Prevalence of Central Venous Stenosis among Black and White ESKD Patients with Dysfunctional Dialysis Access.

In the United States, significant racial and ethnic disparities exist in chronic kidney disease (CKD) and its management. Hemodialysis constitutes the main stay of renal replacement therapy for end-stage kidney disease (ESKD), which is initiated using central venous catheters (CVC) in most CKD patients in the United States. Black ESKD patients have higher usage and greater time on CVC for hemodialysis compared to White patients. This trend places Black patients at a potentially higher risk for CVC-related complications such as central venous stenosis (CVS). We posited that Black patients would have a higher prevalence and a greater risk of CVS. A retrospective review was performed of ESKD patients who underwent a fistulogram for dialysis access malfunction. CVS was defined as > 50% stenosis in the central veins. Fistulograms of 428 ESKD patients were adjudicated, and CVS was noted in 167 of these patients. Of the entire cohort, 370 fistulograms belonged to self-reported unique Black and White ESKD patients, of whom 137 patients were noted to have CVS. There was no difference in the of CVS between Black (40%) and White (41%) ESKD patients. However, a higher severity of stenosis (>70%) (P = 0.03) was noted in White ESKD patients. An unadjusted model showed a significant association between CVS and cardiovascular disease and the use of CVCs. The risk-adjusted model showed a significant association between diabetes and CVS. Unlike arterial stenotic lesions, this work for the first time demonstrated higher prevalence of severe venous stenotic lesions in White ESKD patients and linked diabetes to stenotic venous disease. This work paves the way for future studies investigating the risk and influence of race and ethnicity on CVS using a larger and diverse data set.

Effects of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, on Cardiovascular Disease, Chronic Kidney Disease, and Blood Pressure.

PURPOSE OF REVIEW: Finerenone, an FDA-approved nonsteroidal mineralocorticoid receptor (MR) antagonist, has been evaluated in context of chronic kidney disease (CKD) and associated cardiovascular disease (CVD). In this review, we summarize pre-clinical and clinical studies focused on the impact of finerenone on these disease processes. RECENT FINDINGS: Activation of the MR upregulates genes encoding for facilitators of tissue damage. Finerenone binding to a helix domain in this receptor inhibits receptor function. Studies in murine models of kidney disease, heart failure, hypertension, and vascular injury demonstrate significant protective effects of finerenone against further disease progression, as well as association with reduced oxidative stress, inflammation, and fibrosis. Phase 1-3 clinical trials with finerenone show safety and efficacy in improving renal and cardiovascular outcomes in patients with CKD. Research thus far encourages the addition of finerenone to the standard of care for certain CKD patients, especially those especially at risk for or with pre-existing cardiovascular disease. Continued study of the effect of finerenone in diverse patient populations and different disease states is needed.

Janus Kinase Signaling Pathway and Its Role in COVID-19 Inflammatory, Vascular, and Thrombotic Manifestations.

Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this disease, thrombotic processes drive the catastrophic organ failure and mortality in these patients. In addition to a well-established cytokine storm associated with the disease, perturbations in platelets, endothelial cells, and the coagulation system are key in triggering systemic coagulopathy, involving both the macro- and microvasculatures of different organs. Of the several mechanisms that might contribute to dysregulation of these cells following SARS-CoV-2 infection, the current review focuses on the role of activated Janus kinase (JAK) signaling in augmenting thrombotic processes and organ dysfunction. The review concludes with presenting the current understanding and emerging controversies concerning the potential therapeutic applications of JAK inhibitors for ameliorating the inflammation-thrombosis phenotype in COVID-19 patients.

Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease.

Chronic kidney disease (CKD) imposes a strong and independent risk for peripheral artery disease (PAD). While solutes retained in CKD patients (uremic solutes) inflict vascular damage, their role in PAD remains elusive. Here, we show that the dietary tryptophan-derived uremic solutes including indoxyl sulfate (IS) and kynurenine (Kyn) at concentrations corresponding to those in CKD patients suppress ß-catenin in several cell types, including microvascular endothelial cells (ECs), inhibiting Wnt activity and proangiogenic Wnt targets in ECs. Mechanistic probing revealed that these uremic solutes downregulated ß-catenin in a manner dependent on serine 33 in its degron motif and through the aryl hydrocarbon receptor (AHR). Hindlimb ischemia in adenine-induced CKD and IS solute-specific mouse models showed diminished ß-catenin and VEGF-A in the capillaries and reduced capillary density, which correlated inversely with blood levels of IS and Kyn and AHR activity in ECs. An AHR inhibitor treatment normalized postischemic angiogenic response in CKD mice to a non-CKD level. In a prospective cohort of PAD patients, plasma levels of tryptophan metabolites and plasma's AHR-inducing activity in ECs significantly increased the risk of future adverse limb events. This work uncovers the tryptophan metabolite/AHR/ß-catenin axis as a mediator of microvascular rarefaction in CKD patients and demonstrates its targetability for PAD in CKD models.

Uraemic solutes as therapeutic targets in CKD-associated cardiovascular disease.

Chronic kidney disease (CKD) is characterized by the retention of a myriad of solutes termed uraemic (or uremic) toxins, which inflict damage to several organs, including the cardiovascular system. Uraemic toxins can induce hallmarks of cardiovascular disease (CVD), such as atherothrombosis, heart failure, dysrhythmias, vessel calcification and dysregulated angiogenesis. CVD is an important driver of mortality in patients with CKD; however, reliance on conventional approaches to managing CVD risk is insufficient in these patients, underscoring a need to target risk factors that are specific to CKD. Mounting evidence suggests that targeting uraemic toxins and/or pathways induced by uraemic toxins, including tryptophan metabolites and trimethylamine N-oxide (TMAO), can lower the risk of CVD in patients with CKD. Although tangible therapies resulting from our growing knowledge of uraemic toxicity are yet to materialize, a number of pharmacological and non-pharmacological approaches have the potential to abrogate the effects of uraemic toxins, for example, by decreasing the production of uraemic toxins, by modifying metabolic pathways induced by uraemic toxins such as those controlled by aryl hydrocarbon receptor signalling and by augmenting the clearance of uraemic toxins.

Molecular Mechanisms Underlying the Cardiovascular Toxicity of Specific Uremic Solutes.

Mounting evidence strongly suggests a causal link between chronic kidney disease (CKD) and cardiovascular disease (CVD). Compared with non-CKD patients, patients with CKD suffer disproportionately from CVD and derive suboptimal benefits from interventions targeting conventional CVD risk factors. Uremic toxins (UTs), whose plasma levels rapidly rise as CKD progresses, represent a unique risk factor in CKD, which has protean manifestations on CVD. Among the known UTs, tryptophan metabolites and trimethylamine N-oxide are well-established cardiovascular toxins. Their molecular mechanisms of effect warrant special consideration to draw translational value. This review surveys current knowledge on the effects of specific UTs on different pathways and cell functions that influence the integrity of cardiovascular health, with implication for CVD progression. The effect of UTs on cardiovascular health is an example of a paradigm in which a cascade of molecular and metabolic events induced by pathology in one organ in turn induces dysfunction in another organ. Deciphering the molecular mechanisms underlying such cross-organ pathologies will help uncover therapeutic targets to improve the management of CVD in patients with CKD.

Haploinsufficiency of Casitas B-Lineage Lymphoma Augments the Progression of Colon Cancer in the Background of Adenomatous Polyposis Coli Inactivation.

Casitas B-lineage lymphoma (c-Cbl) is a recently identified ubiquitin ligase of nuclear ß-catenin and a suppressor of colorectal cancer (CRC) growth in cell culture and mouse tumor xenografts. We hypothesized that reduction in c-Cbl in colonic epithelium is likely to increase the levels of nuclear ß-catenin in the intestinal crypt, augmenting CRC tumorigenesis in an adenomatous polyposis coli (APCΔ14/+) mouse model. Haploinsufficient c-Cbl mice (APCΔ14/+ c-Cbl+/-) displayed a significant (threefold) increase in atypical hyperplasia and adenocarcinomas in the small and large intestines; however, no differences were noted in the adenoma frequency. In contrast to the APCΔ14/+ c-Cbl+/+ mice, APCΔ14/+ c-Cbl+/- crypts showed nuclear ß-catenin throughout the length of the crypts and up-regulation of Axin2, a canonical Wnt target gene, and SRY-box transcription factor 9, a marker of intestinal stem cells. In contrast, haploinsufficiency of c-Cbl+/- alone was insufficient to induce tumorigenesis regardless of an increase in the number of intestinal epithelial cells with nuclear ß-catenin and SRY-box transcription factor 9 in APC+/+ c-Cbl+/- mice. This study demonstrates that haploinsufficiency of c-Cbl results in Wnt hyperactivation in intestinal crypts and accelerates CRC progression to adenocarcinoma in the milieu of APCΔ14/+, a phenomenon not found with wild-type APC. While emphasizing the role of APC as a gatekeeper in CRC, this study also demonstrates that combined partial loss of c-Cbl and inactivation of APC significantly contribute to CRC tumorigenesis.

Black Patients Experience Highest Rates of Cancer-associated Venous Thromboembolism.

PURPOSE: Cancer patients are at a higher risk of venous thromboembolism (VTE) than the general population. In the general population, blacks are at a higher risk of VTE compared with whites. The influence of race on cancer-associated VTE remains unexplored. We examined whether black cancer patients are at a higher risk of VTE and whether these differences are present in specific cancer types. DESIGN: A retrospective study was performed in the largest safety net hospital of New England using a cohort of cancer patients characterized by a substantial number of nonwhites. RESULTS: We identified 16,498 subjects with solid organ and hematologic malignancies from 2004 to 2018. Among them, we found 186 unique incident VTE events, of which the majority of the events accrued within the first 2 years of cancer diagnosis. Overall, blacks showed a 3-fold higher incidence of VTE (1.8%) compared with whites (0.6%; P<0.001). This difference was observed in certain cancer types such as lung, gastric and colorectal. In lung cancer, the odds of developing VTE in blacks was 2.77-times greater than those in white patients (confidence interval, 1.33-5.91; P=0.007). Despite the greater incidence of cancer-associated VTE in blacks, their Khorana risk score of VTE was not higher. CONCLUSIONS: In a diverse cancer cohort, we observed a higher incidence of cancer-associated VTE in blacks compared with patients from other races. This study indicates the consideration of race in the risk assessment of cancer-associated VTE. It could also lead to future mechanistic studies aiming at identifying reasons for differential VTE risk depending on cancer type.

c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth.

Casitas B lymphoma (c-Cbl) is an E3 ubiquitin ligase and a negative regulator of colorectal cancer (CRC). Despite its high expression in immune cells, the effect of c-Cbl on the tumor microenvironment remains poorly understood. Here we demonstrate that c-Cbl alters the tumor microenvironment and suppresses Programmed cell death-1 (PD-1) protein, an immune checkpoint receptor. Using syngeneic CRC xenografts, we observed significantly higher growth of xenografts and infiltrating immune cells in c-Cbl+/- compared to c-Cbl+/+ mice. Tumor-associated CD8+ T-lymphocytes and macrophages of c-Cbl+/- mice showed 2-3-fold higher levels of PD-1. Functionally, macrophages from c-Cbl+/- mice showed a 4-5-fold reduction in tumor phagocytosis, which was restored with an anti-PD-1 neutralizing antibody suggesting regulation of PD-1 by c-Cbl. Further mechanistic probing revealed that C-terminus of c-Cbl interacted with the cytoplasmic tail of PD-1. c-Cbl destabilized PD-1 through ubiquitination- proteasomal degradation depending on c-Cbl's RING finger function. This data demonstrates c-Cbl as an E3 ligase of PD-1 and a regulator of tumor microenvironment, both of which were unrecognized components of its tumor suppressive activity. Advancing immune checkpoint and c-Cbl biology, our study prompts for probing of PD-1 regulation by c-Cbl in conditions driven by immune checkpoint abnormalities such as cancers and autoimmune diseases.

Anxious anticipation prolongs emotional interference for rapid visual detection.

When we view emotionally arousing images, our perception of stimuli that follow soon afterward is transiently impaired-a phenomenon known as emotion-induced blindness. Previous studies have demonstrated that the magnitude and time course of this visual processing impairment is exaggerated by the presence of psychopathology and anxiety-related traits. Here, we tested whether emotional interference on a primary task can be modulated on a more dynamic basis, by the anticipation of unpredictable electric shock. We embedded naturalistic scenes in a 10-Hz rapid serial visual presentation (RSVP) stream, while varying the hedonic content of distractor images (aversive or neutral) and their temporal position (200, 400, and 700 ms) with respect to landscape targets. In Experiment 1, we found that, under typical conditions, aversive distractors induced a temporary visual performance decrement that exhibited a full rebound following a 400-ms distractor-target lag. In Experiment 2, subjects performed an identical RSVP task while under continuous threat of electric shock. We found that threat of unpredictable electric shock prolonged the duration of the emotional interference out to 400 ms and 700 ms, without affecting the overall magnitude of the performance impairment. In Experiment 3, the prolonged emotional interference under threat of unpredictable electric shock persisted at the 400-ms lag despite observed practice effects within subjects. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The Relevance of Group II Glutamate Receptors Expression to Anxiety.

The interface of receptor-mediated regulation of cellular signaling and neurological outputs remains an active field of investigation. The metabotropic G protein-coupled glutamate receptors, and in particular, the group II cyclic adenosine mono-phosphate (cAMP)-lowering metabotropic glutamate receptors 2 and 3 (mGlu2/3 glutamate receptors), have gained interest as therapeutic targets in different forms of neurological disorders. This review explores mGlu2/3 glutamate receptors expression, pharmacological activation, and signaling links to anxiety, as assessed in animal models and in clinical trials.

Composition Tunability and (111)-Dominant Facets of Ultrathin Platinum-Gold Alloy Nanowires toward Enhanced Electrocatalysis.

The ability for tuning not only the composition but also the type of surface facets of alloyed nanomaterials is important for the design of catalysts with enhanced activity and stability through optimizing both ensemble and ligand effects. Herein we report the first example of ultrathin platinum-gold alloy nanowires (PtAu NWs) featuring composition-tunable and (111) facet-dominant surface characteristics, and the electrocatalytic enhancement for the oxygen reduction reaction (ORR). PtAu NWs of different bimetallic compositions synthesized by a single-phase and surfactant-free method are shown to display an alloyed, parallel-bundled structure in which the individual nanowires exhibit Boerdijk-Coxeter helix type morphology predominant in (111) facets. Results have revealed intriguing catalytic correlation with the binary composition, exhibiting an activity maximum at a Pt:Au ratio of ∼3:1. As revealed by high-energy synchrotron X-ray diffraction and atomic pair distribution function analysis, NWs of this ratio exhibit a clear shrinkage in interatomic bonding distances. In comparison with PtAu nanoparticles of a similar composition and degree of shrinking of atomic-pair distances, the PtAu NWs display a remarkably higher electrocatalytic activity and stability. The outperformance of NWs over nanoparticles is attributed to the predominant (111)-type facets on the surface balancing the contribution of ensemble and ligand effects, in addition to the composition synergy due to optimal adsorption energies for molecular and atomic oxygen species on the surface as supported by DFT computation of models of the catalysts. The findings open up a new pathway to the design and engineering of alloy nanocatalysts with enhanced activity and durability.