Primary Treatment Target Research Articles

NTRK Gene Expression Analysis in Oral Squamous Cell Carcinoma Mexican Population.

Oral cancer holds the sixth position in malignancies worldwide; 90% correspond to oral squamous cell carcinoma (OSCC). Diverse reports suggest that NTRK genes and their receptors are key oncogenesis regulators to tumor progression in human cancers. Objective: To analyze the NTRK and Trk expression and their association with clinicopathological features of OSCC in Mexican patients' samples. Material and Methods: We analyzed 95 OSCC cases of pan-trk immunoexpression through a software-assisted method. Gene expression was analyzed by RT-qPCR employing the ΔΔCT method. Kruskal-Wallis and Spearman's correlation tests were performed. Results: Our mean age was 62.4 (±16.9) years. A total of 37 cases were tumors in the lateral border of the tongue. Age was significantly associated with the anatomical site. 42% (40 of 95) cases were pan-trk positive. A total of 21 cases showed intense immunoexpression predominantly in poorly differentiated OSCC, with a significant correlation between immunoexpression and age and gender. Gene expression showed that poorly differentiated cases exhibited higher NTRK2 expression, while well-differentiated cases demonstrated NTRK3 significantly higher expression. Conclusions: Our results suggest that NTRK family expression is present in OSCC, with differential expression related to differentiation degree. Additional information about their activation or mutational status could reinforce their potential as a possible primary or adjuvant treatment target.

Synthesis and Structure-Activity Relationship Analysis of 2-Substituted-1,2,4-Triazolo[1,5-a]Pyrimidin-7-Ones and their 6-Carboxylate Derivatives as Xanthine Oxidase Inhibitors.

Hyperuricemia is characterised by high blood levels of uric acid, and it can degenerate into gout when monosodium urate crystals precipitate in joints and other tissues. Uric acid is produced during the catabolism of xanthine by the enzyme xanthine oxidase (XO), which is the primary therapeutic target in gout treatment. Current XO inhibitors approved to treat gout, such as allopurinol and febuxostat, suffer from serious adverse effects, creating the need for new drug molecules. Three libraries comprising 75 purine analogues were designed using a 1,2,4-triazolo[1,5-a]pyrimidine scaffold, synthesised and tested in vitro as potential XO inhibitors. The screening identified that 23 compounds exhibited better inhibitory activity than allopurinol, with 2-(4-isopropoxyphenyl)-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid being 23 times more potent. Enzyme kinetics studies and molecular docking simulations were performed on the most active compounds to identify the mechanism of action and intermolecular interactions between the active site of XO and the inhibitors. The most potent compounds exhibited a mix-type inhibition mechanism and were predicted to interact with the same amino acid residues as allopurinol. These novel purine analogues are promising hits for further new lead development among purine-like drug XO inhibitors with therapeutic potential in the treatment of hyperuricemia and associated diseases.

BACE1 inhibitors: A promising therapeutic approach for the management of Alzheimer’s disease

Alzheimer’s disease is a neurological disorder marked by the accumulation of amyloid beta (Aβ) aggregates, resulting from mutations in the amyloid precursor protein. The enzyme β-secretase, also known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), plays a crucial role in generating Aβ peptides. With no targeted therapy available for Alzheimer’s disease, inhibiting BACE1 aspartic protease has emerged as a primary treatment target. Since 1999, compounds demonstrating potential binding to the BACE1 receptor have advanced to human trials. Structural optimization of synthetically derived compounds, coupled with computational approaches, has offered valuable insights for developing highly selective leads with drug-like properties. This review highlights pivotal studies on the design and development of BACE1 inhibitors as anti-Alzheimer’s disease agents. It summarizes computational methods employed in facilitating drug discovery for potential BACE1 inhibitors and provides an update on their clinical status, indicating future directions for novel BACE1 inhibitors. The promising clinical results of Elenbecestat (E-2609) catalyze the development of effective, selective BACE1 inhibitors in the future.

Analysis of early-pregnancy metabolome in early- and late-onset gestational diabetes reveals distinct associations with maternal overweight.

It is not known whether the early-pregnancy metabolome differs in patients with early- vs late-onset gestational diabetes mellitus (GDM) stratified by maternal overweight. The aims of this study were to analyse correlations between early-pregnancy metabolites and maternal glycaemic and anthropometric characteristics, and to identify early-pregnancy metabolomic alterations that characterise lean women (BMI <25 kg/m2) and women with overweight (BMI ≥25 kg/m2) with early-onset GDM (E-GDM) or late-onset GDM (L-GDM). We performed a nested case-control study within the population-based prospective Early Diagnosis of Diabetes in Pregnancy cohort, comprising 210 participants with GDM (126 early-onset, 84 late-onset) and 209 normoglycaemic control participants matched according to maternal age, BMI class and primiparity. Maternal weight, height and waist circumference were measured at 8-14 weeks' gestation. A 2 h 75 g OGTT was performed at 12-16 weeks' gestation (OGTT1), and women with normal results underwent repeat testing at 24-28 weeks' gestation (OGTT2). Comprehensive metabolomic profiling of fasting serum samples, collected at OGTT1, was performed by untargeted ultra-HPLC-MS. Linear models were applied to study correlations between early-pregnancy metabolites and maternal glucose concentrations during OGTT1, fasting insulin, HOMA-IR, BMI and waist circumference. Early-pregnancy metabolomic features for GDM subtypes (participants stratified by maternal overweight and gestational timepoint at GDM onset) were studied using linear and multivariate models. The false discovery rate was controlled using the Benjamini-Hochberg method. In the total cohort (n=419), the clearest correlation patterns were observed between (1) maternal glucose concentrations and long-chain fatty acids and medium- and long-chain acylcarnitines; (2) maternal BMI and/or waist circumference and long-chain fatty acids, medium- and long-chain acylcarnitines, phospholipids, and aromatic and branched-chain amino acids; and (3) HOMA-IR and/or fasting insulin and L-tyrosine, certain long-chain fatty acids and phospholipids (q<0.001). Univariate analyses of GDM subtypes revealed significant differences (q<0.05) for seven non-glucose metabolites only in overweight women with E-GDM compared with control participants: linolenic acid, oleic acid, docosapentaenoic acid, docosatetraenoic acid and lysophosphatidylcholine 20:4/0:0 abundances were higher, whereas levels of specific phosphatidylcholines (P-16:0/18:2 and 15:0/18:2) were lower. However, multivariate analyses exploring the early-pregnancy metabolome of GDM subtypes showed differential clustering of acylcarnitines and long-chain fatty acids between normal-weight and overweight women with E- and L-GDM. GDM subtypes show distinct early-pregnancy metabolomic features that correlate with maternal glycaemic and anthropometric characteristics. The patterns identified suggest early-pregnancy disturbances of maternal lipid metabolism, with most alterations observed in overweight women with E-GDM. Our findings highlight the importance of maternal adiposity as the primary target for prevention and treatment.

Research Focusing on How Qinge Pill Functions in Managing Stress Urinary Incontinence, Utilizing Network Pharmacology

Objective: Investigating how Qing-e pill aids in managing stress urinary incontinence through network pharmacology. Methods: Utilizing the TCM system's pharmacological database and analytical framework (TCMSP), along with literature exploration, the active components and their respective targets for Qing-e pill were identified, leading to the creation of a network of compound TCM - active ingredients - targets. The focus of SUI was identified using the GeneCards and OMIM databases. The active ingredient SUI-target network model was developed and examined using the Cytoscape 3.10.1 software. The protein interaction network (PPI) was created using the STRING database, incorporating gene ontology functional annotation (GO) and Tokyo Genome Encyclopedia (KEGG) pathway enrichment analysis on key targets through DAVID online, with molecular docking performed using Surflex software. Results: Screening yielded 86 active components, 461 possible targets, 2551 SUI targets, and 187 typical targets for Qing-e pill and SUI. The outcomes of network analysis revealed Qing-e pill's primary targets for SUI treatment were AKT1, IL6, JUN, TNF, HSP90AA1, ESR1, CTNNB1, EGFR, among others. The primary biological mechanisms encompassed reactions to lipopolysaccharide, molecules originating from bacteria, metal ions, growth of epithelial cells, and the control of membrane potential, among others. KEGG enrichment primarily aims to utilize the AGE-RAGE signaling pathway in treating a range of conditions, including diabetes complications, prostate cancer, fluid shear stress, atherosclerosis, lipid and atherosclerosis, IL-17 signaling pathway, and more. Conclusion: Initially, network pharmacology shed light on the foundational materials and operational methods of Qing-e pill in treating SUI, offering a theoretical foundation for their clinical use.

Homotherapy for Heteropathy: A Molecular Mechanism of Poria Sini Decoction for Treatment of Liver Cancer and Chronic Heart Failure.

Poria sini decoction (PSD), a significant traditional Chinese herbal formula, is effective in liver cancer (LC) and chronic heart failure (CHF); however, little is known about its concurrent targeting mechanism. Methods. This study analyzed the potential molecular mechanism of PSD against the two distinct diseases using network pharmacology approaches, including multidatabase search, pharmacokinetic screening, network construction analysis, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and molecular docking to elaborate the active components, signaling pathways, and potential mechanisms of PSD in the treatment of both LC and CHF. Results. A total of 155 active components and 193 potential targets in PSD were identified. Bioinformatics analysis revealed that quercetin, isorhamnetin, and naringenin, etc. may be potential candidate agents. TNF, AKT1, and IL6, etc. could become potential therapeutic targets. TNF-α, NF-κB, PI3K-AKT, and TRP signaling pathways might play an important role in PSD against LC and CHF. Molecular docking results showed that most screened active compounds could embed itself into target proteins with a high binding affinity, and the hydrogen bonds number ≥3 indicated a more stable conformation of the compounds and target proteins. Overall, quercetin and isorhamnetin were the main active components, and TNF and AKT1 were the primary targets for PSD treatment of LC and CHF. Conclusions. This study illustrated that quercetin contained in PSD played an important role in the treatment of LC and CHF by acting on the key gene of TP53 and downregulating the PI3K-AKT signaling pathway.

The human subthalamic nucleus transiently inhibits active attentional processes.

The subthalamic nucleus (STN) of the basal ganglia is key to the inhibitory control of movement. Consequently, it is a primary target for the neurosurgical treatment of movement disorders like Parkinson's disease, where modulating the STN via deep brain stimulation (DBS) can release excess inhibition of thalamocortical motor circuits. However, the STN is also anatomically connected to other thalamocortical circuits, including those underlying cognitive processes like attention. Notably, STN-DBS can also affect these processes. This suggests that the STN may also contribute to the inhibition of non-motor activity and that STN-DBS may cause changes to this inhibition. Here we tested this hypothesis in humans. We used a novel, wireless outpatient method to record intracranial local field potentials (LFP) from STN DBS implants during a visual attention task (Experiment 1, n = 12). These outpatient measurements allowed the simultaneous recording of high-density EEG, which we used to derive the steady state visual evoked potential (SSVEP), a well established neural index of visual attentional engagement. By relating STN activity to this neural marker of attention (instead of overt behaviour), we avoided possible confounds resulting from STN's motor role. We aimed to test whether the STN contributes to the momentary inhibition of the SSVEP caused by unexpected, distracting sounds. Furthermore, we causally tested this association in a second experiment, where we modulated STN via DBS across two sessions of the task, spaced at least 1 week apart (n = 21, no sample overlap with Experiment 1). The LFP recordings in Experiment 1 showed that reductions of the SSVEP after distracting sounds were preceded by sound-related γ-frequency (>60 Hz) activity in the STN. Trial-to-trial modelling further showed that this STN activity statistically mediated the sounds' suppressive effect on the SSVEP. In Experiment 2, modulating STN activity via DBS significantly reduced these sound-related SSVEP reductions. This provides causal evidence for the role of the STN in the surprise-related inhibition of attention. These findings suggest that the human STN contributes to the inhibition of attention, a non-motor process. This supports a domain-general view of the inhibitory role of the STN. Furthermore, these findings also suggest a potential mechanism underlying some of the known cognitive side effects of STN-DBS treatment, especially on attentional processes. Finally, our newly established outpatient LFP recording technique facilitates the testing of the role of subcortical nuclei in complex cognitive tasks, alongside recordings from the rest of the brain, and in much shorter time than peri-surgical recordings.

CAR-T Therapy of Multiple Myeloma, Based on the Congresses ASH-2021 and ASCO-2022

Current treatment of multiple myeloma (ММ) based on proteasome inhibitors, immunomodulating drugs, and monoclonal antibodies has, to a certain extent, reached the limit of its potential. Despite considerable clinical advance, ММ still remains a chronic incurable disease. Tumor-specific T-cell therapy with chimeric antigen receptor (CAR) is a new evolution step towards achieving MM cure. Today, B-cell maturation antigen (BCMA) is regarded as the primary target of CAR-T treatment of MM. This receptor is mainly expressed on the surface of tumor plasma cells in ММ as well as in B-cells of late differentiation stages and normal plasma cells. In 2021–2022, two CAR-T drugs, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), were approved for clinical use in the USA and the European Union for patients with relapsed/refractory MM. The studies of these drugs yielded encouraging clinical results. Other antigen (GPRC5D, SLAMF7) cell-based drugs are now in early stages of development. The present review is concerned with latest advances in CAR-T therapy for MM reported at the recent congresses ASH-2021 and ASCO-2022. The review comprehensively discusses the results of the KarMMa (ide-cel, stage II) and CARTITUDE-1 (cilta-cel, stage IB/II) studies. It also provides historical background of CAR-Т cell generation as well as preclinical and on-going clinical trial data on MM. It outlines potential failure causes and prospects of further improvement of the new technology.of its potential. Despite considerable clinical advance, ММstill remains a chronic incurable disease. Tumor-specific T-cell therapy with chimeric antigen receptor (CAR) isa new evolution step towards achieving MM cure. Today,B-cell maturation antigen (BCMA) is regarded as the primary target of CAR-T treatment of MM. This receptor is mainlyexpressed on the surface of tumor plasma cells in ММ aswell as in B-cells of late differentiation stages and normalplasma cells. In 2021–2022, two CAR-T drugs, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel(cilta-cel), were approved for clinical use in the USA andthe European Union for patients with relapsed/refractoryMM. The studies of these drugs yielded encouraging clinical results. Other antigen (GPRC5D, SLAMF7) cell-baseddrugs are now in early stages of development. The presentreview is concerned with latest advances in CAR-T therapyfor MM reported at the recent congresses ASH-2021 andASCO-2022. The review comprehensively discusses theresults of the KarMMa (ide-cel, stage II) and CARTITUDE-1(cilta-cel, stage IB/II) studies. It also provides historicalbackground of CAR-Т cell generation as well as preclinicaland on-going clinical trial data on MM. It outlines potentialfailure causes and prospects of further improvement of thenew technology.

Caspase-driven cancer therapies: Navigating the bridge between lab discoveries and clinical applications.

Apoptosis is the cell's natural intrinsic regulatory mechanism of normal cells for programmed cell death, which plays an important role in cancer as a classical mechanism of tumor cell death causing minimal inflammation without causing damage to other cells in the vicinity. Induction of apoptosis by activation of caspases is one of the primary targets for cancer treatment. Over the years, a diverse range of natural, synthetic, and semisynthetic compounds and their derivatives have been investigated for their caspase-mediated apoptosis-induced anticancer activities. The review aims to compile the preclinical evidence and highlight the critical mechanistic pathways related to caspase-induced cell apoptosis in cancer treatment. The focus is placed on the key components of the mechanisms, including their chemical nature, and specific attention is given to phytochemicals derived from natural sources and synthetic and semisynthetic compounds. 180+ compounds from the past two decades with potential as anticancer agents are discussed in this review article. By summarizing the current knowledge and advancements in this field, this review provides a comprehensive overview of potential therapeutic strategies targeting apoptosis in cancer cells. The findings presented herein contribute to the ongoing efforts to combat cancer and stimulate further research into the development of effective and targeted anticancer therapies.

Suicidal ideation following internet-delivered tailored CBT for depression - a secondary analysis of a factorial design trial.

Suicidal ideation is common in major depressive disorder (MDD) and a risk factor for suicidal behavior. Although it can be reduced with psychological treatments, the risks often make clinicians hesitant to offer treatment. This concerns remote treatment options, such as internet-delivered cognitive behavior therapy (ICBT), which may be considered unsafe. Although previous studies indicate that ICBT can reduce self-reported suicidal ideation both as primary and indirect treatment target, questions remain about under what circumstances ICBT can be offered as the primary treatment. In this secondary report, we investigated the importance of different treatment factors in reducing suicidal ideation via ICBT, including different kinds of therapist support. We analyzed data from 197 participants from a factorial trial of ICBT for symptoms of MDD. Before inclusion all participants completed a structured clinical interview where obvious suicidal intent lead to exclusion. Suicidal ideation was assessed at pre- and posttreatment using one item of the PHQ-9 and one from BDI-II. The data were analyzed using generalized linear models. The pre- to posttreatment comparisons showed decreases in the reporting of suicidal ideation. Findings were consistent across the two measures that was used. There was no effect of support format and content tailoring. The findings suggest that ICBT can help alleviate suicidal ideation even when it is not the focus of the treatment. This was the case regardless of mode of therapist support, who tailored the treatment content, and if case supervision was available or not.

Effect of Enzymatic Biotransformation on the Hypotensive Potential of Red Grape Pomace Extract.

Hypertension is a widespread health risk, affecting over a billion people and causing 9 million deaths per year. The Renin-Angiotensin-Aldosterone System (RAAS) is a primary target for hypertension treatment, and it is primarily treated through drugs that inhibit the Angiotensin I-Converting Enzyme (ACE). In addition to pharmacological treatment, various plants are recommended in traditional medicine for blood pressure regulation. This study aimed to produce high-phenolic-content extracts with and without enzymatic assistance from red grape pomace and evaluate their antioxidant capacity and ACE inhibitory potential. The total phenolic content (TPC) was measured, and phenolic identification was performed using HPLC analysis. In addition, the antioxidant capacity and anti-hypertensive potential were determined via in vitro assays. There was no statistical difference in the TPC antioxidant capacity between the extraction methods. Otherwise, when considering the extraction yield, the enzymatic process recovered around 70% more phenolic compounds from the pomace, and the phenolic profile was changed. Enzymatic assistance also significantly increased the ACE inhibitory potential in the grape pomace extract. This study demonstrates the viability of upcycling grape pomace to obtain bioactive compounds and to reduce their environmental impact, and highlights the influence of the enzymatic extraction on the hypotensive potential of the extract.

Register-based observational study of associations between inflammatory remission, formal treatment targets and the use of disease-modifying antirheumatic drugs among patients with early rheumatoid arthritis

ObjectiveTo assess associations between inflammatory remission, formal treatment targets and the likelihood of starting a new disease-modifying antirheumatic drug (DMARD), among patients with early rheumatoid arthritis (RA).MethodsPatients newly diagnosed with...

The tumor micro-environment in pediatric glioma: friend or foe?

Brain tumors are the leading cause of morbidity and mortality related to cancer in children, where high-grade glioma harbor the worst prognosis. It has become obvious that pediatric glioma differs significantly from their adult counterparts, rendering extrapolations difficult. Curative options for several types of glioma are lacking, albeit ongoing research efforts and clinical trials. As already proven in the past, inter- and intratumoral heterogeneity plays an important role in the resistance to therapy and thus implicates morbidity and mortality for these patients. However, while less studied, the tumor micro-environment (TME) adds another level of heterogeneity. Knowledge gaps exist on how the TME interacts with the tumor cells and how the location of the various cell types in the TME influences tumor growth and the response to treatment. Some studies identified the presence of several (immune) cell types as prognostic factors, but often lack a deeper understanding of the underlying mechanisms, possibly leading to contradictory findings. Although the TME in pediatric glioma is regarded as "cold", several treatment options are emerging, with the TME being the primary target of treatment. Therefore, it is crucial to study the TME of pediatric glioma, so that the interactions between TME, tumoral cells and therapeutics can be better understood before, during and after treatment. In this review, we provide an overview of the available insights into the composition and role of the TME across different types of pediatric glioma. Moreover, where possible, we provide a framework on how a particular TME may influence responses to conventional- and/or immunotherapy.

Synthesis and application of small molecules approved for the treatment of lymphoma

Lymphoma is a form of cancer that impacts the lymphatic system, which plays a crucial role in defending the body against infections and illnesses. It is characterized by the atypical proliferation of lymphocytes, a type of white blood cell, which can form tumors in the lymph nodes, bone marrow, spleen, etc. Lymphoma is usually treated using a combination of targeted therapy, chemotherapy, and radiation therapy. In recent years, there has been a growing interest in the development of new drugs to treat lymphoma, which has led to the discovery of several promising compounds. The primary targets for lymphoma treatment have been identified as Bruton's tyrosine kinase (BTK), phosphoinositide3-kinase (PI3K), histone deacetylase (HDAC), and DNA polymerase (POLA). This review aims to provide an overview of the clinical applications and synthesis of several notable drugs approved to treat lymphoma, to expedite the exploration of more potent novel medications for the management of lymphoma.

Combined use of CDAI and blood indices for assessing endoscopic activity in ileocolic Crohn’s disease

BackgroundMucosal healing has become the primary treatment target for patients with Crohn’s disease (CD). We aimed to develop a noninvasive and convenient tool to evaluate the endoscopic activity in patients with ileocolic CD.MethodsA retrospective multicenter study including 300 CD patients (training, 210 patients; test, 90 patients) was conducted at two tertiary referral centers. Independent risk factors associated with endoscopic activity were explored, which were then combined into a comprehensive index. The predictive performance was evaluated with the area under receiver operating characteristic curve (ROC). Cohen’s Kappa was adopted to examine the consistency between each indicator and endoscopic activity.ResultsA total of 210 CD patients were recruited in the training cohort. We found that Crohn’s Disease Activity Index (CDAI), C-reactive protein (CRP) and platelet-to-lymphocyte percentage ratio (PLpR) were independently associated with endoscopic activity. Additionally, the comprehensive index generated from the above three indices achieved good discrimination and performed better than CDAI in AUC (0.849 vs. 0.769, P < 0.05). This was further well demonstrated by the external test cohort, which showed good discrimination (AUC: 0.84, 95% CI: 0.744–0.936). Intra-individual comparison revealed the comprehensive index to be superior in the prediction of endoscopic activity. In the subgroup analysis, the AUC of comprehensive index was significantly higher than CDAI especially in inflammatory phenotype (0.824 vs. 0.751, P < 0.05).ConclusionCombining CDAI, CRP and PLpR significantly improved the accuracy for predicting endoscopic activity in ileocolic CD, which can help better monitor an endoscopic flare.

US Veterans Show Improvements in Subjective but Not Objective Sleep following Treatment for Posttraumatic Stress Disorder: Secondary Analyses from a Randomised Controlled Trial

Background. Sleep disturbances are a prominent feature of posttraumatic stress disorder (PTSD), and poorer sleep quality is associated with higher PTSD severity. This highlights the importance of monitoring sleep outcomes alongside PTSD symptoms in treatments targeting PTSD. Yet few studies monitor both sleep and PTSD outcomes, unless sleep is the primary treatment target. Furthermore, inconsistencies remain about the effects of first-line, evidence-based PTSD treatments on sleep. Methods. Here, we explored changes in sleep in secondary analyses from a randomised controlled trial that originally assessed the noninferiority of a breathing-based yoga practice (Sudarshan kriya yoga; SKY) to a first-line PTSD treatment (cognitive processing therapy (CPT)) for clinically significant PTSD symptoms among US veterans (intent-to-treat N = 85 ; per protocol N = 59 ). Sleep was assessed via subjective (self-reported sleep diary), PTSD symptom severity items (self-reported and clinician-administered insomnia/nightmare sleep items), and objective (wrist actigraphy) measures. Results. Following treatment, subjective sleep diary measures of quality, latency, and wake duration showed small effect size ( d = .24 − .39 ) improvements, with no significant differences between treatment groups. Significant improvements were also observed in PTSD sleep symptoms, though CPT ( d = .34 ) more reliably reduced nightmares while SKY (d = .44-.45) more reliably reduced insomnia. In contrast, there were no significant treatment-related effects for any of the actigraphy-measured sleep indices. Conclusions. To our knowledge, this is the first study to investigate sleep as an outcome of CPT or SKY for PTSD, across a combination of subjective diary, PTSD symptom severity, and objective actigraphic measures. Findings lend support to a growing body of evidence that trauma-focused psychotherapy for PTSD improves sleep and suggest that yoga-based interventions may also be beneficial for sleep among individuals with emotional or mental health disorders like PTSD. This trial is registered with NCT02366403.

Disentangling Heart Failure and Physical Frailty: Prospective Study of Patients Undergoing Percutaneous Mitral Valve Repair

BackgroundFrailty and heart failure share pathophysiology and clinical characteristics. ObjectivesThe aim of this study was to analyze the contribution of heart failure to the physical frailty phenotype by examining patients with heart failure before and after percutaneous mitral valve repair (PMVR). MethodsFrailty according to the Fried criteria (weight loss, weakness, exhaustion, slowness, and low activity) was assessed in consecutive patients before and 6 weeks after PMVR. ResultsA total of 118 of 258 patients (45.7%) (mean age: 78 ± 9 years, 42% female, 55% with secondary mitral regurgitation) were frail at baseline, which significantly decreased to 74 patients (28.7 %) at follow-up (P < 0.001). The frequency of frailty domains slowness, exhaustion, and inactivity significantly decreased, whereas weakness remained unchanged. Baseline frailty was significantly associated with comorbidities, N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, and functional capacity, whereas frailty after PMVR was not associated with NT-proBNP levels. Predictors of postprocedural reversibility of frailty were NYHA functional class <IV, absence of weakness, and lower frailty score. In comparison with patients who were persistently nonfrail (reference group HR: 1.00), the risk of mortality continuously increased for patients who experienced new frailty (HR: 1.41 [95% CI: 0.41-4.86]), those who had reversal of frailty (HR: 2.17 [95% CI: 1.03-4.57]), and those who were persistently frail (HR: 3.26 [95%: CI 1.62-6.57]; P = 0.006 for trend). ConclusionsTreatment of mitral regurgitation in patients with heart failure is associated with almost a halved burden of physical frailty, particularly in patients with a less advanced phenotype. Considering the prognostic relevance of frailty dynamics, this data warrants further evaluation of the concept of frailty as a primary treatment target.

Self-compassion and pain disability in adults with chronic pain: The mediating role of future self-identification and self-efficacy.

Pain disability is a primary target of treatment for chronic pain. Self-compassion shows promise as an intervention to reduce pain disability, but mechanisms linking self-compassion with less pain disability remain to be identified. This study examined two potential mechanisms, health self-efficacy and future self-identification (FSI), as parallel mediators of the relation between self-compassion and pain disability. Adults (N = 188; Mage = 40.34, SD = 11.53; 70.9% female) screened for chronic pain were recruited through online convenience sampling. Participants completed self-report measures of demographics, health status, and primary study variables. Self-compassion was positively associated with FSI and self-efficacy, but only self-efficacy was found to mediate the negative relation between self-compassion and pain disability, such that self-compassion was associated with higher self-efficacy, which was associated with less pain disability. Future experimental and longitudinal studies can establish whether the negative relation between self-compassion and pain disability is causal and mediated via health self-efficacy.

Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration.

Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism. Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (H2S) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/H2S system and the findings were confirmed in transgenic mice. Higher plasma H2S levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of CTH, the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the H2S donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD. Decreased plasma H2S levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses CTH, impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.

Weight Loss Versus Glycemic Control as the Primary Treatment Target in Newly Diagnosed Type 2 Diabetes: Why Choose When You Can Have Both?

Weight loss has been associated with significant improvements in glycemic control, quality of life, and comorbidities in people with type 2 diabetes. Furthermore, achieving diabetes remission can reduce the risk of microvascular complications and mitigate the burden of diabetes on healthcare systems. However, preventing weight regain is challenging in the long term. Strict glycemic control, particularly in the early stages of the disease, can reduce the subsequent risk of microvascular complications and specific macrovascular endpoints in the long run; however, its impact on cardiovascular and all-cause mortality remains controversial. New classes of antidiabetic agents, namely glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, have been shown to reduce cardiorenal risk and induce weight loss, in addition to effectively lowering blood glucose with a minimal risk of hypoglycemia. Recently, it has been debated whether weight loss or glycemic control should be the first priority in people with a recent diagnosis of type 2 diabetes. This article aims to discuss the debate from a clinical perspective, evaluate the advantages and disadvantages of each therapeutic strategy, and assess the impact of both approaches on the future risk of diabetic complications, based on the latest evidence. Given that both goals are equally important, the authors suggest that merging the two strategies, with the early and aggressive use of combination therapies consisting of glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, will confer maximum benefits in terms of weight loss and glycemic control, and will reduce the future risk of complications from diabetes. A personalized approach that takes into account specific patient characteristics, including age, sex, race, frailty, and cognitive status, among others, can lead to more effective diabetes care.