Aagaardovergaard6199

NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008-003529-17.

CKD is an independent risk factor for heart failure. Iron dysmetabolism potentially contributes to heart failure, but this relationship has not been well characterized in CKD.

We performed a historical cohort study using data from the Veterans Affairs Corporate Data Warehouse to evaluate the relationship between iron status and heart failure hospitalization. We identified a CKD cohort with at least one set of iron indices between 2006 and 2015. The first available date of serum iron indices was identified as the study index date. The cohort was divided into four iron groups on the basis of the joint quartiles of serum transferrin saturation (shown in percent) and ferritin (shown in nanograms per milliliter) reference (16%-28%, 55-205 ng/ml), low iron (0.4%-16%, 0.9-55 ng/ml), high iron (28%-99.5%, 205-4941 ng/ml), and function iron deficiency (0.8%-16%, 109-2783 ng/ml). We compared 1-year heart failure hospitalization risk between the iron groups using matching weights derived from multinomial propensity ciency, regardless of cause, was associated with higher heart failure hospitalization risk in CKD. Higher iron status was associated with lower heart failure hospitalization risks.Cancer is an important outcome after kidney transplantation because it is the second leading cause of death in most Western countries. The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers. Once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease. More importantly, effective screening and treatment strategies are limited in this high-risk population. In this review, we begin with a patient's journey that maps the experience of living with a kidney transplant and understand the patient's knowledge, education, and experience of cancer in the context of transplantation. The epidemiology and burden of cancer in recipients of kidney transplants, along with the up-to-date screening and treatment strategies, are discussed. We also focus on the current understanding of optimal care for recipients of kidney transplants who are living with cancer from the patients' perspectives.

AKI in coronavirus disease 2019 (COVID-19) is associated with higher morbidity and mortality. The objective of this study was to identify the kidney histopathologic characteristics of deceased patients with diagnosis of COVID-19 and evaluate the association between biopsy findings and clinical variables, including AKI severity.

Our multicenter, observational study of deceased patients with COVID-19 in three third-level centers in Mexico City evaluated postmortem kidney biopsy by light and electron microscopy analysis in all cases. Descriptive and association statistics were performed between the clinical and histologic variables.

A total of 85 patients were included. Median age was 57 (49-66) years, 69% were men, body mass index was 29 (26-35) kg/m

, 51% had history of diabetes, 46% had history of hypertension, 98% received anticoagulation, 66% were on steroids, and 35% received at least one potential nephrotoxic medication. Severe AKI was present in 54% of patients. Biopsy findings included FSGS in 29very from severe AKI was associated with the presence of pigmented casts. Inflammatory markers and medications were associated with specific histopathologic findings in patients dying from COVID-19.

Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations.

Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible.

Targeted exome sequencing of 41 tumors identified common alterations in

(21; 51%) and

(20; 49%), as well as alterations in several emerging biomarkers such as

mutations/deletions (6; 15%),

mutations (4; 10%), and

mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified

amplifications (3; 11%),

amplifications (5; 19%),

mutations (2; 7%), and

mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including

loss in 3 patients, loss of

mutation in 1alysis for treatment selection.

The JAK1/2 inhibitor ruxolitinib has demonstrated significant benefits for patients with myeloproliferative neoplasms (MPN). However, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to devise treatment strategies to improve therapeutic efficacy in combination with ruxolitinib therapy. Activation of JAK-STAT signaling results in dysregulation of key downstream pathways, notably increased expression of cell-cycle mediators including CDC25A and the PIM kinases.

Given the involvement of cell-cycle mediators in MPNs, we sought to examine the efficacy of therapy combining ruxolitinib with a CDK4/6 inhibitor (LEE011) and a PIM kinase inhibitor (PIM447). We utilized JAK2-mutant cell lines, murine models, and primary MPN patient samples for these studies.

Exposure of JAK2-mutant cell lines to the triple combination of ruxolitinib, LEE011, and PIM447 resulted in expected on-target pharmacodynamic effects, as well as increased apoptosis and a decrease in the proportion of cells in S-phase, compared with ruxolitinib. As compared with ruxolitinib monotherapy, combination therapy led to reductions in spleen and liver size, reduction of bone marrow reticulin fibrosis, improved overall survival, and elimination of disease-initiating capacity of treated bone marrow, in murine models of MPN. Finally, the triple combination reduced colony formation capacity of primary MPN patient samples to a greater extent than ruxolitinib.

The triple combination of ruxolitinib, LEE011, and PIM447 represents a promising therapeutic strategy with the potential to increase therapeutic responses in patients with MPN.

The triple combination of ruxolitinib, LEE011, and PIM447 represents a promising therapeutic strategy with the potential to increase therapeutic responses in patients with MPN.

In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors.

In

exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1-staining TCs + immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression.

There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1-positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1-positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1-negative status. Similar results were observed in the NIVO 1 mg/kg + IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes (

, and

), showed associations with response to NIVO ± IPI.

This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.

This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.The plant hormone auxin governs many aspects of normal plant growth and development. Auxin also plays an important role in plant-microbe interactions, including interactions between plant hosts and pathogenic microorganisms that cause disease. It is now well established that indole-3-acetic acid (IAA), the most well-studied form of auxin, promotes disease in many plant-pathogen interactions. Recent studies have shown that IAA can act both as a plant hormone that modulates host signaling and physiology to increase host susceptibility and as a microbial signal that directly impacts the pathogen to promote virulence, but large gaps in our understanding remain. In this article, we review recent studies on the roles that auxin plays during plant-pathogen interactions and discuss the virulence mechanisms that many plant pathogens have evolved to manipulate host auxin signaling and promote pathogenesis.In recent years, our understanding about the functional complexity of CD8+ T-cell populations has increased tremendously. The immunology field is now facing challenges to translate these insights into phenotypic definitions that correlate reliably with distinct functional traits. This is key to adequately monitor and understand compound immune responses including vaccination and immunotherapy regimens. check details Here we will summarize our understanding of the current state in the human CD8+ T-cell subset characterization field. We will address how reliably the currently used cell surface markers are connected to differentiation status and function of particular subsets. By restricting ourselves to CD8+ αβ T cells, we will focus mostly on major histocompatibility complex (MHC) class I-restricted virus- and tumor-specific T cells. This comes with a major advantage as fluorescently labeled peptide-loaded MHC class I multimers have been widely used to identify and characterize these cells.Immunological memory and exhaustion are fundamental features of adaptive immunity. Recent advances reveal increasing heterogeneity and diversity among CD8 T-cell subsets, resulting in new subsets to annotate and understand. Here, we review our current knowledge of differentiation and maintenance of memory and exhausted CD8 T cells, including phenotypic classification, developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors. Additionally, we use this outline to discuss the nomenclature of effector, memory, and exhausted CD8 T cells. Finally, we discuss how new findings about these cell types may impact the therapeutic efficacy and development of immunotherapies targeting effector, memory, and/or exhausted CD8 T cells in chronic infections and cancer.

This is a phase 1, open-label, single-centre, uncontrolled, dose-escalation study to evaluate the feasibility, tolerability and pharmacokinetic profiles of a single dose of liposomal curcumin, administered via an existing tunnelled indwelling pleural catheter (TIPC) directly to the tumour site in individuals with diagnoses of malignant pleural effusion. Primarily, we aim to determine a maximum tolerated dose of liposomal curcumin administered via this method.

We will use a 3+3 expanded cohort for predefined dose-escalation levels or until a predefined number of dose-limiting toxicities are reached. Participants will be administered a single dose of liposomal curcumin (LipoCurc, SignPath Pharma) via their existing TIPC as a sequential enrolling case series with the following dose cohorts 100, 200 and 300 mg/m

. Primary endpoints are determination of the maximum tolerated dose within the predetermined dose range, and determination of the feasibility of intrapleural administration of liposomal curcumin via an existing TIPC.