Semaglutide and Diuretic Use in Obesity-Related Heart Failure with Preserved Ejection Fraction: A Pooled Analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.

BACKGROUND AND AIMS: In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. METHODS: In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. RESULTS: At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (<40 [n=219], 40 [n=309], and >40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. CLINICALTRIALS.GOV REGISTRATION: NCT04788511 and NCT04916470.

Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial.

BACKGROUND: Although sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF. OBJECTIVES: The goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF. METHODS: Targeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed. RESULTS: The mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro-B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro-B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction. CONCLUSIONS: Leveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235).

Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells.

Cardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and vascular endothelial cells (ECs) can screen for drug-induced alterations in cardiovascular cell function and survival. However, most existing hiPSC models for cardiovascular drug toxicity utilize two-dimensional, immature cells grown in static culture. Improved in vitro models to mechanistically interrogate cardiotoxicity would utilize more adult-like, mature hiPSC-derived cells in an integrated system whereby toxic drugs and protective agents can flow between hiPSC-ECs that represent systemic vasculature and hiPSC-CMs that represent heart muscle (myocardium). Such models would be useful for testing the multi-lineage cardiotoxicities of chemotherapeutic drugs such as VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs). Here, we develop a multi-lineage, fully-integrated, cardiovascular organ-chip that can enhance hiPSC-EC and hiPSC-CM functional and genetic maturity, model endothelial barrier permeability, and demonstrate long-term functional stability. This microfluidic organ-chip harbors hiPSC-CMs and hiPSC-ECs on separate channels that can be subjected to active fluid flow and rhythmic biomechanical stretch. We demonstrate the utility of this cardiovascular organ-chip as a predictive platform for evaluating multi-lineage VPTKI toxicity. This study may lead to the development of new modalities for the evaluation and prevention of cancer therapy-induced cardiotoxicity.

Urologist Access for the Male Population: An 18-Year Study on Population Trends.

INTRODUCTION: Our study examines the factors associated with urologist availability for younger and older men across the country over a period of 18 years from 2000 to 2018. METHODS: The Area Health Resource Files and US Census Data were analyzed from 2000, 2010, and 2018. The younger male population was defined as men aged 20 to 49, and the older male population was defined as ages 50 to 79. Urologist availability was determined by county at all time points. Logistic regression analysis and geographically weighted regression was completed. RESULTS: Over an 18-year period, overall urologist availability decreased for men by 19.6%. Access to urologist availability for men in metropolitan and rural counties decreased by 9.4% and 29.5%, respectively. Among the younger male cohort, urologist availability increased in metropolitan counties by 4%, but decreased by 16% in rural counties. There was an overall decrease in urologist availability of 28% and 43% in metropolitan and rural counties in the older male population. Multiple logistic regression analysis demonstrated that metropolitan status was the most significant factor associated with urologist availability for both male populations. The odds of each independent factor predicting urologist availability for the younger and older male population is dependent on geography. CONCLUSIONS: The majority of the male population has seen a decline in urologist availability. This is especially true for the older male residing in a rural county. Predictors of urologist availability depend on geographical regions, and understanding these regional drivers may allow us to better address disparities in urological care.

Assessing equivalent and inverse change in genes between diverse experiments.

Background: It is important to identify when two exposures impact a molecular marker (e.g., a gene's expression) in similar ways, for example, to learn that a new drug has a similar effect to an existing drug. Currently, statistically robust approaches for making comparisons of equivalence of effect sizes obtained from two independently run treatment vs. control comparisons have not been developed. Results: Here, we propose two approaches for evaluating the question of equivalence between effect sizes of two independent studies: a bootstrap test of the Equivalent Change Index (ECI), which we previously developed, and performing Two One-Sided t-Tests (TOST) on the difference in log-fold changes directly. The ECI of a gene is computed by taking the ratio of the effect size estimates obtained from the two different studies, weighted by the maximum of the two p-values and giving it a sign indicating if the effects are in the same or opposite directions, whereas TOST is a test of whether the difference in log-fold changes lies outside a region of equivalence. We used a series of simulation studies to compare the two tests on the basis of sensitivity, specificity, balanced accuracy, and F1-score. We found that TOST is not efficient for identifying equivalently changed gene expression values (F1-score = 0) because it is too conservative, while the ECI bootstrap test shows good performance (F1-score = 0.95). Furthermore, applying the ECI bootstrap test and TOST to publicly available microarray expression data from pancreatic cancer showed that, while TOST was not able to identify any equivalently or inversely changed genes, the ECI bootstrap test identified genes associated with pancreatic cancer. Additionally, when investigating publicly available RNAseq data of smoking vs. vaping, no equivalently changed genes were identified by TOST, but ECI bootstrap test identified genes associated with smoking. Conclusion: A bootstrap test of the ECI is a promising new statistical approach for determining if two diverse studies show similarity in the differential expression of genes and can help to identify genes which are similarly influenced by a specific treatment or exposure. The R package for the ECI bootstrap test is available at https://github.com/Hecate08/ECIbootstrap.

Consensus Guidelines on Interventional Therapies for Knee Pain (STEP Guidelines) from the American Society of Pain and Neuroscience.

Knee pain is second only to the back as the most commonly reported area of pain in the human body. With an overall prevalence of 46.2%, its impact on disability, lost productivity, and cost on healthcare cannot be overlooked. Due to the pervasiveness of knee pain in the general population, there are no shortages of treatment options available for addressing the symptoms. Ranging from physical therapy and pharmacologic agents to interventional pain procedures to surgical options, practitioners have a wide array of options to choose from - unfortunately, there is no consensus on which treatments are "better" and when they should be offered in comparison to others. While it is generally accepted that less invasive treatments should be offered before more invasive ones, there is a lack of agreement on the order in which the less invasive are to be presented. In an effort to standardize the treatment of this extremely prevalent pathology, the authors present an all-encompassing set of guidelines on the treatment of knee pain based on an extensive literature search and data grading for each of the available alternative that will allow practitioners the ability to compare and contrast each option.

The Neurostimulation Appropriateness Consensus Committee (NACC): Recommendations for Surgical Technique for Spinal Cord Stimulation.

INTRODUCTION: The field of neurostimulation for the treatment of chronic pain is a rapidly developing area of medicine. Although neurostimulation therapies have advanced significantly as a result of technologic improvements, surgical planning, device placement, and postoperative care are of equal importance to optimize outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for these often-overlooked areas of neurostimulation practice. MATERIALS AND METHODS: Authors were chosen based on their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from the last NACC publication in 2017 to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on evidence strength and consensus when evidence was scant. RESULTS: This NACC project provides guidance on preoperative assessment, intraoperative techniques, and postoperative management in the form of consensus points with supportive evidence. These results are based on grade of evidence, strength of consensus, and expert opinion. CONCLUSIONS: The NACC has given guidance for a surgical plan that encompasses the patient journey from the planning stage through the surgical experience and postoperative care. The overall recommendations are designed to improve efficacy and the safety of patients undergoing these neuromodulation procedures and are intended to apply throughout the international community.

18-Year Population Trends Determine Factors Associated with Future Access to Urologists.

INTRODUCTION: Our study evaluated urologist availability by United States county since 2000 relative to regional changes in the general population to identify factors associated with access to care. METHODS: County-level data from 2000, 2010 and 2018 from the Department of Health and Human Services, U.S. Census and American Community Survey were analyzed. Availability of urologists by county was defined as urologists per 10,000 adults. Multiple logistic and geographically weighted regression were performed. A predictive model was formulated with tenfold cross-validation (AUC=0.75). RESULTS: Despite a 6.95% increase in urologists over 18 years, local urologist availability declined 13% (-0.03 urologists/10,000 individuals, 95% CI 0.02-0.04, p <0.0001). On multiple logistic regression, metropolitan status was the greatest predictor of urologist availability (OR 1.86, 95% CI 1.47-2.34), followed by prior urologist presence (OR 1.49, 95% CI 1.16-1.89), defined as a higher number of urologists in 2000. The predictive weight of these factors varied by U.S. region. All regions experienced worsening overall urologist availability, with rural areas suffering the most. Large population shifts away from the Northeast to the West and South were outpaced by urologists leaving the Northeast, the only region with a decreasing number of total urologists (-1.36%). CONCLUSIONS: Urologist availability declined in every region over nearly 2 decades likely due to an increasing general population and inequitable regional migration. Predictors of urologist availability differed by region, and thus it will be necessary to investigate regional drivers influencing population shifts and urologist concentration to prevent worsening disparities in care.

Development of a Personalized Intestinal Fibrosis Model Using Human Intestinal Organoids Derived From Induced Pluripotent Stem Cells.

BACKGROUND: Intestinal fibrosis is a serious complication of Crohn's disease. Numerous cell types including intestinal epithelial and mesenchymal cells are implicated in this process, yet studies are hampered by the lack of personalized in vitro models. Human intestinal organoids (HIOs) derived from induced pluripotent stem cells (iPSCs) contain these cell types, and our goal was to determine the feasibility of utilizing these to develop a personalized intestinal fibrosis model. METHODS: iPSCs from 2 control individuals and 2 very early onset inflammatory bowel disease patients with stricturing complications were obtained and directed to form HIOs. Purified populations of epithelial and mesenchymal cells were derived from HIOs, and both types were treated with the profibrogenic cytokine transforming growth factor ß (TGFß). Quantitative polymerase chain reaction and RNA sequencing analysis were used to assay their responses. RESULTS: In iPSC-derived mesenchymal cells, there was a significant increase in the expression of profibrotic genes (Col1a1, Col5a1, and TIMP1) in response to TGFß. RNA sequencing analysis identified further profibrotic genes and demonstrated differential responses to this cytokine in each of the 4 lines. Increases in profibrotic gene expression (Col1a1, FN, TIMP1) along with genes associated with epithelial-mesenchymal transition (vimentin and N-cadherin) were observed in TGFß -treated epithelial cells. CONCLUSIONS: We demonstrate the feasibility of utilizing iPSC-HIO technology to model intestinal fibrotic responses in vitro. This now permits the generation of near unlimited quantities of patient-specific cells that could be used to reveal cell- and environmental-specific mechanisms underpinning intestinal fibrosis.

Intestinal fibrosis is a serious complication of Crohn's disease and novel in vitro models are urgently needed to study this. We describe an induced pluripotent stem cell­derived modeling system whereby a near unlimited number of both epithelial and mesenchymal cells could be used in a personalized intestinal fibrosis model.

Evolutionary Analysis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reveals Genomic Divergence with Implications for Universal Vaccine Efficacy.

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the pressing contemporary public health challenges. Investigations into the genomic structure of SARS-CoV-2 may inform ongoing vaccine development efforts and/or provide insights into vaccine efficacy to fight against COVID-19. Evolutionary analysis of 540 genomes spanning 20 different countries/territories was conducted and revealed an increase in the genomic divergence across successive generations. The ancestor of the phylogeny was found to be the isolate from the 2019/2020 Wuhan outbreak. Its transmission was outlined across 20 countries/territories as per genomic similarity. Our results demonstrate faster evolving variations in the genomic structure of SARS-CoV-2 when compared to the isolates from early stages of the pandemic. Genomic alterations were predominantly located and mapped onto the reported vaccine candidates of structural genes, which are the main targets for vaccine candidates. S protein showed 34, N protein 25, E protein 2, and M protein 3 amino acid variations in 246 genomes among 540. Among identified mutations, 23 in S protein, 1 in E, 2 from M, and 7 from N protein were mapped with the reported vaccine candidates explaining the possible implications on universal vaccines. Hence, potential target regions for vaccines would be ideally chosen from the structural regions of the genome that lack high variation. The increasing variations in the genome of SARS-CoV-2 together with our observations in structural genes have important implications for the efficacy of a successful universal vaccine against SARS-CoV-2.

Nanomedicine for Intranasal Delivery to Improve Brain Uptake.

Intranasal drug delivery system provides distinct advantage over conventional drug delivery system for a drug that is pharmacokenetically or biologically unstable. Major concern for the treatment of central nervous system diseases is, low concentration of therapeutically active molecule within brain as blood brain barrier is creating obstacle, where intranasal drug delivery provides direct transport of therapeutically active moiety into brain via olfactory or trigeminal pathway. Nasal mucosa provides distinct advantages like improved bioavailability, law dose and quick onset of action and high patient compliance, and the major disadvantage is residence time of drug and irreversible entrapment of drug. This article provides anatomical and physiological information about nasal route and various factors. Article discusses various types of nanoparticles used intranasally and moreover article also emphasizes patents, formulation under development and some.

Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27.

G1 phase cell cycle proteins, such as cyclin-dependent kinase 6 (Cdk6) and its activating partners, the D-type cyclins, are important regulators of T-cell development and function. An F-box protein, called F-box only protein 7 (Fbxo7), acts as a cell cycle regulator by enhancing cyclin D-Cdk6 complex formation and stabilising levels of p27, a cyclin-dependent kinase inhibitor. We generated a murine model of reduced Fbxo7 expression to test its physiological role in multiple tissues and found that these mice displayed a pronounced thymic hypoplasia. Further analysis revealed that Fbxo7 differentially affected proliferation and apoptosis of thymocytes at various stages of differentiation in the thymus and also mature T-cell function and proliferation in the periphery. Paradoxically, Fbxo7-deficient immature thymocytes failed to undergo expansion in the thymus due to a lack of Cdk6 activity, while mature T cells showed enhanced proliferative capacity upon T-cell receptor engagement due to reduced p27 levels. Our studies reveal differential cell cycle regulation by Fbxo7 at different stages in T-cell development.

Gsk3ß and Tomm20 are substrates of the SCFFbxo7/PARK15 ubiquitin ligase associated with Parkinson's disease.

Fbxo7 is a clinically relevant F-box protein, associated with both cancer and Parkinson's disease (PD). Additionally, SNPs within FBXO7 are correlated with alterations in red blood cell parameters. Point mutations within FBXO7 map within specific functional domains, including near its F-box domain and its substrate recruiting domains, suggesting that deficiencies in SCFFbxo7/PARK15 ubiquitin ligase activity are mechanistically linked to early-onset PD. To date, relatively few substrates of the ligase have been identified. These include HURP (hepatoma up-regulated protein), whose ubiquitination results in proteasome-mediated degradation, and c-IAP1 (inhibitor of apoptosis protein 1), TNF receptor-associated factor 2 (TRAF2), and NRAGE, which are not destabilized as a result of ubiquitination. None of these substrates have been linked directly to PD, nor has it been determined whether they would directly engage neuronal cell death pathways. To discover ubiquitinated substrates of SCFFbxo7 implicated more directly in PD aetiology, we conducted a high-throughput screen using protein arrays to identify new candidates. A total of 338 new targets were identified and from these we validated glycogen synthase kinase 3ß (Gsk3ß), which can phosphorylate α-synuclein, and translocase of outer mitochondrial membrane 20 (Tomm20), a mitochondrial translocase that, when ubiquitinated, promotes mitophagy, as SCFFbxo7 substrates both in vitro and in vivo Ubiquitin chain restriction analyses revealed that Fbxo7 modified Gsk3ß using K63 linkages. Our results indicate that Fbxo7 negatively regulates Gsk3ß activity, rather than its levels or localization. In addition, Fbxo7 ubiquitinated Tomm20, and its levels correlated with Fbxo7 expression, indicating a stabilizing effect. None of the PD-associated mutations in Fbxo7 impaired Tomm20 ubiquitination. Our findings demonstrate that SCFFbxo7 has an impact directly on two proteins implicated in pathological processes leading to PD.

Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location.

Liver repopulation by transplanted hepatocytes has not been achieved previously in a normal liver microenvironment. Here we report that adult rat hepatocytes transduced ex vivo with a lentivirus expressing a human YapERT2 fusion protein (hYapERT2) under control of the hepatocyte-specific transthyretin (TTR) promoter repopulate normal rat liver in a tamoxifen-dependent manner. Transplanted hepatocytes expand very slowly but progressively to produce 10% repopulation at 6 months, showing clusters of mature hepatocytes that are fully integrated into hepatic parenchyma, with no evidence for dedifferentiation, dysplasia or malignant transformation. Thus, we have developed the first vector designed to regulate the growth control properties of Yap that renders it capable of producing effective cell therapy. The level of liver repopulation achieved has significant translational implications, as it is 2-3x the level required to cure many monogenic disorders of liver function that have no underlying hepatic pathology and is potentially applicable to diseases of other tissues and organs.

Defective erythropoiesis in a mouse model of reduced Fbxo7 expression due to decreased p27 expression.

During the final stages of erythropoiesis, lineage-restricted progenitors mature over three to five cell divisions, culminating with withdrawal from the cell cycle and the loss of most organelles, including mitochondria and nuclei. Recent genome-wide association studies in human populations have associated several SNPs near or within FBXO7 with erythrocyte phenotypes. Fbxo7 encodes a multi-functional F-box protein known to bind p27 and participate in selective mitophagy. One SNP causes an amino acid substitution (Met115Ile) and is associated with smaller erythrocytes. We find that the less common IIe115 allele of Fbxo7 binds less efficiently to p27, and cells expressing this allele proliferate faster than cells expressing Met115. We show that an erythroleukaemic cell line with reduced Fbxo7 expression fails to stabilize p27 levels, exit the cell cycle, and produce haemoglobin. In addition, mice deficient in Fbxo7 expression are anaemic due to a reduction in erythrocyte numbers, and this is associated with lower p27 levels, increased numbers of late-stage erythroblasts with greater than 2N DNA content, and delayed mitophagy during terminal differentiation. Collectively, these data support an important physiological, cell cycle regulatory role for Fbxo7 during erythropoiesis.

Identification of a Novel Link between the Protein Kinase NDR1 and TGFß Signaling in Epithelial Cells.

Transforming growth factor-beta (TGFß) is a secreted polypeptide that plays essential roles in cellular development and homeostasis. Although mechanisms of TGFß-induced responses have been characterized, our understanding of TGFß signaling remains incomplete. Here, we uncover a novel function for the protein kinase NDR1 (nuclear Dbf2-related 1) in TGFß responses. Using an immunopurification approach, we find that NDR1 associates with SnoN, a key component of TGFß signaling. Knockdown of NDR1 by RNA interference promotes the ability of TGFß to induce transcription and cell cycle arrest in NMuMG mammary epithelial cells. Conversely, expression of NDR1 represses TGFß-induced transcription and inhibits the ability of TGFß to induce cell cycle arrest in NMuMG cells. Mechanistically, we find that NDR1 acts in a kinase-dependent manner to suppress the ability of TGFß to induce the phosphorylation and consequent nuclear accumulation of Smad2, which is critical for TGFß-induced transcription and responses. Strikingly, we also find that TGFß reciprocally regulates NDR1, whereby TGFß triggers the degradation of NDR1 protein. Collectively, our findings define a novel and intimate link between the protein kinase NDR1 and TGFß signaling. NDR1 suppresses TGFß-induced transcription and cell cycle arrest, and counteracting NDR1's negative regulation, TGFß signaling induces the downregulation of NDR1 protein. These findings advance our understanding of TGFß signaling, with important implications in development and tumorigenesis.

Use of methylene blue for treatment of severe sepsis in an immunosuppressed patient after liver transplantation.

Sepsis in the immunosuppressed patient is associated with very high mortality and morbidity. Treatment of sepsis in immunocompromised patients is especially challenging due to an unbalanced systemic inflammatory reaction with subsequent development of profound vasoplegia. Methylene blue (MB) has been successfully used for the treatment of refractory hypotension, but its use has not previously been reported for treatment of sepsis in immunosuppressed patients. The mechanism of MB's action is thought to be due to its inhibitory effect on cGMP-mediated vasodilatation. This case report describes the successful use of MB for treatment of severe septic shock in an immunosuppressed patient after liver transplantation. Hypotension in this patient was refractory to volume repletion and a combination of vasopressors. After MB administration, hemodynamic stability was rapidly reestablished. In the setting of severe sepsis in an immunosuppressed patient, MB should be considered early as a therapeutic option for treatment of refractory vasoplegia.

Effect of selenium- and glutathione-enriched yeast supplementation on a combined atherosclerosis and diabetes hamster model.

Selenium has a central role in antioxidant pathways as a cofactor to glutathione peroxidase. The present study evaluated the effects of four different preparations of inactivated yeast containing various concentrations of selenium and glutathione on a combined atherosclerosis and diabetes hamster model. The hamsters were supplemented with the yeast products for three months. The enriched yeast with the highest selenium and glutathione levels reduced the weight loss induced by diabetes, inhibited an increase in plasma cholesterol and triglyceride caused by a high-cholesterol and high-fat diet, increased the time taken for oxidation of lower density lipoproteins (lag time), and inhibited the formation of atherosclerosis better than low selenium/glutathione yeast supplementation. It was concluded that the yeast prepared to provide high selenium and high glutathione was the best for effecting beneficial changes in glutathione, cholesterol, atherosclerosis, and for demonstrating an antioxidant effect. The high selenium and low glutathione yeast was the best for improving selenium and glucose levels.