by physical decline in the same 3-year interval. The decline in cognitive function was weaker in the 1-time interval after the decline in physical function and was not significant in later intervals. When a decline in cognitive function was used to predict a decline in physical function, the results were similar. The strongest association occurred in the same time interval so that declines in cognitive and physical performance tend to occur together. CONCLUSIONS: Decline in cognition and physical function seem to occur together in a short timeframe. It is important to investigate the reasons for these changes that are short-term to guide the development of interventions.