bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pancreatic Inflammation and Proenzyme Activation Are Associated With Clinically Relevant Postoperative Pancreatic Fistulas After Pancreas Resection
Authors: Wüster Carina , Shi Haoyun , Kühlbrey Christian M. , Biesel Esther A. , Hopt Ulrich T. , Fichtner-Feigl Stefan , Wittel Uwe A. 
Published: August 2020

Objective:
We investigated the activation of pancreatic proenzymes and signs of peripancreatic inflammation in patients with clinically relevant postoperative pancreatic fistulas (POPFs).

Summary Background Data:
An increase of systemic amylase concentration was associated with POPFs. This suggested parallels in the pathomechanisms between the development of POPFs and pancreatitis.

Methods:
Trypsinogen, procathepsin B, and IL-6 concentrations as well as cathepsin B, myeloperoxidase and trypsin activities were determined throughout the first 7 postoperative days in drain fluids of 128 consecutive patients after pancreas resection. Histology and immunohistochemistry were performed in pancreatic specimens after total pancreatectomy due to complications and after placing experimental pancreatic sutures in the pancreatic tail of C57/Bl6 mice.

Results:
Trypsin activity, cathepsin B activity and myeloperoxidase activity on the first postoperative day were elevated and predictive for clinically relevant pancreatic fistulas. Drain fluid stabilized trypsin activity and prevented the activation of the cascade of digestive enzymes. Leukocytes were the source of cathepsin B in drain fluid. Findings differed between fistulas after distal pancreatectomy and pancreatoduodenectomy. Immunohistochemistry of the pancreatic remnant revealed an inflammatory infiltrate expressing cathepsin B, independent of the presence of pancreatic fistulas. The infiltrate could be reproduced experimentally by sutures placed in the pancreatic tail of C57/Bl6 mice.

Conclusions:
Trypsinogen activation, increased cathepsin B activity and inflammation around the pancreato-enteric anastomosis on post operative day 1 are associated with subsequent clinically relevant POPFs after pancreatoduodenectomy. The parenchymal damage seems to be induced by placing sutures in the pancreatic parenchyma during pancreatic surgery.
Prognostic Impact of Frozen Section Investigation and Extent of Proximal Safety Margin in Gastric Cancer Resection
Authors: Berlth Felix , Kim Woo-Ho , Choi Jong-Ho , Park Shin-Hoo , Kong Seong-Ho , Lee Hyuk-Joon , Yang Han-Kwang 
Published: August 2020

Background and Aims:
Guidelines propose different extents of macroscopic proximal margin for gastric cancer and frozen margin investigation in selected cases, but data is lacking. This study was to evaluate the necessary extent of macroscopic proximal margin, accuracy of frozen margin investigation, and prognostic impact of tumor-free proximal margin length in pT2-pT4 gastric cancer.

Study Design:
Proximal and distal frozen margins were routinely investigated intraoperatively in all pT2-pT4 gastric cancers resected between 2011 and 2017. Macroscopic and microscopic proximal margin lengths were correlated. For R0-resections, survival analysis was performed for distal gastrectomy (DG) with microscopic proximal margin length ≤3 cm versus >3 cm.

Results:
Overall, 1484 patients were included. Microscopic proximal margin lengths were macroscopically more often misestimated in diffuse histology (P = 0.0004), but extent of underestimation in centimeter was similar to intestinal and mixed/undetermined type (P = 0.134). Fifteen cases (1.0%) resulted in R1-resection, 10 at distal, and 5 at proximal margin but none with macroscopic proximal margin ≥3 cm and negative frozen section. Overall agreement of frozen margin and final pathology was 2951/2968 (99.4%). Proximal margin length in DG did not correlate with survival or recurrence in R0-resected patients.

Discussion:
Diffuse histology is at higher risk for underestimation of proximal margin length, but extent of underestimation is similar in other Laurén subtypes. If ≥3 cm macroscopic proximal margin length is applied with intraoperative frozen margin confirmation, R1-resection can be avoided.

Conclusion:
In pT2-T4a gastric cancer, proximal margin of ≥3 cm plus frozen margin confirmation provides high oncological safety. In DG patients with R0-resection, proximal margin length does not correlate with survival or recurrence.
Hypothermic Oxygenated Perfusion Versus Normothermic Regional Perfusion in Liver Transplantation From Controlled Donation After Circulatory Death
Authors: Muller Xavier , Mohkam Kayvan , Mueller Matteo , Schlegel Andrea , Dondero Federica , Sepulveda Ailton , Savier Eric , Scatton Olivier , Bucur Petru , Salame Ephrem , Jeddou Heithem , Sulpice Laurent , Pittau Gabriella , Allard Marc-Antoine , Mabrut Jean-Yves , Dutkowski Philipp , Clavien Pierre-Alain , Lesurtel Mickael 
Published: August 2020

Objective:
To compare HOPE and NRP in liver transplantation from cDCD.

Summary of Background Data:
Liver transplantation after cDCD is associated with higher rates of graft loss. Dynamic preservation strategies such as NRP and HOPE may offer safer use of cDCD grafts.

Methods:
Retrospective comparative cohort study assessing outcomes after cDCD liver transplantation in 1 Swiss (HOPE) and 6 French (NRP) centers. The primary endpoint was 1-year tumor-death censored graft and patient survival.

Results:
A total of 132 and 93 liver grafts were transplanted after NRP and HOPE, respectively. NRP grafts were procured from younger donors (50 vs 61 years, P < 0.001), with shorter functional donor warm ischemia (22 vs 31 minutes, P < 0.001) and a lower overall predicted risk for graft loss (UK-DCD-risk score 6 vs 9 points, P < 0.001). One-year tumor-death censored graft and patient survival was 93% versus 86% (P = 0.125) and 95% versus 93% (P = 0.482) after NRP and HOPE, respectively. No differences in non-anastomotic biliary strictures, primary nonfunction and hepatic artery thrombosis were observed in the total cohort and in 32 vs. 32 propensity score-matched recipients

Conclusion:
NRP and HOPE in cDCD achieved similar post-transplant recipient and graft survival rates exceeding 85% and comparable to the benchmark values observed in standard DBD liver transplantation. Grafts in the HOPE cohort were procured from older donors and had longer warm ischemia times, and consequently achieved higher utilization rates. Therefore, randomized controlled trials with intention-to-treat analysis are needed to further compare both preservation strategies, especially for high-risk donor-recipient combinations.
Centralization and Oncologic Training Reduce Postoperative Morbidity and Failure-to-rescue Rates After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies
Authors: Noiret Barbara , Clement Guillaume , Lenne Xavier , Bruandet Amelie , Glehen Olivier , Voron Thibault , Piessen Guillaume , Eveno Clarisse 
Published: August 2020

Objective:
Evaluate at a national level the postoperative mortality (POM), major morbidity (MM) and failure-to-rescue (FTR) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) across time and according to hospital-volume.

Background:
CRS/HIPEC is an effective therapeutic strategy commonly used to treat peritoneal surface malignancies. However, this aggressive approach has the reputation to be associated with a high POM and MM.

Methods:
All patients treated with CRS/HIPEC between 2009 and 2018 in France were identified through a national medical database. Patients and perioperative outcomes were analyzed. A cut-off value of the annual CRS/HIPEC caseload affecting the 90-day POM was calculated using the Chi-squared Automatic Interaction Detector method. A multivariable logistic model was used to identify factors mediating 90-day POM.

Results:
A total of 7476 CRS/HIPEC were analyzed. Median age was 59 years with a mean Elixhauser comorbidity index of 3.1, both increasing over time (P < 0.001). Ninety-day POM was 2.6%. MM occurred in 44.2% with a FTR rate of 5.1%. The threshold of CRS/HIPEC number per center per year above which the 90-day POM was significantly reduced was 45 (3.2% vs 1.9%, P = 0.01). High-volume centers had more extended surgery (P < 0.001) with increased MM (55.8% vs 40.4%, P < 0.001) but lower FTR (3.1% vs 6.3%, P = 0.001). After multivariate analysis, independent factors associated with 90-day POM were: age >70 years (P = 0.002), Elixhauser comorbidity index ≥8 (P = 0.006), lower gastro-intestinal origin, (P < 0.010), MM (P < 0.001), and <45 procedures/yr (P = 0.002).

Conclusion:
In France, CRS/HIPEC is a safe procedure with an acceptable 90-day POM that could even be improved through centralization in high-volume centers.
Neuronal immunoglobulin superfamily cell adhesion molecules in epithelial morphogenesis: insights fromDrosophila
Authors: Finegan Tara M. , Bergstralh Dan T. 
Published: August 2020

In this review, we address the function of immunoglobulin superfamily cell adhesion molecules (IgCAMs) in epithelia. Work in theDrosophilamodel system in particular has revealed novel roles for calcium-independent adhesion molecules in the morphogenesis of epithelial tissues. We review the molecular composition of lateral junctions with a focus on their IgCAM components and reconsider the functional roles of epithelial lateral junctions. The epithelial IgCAMs discussed in this review have well-defined roles in the nervous system, particularly in the process of axon guidance, suggesting functional overlap and conservation in mechanism between that process and epithelial remodelling. We expand on the hypothesis that epithelial occluding junctions and synaptic junctions are compositionally equivalent and present a novel hypothesis that the mechanism of epithelial cell (re)integration and synaptic junction formation are shared. We highlight the importance of considering non-cadherin-based adhesion in our understanding of the mechanics of epithelial tissues and raise questions to direct future work.This article is part of the discussion meeting issue ‘Contemporary morphogenesis’.
TheDrosophilamicropyle as a system to study how epithelia build complex extracellular structures
Authors: Horne-Badovinac Sally 
Published: August 2020

Dynamic rearrangements of epithelial cells play central roles in shaping tissues and organs during development. There are also scenarios, however, in which epithelial cell movements synergize with the secretion of extracellular matrix to build rigid, acellular structures that persist long after the cells are gone. The formation of theDrosophilamicropyle provides an elegant example of this epithelial craftsmanship. The micropyle is a cone-shaped projection of the eggshell through which the sperm will enter to fertilize the oocyte. Though simple on the surface, both the inner structure and construction of the micropyle are remarkably complex. In this review, I first provide an overview of egg development, focusing on the key events required to understand micropyle formation. I then describe the structure of the micropyle, the cellular contributions to its morphogenesis and some interesting open questions about this process. There is a brief discussion of micropyle formation in other insects and fish to highlight the potential for comparative studies. Finally, I discuss how new studies of micropyle formation could reveal general mechanisms that epithelia use to build complex extracellular structures.This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.
On folding morphogenesis, a mechanical problem
Authors: Tozluoǧlu Melda , Mao Yanlan 
Published: August 2020

Tissue folding is a fundamental process that sculpts a simple flat epithelium into a complex three-dimensional organ structure. Whether it is the folding of the brain, or the looping of the gut, it has become clear that to generate an invagination or a fold of any form, mechanical asymmetries must exist in the epithelium. These mechanical asymmetries can be generated locally, involving just the invaginating cells and their immediate neighbours, or on a more global tissue-wide scale. Here, we review the different mechanical mechanisms that epithelia have adopted to generate folds, and how the use of precisely defined mathematical models has helped decipher which mechanisms are the key driving forces in different epithelia.
This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.
Identification ofMYOM2as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot and its functional evaluation in theDrosophilaheart
Authors: Auxerre-Plantié Emilie , Nielsen Tanja , Grunert Marcel , Olejniczak Olga , Perrot Andreas , Özcelik Cemil , Harries Dennis , Matinmehr Faramarz , Remedios Cristobal Dos , Mühlfeld Christian , Kraft Theresia , Bodmer Rolf , Vogler Georg , Sperling Silke R. 
Published: August 2020

ABSTRACTThe causal genetic underpinnings of congenital heart diseases, which are often complex and with multigenic background, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in theDrosophilaanimal model reveal that the so far uncharacterized fly geneCG14964may be an ortholog ofMYOM2, as well as other myosin binding proteins (henceforth named asDrosophilaMyomesin andMyosin Binding protein (dMnM)). Its partial loss-of-function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations ofCG14964and the sarcomere geneMhc(MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest thatMYOM2not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart.SUMMARY STATEMENTMYOM2plays a critical role in establishing or maintaining robust heart function and is a candidate gene for heart diseases such as hypertrophic cardiomyopathy and Tetralogy of Fallot.
The medakaalg2mutant is a model for hypo-N-glycosylation-associated retinitis pigmentosa
Authors: Gücüm Sevinç , Sakson Roman , Hoffmann Marcus , Grote Valerian , Beedgen Lars , Thiel Christian , Rapp Erdmann , Ruppert Thomas , Wittbrodt Joachim , Thumberger Thomas 
Published: August 2020

AbstractPatients suffering from Congenital Disorders of Glycosylation (CDG) carry mutations in components of the evolutionarily highly conserved protein-glycosylation-machinery. Employing targeted genome editing, we modeled alleles in medaka fish based on a mutation described in an ALG2-index patient. The multisystemic phenotypes in ouralg2model closely resembled the patient’s syndromes. Molecularly, the mutation results in a reduction of the abundance ofN-glycans without altering the profile of glycan structures in fish as well as in patient fibroblasts. This hypo-N-glycosylation impacted on protein abundance in two directions. We discovered a putative compensatory upregulation of the basic glycosylation and glycoprotein processing machinery highlighting the regulatory topology of the network. Conversely, proteins of the retinal phototransduction machinery were massively downregulated in thealg2model. Those relate to the specific loss of rod photoreceptors that fail to be maintained in thealg2mutants, a condition known as retinitis pigmentosa. Transient supply of human or medakaalg2mRNA efficiently rescued the phenotypic spectrum and restored viability demonstrating that ouralg2model delivers key traits for the potential treatment of the disorder.
SARS-CoV-2 infection and transmission in educational settings: cross-sectional analysis of clusters and outbreaks in England
Authors: Ismail Sharif A , Saliba Vanessa , Lopez Bernal Jamie , Ramsay Mary E , Ladhani Shamez N 
Published: August 2020

ABSTRACTBackgroundThere are limited data on SARS-CoV-2 infection and transmission in educational settings. This information is critical for policy makers and practitioners to ensure the safety of staff, students and the wider community during the COVID-19 pandemic.MethodsPublic Health England initiated enhanced national surveillance following the reopening of educational settings during the summer mini-term on 01 June 2020. COVID-19 related situations in educational settings across England were reviewed daily and followed-up until 31 July 2020. SARS-CoV-2 infection and outbreak rates were calculated for staff and students attending early year settings, primary and secondary schools during June 2020.FindingsThere were 67 single confirmed cases, 4 co-primary cases and 30 COVID-19 outbreaks during June 2020, with a strong correlation between number of outbreaks and regional COVID-19 incidence (0.51 outbreaks for each SARS-CoV-2 infection per 100,000 in the community; p=0.001). Overall, SARS-CoV-2 infections and outbreaks were uncommon across all educational settings. Staff members had an increased risk of SARS-CoV-2 infections compared to students in any educational setting, and the majority of cases linked to outbreaks were in staff. The probable transmission direction for the 30 confirmed outbreaks was: staff-to-staff (n=15), staff-to-student (n=7), student-to-staff (n=6) and student-to-student (n=2).InterpretationSARS-CoV-2 infections and outbreaks were uncommon in educational settings during the first month after the easing of national lockdown in England. The strong correlation with regional SARS-CoV-2 incidence emphasises the importance of controlling community transmission to protect educational settings. Additional interventions should focus on reducing transmission in and among staff members.Fundingnone
Prognostic and theragnostic biomarkers in ovarian clear cell carcinoma
Authors: Wiedemeyer Katharina , Wang Linyuan , Kang Eun Young , Liu Shuhong , Ou Young , Kelemen Linda E. , Feil Lukas , Anglesio Michael S. , Glaze Sarah , Ghatage Prafull , Nelson Gregg S. , Köbel Martin 
Published: August 2020

SummaryIn this study, we aimed to test whether prognostic biomarkers can achieve a clinically relevant stratification of patients with stage I ovarian clear cell carcinoma (OCCC) and to survey the expression of 10 selected actionable targets (theragnostic biomarkers) in stage II to IV cases. From the population-based Alberta Ovarian Tumor Type study, 160 samples of OCCC were evaluated by immunohistochemistry and/or silver-enhanced in-situ hybridization for the status of 5 prognostic (p53, p16, IGF2BP3, CCNE1, FOLR1) and 10 theragnostic biomarkers (ALK, BRAF, ERBB2, ER, MET, MMR, PR, ROS1, NTRK1-3, VEGFR2). Kaplan-Meier survival analyses were performed. Cases with abnormal p53 or combined p16/IFG2BP3 abnormal expression identified a small subset of patients (6/54 cases) with stage I OCCC with an aggressive course (5-year ovarian cancer specific survival of 33.3%, compared to 91.5% in the other stage I cases). Among theragnostic targets,ERBB2amplification was present in 11/158 (7%) of OCCC, while MET was ubiquitously expressed in OCCC similar to a variety of normal control tissues. ER/PR showed a low prevalence of expression. No abnormal expression was detected for any of the other targets. We propose a combination of 3 biomarkers (p53, p16, IGF2BP3) to predict prognosis and the potential need for adjuvant therapy for patients with stage I OCCC. This finding requires replication in larger cohorts. Additionally, OCCC could be tested forERBB2amplification for inclusion in gynecological basket trials targeting this alteration.
Distinct mutational profile of Lynch syndrome colorectal cancers diagnosed under regular colonoscopy surveillance
Authors: Ahadova Aysel , Pfuderer Pauline L. , Ahtiainen Maarit , Ballhausen Alexej , Bohaumilitzky Lena , Kösegi Svenja , Müller Nico , Tang Yee Lin , Kosmalla Kosima , Witt Johannes , Endris Volker , Stenzinger Albrecht , von Knebel Doeberitz Magnus , Bläker Hendrik , Renkonen-Sinisalo Laura , Lepistö Anna , Böhm Jan , Mecklin Jukka-Pekka , Seppälä Toni T. , Kloor Matthias 
Published: August 2020

ABSTRACTBackgroundRegular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers).MethodsWe analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high through-put coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs.ResultsIncident cancers presented with lower UICC and T stage compared to prevalent cancers (p< 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lowerKRAScodon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenicTP53mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncatingAPCmutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018).ConclusionsLS CRC diagnosed under regular colonoscopy surveillance are biologically distinct, suggesting that the preventive effectiveness of colonoscopy in LS depends on the molecular subtypes of tumors.