Fused core-modified meso-aryl expanded porphyrins

The synthesis and characterization of the first examples of singly and doubly fused expanded porphyrins containing dithienothiophene (DTT) cores are reported

Indian commentary on the 2009 KDIGO clinical practice guideline for the diagnosis, evaluation, and treatment of chronic kidney disease-mineral and bone disorders

This commentary presents the view of an Expert Group of Indian nephrologists on adaptation and implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and management of mineral and bone disorder in chronic kidney disease (CKD-MBD) for practice in India. Zonal meetings of nephrologists drawn from the cross-section were convened to discuss the KDIGO guidelines. Recommendations were presented in a central meeting of zonal representatives. The finalized recommendations were reviewed by all the participants. There was a broad agreement on most of the recommendations made by the KDIGO workgroup. Significant departures in the current guidelines from the previous Kidney Disease Outcome Quality Initiative (KDOQI) guidelines were also noted. The participants agreed that the available evidence did not allow more precise recommendations, and the recommended best practice suggestions were often based on relatively weak evidence. There is a remarkable lack of data from Indian patients. We comment on specific areas and amplify certain concepts where we feel that further guidance that goes beyond what is stated in the document might help Indian nephrologists in appropriate implementation of the KDIGO guidelines. This commentary is intended to help define practically implementable best practices based on current disease concepts and available research evidence, thereby positively affecting the quality of management of CKD-MBD in India, and eventually improving patient outcomes

PAX8 expression in high-grade serous ovarian cancer positively regulates attachment to ECM via Integrin β3

Background: Ovarian cancer is the third most common cause of death among gynecologic malignancies worldwide. Understanding the biology and molecular pathogenesis of ovarian epithelial tumors is key to developing improved prognostic indicators and effective therapies. We aimed to determine the effects of PAX8 expression on the migrative, adhesive and survival capabilities of high-grade serous carcinoma cells. Methods: PAX8 depleted Fallopian tube secretory cells and ovarian cancer cells were generated using short interfering siRNA. Anoikis resistance, cell migration and adhesion properties of PAX8 silenced cells were analyzed by means of specific assays. Chromatin immunoprecipitation (ChIP) was carried out using a PAX8 polyclonal antibody to demonstrate that PAX8 is able to bind to the 5′-flanking region of the ITGB3 gene positively regulating its expression. Results: Here, we report that RNAi silencing of PAX8 sensitizes non-adherent cancer cells to anoikis and affects their tumorigenic properties. We show that PAX8 plays a critical role in migration and adhesion of both Fallopian tube secretory epithelial cells and ovarian cancer cells. Inhibition of PAX8 gene expression reduces the ability of ovarian cancer cells to migrate and adhere to the ECM and specifically to fibronectin and/or collagen substrates. Moreover, loss of PAX8 strongly reduces ITGB3 expression and consequently the correct expression of the αvβ3 heterodimer on the plasma membrane. Conclusions: Our results demonstrate that PAX8 modulates the interaction of tumor cells with the extracellular matrix (ECM). Notably, we also highlight a novel pathway downstream this transcription factor. Overall, PAX8 could be a potential therapeutic target for high-grade serous carcinoma

Identification of novel HPFH-like mutations by CRISPR baseediting that elevate the expression of fetal hemoglobin

Naturally occurring point mutations in the HBG promoter switch hemoglobin synthesis from defective adult beta-globin to fetal gamma-globin in sickle cell patients with hereditary persistence of fetal hemoglobin (HPFH) and ameliorate the clinical severity. Inspired by this natural phenomenon, we tiled the highly homologous HBG proximal promoters using adenine and cytosine base editors that avoid the generation of large deletions and identified novel regulatory regions including a cluster at the -123 region. Base editing at -123 and -124 bp of HBG promoter induced fetal hemoglobin (HbF) to a higher level than disruption of well-known BCL11A binding site in erythroblasts derived from human CD34+ hematopoietic stem and progenitor cells (HSPC). We further demonstrated in vitro that the introduction of -123T > C and -124T > C HPFH-like mutations drives gamma-globin expression by creating a de novo binding site for KLF1. Overall, our findings shed light on so far unknown regulatory elements within the HBG promoter and identified additional targets for therapeutic upregulation of fetal hemoglobin.ISSN:2050-084