De novo pathway-based biomarker identification

Gene expression profiles have been extensively discussed as an aid to guide the therapy by predicting disease outcome for the patients suffering from complex diseases, such as cancer. However, prediction models built upon single-gene (SG) features show poor stability and performance on independent datasets. Attempts to mitigate these drawbacks have led to the development of network-based approaches that integrate pathway information to produce meta-gene (MG) features. Also, MG approaches have only dealt with the two-class problem of good versus poor outcome prediction. Stratifying patients based on their molecular subtypes can provide a detailed view of the disease and lead to more personalized therapies. We propose and discuss a novel MG approach based on de novo pathways, which for the first time have been used as features in a multi-class setting to predict cancer subtypes. Comprehensive evaluation in a large cohort of breast cancer samples from The Cancer Genome Atlas (TCGA) revealed that MGs are considerably more stable than SG models, while also providing valuable insight into the cancer hallmarks that drive them. In addition, when tested on an independent benchmark non-TCGA dataset, MG features consistently outperformed SG models. We provide an easy-touse web service at http:// pathclass. compbio. sdu. dk where users can upload their own gene expression datasets from breast cancer studies and obtain the subtype predictions from all the classifiers

Robot-assisted kidney transplantation with regional hypothermia using grafts with Multiple Vessels After Extracorporeal Vascular Reconstruction: results from the European Association of Urology Robotic Urology Section Working Group

Background: Kidney transplantation using grafts with multiple vessels (GMVs) is technically demanding and may be associated with increased risk of complications or suboptimal graft function. To date, no studies have reported on robot-assisted kidney transplantation (RAKT) using GMVs. Objective: To report our experience with RAKT using GMVs from living donors, focusing on technical feasibility and early postoperative outcomes. Design, setting, and participants: We reviewed the multi-institutional, prospectively collected European Association of Urology (EAU) Robotic Urology Section (ERUS)-RAKT database to select consecutive patients undergoing RAKT from living donors using GMVs between July 2015 and January 2018. Patients undergoing RAKT using grafts with single vessels (GSVs) served as controls. In case of GMVs, ex vivo vascular reconstruction techniques were performed during bench surgery according to the case-specific anatomy. Intervention: RAKT with regional hypothermia. Outcome measurements and statistical analysis: Intraoperative outcomes and early (30 d) postoperative complications and functional results were the main study endpoints. Multivariable logistic regression analysis evaluated potential predictors of suboptimal renal function at 1 mo. Results and limitations: Overall, 148 RAKTs were performed during the study period. Of these, 21/148 (14.2%) used GMVs; in all cases, single arterial and venous anastomoses could be performed after vascular reconstruction. Median anastomoses and rewarming times did not differ significantly between the GMV and GSV groups. Total and cold ischemia times were significantly higher in the GMV cohort (112 vs 88 min, p = 0.004 and 50 vs 34 min, p = 0.003, respectively). Overall complication rate and early functional outcomes were similar among the two groups. No major intra-or postoperative complications were recorded in the GMV cohort. At multivariable analysis, use of GMVs was not significantly associated with suboptimal renal function at 1 mo. Small sample size and short follow-up represent the main study limitations. Conclusions: RAKT using GMVs from living donors is technically feasible and achieved favorable perioperative and short-term functional outcomes. Larger studies with longer follow-up are needed to confirm our findings. Patient summary: In this study, we evaluated for the first time in literature the results of RAKT from living donors using kidneys with multiple arteries and veins. We found that, in experienced centers, RAKT using kidneys with multiple vessels is feasible and achieves optimal results in terms of postoperative kidney function with a low number of postoperative complications. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved

Effective Field Theory for Nonstandard Top Quark Couplings

We present an effective-field-theory calculation of the effect of a dimension-six operator involving the top quark on precision electroweak data via a top-quark loop. We demonstrate the renormalizability, in the modern sense, of the effective field theory. We use the oblique parameter U to bound the coefficient of the operator, and compare with the bound derived from top-quark decay.Comment: 10 pages, 3 figure

Comparative transcriptome analysis reveals key epigenetic targets in SARS-CoV-2 infection

COVID-19 is an infection caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), which has caused a global outbreak. Current research efforts are focused on the understanding of the molecular mechanisms involved in SARS-CoV-2 infection in order to propose drug-based therapeutic options. Transcriptional changes due to epigenetic regulation are key host cell responses to viral infection and have been studied in SARS-CoV and MERS-CoV; however, such changes are not fully described for SARS-CoV-2. In this study, we analyzed multiple transcriptomes obtained from cell lines infected with MERS-CoV, SARS-CoV and SARS-CoV-2, and from COVID-19 patient-derived samples. Using integrative analyses of gene co-expression networks and de-novo pathway enrichment, we characterize different gene modules and protein pathways enriched with Transcription Factors or Epifactors relevant for SARS-CoV-2 infection. We identified EP300, MOV10, RELA and TRIM25 as top candidates, and more than 60 additional proteins involved in the epigenetic response during viral infection that have therapeutic potential. Our results show that targeting the epigenetic machinery could be a feasible alternative to treat COVID-19.Comment: 33 pages, 2 tables, 5 figures, 4 supplementary figure

Preventive and Therapeutic Strategies for Bovine Leukemia Virus: Lessons for HTLV

Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1). BLV is a major animal health problem worldwide causing important economic losses. A series of attempts were developed to reduce prevalence, chiefly by eradication of infected cattle, segregation of BLV-free animals and vaccination. Although having been instrumental in regions such as the EU, these strategies were unsuccessful elsewhere mainly due to economic costs, management restrictions and lack of an efficient vaccine. This review, which summarizes the different attempts previously developed to decrease seroprevalence of BLV, may be informative for management of HTLV-1 infection. We also propose a new approach based on competitive infection with virus deletants aiming at reducing proviral loads

Robot-assisted Kidney Transplantation: The European Experience.

BACKGROUND: Robot-assisted kidney transplantation (RAKT) has recently been introduced to reduce the morbidity of open kidney transplantation (KT). OBJECTIVE: To evaluate perioperative and early postoperative RAKT outcomes. DESIGN, SETTING AND PARTICIPANTS: This was a multicenter prospective observational study of 120 patients who underwent RAKT, predominantly with a living donor kidney, in eight European institutions between July 2015 and May 2017, with minimum follow-up of 1 mo. The robot-assisted surgical steps were transperitoneal dissection of the external iliac vessels, venous/arterial anastomosis, graft retroperitonealization, and ureterovesical anastomosis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive analysis of surgical data and their correlations with functional outcomes. RESULTS AND LIMITATIONS: The median operative and vascular suture time was 250 and 38min, respectively. The median estimated blood loss was 150ml. No major intraoperative complications occurred, although two patients needed open conversion. The median postoperative estimated glomerular filtration rate was 21.2, 45.0, 52.6, and 58.0ml/min on postoperative day 1, 3, 7, and 30, respectively. Both early and late graft function were not related to overall operating time or rewarming time. Five cases of delayed graft function (4.2%) were reported. One case (0.8%) of wound infection, three cases (2.5%) of ileus, and four cases of bleeding (3.3%; three of which required blood transfusion), managed conservatively, were observed. One case (0.8%) of deep venous thrombosis, one case (0.8%) of lymphocele, and three cases (2.5%) of transplantectomy due to massive arterial thrombosis were recorded. In five cases (4.2%), surgical exploration was performed for intraperitoneal hematoma. Limitations of the study include selection bias, the lack of an open control group, and failure to report on patient cosmetic satisfaction. CONCLUSIONS: When performed by surgeons with robotic and KT experience, RAKT is safe and reproducible in selected cases and yields excellent graft function. PATIENT SUMMARY: We present the largest reported series on robot-assisted kidney transplantation. Use of a robotic technique can yield low complication rates, rapid recovery, and excellent graft function. Further investigations need to confirm our promising data

Robotic kidney transplantation using right-versus left-sided grafts from living donors: an european multicentre experience (ERUS-RAKT working group)

Introduction: RAKT from living donors (LD) is increasingly performedin selected centers with experience in robotic surgery and kidneytransplantation (KT). Of note, KT from LD using right-sided graft (RSG)is challenging due to the brevity of the right renal vein and has beenassociated with a higher riskof perioperative complications in selectedseries. In this scenario, RAKT may facilitate the performance ofvascular anastomoses in case of short renal vessels thanks to theadvantages of the robotic platform. However, the evidence on thesafety and feasibility of RAKT using RSGs is lacking. The aim of thisstudy is to compare the surgical andearly perioperative outcomes after RAKT from LD using right- vs. left-sided grafts in a large prospectivemulticenter cohort (ERUS-RAKT working group)