Another Look at Minimal Lepton Flavour Violation, l_i -> l_j gamma, Leptogenesis, and the Ratio M_nu/ Lambda_LFV

We analyze lepton flavour violation (LFV), as well as generation of the observed baryon-antibaryon asymmetry of the Universe (BAU) within a generalized minimal lepton flavour violation (MLFV) framework where we allow for CP violation both at low and high energies. The generation of BAU is obtained through radiative resonant leptogenesis (RRL), where starting with three exactly degenerate right-handed neutrinos at Lambda_GUT, we demonstrate explicitly within the SM and the MSSM that the splittings between their masses at the see-saw scale M_nu, generated by renormalization group effects, are sufficient for a successful leptogenesis for M_nu even as low as 10^6 GeV. The inclusion of flavour effects plays an important role in this result and can lead to the observed BAU even in the absence of CP violation beyond the PMNS phases. The absence of a stringent lower bound on M_nu in this type of leptogenesis allows to easily satisfy present and near future upper bounds on mu -> e gamma and other charged lepton flavour violating (LFV) processes even for Lambda_LFV = O(1 TeV). We find, that the MLFV framework in the presence of heavy right-handed neutrinos and leptogenesis is not as predictive as MFV in the quark sector and point out that without a specific MLFV model, there is a rich spectrum of possibilities for charged LFV processes and for their correlation with low energy neutrino physics and the LHC physics, even if the constraint from the observed BAU is taken into account. While certain qualitative features of our analysis confirm findings of Cirigliano et al., at the quantitative level we find phenomenologically important differences. We explain the origin of these differences.Comment: 48 pages, 9 figure

Beherrschung stark korrelierter Logistik- und Produktions-Prozesse: Schlussbericht zu dem IGF-Vorhaben Beherrschung stark korrelierter Logistik- und Produktions-Prozesse (Autokorrelierte Auftragsstroeme)

Im Rahmen des Forschungsvorhabens wurde das Wirken von Autokorrelation auf das Verhalten von Materialflusssystemen anhand von Realdaten analysiert. Hintergrund waren theoretische Untersuchungen, die einen deutlichen Einfluss von abhängigen Ereignissen auf die Leistung von Materialflusssystemen erkennen lassen. Mit Hilfe der Projektpartner konnte eine große Menge von Echtdaten zusammengetragen werden. Insgesamt wurden 52 Datensätze auf zeitliche Abhängigkeiten der Ereignisse untersucht. Dabei bestätigte sich die Vermutung, dass Autokorrelation durch z. B. Batchbildung oder Prioritätsregeln allgegenwärtig in Erscheinung tritt. In ca. 95 % aller Datensätze konnte signifikant Autokorrelation nachgewiesen werden. Im Rahmen der Untersuchung konnten eine Reihe unterschiedlicher Korrelationsstrukturen nachgewiesen werden. Diese unterschieden sich sowohl in der Stärke, in der Ausprägung (positiv oder negativ) als auch im Abklingverhalten. Der größte Einfluss auf das Systemverhalten geht von der Stärke und der Ausprägung der Autokorrelationskoefizienten aus. Im Rahmen des Projektes konnten unterschiedliche Verfahren zur Erzeugung autokorrelierter Ereignisse identifiziert und bewertet werden. Beispielhaft zu erwähnen ist die TES-Methode, der Minification- bzw. Maxification-Ansatz oder spezielle Markov-Ketten. Als am besten geeignet hat sich der sog. ARTA-Ansatz herausgestellt. Der ARTA-Ansatz wurde in einer Java-basierenden Software-Bibliothek namens „JARTA“ umgesetzt. Diese ist frei verfügbar sowie variabel und einfach einsetzbar. Durch das Forschungsvorhaben wurde das Bewusstsein um das Auftreten und Wirken von Autokorrelation in logistischen Systemen geschärft. Projektpartner bestätigen, dass durch gezielte Untersuchung auf Abhängigkeiten Fehler bei der Systementwicklung und beim Systembetrieb verringert werden konnten

Superior vena caval syndrome caused by the tumor of the left hilum in a patient with unilateral persistent left superior vena cava diagnosed with multislice spiral computed tomography : a case report

Background: Unilateral persistent left superior vena cava (PLSVC) is an infrequent finding with incidence of 18-20% among the individuals with PLSVC. The persistence of the left-sided superior vena cava is an effect of disturbances in development of the connection between the precardinal veins (anterior cardinal veins) and formation of the sinus venosus in early stages of embryogenesis. Case report: The paper presents a case of a 62-year-old patient with a mass lesion of the left hilum, which caused left-sided superior vena caval syndrome in the presence of unilateral PLSVC. Conclusions: Developmental mechanisms of superior vena caval syndrome are discussed. The evolution of changes related to infiltration and occlusion of PLSVC is shown on the basis of three selected MSCT examinations

Gender-specific outcomes in immune checkpoint inhibitor therapy for advanced or metastatic urothelial cancer: a systematic review and meta-analysis.

PURPOSE To analyze gender-specific differences in survival parameters in advanced or metastatic urothelial cancer patients undergoing immune checkpoint inhibition. METHODS The primary aim of this systematic review and meta-analysis was to evaluate gender-specific differences in disease-free (DFS), progression-free (PFS), cancer-specific survival (CSS), event-free survival (EFS), overall survival (OS) and objective response rate (ORR). The sources MEDLINE, Embase and Cochrane Library were systematically searched from January 2010 to June 2022. No restrictions were made concerning language, study region or publication type. A comparison of gender-specific differences in survival parameters was performed using a random-effects meta-analysis. A risk of bias assessment was done using the ROBINS-I tool. RESULTS Five studies were included. In a random-effect meta-analysis of the studies, PCD4989g and IMvigor 211 with both using atezolizumab, females were more likely to have better objective response rate (ORR) than men (OR 2.24; 95% CI 1.20-4.16; p = 0.0110). In addition, females had a comparable median OS to men (MD 1.16; 95% CI - 3.15-5.46; p = 0.598). In summary, comparing all results, a tendency was seen toward better response rates and survival parameters in female patients. The risk of bias assessment yielded an overall low risk of bias. CONCLUSIONS There is a tendency toward better outcomes in women for immunotherapy in advanced or metastatic urothelial cancer, but only for the antibody atezolizumab women have a significantly better ORR. Unfortunately, many studies fail to report gender-specific outcomes. Therefore, further research is essential when aiming for individualized medicine. This research should address immunological confounders

Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field