bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Impact of Tumor Size on Pancreatic Neuroendocrine Tumor Recurrence May Have Racial Variance
Authors: Zheng-Pywell Rui , Fang Amanda , AlKashash Ahmad , Awad Seifeldin , Reddy Sushanth , Vickers Selwyn , Heslin Martin , Dudeja Vikas , Chen Herbert , Rose John Bart 
Published: April 2021

Objective
The incidence of pancreatic neuroendocrine tumors (PNETs) has increased over the last decade. Black patients have worse survival outcomes. This study investigates whether oncologic outcomes are racially disparate at a single institution.

Methods
Retrospective analysis was performed on 151 patients with resected PNETs between 2010 and 2019.

Results
More White males and Black females presented with PNETs (P = 0.02). White patients were older (65 years vs 60 years; P = 0.03), more likely to be married (P < 0.01), and had higher median estimated yearly incomes ($28,973 vs $17,767; P < 0.01) than Black patients. Overall and disease-free survival were not different. Black patients had larger median tumor sizes (30 mm vs 23 mm; P = 0.02). Tumor size was predictive of recurrence only for White patients (hazard ratio, 1.02; P = 0.01). Collectively, tumors greater than 20 mm in size were more likely to have recurrence (P = 0.048), but this cutoff was not predictive in either racial cohort independently.

Conclusions
Black patients undergoing curative resection of PNETs at our institution presented with larger tumors, but that increased size is not predictive of disease-free survival in this population.
Prognostic Nomograms to Predict Overall Survival and Cancer-Specific Survival of Patients With Pancreatic Neuroendocrine Tumors
Authors: Song Zuoli , Wang Sumei , Wu Yujing , Zhang Jinjuan , Liu Shuye 
Published: April 2021

Objective
The objective of this research was to construct and validate prognostic nomograms predicting overall survival (OS) and cancer-specific survival (CSS) in patients with pancreatic neuroendocrine tumors (pNETs).

Methods
We extracted 3787 patients with pNETs from the Surveillance, Epidemiology and End Results database. Nomograms for estimating 3- and 5-year OS and CSS were first established. Then, we used Harrell's Concordance Index, calibration plots, and the area under receiver operating characteristic curve to evaluate the nomograms. The Kaplan-Meier curve was plotted to evaluate the different survival outcomes.

Results
In the multivariate analysis, age, grade, functional status, American Joint Committee on Cancer stage, and surgery were associated with OS and CSS. The established nomograms had good discriminative ability, with a Harrell’s Concordance Index of 0.830 for OS and 0.855 for CSS. The calibration plots also revealed good agreement. The area under receiver operating characteristic curve values of the nomograms predicting 3- and 5-year OS and CSS rates were 0.836, 0.816 and 0.859, 0.841, respectively. In addition, Kaplan-Meier curve indicated that patients with higher risk had worse survival outcomes.

Conclusions
We have proposed and validated the nomograms predicting OS and CSS of pNETs. They can be convenient individualized tools to facilitate clinical decision making.
A National Assessment of Optimal Oncologic Surgery for Distal Pancreatic Adenocarcinomas
Authors: Hrebinko Katherine , Tohme Samer , Hoehn Richard S. , AlMasri Samer , Khan Sidrah , Kaltenmeier Christof , Lee Kenneth K. , Paniccia Alessandro , Zureikat Amer , Nassour Ibrahim 
Published: April 2021

Objectives
The objective of this study was to create a composite measure, optimal oncologic surgery (OOS), for patients undergoing distal pancreatectomy for pancreatic adenocarcinoma and identify factors associated with OOS.

Methods
Adult patients undergoing distal pancreatectomy were identified from the National Cancer Database between 2010 and 2016. Patients were stratified based on receipt of OOS. Criteria for OOS included 90-day survival, no 30-day readmission, length of stay ≤7 days, negative resection margins, ≥12 lymph nodes harvested, and receipt of chemotherapy. Multivariate logistic regression was performed to identify predictors of OOS. Survival curves and a Cox proportional hazards model were created to compare survival and identify risk factors for mortality.

Results
Three thousand five hundred forty-six patients were identified. The rate of OOS was 22.3%. Diagnosis after 2012, treatment at an academic medical center, and a minimally invasive surgical approach (MIS) were associated with OOS. Survival was superior for patients undergoing OOS. Decreasing age at diagnosis, fewer comorbidities, surgery at an academic medical center, MIS, and lower pathologic stage were also associated with improved survival on multivariate analysis.

Conclusions
Rates of OOS for distal pancreatectomy are low. Time trends show increasing rates of OOS that may be related to increasing MIS, adjuvant chemotherapy, and referrals to academic medical centers.
Covid-19 and Excess Mortality in Medicare Beneficiaries
Authors: Greenwald Scott , Chamoun Nassib G , Manberg Paul J , Gray Josh , Clain David , Maheshwari Kamal , Sessler Daniel I. 
Published: April 2021

AbstractWe estimated excess mortality in Medicare recipients with probable and confirmed Covid-19 infections in the general community and amongst residents of long-term care (LTC) facilities. We considered 28,389,098 Medicare and dual-eligible recipients from one year before February 29, 2020 through September 30, 2020, with mortality followed through November 30th, 2020. Probable and confirmed Covid-19 diagnoses, presumably mostly symptomatic, were determined from ICD-10 codes. We developed a Risk Stratification Index (RSI) mortality model which was applied prospectively to establish baseline mortality risk. Excess deaths attributable to Covid-19 were estimated by comparing actual-to-expected deaths based on historical comparisons and in closely matched cohorts with and without Covid-19. 677,100 (2.4%) beneficiaries had confirmed Covid-19 and 2,917,604 (10.3%) had probable Covid-19. 472,329 confirmed cases were community living and 204,771 were in LTC. Mortality following a probable or confirmed diagnosis in the community increased from an expected incidence of about 4% to actual incidence of 7.5%. In long-term care facilities, the corresponding increase was from 20.3% to 24.6%. The absolute increase was therefore similar at 3-4% in the community and in LTC residents. The percentage increase was far greater in the community (89%) than among patients in chronic care facilities (21%) who had higher baseline risk. The LTC population without probable or confirmed Covid-19 diagnoses experienced 38,932 excess deaths (35%) compared to historical estimates. Limitations in access to Covid-19 testing and disease under-reporting in LTC patients probably were important factors, although social isolation and disruption in usual care presumably also contributed. Remarkably, there were 31,360 fewer deaths than expected in community dwellers without probable or confirmed Covid-19 diagnoses, representing a 6% reduction. Disruptions to the healthcare system and avoided medical care were thus apparently offset by other factors, representing overall benefit. The Covid-19 pandemic had marked effects on mortality, but the effects were highly context-dependent.
Pre-existing partner-drug resistance facilitates the emergence and spread of artemisinin resistance: a consensus modelling study
Authors: Watson Oliver J , Gao Bo , Nguyen Tran Dang , Tran Thu Nguyen-Anh , Penny Melissa A , Smith David L , Okell Lucy , Aguas Ricardo , Boni Maciej F 
Published: April 2021

AbstractBackgroundArtemisinin-resistant genotypes have now emerged a minimum of five times on three continents despite recommendations that all artemisinins be deployed as artemisinin combination therapies (ACTs). Widespread resistance to the non-artemisinin partner drugs in ACTs has the potential to limit the clinical and resistance benefits provided by combination therapy.MethodsUsing a consensus modelling approach with three individual-based mathematical models ofPlasmodium falciparumtransmission, we evaluate the effects of pre-existing partner-drug resistance and ACT deployment on artemisinin resistance evolution. We evaluate settings where dihydroartemisinin-piperaquine (DHA-PPQ), artesunate-amodiaquine (ASAQ), or artemether-lumefantrine (AL) are deployed as first-line therapy. We use time until 0.25 artemisinin resistance allele frequency (the establishment time) as the primary outcome measure.FindingsHigher frequencies of pre-existing partner-drug resistant genotypes lead to earlier establishment of artemisinin resistance. Across all scenarios and pre-existing frequencies of partner-drug resistance explored, a 0.10 increase in partner-drug resistance frequency on average corresponded to 0.7 to 5.0 years loss of artemisinin efficacy. However, the majority of reductions in time to artemisinin establishment were observed after the first increment from 0.0 to 0.10 partner-drug resistance genotype frequency.InterpretationPartner-drug resistance in ACTs facilitates the early emergence of artemisinin resistance and is a major public health concern. Higher grade partner-drug resistance has the largest effect, with piperaquine-resistance accelerating early emergence of artemisinin-resistant alleles the most. Continued investment in molecular surveillance of partner-drug resistant genotypes to guide choice of first-line ACT is paramount.FundingBill and Melinda Gates Foundation; Wellcome Trust.
Hypomethylation inFASTKD1detected in the association betweenin uterotobacco exposure and conduct problem in a New Zealand longitudinal study
Authors: Noble Alexandra J. , Pearson John F. , Boden Joseph M. , Horwood L. John , Kennedy Martin A. , Osborne Amy J. 
Published: April 2021

AbstractDespite the known adverse effects ofin uterotobacco exposure on offspring health, maternal tobacco use during pregnancy remains prevalent and is a major driver of health inequalities. One such health inequality is the development of conduct problem (CP) in exposed offspring which may be mediated by methylation changes that persist into adulthood. Here we apply a genome-wide approach to probe the association between maternal tobacco use during pregnancy and CP outcomes in exposed offspring. We examined maternal tobacco use during pregnancy (in uteroexposure) in the Christchurch Health and Development Study, a longitudinal birth cohort studied for over 40 years. We then evaluated the interaction between methylation effects ofin uteroexposure and CP score. When modelling this interaction betweenin uteroexposure and CP score we detected nominal DNA methylation differences, atFASTKD1which has roles in early development. Our observations are consistent with DNA methylation mediating the development of CP followingin uterotobacco exposure. In addition, we detected nominal significance inFRMDA4andMYO1Gbetween individuals exposed to tobaccoin uteroand those that were unexposed, however these did not reach significance after adjustment for multiple testing. However due to limited power in our analysis, further studies are needed to investigate the interaction betweenin uterotobacco exposure and high CP health outcomes.
Nanobody Repertoires for Exposing Vulnerabilities of SARS-CoV-2
Authors: Mast Fred D. , Fridy Peter C. , Ketaren Natalia E. , Wang Junjie , Jacobs Erica Y. , Olivier Jean Paul , Sanyal Tanmoy , Molloy Kelly R. , Schmidt Fabian , Rutkowska Magda , Weisblum Yiska , Rich Lucille M. , Vanderwall Elizabeth R. , Dambrauskas Nicolas , Vigdorovich Vladimir , Keegan Sarah , Jiler Jacob B. , Stein Milana E. , Olinares Paul Dominic B. , Hatziioannou Theodora , Sather D. Noah , Debley Jason S. , Fenyö David , Sali Andrej , Bieniasz Paul D. , Aitchison John D. , Chait Brian T. , Rout Michael P. 
Published: April 2021

SUMMARYDespite the great promise of vaccines, the COVID-19 pandemic is ongoing and future serious outbreaks are highly likely, so that multi-pronged containment strategies will be required for many years. Nanobodies are the smallest naturally occurring single domain antigen binding proteins identified to date, possessing numerous properties advantageous to their production and use. We present a large repertoire of high affinity nanobodies against SARS-CoV-2 Spike protein with excellent kinetic and viral neutralization properties, which can be strongly enhanced with oligomerization. This repertoire samples the epitope landscape of the Spike ectodomain inside and outside the receptor binding domain, recognizing a multitude of distinct epitopes and revealing multiple neutralization targets of pseudoviruses and authentic SARS-CoV-2, including in primary human airway epithelial cells. Combinatorial nanobody mixtures show highly synergistic activities, and are resistant to mutational escape and emerging viral variants of concern. These nanobodies establish an exceptional resource for superior COVID-19 prophylactics and therapeutics.
Gene co-expression analyses of health(span) across multiple species
Authors: Möller Steffen , Saul Nadine , Barrantes Israel , Gézsi András , Walter Michael , Antal Péter , Fuellen Georg 
Published: April 2021

AbstractHealth(span)-related gene clusters/modules were recently identified based on knowledge about the cross-species genetic basis of health, to interpret transcriptomic datasets describing health-related interventions. However, the cross-species comparison of health-related observations reveals a lot of heterogeneity, not least due to widely varying health(span) definitions and study designs, posing a challenge for the exploration of conserved healthspan modules and, specifically, their transfer across species.To improve the identification and exploration of conserved/transferable healthspan modules, here we apply an established workflow based on gene co-expression network analyses employing GEO/ArrayExpress data for human and animal models, and perform a comprehensive meta-analysis of the resulting modules related to health(span), yielding a small set of health(span) candidate genes, backed by the literature.For each experiment, WGCNA (weighted gene correlation network analysis) was thus used to infer modules of genes which correlate in their expression with a “health phenotype score” and to determine the most-connected (hub) genes for each such module, and their interactions. After mapping these hub genes to their human orthologs, 12 health(span) genes were identified in at least two species (ACTN3, ANK1, MRPL18, MYL1, PAXIP1, PPP1CA, SCN3B, SDCBP, SKIV2L, TUBG1, TYROBP, WIPF1), for which enrichment analysis by g:profiler finds an association with actin filament-based movement and associated organelles as well as muscular structures.We conclude that a meta-study of hub genes from co-expression network analyses for the complex phenotype health(span), across multiple species, can yield molecular-mechanistic insights and can direct experimentalists to further investigate the contribution of individual genes and their interactions to health(span).
Misrouting of Glucagon and Stathmin-2 Towards Lysosomal System of α-Cells in Glucagon Hypersecretion of Diabetes
Authors: Asadi Farzad , Dhanvantari Savita 
Published: April 2021

AbstractGlucagon hypersecretion from the pancreatic α-cell is a characteristic sign of diabetes, which exacerbates fasting hyperglycemia. Thus, targeting glucagon secretion from α-cells may be a promising approach for combating hyperglucagonemia. We have recently identified stathmin-2 as a protein that resides in α-cell secretory granules, and showed that it regulates glucagon secretion by directing glucagon towards the endolysosomal system in αTC1-6 cells. Here, we hypothesized that disruption of Stmn2-mediated trafficking of glucagon to the endolysosomes contributes to hyperglucagonemia. In isolated islets from male mice treated with streptozotocin (STZ) to induce diabetes, Arg-stimulated secretion of glucagon and Stmn2 was augmented. However, cell glucagon content was significantly increased (p<0.001), but Stmn2 levels were reduced (p<0.01) in STZ-treated mice, as measured by both ELISA and immunofluorescence intensity. Expression ofGcgmRNA increased ~4.5 times, whileStmn2mRNA levels did not change. Using confocal immunofluorescence microscopy, the colocalization of glucagon and Stmn2 in Lamp2A+lysosomes was dramatically reduced (p<0.001) in islets from diabetic mice, and the colocalization of Stmn2, but not glucagon, with the late endosome marker, Rab7, significantly (p<0.01) increased. Further studies were conducted in αTC1-6 cells cultured in media containing high glucose (16.7 mM) for two weeks to mimic glucagon hypersecretion of diabetes. Surprisingly, treatment of αTC1-6 cells with the lysosomal inhibitor bafilomycin A1 reduced K+-induced glucagon secretion, suggesting that high glucose may induce glucagon secretion from another lysosomal compartment. Both glucagon and Stmn2 co-localized with Lamp1, which marks secretory lysosomes, in cells cultured in high glucose. We propose that, in addition to enhanced trafficking and secretion through the regulated secretory pathway, the hyperglucagonemia of diabetes may also be due to re-routing of glucagon from the degradative Lamp2A+lysosome towards the secretory Lamp1+lysosome.
The homology analysis of ACE2 gene and its distinct expression in laboratory and wild animals
Authors: Wang Gang , Zhang A-Mei , Wang Binghui , Yin Jianhua , Feng Yue , Baloch zulqarnain , Xia Xueshan 
Published: April 2021

AbstractAngiotensin-converting enzyme-2 (ACE2) has been recognized as an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cells while bats has been suspected as natural host of SARS-CoV-2. However, the detail of intermediate host or the route of transmission of SARS-CoV-2 is still unclear. In this study, we analyze the conservation of ACE2 gene in 11 laboratory and wild animals that live in close proximity either with Bats or human and further investigated its RNA and protein expression pattern in wild bats, mice and tree shrew. We verified that the wild-bats and mice were belonged to Hipposideros pomona and Rattus norvegicus, respectively. ACE2 gene is highly conserved among all 11 animals species at the DNA level. Phylogenetic analysis based on the ACE2 nucleotide sequences revealed that wild bat and Tree shrew were forming a cluster close to human. We further report that ACE2 RNA expression pattern is highly species-specific in different tissues of different animals. Most notably, we found that the expression pattern of ACE2 RNA and protein are very different in each animal species. In summary, our results suggested that ACE2 gene is highly conserved among all 11 animals species. However, different relative expression pattern of ACE2 RNA and protein in each animal species is interesting. Further research is needed to clarify the possible connection between different relative expression pattern of ACE2 RNA and protein in different laboratory and wild animal species and the susceptibility to SARS-CoV-2 infection.
The structure and flexibility analysis of the Arabidopsis Synaptotagmin 1 reveal the basis of its regulation at membrane contact sites
Authors: Benavente Juan Luis , Siliqi Dritan , Infantes Lourdes , Lagartera Laura , Mills Alberto , Gago Federico , Ruiz-López Noemí , Ángel Botella Miguel , Sánchez-Barrena María José , Albert Armando 
Published: April 2021

AbstractCell function requires the maintenance of membrane lipid homeostasis as changes in cellular environment unbalance this equilibrium. The non-vesicular lipid transfer at endoplasmic reticulum (ER) and plasma membrane (PM) contact sites (CS) is central to restore it. Extended synaptotagmins (E-Syts) are ER proteins that play a central role in this process as they act as molecular tethers with PM and as lipid transfer proteins between these organelles. E-Syts are constitutively anchored to the ER through an N-terminal hydrophobic segment and bind to the PM via C-terminal C2 domains. In plants, synaptotagmins (SYTs) are orthologous of E-Syts and regulate the ER-PM communication by the activity of their two C2 domains in response to abiotic stresses. We have combined macromolecular crystallography, small-angle X-ray scattering, structural bioinformatics and biochemical data to analyze the regulation of plant synaptotagmin 1 (SYT1). Our data show that the binding of SYT1 to the PM is regulated by the interaction of the first C2 domain through a Ca2+-dependent lipid binding site and by a site for phosphorylated forms of phosphatidylinositol in such a way that two different molecular signals are integrated in response to stress. In addition, our data show that SYT1 is highly flexible by virtue of up to three hinge points, including one that connects the two C2 domains. This feature provides conformational freedom to SYT1 to define a large and complementary interaction surface with the PM. This structural plasticity, in turn, may facilitate lipid extraction, protein loading and subsequent transfer between PM and ER.Data DepositionThe atomic coordinates and structure factors have been deposited in the Protein Data Bank, https://www.pdb.org/ [PDB ID codes Ca2+ and Cd2+ complexes of SYT1C2A (7AS6 and 7ATP, respectively)]. The final SAXS models were deposited and are available at SASBDB https://www.sasbdb.org/ [ID codes SASDKG6 for the SMP2C2A construct SASDKJ9 for the C2AB construct and SASDKK9 in presence of Ca2+]
Rho and F-actin self-organize within an artificial cell cortex
Authors: Landino Jennifer , Leda Marcin , Michaud Ani , Swider Zachary T. , Prom Mariah , Field Christine M. , Bement William M. , Vecchiarelli Anthony G. , Goryachev Andrew B. , Miller Ann L. 
Published: April 2021

SummaryThe cell cortex, comprised of the plasma membrane and underlying cytoskeleton, undergoes dynamic reorganizations during a variety of essential biological processes including cell adhesion, cell migration, and cell division1,2. During cell division and cell locomotion, for example, waves of filamentous-actin (F-actin) assembly and disassembly develop in the cell cortex in a process termed “cortical excitability”3–7. In developing frog and starfish embryos, cortical excitability is generated through coupled positive and negative feedback, with rapid activation of Rho-mediated F-actin assembly followed in space and time by F-actin-dependent inhibition of Rho8,9. These feedback loops are proposed to serve as a mechanism for amplification of active Rho signaling at the cell equator to support furrowing during cytokinesis, while also maintaining flexibility for rapid error correction in response to movement of the mitotic spindle during chromosome segregation10. In this paper, we develop an artificial cortex based onXenopusegg extract and supported lipid bilayers (SLBs), to investigate cortical Rho and F-actin dynamics11. This reconstituted system spontaneously develops two distinct dynamic patterns: singular excitable Rho and F-actin waves and non-traveling oscillatory Rho and F-actin patches. Both types of dynamic patterns have properties and dependencies similar to the cortical excitability previously characterizedin vivo9. These findings directly support the longstanding speculation that the cell cortex is a self-organizing structure and present a novel approach for investigating mechanisms of Rho-GTPase-mediated cortical dynamics.HighlightsAn artificial cell cortex comprisingXenopusegg extract on a supported lipid bilayer self-organizes into complex, dynamic patterns of active Rho and F-actinWe identified two types of reconstituted cortical dynamics – excitable waves and coherent oscillationsReconstituted waves and oscillations require Rho activity and F-actin polymerization