Regulatory T cells (Tregs) are essential to suppress unwanted immunity or inflammation. After islet allo-transplant Tregs must migrate from blood to allograft, then via afferent lymphatics to draining LN to protect allografts. Here we show that Tregs but not non-Treg T cells use lymphotoxin (LT) during migration from allograft to draining LN, and that LT deficiency or blockade prevents normal migration and allograft protection. Treg LTαβ rapidly modulates cytoskeletal and membrane structure of lymphatic endothelial cells; dependent on VCAM-1 and non-canonical NFκB signalling via LTβR. These results demonstrate a form of T-cell migration used only by Treg in tissues that serves an important role in their suppressive function and is a unique therapeutic focus for modulating suppression.

Oncolytic viral therapy is a promising therapeutic modality for brain tumors. Vasculostatin (Vstat120), is the cleaved and secreted extracellular fragment of BAI1, a brain specific receptor. However, the therapeutic efficacy of Vstat120 delivery into established tumors has not been investigated. Here we tested therapeutic efficacy of combining Vstat120 gene delivery in conjunction with oncolytic viral therapy. We constructed a novel oncolytic virus RAMBO: Rapid Anti-angiogensis Mediated By Oncolytic virus, which expresses Vsta120 under the control of an immediate early viral promotor. Secreted Vstat120 was detectable in infected cells as soon as four hours post infection. Vstat120 produced by RAMBO efficiently inhibited endothelial cell migration and tube formation in vitro (P=0.0005 and P=0.0184 respectively) and inhibited angiogeneisis (P=0.007) in vivo. There was a significant suppression of tumors growth in mice bearing intracranial and subcutaneous gliomas treated with RAMBO compared to the control HSVQ treated mice (P=0.0021, and P<0.05 respectively). Statistically significant reduction in tumor vascular volume fraction and microvessel density was observed in tumors treated with RAMBO. This study is the first report of antitumor effects of Vstat120 in established tumors and supports the further development of RAMBO as a possible treatment for cancer.

As marijuana (MJ) legalization is increasing, kidney transplant programs must develop listing criteria for marijuana users. However, no data exist on the effect of MJ on kidney allograft outcomes, and there is no consensus on whether MJ use should be a contraindication to transplantation. We retrospectively reviewed 1225 kidney recipients from 2008 to 2013. Marijuana use was defined by positive urine toxicology screen and/or self-reported recent use. The primary outcome was death at 1 year or graft failure (defined as GFR<20 mL/min/1.73 m ). The secondary outcome was graft function at 1 year. Using logistic regression analyses, we compared these outcomes between MJ users and non-users. Marijuana use was not associated with worse primary outcomes by unadjusted (odds ratio 1.07, 95% CI 0.45-2.57, P=.87) or adjusted (odds ratio 0.79, 95% CI 0.28-2.28, P=.67) analysis. Ninety-two percent of grafts functioned at 1 year. Among these, the mean creatinine (1.52, 95% CI 1.39-1.69 vs 1.46, 95% CI 1.42-1.49; P=.38) and MDRD GFR (50.7, 95% CI 45.6-56.5 vs 49.5, 95% CI 48.3-50.7; P=.65) were similar between groups. Isolated recreational MJ use is not associated with poorer patient or kidney allograft outcomes at 1 year. Therefore, recreational MJ use should not necessarily be considered a contraindication to kidney transplantation.

Summary Background 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov , NCT03471494 . Findings Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding National Institute for Health Research Global Health Research Unit.

Therapeutic study, level V.

T-bet is essential for nTreg to regulate Th1 inflammation, but whether T-bet controls other Treg functions after entering the inflammatory site, is unknown. In an islet allograft model, T-bet−/−nTreg but not iTreg failed to prolong graft survival as effectively as wild type Treg. T-bet−/− nTreg had no functional deficiency in vitro but failed to home from the graft to dLN as efficiently as wild type. T-bet regulated expression of adhesion and migration related molecules, influencing nTreg distribution in tissues, so that T-bet−/− nTreg remained in the grafts rather than migrating to lymphatics and dLN. In contrast, both wild type and T-bet−/− CD4+ Tconv and iTreg migrated normally toward afferent lymphatics. T-bet−/− nTreg displayed instability in the graft, failing to suppress antigen-specific CD4+ T cells and prevent their infiltration into the graft and dLN. Thus, T-bet regulates nTreg migration into afferent lymphatics and dLN and consequently their suppressive stability in vivo.

Background Timing of BN is controversial in patients with refractory symptoms of autosomal dominant polycystic kidney disease (APKD) in need of a renal transplant. Methods Adults who underwent LRT+SBN from August 2003–2013 at a single transplant center (n=66) were retrospectively compared to a matched group of APKD patients who underwent LRT alone (n=52). All patients received general health and polycystic kidney symptom surveys. Results SBN increased operative duration, EBL, transfusions, IV fluid, and hospital length of stay. Most common indications for BN were pain, loss of abdominal domain, and early satiety. There were more intraoperative complications for LRT+SBN (6 vs. 0, p=0.03; 2 vascular, 2 splenic, and 1 liver injury; 1 re-exploration to adjust graft positioning). There were no differences in Clavien-Dindo grade I or II (39% vs. 25%, p=0.12) or grade III or IV (7.5% vs. 5.7%, p=1.0) complications during the hospital course. There were no surgery related mortalities. There were no differences in readmission rates (68% vs. 48%, p=0.19) or readmissions requiring procedures (25% vs. 20%, p=0.51) over 12 months. 100% of LRT+SBN allografts functioned at >1 year for those available for follow-up. Survey response rate was 40% for LRT-alone and 56% for LRT+SBN. 100% of LRT+SBN survey responders were satisfied with their choice of having BN done simultaneously. Conclusions Excellent outcomes for graft survival, satisfaction, and morbidity suggest that the combined operative approach be preferred for patients with symptomatic APKD to avoid multiple procedures, dialysis, and costs of staged operations.

Researchers have begun to identify dysbioses associated with clinical conditions, including chronic kidney disease, posttransplant infection, and rejection. This information will allow clinicians not only to select at-risk patients for early intervention, but also to develop therapies that restore the microbiota to a state of homeostasis or tolerance.