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Fission yeast cells prevent mitotic entry until a threshold cell surface area is reached. The protein kinase Cdr2 contributes to this size control system by forming multiprotein nodes that inhibit Wee1 at the medial cell cortex. Cdr2 node anchoring at the cell cortex is not fully understood. Through a genomic screen, we identified the conserved GTPase Arf6 as a component of Cdr2 signaling. Cells lacking Arf6 failed to divide at a threshold surface area and instead shifted to volume-based divisions at increased overall size. Arf6 stably localized to Cdr2 nodes in its GTP-bound but not GDP-bound state, and its GEF (guanine nucleotide exchange factor) Syt22 was required for both Arf6 node localization and proper size at division. In arf6Δ mutants, Cdr2 nodes detached from the membrane and exhibited increased dynamics. These defects were enhanced when arf6Δ was combined with other node mutants. Our work identifies a regulated anchor for Cdr2 nodes that is required for cells to sense surface area.

Background: The need to identify patients with hormone receptor-positive (HR+) early invasive breast cancer (EIBC) who could benefit from adjuvant chemotherapy has been enhanced with the development of molecular signature tests. However, due to their high cost and limited availability alternative low-cost prognostic and predictive tests are used in clinical practice. Here, we sought to evaluate the performance of the proliferation marker Ki-67 to identify these patients and explore its association with molecular signatures and risk stratification markers. Methods: From our prospectively maintained multicenter breast cancer registry, we identified EIBC HR+ patients tested with EndoPredict or MammaPrint and Ki-67 as part of their routine workup. Patients were categorized into two groups: Group 1 (2016-2018) was evaluated using EndoPredict and Group 2 (2011 to 2018) with MammaPrint. A ≥20% Ki67 cutoff was utilized for identify high proliferative EIBC and a receiver-operative curve area under the curve (AUC) and kappa concordance were utilized to evaluate the performance of Ki-67 compared to molecular signature tests. Results: In the EndoPredict group, 54/96 patients were considered high-risk by EPclin. 57/96 patients had a Ki-67 ≥20%. However, there was no significant overall concordance between them (59.37%, κ = 0.168, p=0.09). In the MammaPrint group, 21/70 patients were considered high-risk. Ki67 ≥20% was present in 36 patients with a significant overall concordance (67.14%, κ 0.35, pConclusion: There is a fair concordance between Ki-67 and MammaPrint risk stratification of HR + EIBC and no concordance with EndoPredict molecular signature. Cost-effectiveness analysis of these tests in developing countries are needed, until then, the use of Ki-67 seems reasonable to aid clinical decision.

BackgroundAlport syndrome is a progressive and hereditary nephropathy, characterized by hematuria and proteinuria, and extrarenal manifestations as hearing loss and eye abnormalities. The disease can be expressed as autosomal recessive or dominant, caused by variants in COL4A3 and COL4A4 loci, respectively, or X-linked caused by variants in COL4A5 locus.MethodsTwo unrelated families with Alport Syndrome from northeast of Brazil were studied and whole exome sequencing were performed. DNA sequences were mapped against the human genome (GRCh38/hg38 build) to identify associated mutations.ResultsVariant analysis showed deleterious variants in COL4A3 and COL4A4 loci in chromosome 2. Two variants were detected with alternative alleles in a homozygous state in the probands. One novel premature stop codon at position 481 of COL4A3 protein is present in one family and one frameshift mutation leading to a premature stop codon at position 786 of COL4A4 protein in the other family. Both Alport cases presented their variants surrounded by a broad runs of homozygosity (ROH).ConclusionsThe autosome recessive inheritance coupled with the runs of homozygosity in both families suggest inbreeding.

Background: Clinical practice guidelines (CPG) represent important tools for healthcare quality improvement and their implementation has proven challenging. Handheld devices (HD) as smart phones (SP) and tablets, constitute pervasive tools for guideline diffusion and medical education. High use rates[for full text, please go to the a.m. URL], G-I-N Conference 2012

Background: The increasingly pervasive computing phenomena in healthcare impacts clinical practice guideline (CPG) implementation projects. Currently, institutions like NICE or SIGN are exploring handheld devices (HD) as platforms for CPG delivery. These HD are portable, can store many different CPG[for full text, please go to the a.m. URL], G-I-N Conference 2012

Item does not contain fulltext PURPOSE: To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia. DESIGN: Randomized (1:1), sham-controlled, multicenter, parallel-group trial. PARTICIPANTS: Subjects with DME. INTERVENTION: Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion gaining >/= 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout. RESULTS: In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of >/= 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P