bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of a Novel Iterative Denoising and Image Enhancement Technique in T1-Weighted Precontrast and Postcontrast Gradient Echo Imaging of the Abdomen
Authors: Gassenmaier Sebastian , Afat Saif , Nickel Dominik , Kannengiesser Stephan , Herrmann Judith , Hoffmann Rüdiger , Othman Ahmed E.
Published: November 2020

Objectives

The aim of this study was to investigate the impact of a novel iterative denoising and image enhancement technique in T1-weighted precontrast and postcontrast volume-interpolated breath-hold examination (VIBE) of the abdomen on image quality, noise levels, and diagnostic confidence without change of acquisition parameters.

Materials and Methods

Fifty patients were included in this retrospective, monocentric, institutional review board–approved study after clinically indicated magnetic resonance imaging of the abdomen including T1-weighted precontrast and postcontrast imaging. After acquisition of the standard VIBE (VIBES), images were processed with a novel reconstruction algorithm using the same raw data as for VIBES, resulting in a denoised and enhanced dataset (VIBEDE). Two different radiologists evaluated both datasets in a randomized order regarding sharpness of organs as well as vessels, noise levels, artifacts, overall image quality, and diagnostic confidence using a Likert scale ranging from 1 to 4 with 4 being the best. Furthermore, in the presence of focal liver lesions, the largest lesion was measured in the postcontrast dataset, and lesion detectability was analyzed using a Likert scale (1–4).

Results

Precontrast and postcontrast sharpness of organs and sharpness of vessels were rated significantly superior by both readers in VIBEDE with a median of 4 (interquartile range, 0) compared with VIBES with a median of 3 (1) (all P's < 0.0001). Precontrast and postcontrast noise levels were also rated superior by both readers in VIBEDE with a median of 4 (0) compared with VIBES with a median of 3 (1) for precontrast and a median of 3 (0) (median of 3 [1] for reader 2) for postcontrast imaging (all P's < 0.0001).

Overall image quality was also rated higher with a median of 4 (0) in VIBEDE versus 3 (1) in VIBES (P < 0.0001). Twenty-seven imaging studies contained liver lesions. There was no difference regarding the number and localization between the readers and between VIBES and VIBEDE. Lesion detectability was rated by both readers significantly better in VIBEDE with a median of 4 (0) compared with a median of 4 (1) for reader 1 and a median of 3 (1) for reader 2 (P = 0.001 for reader 1; P < 0.001 for reader 2). Consequently, diagnostic confidence was also significantly superior in VIBEDE versus VIBES with a median of 4 (0) for both (P = 0.001). Interreader agreement resulted in a Cohen κ of 0.76 for precontrast analysis as well as of 0.76 for postcontrast analysis.

Conclusions

Application of a novel iterative denoising and image enhancement technique in T1-weighted VIBE precontrast and postcontrast imaging of the abdomen is feasible, providing superior image quality, noise levels, and diagnostic confidence.
Consensus Conference Statement on the General Use of Near-infrared Fluorescence Imaging and Indocyanine Green Guided Surgery
Authors: Dip Fernando , Boni Luigi , Bouvet Michael , Carus Thomas , Diana Michele , Falco Jorge , Gurtner Geoffrey C. , Ishizawa Takeaki , Kokudo Norihiro , Lo Menzo Emanuele , Low Philip S. , Masia Jaume , Muehrcke Derek , Papay Francis A. , Pulitano Carlo , Schneider-Koraith Sylke , Sherwinter Danny , Spinoglio Giuseppe , Stassen Laurents , Urano Yasuteru , Vahrmeijer Alexander , Vibert Eric , Warram Jason , Wexner Steven D. , White Kevin , Rosenthal Raul J.
Published: November 2020

Background:

In recent decades, the use of near-infrared light and fluorescence-guidance during open and laparoscopic surgery has exponentially expanded across various clinical settings. However, tremendous variability exists in how it is performed.

Objective:

In this first published survey of international experts on fluorescence-guided surgery, we sought to identify areas of consensus and nonconsensus across 4 areas of practice: fundamentals; patient selection/preparation; technical aspects; and effectiveness and safety.

Methods:

A Delphi survey was conducted among 19 international experts in fluorescence-guided surgery attending a 1-day consensus meeting in Frankfurt, Germany on September 8th, 2019. Using mobile phones, experts were asked to anonymously vote over 2 rounds of voting, with 70% and 80% set as a priori thresholds for consensus and vote robustness, respectively.

Results:

Experts from 5 continents reached consensus on 41 of 44 statements, including strong consensus that near-infrared fluorescence-guided surgery is both effective and safe across a broad variety of clinical settings, including the localization of critical anatomical structures like vessels, detection of tumors and sentinel nodes, assessment of tissue perfusion and anastomotic leaks, delineation of segmented organs, and localization of parathyroid glands. Although the minimum and maximum safe effective dose of ICG were felt to be 1 to 2 mg and >10 mg, respectively, there was strong consensus that determining the optimum dose, concentration, route and timing of ICG administration should be an ongoing research focus.

Conclusions:

Although fluorescence imaging was almost unanimously perceived to be both effective and safe across a broad range of clinical settings, considerable further research remains necessary to optimize its use.
The Impact of Clinical and Pathological Features on Intraductal Papillary Mucinous Neoplasm Recurrence After Surgical Resection
Authors: Pflüger Michael J. , Griffin James F. , Hackeng Wenzel M. , Kawamoto Satomi , Yu Jun , Chianchiano Peter , Shin Eunice , Lionheart Gemma , Tsai Hua-Ling , Wang Hao , Rezaee Neda , Burkhart Richard A. , Cameron John L. , Thompson Elizabeth D. , Wolfgang Christopher L. , He Jin , Brosens Lodewijk A. A. , Wood Laura D.
Published: November 2020

Objective:

This study aimed to identify risk factors for recurrence after pancreatic resection for intraductal papillary mucinous neoplasm (IPMN).

Summary Background Data:

Long-term follow-up data on recurrence after surgical resection for IPMN are currently lacking. Previous studies have presented mixed results on the role of margin status in risk of recurrence after surgical resection.

Methods:

A total of 126 patients that underwent resection for noninvasive IPMN were followed for a median of 9.5 years. Dedicated pathological and radiological reviews were performed to correlate clinical and pathological features (including detailed pathological features of the parenchymal margin) with recurrence after surgical resection. In addition, in a subset of 32 patients with positive margins, we determined the relationship between the margin and original IPMN using driver gene mutations identified by next-generation sequencing.

Results:

Family history of pancreatic cancer and high-grade IPMN was identified as risk factors for recurrence in both uni- and multivariate analysis (adjusted hazard ratio 3.05 and 1.88, respectively). Although positive margin was not significantly associated with recurrence in our cohort, the size and grade of the dysplastic focus at the margin were significantly correlated with recurrence in margin-positive patients. Genetic analyses showed that the neoplastic epithelium at the margin was independent from the original IPMN in at least 9 of 32 cases (28%). The majority of recurrences (74%) occurred after 3 years, and a significant minority (32%) occurred after 5 years.

Conclusion:

Sustained postoperative surveillance for all patients is indicated, particularly those with risk factors such has family history and high-grade dysplasia.
Expert Consensus Recommendations for Robotic Surgery Credentialing
Authors: Stefanidis Dimitrios , Huffman Elizabeth M. , Collins Justin W. , Martino Martin A. , Satava Richard M. , Levy Jeffrey S.
Published: November 2020

Objective:

To define criteria for robotic credentialing using expert consensus.

Background:

A recent review of institutional robotic credentialing policies identified significant variability and determined current policies are largely inadequate to ensure surgeon proficiency and may threaten patient safety.

Methods:

Twenty-eight national robotic surgery experts were invited to participate in a consensus conference. After review of available institutional policies and discussion, the group developed a 91 proposed criteria. Using a modified Delphi process the experts were asked to indicate their agreement with the proposed criteria in three electronic survey rounds after the conference. Criteria that achieved 80% or more in agreement (consensus) in all rounds were included in the final list.

Results:

All experts agreed that there is a need for standardized robotic surgery credentialing criteria across institutions that promote surgeon proficiency. Forty-nine items reached consensus in the first round, 19 in the second, and 8 in the third for a total of 76 final items. Experts agreed that privileges should be granted based on video review of surgical performance and attainment of clearly defined objective proficiency benchmarks. Parameters for ongoing outcome monitoring were determined and recommendations for technical skills training, proctoring, and performance assessment were defined.

Conclusions:

Using a systematic approach, detailed credentialing criteria for robotic surgery were defined. implementation of these criteria uniformly across institutions will promote proficiency of robotic surgeons and has the potential to positively impact patient outcomes.
The Association Between Factors Promoting Nonbeneficial Surgery and Moral Distress
Authors: Zimmermann Christopher J. , Taylor Lauren J. , Tucholka Jennifer L. , Buffington Anne , Brasel Karen , Arnold Robert , Cooper Zara , Schwarze Margaret L.
Published: November 2020

Objective:

To assess the prevalence of moral distress among surgeons and test the association between factors promoting non-beneficial surgery and surgeons’ moral distress.

Summary Background Data:

Moral distress experienced by clinicians can lead to low-quality care and burnout. Older adults increasingly receive invasive treatments at the end of life that may contribute to surgeons’ moral distress, particularly when external factors, such as pressure from colleagues, institutional norms, or social demands, push them to offer surgery they consider non-beneficial.

Methods:

We mailed surveys to 5200 surgeons randomly selected from the American College of Surgeons membership, which included questions adapted from the revised Moral Distress Scale. We then analyzed the association between factors influencing the decision to offer surgery to seriously ill older adults and surgeons’ moral distress.

Results:

The weighted adjusted response rate was 53% (n = 2161). Respondents whose decision to offer surgery was influenced by their belief that pursuing surgery gives the patient or family time to cope with the patient's condition were more likely to have high moral distress (34% vs 22%, P < 0.001), and this persisted on multivariate analysis (odds ratio 1.44, 95% confidence interval 1.02–2.03). Time required to discuss nonoperative treatments or the consulting intensivists’ endorsement of operative intervention, were not associated with high surgeon moral distress.

Conclusions:

Surgeons experience moral distress when they feel pressured to perform surgery they believe provides no clear patient benefit. Strategies that empower surgeons to recommend nonsurgical treatments when they believe this is in the patient's best interest may reduce nonbeneficial surgery and surgeon moral distress.
Failure to Rescue in Emergency General Surgery
Authors: Hanna Kamil , Chehab Mohamad , Bible Letitia , Asmar Samer , Ditillo Michael , Castanon Lourdes , Tang Andrew , Joseph Bellal
Published: November 2020

Objective:

Compare EGS patient outcomes after index and nonindex hospital readmissions, and explore predictive factors for nonindex readmission.

Background:

Readmission to a different hospital leads to fragmentation of care. The impact of nonindex readmission on patient outcomes after EGS is not well established.

Methods:

The Nationwide Readmissions Database (2017) was queried for adult patients readmitted after an EGS procedure. Patients were stratified and propensity-matched according to readmission destination: index versus nonindex hospital. Outcomes were failure to rescue (FTR), mortality, number of subsequent readmissions, overall hospital length of stay, and total costs. Hierarchical logistic regression was performed to account for clustering effect within hospitals and adjusting for patient- and hospital-level potential confounding factors.

Results:

A total of 471,570 EGS patients were identified, of which 79,127 (16.8%) were readmitted within 30 days: index hospital (61,472; 77.7%) versus nonindex hospital (17,655; 22.3%). After 1:1 propensity matching, patients with nonindex readmission had higher rates of FTR (5.6% vs 4.3%; P < 0.001), mortality (2.7% vs 2.1%; P < 0.001), and overall hospital costs [in $1000; 37 (27–64) vs 28 (21–48); P < 0.001]. Nonindex readmission was independently associated with higher odds of FTR [adjusted odds ratio 1.18 (1.03–1.36); P < 0.001]. Predictors of nonindex readmission included top quartile for zip code median household income [1.35 (1.08–1.69); P < 0.001], fringe county residence [1.08 (1.01–1.16); P = 0.049], discharge to a skilled nursing facility [1.28 (1.20–1.36); P < 0.001], and leaving against medical advice [2.32 (1.81–2.98); P < 0.001].

Conclusion:

One in 5 readmissions after EGS occur at a different hospital. Nonindex readmission carries a heightened risk of FTR.

Level of Evidence:

Level III Prognostic.

Study Type:

Prognostic.
Factors Associated With Postprocedure Opioid Prescribing and Persistent Opioid Use Among Opioid-naive Patients
Authors: Parikh Megha A. , Fabiyi Camille , Mistry Kamila B.
Published: November 2020

Objective:

Examine factors associated with postprocedure opioid receipt and persistent opioid use among opioid-naive patients in a nationally representative sample.

Summary Background Data:

We used panels 18-20 in the Medical Expenditures Panel Survey (MEPS) between the years 2013 and 2015. Respondents ages 18 and over with any self-reported procedure in the previous year with complete data on the outcome variables for the remainder of the 2-year study period.

Methods:

This prospective observational study used multivariable regression to determine factors associated with postprocedure opioid receipt and persistent opioid use among opioid-naive patients, adjusting for sociodemographic, health, and procedure-related characteristics.

Results:

Adjusted models showed younger age, Western location (AOR = 1.38; 95% CI = 1.02, 1.86), and high-school degree (AOR = 1.60; CI = 1.14, 2.26) were associated with higher odds of postprocedure opioid receipt. Patients who had procedures in an inpatient (AOR: 5.71; CI: 4.31-7.56), outpatient (AOR = 3.77; CI = 2.87,4.95), and dental setting (AOR = 2.86; CI = 1.45, 5.63), and musculoskeletal diagnoses (AOR = 2.23; CI = 1.39, 3.58) and injuries (AOR = 2.04; CI = 1.29, 3.23) were more likely to have postprocedure opioid receipt. Persistent opioid use was associated with Midwest (AOR = 2.06; CI = 1.08, 3.95) and Northeast location (AOR = 2.45; CI = 1.03, 3.95), musculoskeletal diagnosis (AOR = 3.91; CI = 1.23, 8.31), public insurance (AOR = 2.07; CI = 1.23-3.49), and positive depression screener (AOR = 3.36; CI = 2.04, 5.55).

Conclusions:

Procedures account for a large portion of opioid prescriptions among opioid-naive patients. This study provides evidence to inform national guidelines for opioid prescribing and postprocedure pain management.
Pathophysiological Mechanisms of Gastro-esophageal Reflux After Sleeve Gastrectomy
Authors: Johari Yazmin , Lim Gillian , Wickremasinghe Anagi , Yue Helen , Seah Jarrel , Ooi Geraldine , Playfair Julie , Laurie Cheryl , Beech Paul , Yap Kenneth , Hebbard Geoff , Brown Wendy , Burton Paul
Published: November 2020

Objective:

To evaluate the mechanisms associated with reflux events after sleeve gastrectomy (SG).

Summary Background Data:

Gastro-esophageal reflux (GERD) post-SG is a critical issue due to symptom severity, impact on quality of life, requirement for reoperation, and potential for Barrett esophagus. The pathophysiology is incompletely delineated.

Methods:

Post-SG patients, stratified into asymptomatic and symptomatic, underwent protocolized nuclear scintigraphy (n = 83), 24-hour esophageal pH monitoring, and stationary manometry (n = 143) to characterize reflux patterns. Ten patients underwent fasting and postprandial concurrent manometry and pH for detailed analysis of reflux events.

Results:

Baseline demographics between cohorts were similar: Age 47.2 ± 11.6 versus 44.1 ± 11.3 years (P = 0.121); females 73.2% versus 90.8% (P = 0.005); excess weight loss 53.8 ± 28.1% versus 57.4 ± 25.5% (P = 0.422), follow-up duration 12.3 versus 7.4 months (P = 0.503). Nuclear scintigraphy delineated bolus-induced deglutitive reflux events (29.6% vs 62.5%, P = 0.005) and postprandial reflux events [4 (IQR2) versus 4 (IQR 3) events, P = 0.356]. Total acid exposure was significantly elevated in the symptomatic population (7.7% vs 3.6%, P < 0.001), especially fasting acid exposure (6.0% vs 1.3%, P < 0.001). pH/manometry analysis demonstrated acute elevations of the gastro-esophageal pressure gradient (>10 mm Hg) underpinned most reflux events. Swallow-induced intragastric hyper-pressur-ization was associated with individual reflux events in most patients (90% in fasting state and 40% postprandial).

Conclusions:

We found reflux to be strongly associated with SG and identified 3 unique categories. Bolus-induced deglutitive and postprandial reflux occurred in most patients. Elevated fasting esophageal acid exposure mediated symptoms. Frequent, significant elevation in the gastro-esophageal pressure gradient was the mechanism of reflux and seemed to relate to the noncompliant proximal stomach.
Randomized Trial of Laparoscopic Nissen Versus Anterior 180 Degree Partial Fundoplication – Late Clinical Outcomes at 15 to 20 years
Authors: Rudolph-Stringer Victoria , Bright Tim , Irvine Tanya , Thompson Sarah K. , Devitt Peter G. , Game Philip A. , Jamieson Glyn G. , Watson David I.
Published: November 2020

Objective:

To determine very late clinical outcomes at up to 20 years follow-up from a randomized controlled trial of Nissen versus anterior 180-degree partial fundoplication.

Summary Background Data:

Nissen fundoplication for gastroesophageal reflux can be followed by troublesome side effects. To address this, partial fundoplications have been proposed. Previously reports from a randomized controlled trial of Nissen versus anterior 180-degree partial fundoplication at up to 10 years follow-up showed good outcomes for both procedures.

Methods:

One hundred seven participants were randomized to Nissen versus anterior 180-degree partial fundoplication. Fifteen to 20 year follow-up data was available for 79 (41 Nissen, 38 anterior). Outcome was assessed using a standardized questionnaire with 0 to 10 analog scores and yes/no questions to determine reflux symptoms, side-effects, and satisfaction with surgery.

Results:

After anterior fundoplication heartburn (mean score 3.2 vs 1.4, P = .001) and proton pump inhibitor use (41.7% vs 17.1%, P = .023) were higher, offset by less dysphagia for solids (mean score 1.8 vs 3.3, P = .015), and better ability to belch (84.2% vs 65.9%, P = .030). Measures of overall outcome were similar for both groups (mean satisfaction score 8.4 vs 8.0, P = .444; 86.8% vs 90.2% satisfied with outcome). Six participants underwent revision after anterior fundoplication (Nissen conversion for reflux – 6), and 7 underwent revision after Nissen fundoplication (Nissen to partial fundoplication for dysphagia – 5; redo Nissen for reflux – 1; paraesophageal hernia –1).

Conclusions:

At 15 to 20 years follow-up Nissen and anterior 180-degree partial fundoplication achieved similar success, but with trade-offs between better reflux control versus more side-effects after Nissen fundoplication.
Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS
Authors: Nunns Geoffrey R. , Vigneshwar Navin , Kelher Marguerite R. , Stettler Gregory R. , Gera Lajos , Reisz Julie A. , D’Alessandro Angelo , Ryon Joshua , Hansen Kirk C. , Gamboni Fabia , Moore Ernest E. , Peltz Erik D. , Cohen Mitchell J. , Jones Kenneth L. , Sauaia Angela , Liang Xiayuan , Banerjee Anirban , Ghasabyan Arsen , Chandler James G. , Rodawig Sophia , Jones Carter , Eitel Andrew , Hom Patrick , Silliman Christopher C.
Published: November 2020

Objectives:

Identify the metabolites that are increased in the plasma of severely injured patients that developed ARDS versus severely injured patients that did not, and assay if these increased metabolites prime pulmonary sequestration of neutrophils (PMNs) and induce pulmonary sequestration in an animal model of ARDS. We hypothesize that metabolic derangement due to advanced shock in critically injured patients leads to the PMNs, which serves as the first event in the ARDS. Summary of Background Data: Intracellular metabolites accumulate in the plasma of severely injured patients.

Methods:

Untargeted metabolomics profiling of 67 critically injured patients was completed to establish a metabolic signature associated with ARDS development. Metabolites that significantly increased were assayed for PMN priming activity in vitro. The metabolites that primed PMNs were tested in a 2-event animal model of ARDS to identify a molecular link between circulating metabolites and clinical risk for ARDS.

Results:

After controlling for confounders, 4 metabolites significantly increased: creatine, dehydroascorbate, fumarate, and succinate in trauma patients who developed ARDS (P < 0.05). Succinate alone primed the PMN oxidase in vitro at physiologically relevant levels. Intravenous succinate-induced PMN sequestration in the lung, a first event, and followed by intravenous lipopolysaccharide, a second event, resulted in ARDS in vivo requiring PMNs. SUCNR1 inhibition abrogated PMN priming, PMN sequestration, and ARDS. Conclusion: Significant increases in plasma succinate post-injury may serve as the first event in ARDS. Targeted inhibition of the SUCNR1 may decrease ARDS development from other disease states to prevent ARDS globally.
Murine Cytomegalovirus–induced Complement-fixing Antibodies Deposit in Murine Renal Allografts During Acute Rejection
Authors: Saunders Ute , Li Mao , Boddeda Srinivasa R. , Maher Sonya , Ghere Jessica , Kaptsan Irina , Dhital Ravi , Velazquez Victoria , Guo Lingling , Chen Bo , Zeng Qiang , Schoeb Trenton R. , Cianciolo Rachel , Shimamura Masako
Published: November 2020

Background.

Human cytomegalovirus (CMV) infection is associated with renal allograft dysfunction and loss, particularly in combination with acute rejection. Emerging literature suggests that non-HLA antibodies may contribute to antibody-mediated rejection, but pathogen-induced antibodies have not been investigated in this context. This study examines the presence of CMV-induced antibodies in murine CMV (MCMV)–infected renal allografts during acute rejection.

Methods.

Intragraft immunoglobulin G (IgG) and complement C3 immunostaining were compared among allogeneic MCMV D−/R−, D+/R−, and D+/R+ renal transplants. Intragraft antibody deposition was examined in B cell–deficient recipients treated with MCMV immune sera. Antibody binding and complement-dependent cytotoxicity (CDC) of D−/R− and D+/R+ sera against infected renal tubular epithelial cells (TECs) were measured in vitro. IgG immunostaining was performed in D+/R+ allografts and native kidneys and in D+/R− allografts treated with ganciclovir to inhibit viral replication.

Results.

D+/R− and D+/R+ transplants had more abundant IgG and C3 deposition compared with D−/R− recipients. Greater IgG deposition was associated with more severe allograft injury in B cell–deficient recipients treated with MCMV immune sera compared with nonimmune sera. D+/R+ sera induced greater CDC of infected TECs compared with D−/R− sera. Native kidneys had lower IgG deposition compared with allografts, despite similar organ viral loads. Ganciclovir-treated allografts had reduced IgG deposition compared with untreated allografts.

Conclusions.

In this murine model, complement-fixing antibodies can deposit into MCMV-infected renal allografts, are associated with allograft damage, and can induce CDC of MCMV-infected renal TECs. The allogeneic response and viral replication may also contribute to intragraft antibody deposition.
scDesign2: a transparent simulator that generates high-fidelity single-cell gene expression count data with gene correlations captured
Authors: Sun Tianyi , Song Dongyuan , Li Wei Vivian , Li Jingyi Jessica
Published: November 2020

In the burgeoning field of single-cell transcriptomics, a pressing challenge is to benchmark various experimental protocols and numerous computational methods in an unbiased manner. Although dozens of simulators have been developed for single-cell RNA-seq (scRNA-seq) data, they lack the capacity to simultaneously achieve all the three goals: preserving genes, capturing gene correlations, and generating any number of cells with varying sequencing depths. To fill in this gap, here we propose scDesign2, a transparent simulator that achieves all the three goals and generates high-fidelity synthetic data for multiple scRNA-seq protocols and other single-cell gene expression count-based technologies. Compared with existing simulators, scDesign2 is advantageous in its transparent use of probabilistic models and is unique in its ability to capture gene correlations via copula. We verify that scDesign2 generates more realistic synthetic data for four scRNA-seq protocols (10x Genomics, CEL-Seq2, Fluidigm C1, and Smart-Seq2) and two single-cell spatial transcriptomics protocols (MERFISH and pciSeq) than existing simulators do. Under two typical computational tasks, cell clustering and rare cell type detection, we demonstrate that scDesign2 provides informative guidance on deciding the optimal sequencing depth and cell number in single-cell RNA-seq experimental design, and that scDesign2 can effectively benchmark computational methods under varying sequencing depths and cell numbers. With these advantages, scDesign2 is a powerful tool for single-cell researchers to design experiments, develop computational methods, and choose appropriate methods for specific data analysis needs.
cancerAlign: Stratifying tumors by unsupervised alignment across cancer types
Authors: Gao Bowen , Luo Yunan , Ma Jianzhu , Wang Sheng
Published: November 2020

Tumor stratification, which aims at clustering tumors into biologically meaningful subtypes, is the key step towards personalized treatment. Large-scale profiled cancer genomics data enables us to develop computational methods for tumor stratification. However, most of the existing approaches only considered tumors from an individual cancer type during clustering, leading to the overlook of common patterns across cancer types and the vulnerability to the noise within that cancer type. To address these challenges, we proposed cancerAlign to map tumors of the target cancer type into latent spaces of other source cancer types. These tumors were then clustered in each latent space rather than the original space in order to exploit shared patterns across cancer types. Due to the lack of aligned tumor samples across cancer types, cancerAlign used adversarial learning to learn the mapping at the population level. It then used consensus clustering to integrate cluster labels from different source cancer types. We evaluated cancerAlign on 7,134 tumors spanning 24 cancer types from TCGA and observed substantial improvement on tumor stratification and cancer gene prioritization. We further revealed the transferability across cancer types, which reflected the similarity among them based on the somatic mutation profile. cancerAlign is an unsupervised approach that provides deeper insights into the heterogeneous and rapidly accumulating somatic mutation profile and can be also applied to other genome-scale molecular information.

Availability

https://github.com/bowen-gao/cancerAlign
Genetic and environmental regulation of caudate nucleus transcriptome: insight into schizophrenia risk and the dopamine system
Authors: Benjamin Kynon JM , Feltrin Arthur S , Barbosa André Rocha , Jaffe Andrew E , Collado-Torres Leonardo , Burke Emily E , Shin Joo Heon , Ulrich William S , Deep-Soboslay Amy , Tao Ran ,   the BrainSeq Consortium, Hyde Thomas M , Kleinman Joel E , Erwin Jennifer A , Weinberger Daniel R , Paquola Apuã CM
Published: November 2020

Increased dopamine (DA) signaling in the striatum has been a cornerstone hypothesis about psychosis for over 50 years. Increased dopamine release results in psychotic symptoms, while D2 dopamine receptor (DRD2) antagonists are antipsychotic. Recent schizophrenia GWAS identified risk-associated common variants near the DRD2 gene, but the risk mechanism has been unclear. To gain novel insight into risk mechanisms underlying schizophrenia, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in postmortem caudate nucleus from a cohort of 444 individuals. Integrating expression quantitative trait loci (eQTL) analysis, transcriptome wide association study (TWAS), and differential expression analysis, we found many new genes associated with schizophrenia through genetic modulation of gene expression. Using a new approach based on deep neural networks, we construct caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. Interestingly, we found that genetic risk for schizophrenia is associated with decreased expression of the short isoform of DRD2, which encodes the presynaptic autoreceptor, and not with the long isoform, which encodes the postsynaptic receptor. This association suggests that decreased control of presynaptic DA release is a potential genetic mechanism of schizophrenia risk. Altogether, these analyses provide a new resource for the study of schizophrenia that can bring insight into risk mechanisms and potential novel therapeutic targets.
Multiple routes of functional diversification of the plant BAHD acyltransferase family revealed by comparative biochemical and genomic analyses
Authors: Kruse Lars H. , Weigle Austin T. , Irfan Mohammad , Martínez-Gómez Jesús , Chobirko Jason D. , Schaffer Jason E. , Bennett Alexandra A. , Specht Chelsea D. , Jez Joseph M. , Shukla Diwakar , Moghe Gaurav D.
Published: November 2020

Large enzyme families catalyze metabolic diversification by virtue of their ability to use diverse chemical scaffolds. How enzyme families attain such functional diversity is not clear. Here, we addressed this question using BAHD acyltransferases as a model, and identified the routes by which duplication, promiscuity and sequence changes influenced BAHD diversification. This fast-evolving family expanded drastically during land plant evolution from 1-5 copies in algae to ∼100 copies in diploid angiosperm genomes.In vitrocharacterization of fourteen BAHDs against a substrate panel and compilation of >160 published activities revealed the wide prevalence of promiscuity among BAHDs. Using phylogenetic analysis, we predicted the substrate classes that the ancestral enzymes were likely capable of using prior to land plant origins. While the anthocyanin acylation activity was fixed in BAHDs later near the origin of angiosperms,in vitrotesting of BAHDs from non-seed plant lineages suggested that the ability to acylate anthocyanins likely existed promiscuously millions of years prior to its fixation. Motif enrichment analysis in anthocyanin-acylating BAHDs identified two motifs fixed in the largest anthocyanin acylating clade. Molecular dynamic simulations and enzyme kinetics revealed the important role of an active site tryptophan, whose bulkiness, hydrophobicity and aromaticity are critical for anthocyanin acylation. Our results thus describe the molecular processes in robust, evolvable enzymes that drive emergence of functional diversity in enzyme families.

One sentence summary

Using a combination of phylogenetics, biochemistry and protein structure analysis, we investigated how the BAHD acyltransferase family evolved to use a structurally diverse array of substrates.
scPretrain: Multi-task self-supervised learning for cell type classification
Authors: Zhang Ruiyi , Luo Yunan , Ma Jianzhu , Zhang Ming , Wang Sheng
Published: November 2020

Rapidly generated scRNA-seq datasets enable us to understand cellular differences and the function of each individual cell at single-cell resolution. Cell type classification, which aims at characterizing and labeling groups of cells according to their gene expression, is one of the most important steps for single-cell analysis. To facilitate the manual curation process, supervised learning methods have been used to automatically classify cells. Most of the existing supervised learning approaches only utilize annotated cells in the training step while ignoring the more abundant unannotated cells. In this paper, we proposed scPretrain, a multi-task self-supervised learning approach that jointly considers annotated and unannotated cells for cell type classification. scPretrain consists of a pre-training step and a fine-tuning step. In the pre-training step, scPretrain uses a multi-task learning framework to train a feature extraction encoder based on each dataset’s pseudo-labels, where only unannotated cells are used. In the fine-tuning step, scPretrain fine-tunes this feature extraction encoder using the limited annotated cells in a new dataset. We evaluated scPretrain on 60 diverse datasets from different technologies, species and organs, and obtained a significant improvement on both cell type classification and cell clustering. Moreover, the representations obtained by scPretrain in the pre-training step also enhanced the performance of conventional classifiers such as random forest, logistic regression and support vector machines. scPretrain is able to effectively utilize the massive amount of unlabelled data and be applied to annotating increasingly generated scRNA-seq datasets.

Availability

https://github.com/ruiyi-zhang/scPretrain\
Repeated blast mild traumatic brain injury and oxycodone self-administration produce interactive effects on neuroimaging outcomes
Authors: Muelbl Matthew J. , Glaeser Breanna , Shah Alok S. , Chiariello Rachel , Nawarawong Natalie N. , Stemper Brian D. , Budde Matthew D. , Olsen Christopher M.
Published: November 2020

Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated oxycodone seeking after drug self-administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self-administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc), and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the BOLD response, and that interhemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self-administration had interactive effects on structural and functional MRI measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability.
A global overview of single-cell type selectivity and pleiotropy in complex diseases and traits
Authors: Xue Chao , Jiang Lin , Long Qihan , Chen Ying , Li Xiangyi , Li Miaoxin
Published: November 2020

After centuries of genetic studies, one of the most fundamental questions, i.e. in what cell types do DNA mutations regulate a phenotype, remains unanswered for most complex phenotypes. The current availability of hundreds of genome-wide association studies (GWASs) and single-cell RNA sequencing (scRNA-seq) of millions of cells provides a unique opportunity to address the question. In the present study, we firstly constructed an association landscape between over 20,000 single cell clusters and 997 complex phenotypes by a cross annotation framework with scRNA-seq expression profiles and GWAS summary statistics. We then performed an extensive overview of cell-type specificity and pleiotropy in human phenotypes and found most phenotypes (>90%) were moderately selectively associated with a limited number of cell types while a small fraction cell types (<10%) had strong pleiotropy in multiple phenotypes (~100). Moreover, we identified three cell type-phenotype mutual pleiotropy blocks in the landscape. The application of the single cell type-phenotype cross annotation framework (named SPA) also explained the T cell biased lymphopenia and suggested important supporting genes in severe COVID-19 from human genetics angle. All the cell type-phenotype association results can be queried and visualized athttp://pmglab.top/spa.
BOSO: a novel feature selection algorithm for linear regression with high-dimensional data
Authors: Valcarcel Luis V. , San José-Enériz Edurne , Cendoya Xabier , Rubio Ángel , Agirre Xabier , Prósper Felipe , Planes Francisco J.
Published: November 2020

Motivation

With the frenetic growth of high-dimensional datasets in different biomedical domains, there is an urgent need to develop predictive methods able to deal with this complexity. Feature selection is a relevant strategy in machine learning to address this challenge.

Results

We introduce a novel feature selection algorithm for linear regression called BOSO (Bilevel Optimization Selector Operator). We conducted a benchmark of BOSO with key algorithms in the literature, finding a superior performance in highdimensional datasets. Proof-of-concept of BOSO for predicting drug sensitivity in cancer is presented. A detailed analysis is carried out for methotrexate, a well-studied drug targeting cancer metabolism.

Availability

A Matlab implementation of BOSO is available as a Supplementary Material.

Contact

fplanes@tecnun.es

Supplementary Information

Supplementary data are available at Bioinformatics online.
Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity
Authors: Murad John P. , Tilakawardane Dileshni , Park Anthony K. , Kennewick Kelly T. , Lopez Lupita S. , Lee Hee Jun , Gittins Brenna J. , Chang Wen-Chung , Tran Chau P. , Martinez Catalina , Wu Anna M. , Reiter Robert E. , Dorff Tanya B. , Forman Stephen J. , Priceman Saul J.
Published: November 2020

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed anin vivorequirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity.
Large-Scale Analysis of Circulating Amino Acids and Adipose Gene Expression in Relation to Abdominal Obesity
Authors: Ina Maltais-Payette , Jinchu Vijay , Marie-Michelle Simon , Corbeil Jacques , Brière Francis , Elin Grundberg , André Tchernof
Published: November 2020

Background

Circulating level of the amino acid glutamate is associated with central fat accumulation, yet the pathophysiology of this relationship remains unknown. We aimed to: i) refine and validate the association between circulating glutamate and abdominal obesity in a large population-based twin cohort; and ii) investigate whether transcriptomic profiles in adipose tissue could provide insight into biological mechanisms underlying the association.

Methods

First, in a cohort of 4,665 individuals from the TwinsUK resource, we identified individuals with abdominal obesity and compared prevalence of the latter across circulating glutamate quintiles. Second, we used transcriptomic signatures generated from adipose tissue, both subcutaneous and visceral, to investigate associations with circulating glutamate levels.

Results

Individuals in the top circulating glutamate quintile had a 7-fold higher prevalence of abdominal obesity compared to those in the bottom quintile. The adipose tissue transcriptomic analyses identifiedGLUL, encoding Glutamate-Ammonia Ligase, as being associated with circulating glutamate and abdominal obesity, with pronounced signatures in the visceral depot.

Conclusion

Circulating glutamate is positively associated with the prevalence of abdominal obesity which relates to dysregulated GLUL expression specifically in visceral adipose tissue.
Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge
Authors: Douguet Laetitia , dit Hreich Serena Janho , Benzaquen Jonathan , Seguin Laetitia , Juhel Thierry , Dezitter Xavier , Duranton Christophe , Ryffel Bernhard , Kanellopoulos Jean , Delarasse Cecile , Renault Nicolas , Furman Christophe , Homerin Germain , Féral Chloé , Cherfils-Vicini Julien , Millet Régis , Adriouch Sahil , Ghinet Alina , Hofman Paul , Vouret-Craviari Valérie
Published: November 2020

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop new therapeutic strategies to improve patient outcome. We developed a new chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7 expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a promising novel strategy that may be active against NSCLC.
Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms
Authors: Lindholm Malene E , Jimenez-Morales David , Zhu Han , Seo Kinya , Amar David , Zhao Chunli , Raja Archana , Madhvani Roshni , Espenel Cedric , Sutton Shirley , Caleshu Colleen , Berry Gerald J , Motonaga Kara S. , Dunn Kyla , Platt Julia , Ashley Euan A , Wheeler Matthew T
Published: November 2020

Alpha-actinin 2 (ACTN2) anchors actin within cardiac sarcomeres. The mechanisms linkingACTN2mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novelACTN2mutations to reveal insights into the physiological function of ACTN2. Patient-derived iPSC-cardiomyocytes harboring ACTN2 protein-truncating variants were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc structure. In homozygous stop-gain cells, affinity-purification mass spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 and GJA1, two sarcolemma-associated proteins, that may lead to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing. Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance ofACTN2truncation as causative of disease.
Genomic Resources of Broomcorn Millet: Demonstration and Application of a High-throughput BAC Mapping Pipeline
Authors: Xu Wei , Liang Mengjie , Yang Xue , Wang Hao , Luo Meizhong
Published: November 2020

Background

With high-efficient water-use and drought tolerance, broomcorn millet has emerged as a candidate for food security. To promote its research process for molecular breeding and functional research, a comprehensive genome resource is of great importance.

Results

Herein, we constructed a BAC library for broomcorn millet, generated BAC end sequences based on the clone-array pooled shotgun sequencing strategy and Illumina sequencing technology, and integrated BAC clones into genome by a novel pipeline for BAC end profiling. The BAC library is consisted of 76,023 clones with an average insert length of 123.48 Kb, covering about 9.9-fold of the 850 Mb genome. Of 9,216 clones tested using our pipeline, 8,262 clones were mapped on the broomcorn millet cultivar longmi4 genome. These mapped clones covered 308 of the 829 gaps left by the genome. To our knowledge, this is the only BAC resource for broomcorn millet.

Conclusions

We constructed a high-quality BAC libraray for broomcorn millet and designed a novel pipeline for BAC end profiling. BAC clones can be browsed and obtained from our website (http://eightstarsbio.com/gresource/JBrowse-1.16.5/index.html). The high-quality BAC clones mapped on genome in this study will provide a powerful genomic resource for genome gap filling, complex segment sequencing, FISH, functional research, and genetic engineering of broomcorn millet.