Altered retinal cerebral vessel oscillation frequencies in Alzheimer's disease compatible with impaired amyloid clearance.

Retinal vessels are similar to cerebral vessels in their structure and function. Moderately low oscillation frequencies of around 0.1 Hz have been reported as the driving force for paravascular drainage in gray matter in mice and are known as the frequencies of lymphatic vessels in humans.

Lu-PSMA-617 and Idronoxil in Men with End-Stage Metastatic Castration-Resistant Prostate Cancer (LuPIN): Patient Outcomes and Predictors of Treatment Response in a Phase I/II Trial.

Lu-PSMA-617 is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently, and combination therapies may improve outcomes. We report the final safety and efficacy results of a phase I/II study combining Lu-PSMA-617 with idronoxil (NOX66), a radiosensitizer, and examine potential clinical, blood-based, and imaging biomarkers.

Independent prognostic impact of plasma NCOA2 alterations in metastatic castration-resistant prostate cancer.

Background: The androgen receptor (AR) pathway-associated gene nuclear receptor coactivator 2 (NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic disease and castration-resistant prostate cancer. However, its significance as a biomarker in metastatic castration-resistant prostate cancer (mCRPC), both alone and in conjunction with co-occurring AR alterations using a liquid biopsy approach has not been investigated.

Methods: Ninety-one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitor and n = 23 receiving taxane chemotherapy).

Plasma Cell-Free DNA Profiling of PTEN-PI3K-AKT Pathway Aberrations in Metastatic Castration-Resistant Prostate Cancer.

Unlabelled: Tumor tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the PTEN-PI3K-AKT pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven to be challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, we profiled PTEN-PI3K-AKT pathway aberrations in patients with mCRPC using a novel cfDNA assay optimized for CNV detection.

Whole blood expression as a prognostic biomarker in metastatic hormone-sensitive and castration-resistant prostate cancer.

Background: As potent systemic therapies transition earlier in the prostate cancer disease course, molecular biomarkers are needed to guide optimal treatment selection for metastatic hormone-sensitive prostate cancer (mHSPC). The value of whole blood RNA to detect candidate biomarkers in mHSPC remains largely undefined.

Methods: In this cohort study, we used a previously optimised whole blood reverse transcription polymerase chain reaction assay to assess the prognostic utility [measured by seven-month undetectable prostate-specific antigen (PSA) and time to castration-resistance (TTCR)] of eight prostate cancer-associated gene transcripts in 43 mHSPC patients.

Prognostic Impact of Total Plasma Cell-free DNA Concentration in Androgen Receptor Pathway Inhibitor-treated Metastatic Castration-resistant Prostate Cancer.

Total plasma cell-free DNA (cfDNA) levels were recently shown to be prognostic in two large phase III trials of taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). However, whether cfDNA concentration is predictive of treatment outcomes with androgen receptor pathway inhibitors (ARPIs) is unknown. We quantified plasma cfDNA levels at baseline (n = 74) and 4 weeks on treatment (n = 56) in a prospective cohort of mCRPC patients treated with the ARPIs abiraterone acetate or enzalutamide.

Analytical validation of an error-corrected ultra-sensitive ctDNA next-generation sequencing assay.

Plasma circulating tumor DNA (ctDNA) analysis has emerged as a minimally invasive means to perform molecular tumor typing. Here we developed a custom ultra-sensitive ctDNA next-generation sequencing assay using molecular barcoding technology and off-the-shelf reagents combined with bioinformatics tools for enhanced ctDNA analysis. Assay performance was assessed via a spike-in experiment and the technique was applied to analyze 41 plasma samples from men with advanced prostate cancer.

Combined Cell-free DNA and RNA Profiling of the Androgen Receptor: Clinical Utility of a Novel Multianalyte Liquid Biopsy Assay for Metastatic Prostate Cancer.

Background: The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive and/or prognostic biomarkers in the context of contemporary systemic therapy.

Objective: To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes.

Decreased Vascular Pulsatility in Alzheimer's Disease Dementia Measured by Transcranial Color-Coded Duplex Sonography.

Purpose: Impaired paravascular drainage of β-Amyloid (Aβ) has been proposed as a contributing cause for sporadic Alzheimer's disease (AD), as decreased cerebral blood vessel pulsatility and subsequently reduced propulsion in this pathway could lead to the accumulation and deposition of Aβ in the brain. Therefore, we hypothesized that there is an increased impairment in pulsatility across AD spectrum.

Patients And Methods: Using transcranial color-coded duplex sonography (TCCS) the resistance and pulsatility index (RI; PI) of the middle cerebral artery (MCA) in healthy controls (HC, n=14) and patients with AD dementia (ADD, n=12) were measured.

Impaired Retinal Vessel Dilation Predicts Mortality in End-Stage Renal Disease.

Rationale: Patients with end-stage renal disease (ESRD) are characterized by increased cardiovascular (CV) and all-cause mortality due to advanced remodeling of the macro- and microvascular beds.

Objective: The aim of this study was to determine whether retinal microvascular function can predict all-cause and CV mortality in patients with ESRD.

Methods And Results: In the multicenter prospective observational ISAR (Risk Stratification in End-Stage Renal Disease) study, data on dynamic retinal vessel analysis (DVA) was available in a sub-cohort of 214 dialysis patients (mean age 62.

Comparison of 24-hour and Office Pulse Wave Velocity for Prediction of Mortality in Hemodialysis Patients.

Background: Mortality in hemodialysis patients still remains unacceptably high. Enhanced arterial stiffness is a known cardiovascular risk factor, and pulse wave velocity (PWV) has proven to be a valid parameter to quantify risk. Recent studies showed controversial results regarding the prognostic significance of PWV for mortality in hemodialysis patients, which may be due to methodological issues, such as assessment of PWV in the office setting (Office-PWV).

Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer.

Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors.

Cognitive Impairment is Associated with Mortality in Hemodialysis Patients.

Background: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studises performed in the general population, cognitive impairment has been associated with increased mortality.

Objective: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients.

A novel citrate-based protocol versus heparin anticoagulation for sustained low-efficiency dialysis in the ICU: safety, efficacy, and cost.

Background: The high cost, complexity of the available protocols, and metabolic complications are the major barriers that impede the clinical utilization of regional citrate anticoagulation (RCA) for sustained low efficiency dialysis (SLED) in critically ill patients. By comparing a novel protocol for SLED using 30% citrate solution with common protocol using unfractionated heparin, this study aimed to provide new insights for clinical applications of RCA.

Methods: In this retrospective study, a total of 282 critically ill patients who underwent SLED with citrate and/or heparin anticoagulation in six adult ICUs were enrolled.

Altered neurovascular coupling as measured by optical imaging: a biomarker for Alzheimer's disease.

Neurovascular coupling can be directly assessed by retinal vessel response to flickering light using optical imaging methods. The response is altered in a number of ocular and cardiovascular diseases. Whether it is altered in Alzheimer's disease (AD) is investigated.

Cognitive impairment in hemodialysis patients: Implementation of cut-off values for the Montreal Cognitive Assessment (MoCA)-test for feasible screening.

Objective: Reliable identification of cognitive impairment in hemodialysis patients is of utmost importance, as it is associated with poor outcomes including dialysis withdrawal and death. High prevalence of cognitive impairment has been demonstrated in several studies using brief screening instruments or neuropsychological test batteries. However, the relevance of cognitive impairment as well as the accuracy of screening procedures have never been studied in this patient population.

Mortality prediction in stable hemodialysis patients is refined by YKL-40, a 40-kDa glycoprotein associated with inflammation.

Chronic inflammation contributes to increased mortality in hemodialysis (HD) patients. YKL-40 is a novel marker of inflammation, tissue remodeling, and highly expressed in macrophages inside vascular lesions. Elevated levels of YKL-40 have been reported for HD patients but how it integrates into the proinflammatory mediator network as a predictor of mortality remains elusive.

Fluorescence optical imaging and 3T-MRI for detection of synovitis in patients with rheumatoid arthritis in comparison to a composite standard of reference.

Objectives: To address whether Indocyanine Green (ICG) enhanced fluorescence optical imaging (FOI) is more sensitive than magnetic resonance imaging (MRI) in the detection of synovitis of the wrist and finger joints in rheumatoid arthritis and to analyze the performance of FOI depending on the grade of synovitis.

Methods: Twenty patients with highly active rheumatoid arthritis (mean DAS28-ESR 5.25±1.

Pulse wave velocity is associated with cognitive impairment in hemodialysis patients.

Cognitive impairment in hemodialysis patients is common and associated with adverse outcomes. So far, the underlying pathogenesis remains unclear. Therefore, we examined the potential relationship between cognitive impairment and three different categories of risk factors with particular focus on arterial stiffness measured by pulse wave velocity (PWV).

Rationale and study design of the prospective, longitudinal, observational cohort study "rISk strAtification in end-stage renal disease" (ISAR) study.

Background: The ISAR study is a prospective, longitudinal, observational cohort study to improve the cardiovascular risk stratification in endstage renal disease (ESRD). The major goal is to characterize the cardiovascular phenotype of the study subjects, namely alterations in micro- and macrocirculation and to determine autonomic function.

Methods/design: We intend to recruit 500 prevalent dialysis patients in 17 centers in Munich and the surrounding area.

TCPTP regulates SFK and STAT3 signaling and is lost in triple-negative breast cancers.

Tyrosine phosphorylation-dependent signaling, as mediated by members of the epidermal growth factor receptor (EGFR) family (ErbB1 to -4) of protein tyrosine kinases (PTKs), Src family PTKs (SFKs), and cytokines such as interleukin-6 (IL-6) that signal via signal transducer and activator of transcription 3 (STAT3), is critical to the development and progression of many human breast cancers. EGFR, SFKs, and STAT3 can serve as substrates for the protein tyrosine phosphatase TCPTP (PTPN2). Here we report that TCPTP protein levels are decreased in a subset of breast cancer cell lines in vitro and that TCPTP protein is absent in a large proportion of "triple-negative" primary human breast cancers.

Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance.

In obesity, anorectic responses to leptin are diminished, giving rise to the concept of "leptin resistance." Increased expression of protein tyrosine phosphatase 1B (PTP1B) has been associated with the attenuation of leptin signaling and development of cellular leptin resistance. Here we report that hypothalamic levels of the tyrosine phosphatase TCPTP are also elevated in obesity to attenuate the leptin response.

Oncostatin M is a novel inhibitor of TGF-β1-induced matricellular protein expression.

Matricellular proteins in the kidney have been associated with the development of tubulointerstitial fibrogenesis and the progression of renal disease. This study investigated potential antifibrotic effects of the cytokine oncostatin M (OSM) in human proximal tubule cells (PTC), particularly with regard to inhibition of profibrotic events initiated by TGF-β1. In human PTC, OSM diminished transforming growth factor (TGF)-β1-induced expression of the transcriptional epithelial-mesenchymal transition mediator FoxC2.

Cell cycle-dependent regulation of SFK, JAK1 and STAT3 signalling by the protein tyrosine phosphatase TCPTP.

Janus-activated kinases (JAKs) and Src family kinases (SFKs) and their common substrate signal transducer and activator of transcription (STAT)-3 are frequently hyperactivated in human cancer contributing to the proliferative drive by promoting G(1)/S and G(2)/M progression. Previous studies have established that the protein tyrosine phosphatase TCPTP can dephosphorylate and inactivate the SFK and JAK protein tyrosine kinases (PTKs) to attenuate cytokine signalling in vivo. In this study we determined whether TCPTP regulates SFK and JAK signalling during the cell cycle.