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ACS Chemical Biology Jun 2024Small molecular tool compounds play an essential role in the study of G protein-coupled receptors (GPCRs). However, tool compounds most often occupy the orthosteric...
Small molecular tool compounds play an essential role in the study of G protein-coupled receptors (GPCRs). However, tool compounds most often occupy the orthosteric binding site, hampering the study of GPCRs upon ligand binding. To overcome this problem, ligand-directed labeling techniques have been developed that leave a reporter group covalently bound to the GPCR, while allowing subsequent orthosteric ligands to bind. In this work, we applied such a labeling strategy to the adenosine A receptor (AAR). We have synthetically implemented the recently reported -acyl--alkyl sulfonamide (NASA) warhead into a previously developed ligand and show that the binding of the AAR is not restricted by NASA incorporation. Furthermore, we have investigated ligand-directed labeling of the AAR using SDS-PAGE, flow cytometric, and mass spectrometry techniques. We have found one of the synthesized probes to specifically label the AAR, although detection was hindered by nonspecific protein labeling most likely due to the intrinsic reactivity of the NASA warhead. Altogether, this work aids the future development of ligand-directed probes for the detection of GPCRs.
PubMed: 38920052
DOI: 10.1021/acschembio.4c00210 -
Open Forum Infectious Diseases Jun 2024While use of some older antiretroviral drugs (ARVs) is associated with chronic liver enzyme elevation (cLEE), the impact of newer ARVs remains unknown.
BACKGROUND
While use of some older antiretroviral drugs (ARVs) is associated with chronic liver enzyme elevation (cLEE), the impact of newer ARVs remains unknown.
METHODS
People with HIV enrolled in the RESPOND cohort who started an ARV after January 1, 2012 were included (baseline). The primary outcome was first cLEE individuals were censored at first of cLEE, last visit, death, or December 31, 2021. Incidence rates (IRs; events/1000 person-years) were calculated for each ARV overall and by ARV exposure (6-12 months, 1-2 years, and 2+ years). Poisson regression was used to estimate the incidence rate ratio (IRR) of cLEE and its association with individual ARVs and ARV class.
RESULTS
Of 17 106 individuals included contributing 87 924 person-years of follow-up, 1932 (11.3%) experienced cLEE (incidence rate [IR], 22.0; 95% CI, 21.0-23.0). There was no evidence of a cumulative ARV effect on cLEE incidence, (6-12 months: IR, 45.8; 95% CI, 41.4-50.19; 1-2 years: IR, 34.3; 95% CI, 31.5-37.4; and 2+ years: IR, 18.5; 95% CI, 17.4-19.7). Any use (vs no prior use) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class and tenofovir disoproxil fumarate (TDF) was independently associated with an increased IRR of cLEE, and any use of darunavir (DRV) was associated with a decreased risk of cLEE.
CONCLUSIONS
cLEE is common and more frequent during the first year after initiating new ARVs. With a >5-year median follow-up, we found no short-term liver safety concerns with the use of INSTIs. Use of NNRTIs and TDF was associated with an increased cLEE risk, while DRV was associated with lower risk.
PubMed: 38919512
DOI: 10.1093/ofid/ofae308 -
Medical Review (2021) Jun 2024A major worldwide health concern, chronic hepatitis B necessitates precise prognostic and diagnostic indicators for clinical guidance. This article highlights the... (Review)
Review
A major worldwide health concern, chronic hepatitis B necessitates precise prognostic and diagnostic indicators for clinical guidance. This article highlights the clinical importance and current issues of the major markers used in both the detection and prognosis of chronic hepatitis B. An important indicator of an ongoing and persistent infection is the hepatitis B surface antigen. Hepatitis B virus DNA quantification monitoring aids in assessing viral load and hepatic cancer risk. While limited evidence of liver damage is provided by alanine aminotransferase levels, the hepatitis B core antibody verifies acute infection. Seroconversion to the hepatitis B e antibody is linked to a lower risk of disease development, and the hepatitis B e antigen status is a critical prognostic factor. Treatment choices are guided by a biopsy of the liver or minimally invasive liver fibrosis detection. Genotypes of the hepatitis B virus and host variables influence the prognosis by adding to the disease's variability. Noninvasive techniques to evaluate the severity of the disease are provided by serum markers of fibrosis, such as the fibrosis score based on four criteria and the aspartate aminotransferase-to-platelet ratio index. The requirement for indicators that distinguish between distinct viral phases and increase specificity in evaluating liver damage is one of the challenges facing chronic hepatitis B research. Even though it is quite difficult to find reliable biomarkers for resistance especially when it comes to hepatocellular cancer risk estimation, there are advanced methods, which include imaging and omics that can help in improving the accuracy of the diagnostics and prognosis. Interventions early point that improve patient outcomes are made possible using diagnostics and prognostics as they are quite effective in managing the complicated landscape of chronic hepatitis B. Key in addressing these challenges today and improving the diagnostic and prognostic markers in the future, particularly those that would support the development of successful treatment plans for people living with chronic hepatitis B virus (HBV), are scientific research, technological advances and collaborations.
PubMed: 38919396
DOI: 10.1515/mr-2024-0022 -
The Iowa Orthopaedic Journal 2024Patients often access online resources to educate themselves prior to undergoing elective surgery such as carpal tunnel release (CTR). The purpose of this study was to...
BACKGROUND
Patients often access online resources to educate themselves prior to undergoing elective surgery such as carpal tunnel release (CTR). The purpose of this study was to evaluate available online resources regarding CTR on objective measures of readability (syntax reading grade-level), understandability (ability to convey key messages in a comprehensible manner), and actionability (providing actions the reader may take).
METHODS
The study conducted two independent Google searches for "Carpal Tunnel Surgery" and among the top 50 results, analyzed articles aimed at educating patients about CTR. Readability was assessed using six different indices: Flesch-Kincaid Grade Level Index, Flesch Reading Ease, Gunning Fog Index, Simple Measure of Gobbledygook (SMOG) Index, Coleman Liau Index, Automated Readability Index. The Patient Education Materials Assessment Tool evaluated understandability and actionability on a 0-100% scale. Spearman's correlation assessed relationships between these metrics and Google search ranks, with p<0.05 indicating statistical significance.
RESULTS
Of the 39 websites meeting the inclusion criteria, the mean readability grade level exceeded 9, with the lowest being 9.4 ± 1.5 (SMOG index). Readability did not correlate with Google search ranking (lowest p=0.25). Mean understandability and actionability were 59% ± 15 and 26% ± 24, respectively. Only 28% of the articles used visual aids, and few provided concise summaries or clear, actionable steps. Notably, lower grade reading levels were linked to higher actionability scores (p ≤ 0.02 in several indices), but no readability metrics significantly correlated with understandability. Google search rankings showed no significant association with either understandability or actionability scores.
CONCLUSION
Online educational materials for CTR score poorly in readability, understandability, and actionability. Quality metrics do not appear to affect Google search rankings. The poor quality metric scores found in our study highlight a need for hand specialists to improve online patient resources, especially in an era emphasizing shared decision-making in healthcare. .
Topics: Humans; Comprehension; Patient Education as Topic; Carpal Tunnel Syndrome; Internet; Health Literacy; Reading
PubMed: 38919356
DOI: No ID Found -
Iranian Journal of Public Health Mar 2024We aimed to investigate miR-21-5p inhibition effect on lncRNA-XIST expression and apoptosis status of MCF-7 cells.
BACKGROUND
We aimed to investigate miR-21-5p inhibition effect on lncRNA-XIST expression and apoptosis status of MCF-7 cells.
METHODS
The MCF-7 cells were cultured and transfected by the anti-miR-21-5p oligonucleotide and expression of miR-21-5p, lncRNA-XIST, apoptosis-associated genes ( and ) and one miR-21-5p-unrelated lncRNA (BC200) was assessed by RT-qPCR. Furthermore, cell viability checked by MTT assay and apoptosis and cell cycle in transfected cells were detected by flow cytometry. Also, bioinformatics analysis on the transcriptome data confirmed that the lncRNA XIST might have a critical role in breast cancer (BC) cell apoptosis through ceRNAs mechanism and possible regulatory interactions with miR-21-5p.
RESULTS
Expression of miR-21-5p and lncRNA-XIST was significantly down- and up-regulated respectively (<0.05). However, there was no significant change in lncRNA-BC200 expression. Also, the expression of and upraised significantly (<0.05). In transfected cells, MTT and flow cytometry assays reported a highly significant decrease and increase in viability and apoptosis respectively.
CONCLUSION
Inhibition of miR-21-5p resulted in significant upregulation of lncRNA-XIST and apoptosis-associated genes and , which led to the induction of apoptosis in MCF-7 cells. Therefore, more investigations may provide a valuable target for studies on molecular therapies for BC.
PubMed: 38919297
DOI: 10.18502/ijph.v53i3.15154 -
Current Topics in Medicinal Chemistry Jun 2024Tuberculosis (TB) is one of the leading causes of death world-wide after AIDS. It infects around one-third of global population and approximately two million people die...
Tuberculosis (TB) is one of the leading causes of death world-wide after AIDS. It infects around one-third of global population and approximately two million people die annually from this disease because it is a very contagious disease spread by Mycobacterium tuberculosis. The increasing number of drug-resistant strains and the failure of conventional treatments against this strain are the challenges of the coming decades. New therapeutic techniques aim to confirm cure without deterioration, to reduce deaths, contagions and the formation of drug-resistant strains. A plethora of new diagnostic tests are available to diagnose the active tuberculosis, screen latent M. tuberculosis infection, and to identify drug-resistant strains of M. tuberculosis. When effective prevention strategies do not prevail, high rates of early case detection and successive cures to control TB emergence would not be possible. In this review, we discussed the structural features of M. tuberculosis, Multi drug resistance tuberculosis (MDR-TB), extremely drug-resistant tuberculosis (XDR-TB), the mechanism of M. tuberculosis infection, the mode of action of first and second-line antitubercular drugs, the mechanism of resistance to the existing drugs, compounds in preclinical and clinical trial and drugs presently available for the treatment of tuberculosis. Moreover, the new diagnostic techniques to detect M. Tuberculosis are also discussed in this review.
.PubMed: 38919089
DOI: 10.2174/0115680266286294240610102911 -
BMB Reports Jun 2024Immunotherapy represents a promising treatment strategy for targeting various tumor types. However, the overall response rate is low due to the tumor microenvironment...
Immunotherapy represents a promising treatment strategy for targeting various tumor types. However, the overall response rate is low due to the tumor microenvironment (TME). In the TME, numerous distinct factors actively induce immunosuppression, restricting the efficacy of anticancer immune reactions. Recently, metabolic reprogramming of tumors has been recognized for its role in modulating the tumor microenvironment to enhance immune cell responses in the TME. Furthermore, recent elucidations underscore the critical role of metabolic limitations imposed by the tumor microenvironment on the effectiveness of antitumor immune cells, guiding the development of novel immunotherapeutic approaches. Hence, achieving a comprehensive understanding of the metabolic requirements of both cancer and immune cells within the TME is pivotal. This insight not only aids in acknowledging the current limitations of clinical practices but also significantly shapes the trajectory of future research endeavors in the domain of cancer immunotherapy. In addition, therapeutic interventions targeting metabolic limitations have exhibited promising potential as combinatory treatments across diverse cancer types. In this review, we first discuss the metabolic barriers in the TME. Second, we explore how the immune response is regulated by metabolites. Finally, we will review the current strategy for targeting metabolism to not simply inhibit tumor growth but also enhance antitumor immune responses. Thus, we could suggest potent combination therapy for improving immunotherapy with metabolic inhibitors.
PubMed: 38919017
DOI: No ID Found -
Journal of Burn Care & Research :... Jun 2024Appropriate identification of burn depth and size is paramount. Despite the development of burn depth assessment aids [e.g., laser doppler imaging (LDI)], clinical...
Appropriate identification of burn depth and size is paramount. Despite the development of burn depth assessment aids [e.g., laser doppler imaging (LDI)], clinical assessment, which assesses partial thickness burn depth with 67% accuracy, currently remains the most consistent standard of practice. We sought to develop an image-based artificial intelligence system that predicts burn severity and wound margins for use as a triaging tool in thermal injury management. Modified EfficientNet architecture trained by 1684 mobile-device-captured images of different burn depths were previously utilized to create a convoluted neural network (CNN). The CNN was modified to a novel Boundary-Attention Mapping (BAM) algorithm using elements of saliency mapping, which was utilized to recognize the boundaries of burns. For validation, 144 patient charts that included clinical assessment, burn location, total body surface area, and LDI assessment were retrieved for a retrospective study. The clinical images underwent CNN-BAM assessment and were directly compared with the LDI assessment. CNN using a four-level burn severity classification achieved an accuracy of 85% (micro/macro-averaged ROC scores). The CNN-BAM system can successfully highlight burns from surrounding tissue with high confidence. CNN-BAM burn area segmentations attained a 91.6% accuracy, 78.2% sensitivity, and 93.4% specificity, when compared to LDI methodology. Results comparing the CNN-BAM outputs to clinical and LDI assessments have shown a high degree of correlation between the CNN-BAM burn severity predictions to those extrapolated from LDI healing potential (66% agreement). CNN-BAM algorithm gives equivalent burn-depth detection accuracy as LDI with a more economical and accessible application when embedded in a mobile device.
PubMed: 38918900
DOI: 10.1093/jbcr/irae121 -
AIDS Research and Therapy Jun 2024Despite remarkable progress, HIV's influence on global health remains firm, demanding continued attention. Understanding the effectiveness of third-line antiretroviral... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite remarkable progress, HIV's influence on global health remains firm, demanding continued attention. Understanding the effectiveness of third-line antiretroviral therapy in individuals who do not respond to second-line drugs is crucial for improving treatment strategies. The virological outcomes of third-line antiretroviral therapy vary from study to study, highlighting the need for robust global estimates.
METHODS
A comprehensive search of databases including PubMed, MEDLINE, International Scientific Indexing, Web of Science, and Google Scholar, was conducted. STATA version 17 statistical software was used for analysis. A random-effects model was applied to compute the pooled estimates. Subgroup analysis, heterogeneity, publication bias, and sensitivity analysis were also performed. The prediction interval is computed to estimate the interval in which a future study will fall. The GRADE tool was also used to determine the quality of the evidence.
RESULTS
In this systematic review and meta-analysis, 15 studies involving 1768 HIV patients receiving third-line antiretroviral therapy were included. The pooled viral suppression of third-line antiretroviral therapy was 76.6% (95% CI: 71.5- 81.7%). The viral suppression rates at 6 and 12 months were 75.5% and 78.6%, respectively. Furthermore, third-line therapy effectively suppressed viral RNA copy numbers to ≤ 50 copies/mL, ≤ 200 copies/mL, and ≤ 400 copies/mL with rates of 70.7%, 85.4%, and 85.7%, respectively.
CONCLUSION
More than three-fourths of patients on third-line antiretroviral therapy achieve viral suppression. Consequently, improving access to and timely initiation of third-line therapy may positively impact the quality of life for those with second-line treatment failure.
Topics: Humans; HIV Infections; Anti-HIV Agents; Treatment Outcome; Viral Load; Antiretroviral Therapy, Highly Active; HIV-1; Global Health
PubMed: 38918866
DOI: 10.1186/s12981-024-00630-7 -
AIDS Research and Therapy Jun 2024Tuberculosis preventive therapy is vital in caring for HIV-positive individuals, as it prevents the progression from latent tuberculosis infection to tuberculosis...
Completion of tuberculosis preventive therapy and associated factors among clients on antiretroviral therapy at Debre Berhan town health facilities, North Shoa Zone, Ethiopia.
BACKGROUND
Tuberculosis preventive therapy is vital in caring for HIV-positive individuals, as it prevents the progression from latent tuberculosis infection to tuberculosis disease. The aim of the study is to assess the completion of tuberculosis preventive therapy and associated factors among clients receiving antiretroviral therapy in Debre Berhan town, Ethiopia, in 2022.
METHOD
Institutional based cross sectional study was conducted. Random sampling methods were used to select both study participants and health facilities. Both bivariate and multivariate logistic regression analyses were performed. P-values less than 0.05 were statistically significant.
RESULT
The study found that, 83% of participants were completed tuberculosis preventive therapy. Completed tuberculosis preventive therapy was associated with no adverse drug events, taking first-line ART, and good ART adherence.
CONCLUSION
According to the Ethiopian ART guidelines, the study found a low completion rate of tuberculosis preventive therapy among HIV-positive clients on antiretroviral therapy. Factors like no adverse drug events, first-line antiretroviral regimen, and good adherence were significantly associated with completing tuberculosis preventive therapy.
Topics: Humans; Ethiopia; Male; Female; Cross-Sectional Studies; Adult; HIV Infections; Tuberculosis; Middle Aged; Medication Adherence; Antitubercular Agents; Young Adult; Anti-HIV Agents; Health Facilities; Adolescent
PubMed: 38918790
DOI: 10.1186/s12981-024-00629-0