Citations

ABSTRACT Here, we show that cells expressing the adherens junction protein nectin-1 capture nectin-4-containing membranes from the surface of adjacent cells in a trans-endocytosis process. We find that internalized nectin-1–nectin-4 complexes follow the endocytic pathway. The nectin-1 cytoplasmic tail controls transfer: its deletion prevents trans-endocytosis, while its exchange with the nectin-4 tail reverses transfer direction. Nectin-1-expressing cells acquire dye-labeled cytoplasmic proteins synchronously with nectin-4, a process most active during cell adhesion. Some cytoplasmic cargo remains functional after transfer, as demonstrated with encapsidated genomes of measles virus (MeV). This virus uses nectin-4, but not nectin-1, as a receptor. Epithelial cells expressing nectin-4, but not those expressing another MeV receptor in its place, can transfer infection to nectin-1-expressing primary neurons. Thus, this newly discovered process can move cytoplasmic cargo, including infectious material, from epithelial cells to neurons. We name the process nectin-elicited cytoplasm transfer (NECT). NECT-related trans-endocytosis processes may be exploited by pathogens to extend tropism. This article has an associated First Person interview with the first author of the paper.

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p‐value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p‐value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p‐value of 5.8 × 10−6. Ninety‐four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis‐eQTL suggesting possible mechanisms of carcinogenesis.

Background:PRM‐151, a recombinant human pentraxin‐2 molecule, prevents and reverses fibrosis in animal models of myelofibrosis (MF) in part by targeting differentiation of fibrocytes from monocytes. In the first stage of a two‐stage trial, treatment of patients (pts) with primary (PMF), post‐essential thrombocythemia/polycythemia vera (post‐ET/PV) MF with PRM‐151 ± ruxolitinib (Rux) was associated with decreases in bone marrow fibrosis (BMF), improvements in hemoglobin (Hgb) and platelets (PLT), reductions in transfusions and symptoms, and modest reductions in splenomegaly.Aims:Here, we report efficacy and safety data from a stage 2 randomized, double‐blind evaluation of single agent PRM‐151.Methods:Pts with DIPPS Int‐1, Int‐2, and high risk PMF or post‐ET/PV MF who were ineligible for, intolerant of, or had an inadequate response to Rux were randomized between 0.3, 3, and 10 mg/kg of PRM‐151 as a sole agent. PRM‐151 was to be administered by IV infusion at one of the three assigned doses on Days 1, 3, and 5 of Cycle 1 and on Day 1 of each subsequent 28‐day cycle for at least 9 cycles. Randomization was stratified according to baseline (BL) Hgb <100 g/L receiving transfusions and/or PLT <50 x 109/L. Bone marrow biopsies and imaging for spleen volume were obtained at BL, C4D1, C7D1, and C9D29. BMF score was evaluated centrally by three independent, blinded hematopathologists. The primary objective of the study was to determine the effect size of three different doses of PRM‐151 on reduction in BMF by ≥ 1 grade at any time during the study.Results:Of the 98 randomized patients, 97 were treated with 0.3 mg/kg (n = 33), 3 mg/kg (n = 32), or 10 mg/kg (n = 32). BL characteristics are provided in Table 1. Forty‐six pts discontinued treatment prior to Cycle 9. Decrease in BMF grade at any time was observed in 10 of 33 pts (30%) at 0.3 mg/kg, 9 of 31 pts (28%) at 3 mg/kg, and 8 of 32 pts (25%) at 10 mg/kg. Decrease in BM collagen grade was observed in 31–37% of pts. In pts who were RBC transfusion dependent or with Hgb <100 g/L and transfusion independent at BL, 16–29% of pts had ≥50% reduction in RBC transfusions or Hgb increases ≥10 g/L for ≥12 consecutive weeks. In pts who were PLT transfusion dependent or with PLT<25 or PLT25‐<50 x 109/L and transfusion independent at BL, 31–40% of pts had ≥50% reduction in PLT transfusions, PLT ≥25 x 109/L or PLT ≥50 x 109/L or doubling of PLT count, without transfusions for ≥12 consecutive weeks. Improvement from BL in MPN‐SAF TSS of ≥25% for ≥12 consecutive weeks was observed in 10–26% of pts. Reduction in spleen volume was observed with a maximum reduction of 34% in one pt. Response rates for BM collagen, Hgb, PLT, MPN‐SAF, and spleen were generally similar across the three dose levels. The most common treatment emergent adverse events (AEs) were fatigue, cough, thrombocytopenia, and abnormal weight loss. A majority of the AEs were Grade 2 or lower in severity and consistent with disease progression. Grade 3 and 4 related AEs were reported in 12% and 6% of pts, respectively.Summary/Conclusion:The study enrolled a large proportion of MF pts with advanced disease (Int‐2 or high risk, BMF grade 3, anemic/transfusion dependent, and PLT <50 x 109/L). Decrease in BMF and collagen grade were observed across all dose levels. Increases in Hgb and PLT count or reduction in transfusion requirements were also reported across all dose levels. Improvements in MPN‐SAF TSS and spleen volume were observed in a proportion of pts. PRM‐151 treatment for up to 9 cycles was well tolerated. These data warrant confirmation in a larger controlled study.image

Abstract Objective Despite increased use of electronic health records (EHRs), the clinical impact of system downtime is unknown. Materials and Methods This retrospective matched cohort study evaluated the impact of EHR downtime episodes lasting more than 60 minutes over a 6-year study period. Patients age 18 years or older who underwent surgical procedures at least 60 minutes in duration with an inpatient stay exceeding 24 hours within the study period were eligible for inclusion. Out of 4115 patients exposed to 1 of 176 EHR downtime episodes, 4103 patients were matched to an unexposed cohort in a 1:1 ratio. Multivariable regression analysis, as well as trend analysis for effect of duration of downtime on outcomes, was performed. Results Downtime-exposed patients had operating room duration 1.1 times longer (p &lt; .001) and postoperative length of stay 1.04 times longer (p = .007) compared to unexposed patients. The 30-day mortality rates were similar between these groups (odds ratio 1.26, p &gt; .05). In trend analysis, there was no association between duration of downtime with respect to evaluated outcomes, postoperative length of stay, and 30-day mortality. Conclusion EHR downtime had no impact on 30-day mortality. Potential associations for increased postoperative length of stay and duration of time spent in the operating room were observed among downtime-exposed patients. No trend effect was observed with respect to duration of downtime and postoperative length of stay and 30-day mortality rates.

Background: The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R ) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R -Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection. Methods: Using data from 2863 participants with AAA from 9 prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R -Asp358Ala variant and annual change in AAA diameter (mm/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter, and time to aortic rupture and death. Results: After adjusting for age and sex, baseline aneurysm size was 0.55 mm (95% CI, 0.13–0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was −0.06 mm per year (−0.18 to 0.06) per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival ( P <0.05). Conclusions: Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.