A Compendium of Urinary Biomarkers Indicative of Glomerular Podocytopathy

It is well known that glomerular podocyte injury and loss are present in numerous nephropathies and that the pathophysiologic consecution of disease hinges upon the fate of the podocyte. While multiple factors play a hand in glomerulopathy progression, basic logic lends that if one monitors the podocyte's status, that may reflect the status of disease. Recent investigations have focused on what one can elucidate from the noninvasive collection of urine, and have proven that certain, specific biomarkers of podocytes can be readily identified via varying techniques. This paper has brought together all described urinary biomarkers of podocyte injury and is made to provide a concise summary of their utility and testing in laboratory and clinical theatres. While promising in the potential that they hold as tools for clinicians and investigators, the described biomarkers require further comprehensive vetting in the form of larger clinical trials and studies that would give their value true weight. These urinary biomarkers are put forth as novel indicators of glomerular disease presence, disease progression, and therapeutic efficacy that in some cases may be more advantageous than the established parameters/measures currently used in practice

Clear Cell Renal Cell Carcinoma is linked to Epithelial‐to‐Mesenchymal Transition and to Fibrosis

Clear cell renal cell carcinoma (ccRCC) represents the most common type of kidney cancer with high mortality in its advanced stages. Our study aim was to explore the correlation between tumor epithelial‐to‐mesenchymal transition (EMT) and patient survival. Renal biopsies of tumorous and adjacent nontumorous tissue were taken with a 16 g needle from our patients (n = 26) undergoing partial or radical nephrectomy due to ccRCC. RNA sequencing libraries were generated using Illumina TruSeq® Access library preparation protocol and TruSeq Small RNA library preparation kit. Next generation sequencing (NGS) was performed on Illumina HiSeq2500. Comparative analysis of matched sample pairs was done using the Bioconductor Limma/voom R‐package. Liquid chromatography‐tandem mass spectrometry and immunohistochemistry were applied to measure and visualize protein abundance. We detected an increased generic EMT transcript score in ccRCC. Gene expression analysis showed augmented abundance of AXL and MMP14, as well as down‐regulated expression of KL (klotho). Moreover, microRNA analyses demonstrated a positive expression correlation of miR‐34a and its targets MMP14 and AXL. Survival analysis based on a subset of genes from our list EMT‐related genes in a publicly available dataset showed that the EMT genes correlated with ccRCC patient survival. Several of these genes also play a known role in fibrosis. Accordingly, recently published classifiers of solid organ fibrosis correctly identified EMT‐affected tumor samples and were correlated with patient survival. EMT in ccRCC linked to fibrosis is associated with worse survival and may represent a target for novel therapeutic interventions.Peer reviewe

Systems analyses of the Fabry kidney transcriptome and its response to enzyme replacement therapy identified and cross-validated enzyme replacement therapy-resistant targets amenable to drug repurposing

Fabry disease is a rare disorder caused by variations in the alpha-galactosidase gene. To a degree, Fabry disease is manageable via enzyme replacement therapy (ERT). By understanding the molecular basis of Fabry nephropathy (FN) and ERT's long-term impact, here we aimed to provide a framework for selection of potential disease biomarkers and drug targets. We obtained biopsies from eight control individuals and two independent FN cohorts comprising 16 individuals taken prior to and after up to ten years of ERT, and performed RNAseq analysis. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from four nephron compartments and their integration with existing proteome and drug-target interactome data. Comparing these transcriptional landscapes revealed high inter-cohort heterogeneity. Kidney compartment transcriptional landscapes comprehensively reflected differences in FN cohort characteristics. With exception of a few aspects, in particular arteries, early ERT in patients with classical Fabry could lastingly revert FN gene expression patterns to closely match that of control individuals. Pathways nonetheless consistently altered in both FN cohorts pre-ERT were mostly in glomeruli and arteries and related to the same biological themes. While keratinization-related processes in glomeruli were sensitive to ERT, a majority of alterations, such as transporter activity and responses to stimuli, remained dysregulated or reemerged despite ERT. Inferring an ERT-resistant genetic module of expressed genes identified 69 drugs for potential repurposing matching the proteins encoded by 12 genes. Thus, we identified and cross-validated ERT-resistant gene product modules that, when leveraged with external data, allowed estimating their suitability as biomarkers to potentially track disease course or treatment efficacy and potential targets for adjunct pharmaceutical treatment

Renal and Vascular Functional Decline in Aged Low Birth Weight Murine Adults

Introduction: Maternal undernutrition (MUN)-induced low birth weight (LBW) neonates are susceptible to the development of high blood pressure and kidney disease later in life, although the underlying pathological causes remain unclear. The study here investigated the role of renal oxidative stress, impairment of vascular function, and altered sensitivity to angiotensin II (Ang II) as factors that contribute to these pathologies in aged LBW mice. Methods: LBW offspring were generated using a combined protein and caloric restricted MUN mouse model. The resulting LBW offspring were examined 1 year after birth for mean arterial blood pressure (MABP) (carotid artery catheterization), renal blood flow (RBF) (laser Doppler flowmetry), glomerular filtration rate (GFR) (sinistrin clearance), vasoreactivity (myograph), renal vascular density (CD31 staining), and reactive oxygen species (ROS) (ROS probes). Immunoblotting examined Ang II type 1 receptor (AT1R), soluble guanylate cyclase (sGC), and antioxidant systems. Pharmacological agents delivered to animals included the sGC stimulator δ-aminolevulinic acid (ALA), the AT1R inhibitor losartan, the antioxidant ethyl pyruvate (EP), and the toll-like receptor 4 inhibitor TAK242. Results: After 1 year, MABP was increased, while RBF, GFR, vascular reactivity, renal vascular density, and sGC were all reduced in the LBW aged adult. All four pharmacological agents improved MABP, RBF, GFR, vascular density, and vascular reactivity. Renal ROS was increased in the LBW adult but was reduced by ALA, EP, and TAK242 treatment. AT1R was upregulated in the LBW adult, while sGC was decreased, an effect reversed by ALA treatment. Endogenous antioxidant systems, including SOD1, catalase, and glutathione were downregulated in the LBW adult. Conclusion: MUN-induced LBW mice experience increased Ang II sensitivity and oxidative stress. The increased Ang II sensitivity and ROS generation influences vascular density and reactivity, which drive an increase in MABP, and a concomitantly decrease in RBF and glomerular filtration. Pharmacological intervention that inhibits AT1R, enhances levels of sGC, reduces ROS, or inhibits toll-like receptor 4 improves vascular and renal function in the LBW adult

Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance

Proceedings of the 12th International Conference on Kinanthropology

Proceedings of the 12th Conference of Sport and Quality of Life 2019 gatheres submissions of participants of the conference. Every submission is the result of positive evaluation by reviewers from the corresponding field. Conference is divided into sections – Analysis of human movement; Sport training, nutrition and regeneration; Sport and social sciences; Active ageing and sarcopenia; Strength and conditioning training; section for PhD students

Case Report: Isolated and Focal Non-necrotizing Granulomatous Inflammation of Mitral Valves: A Report of Two Cases

Cardiac valve inflammation is seen in the setting of autoimmune or infectious processes, and rarely is valvulitis characterized by granulomatous inflammation. We present two patients who underwent surgical repair of prolapsing/regurgitating mitral valves. Excised valve tissue in both cases revealed commonly encountered nodular fibrosis and calcification, however each also revealed an isolated focus of non-necrotizing granulomatous inflammation. Typical implicating etiologies for non-necrotizing granulomatous inflammation were not present for either patient based on clinical history, or radiologic and laboratory data. In a review of 1048 cardiac valves excised at our institution, the finding of non-necrotizing granulomatous inflammation was seen in only the two described cases (prevalence of 0.19%). The description of non-necrotizing granulomatous inflammation within cardiac valves is limited in the literature, and the significance of the detailed isolated and incidental finding is unclear and requiring further investigation.</jats:p