bluuebunny/crossref_metadata_2025_split huggingface dataset:
Active Surveillance Versus Immediate Surgery in Clinically Complete Responders After Neoadjuvant Chemoradiotherapy for Esophageal Cancer
Authors: van der Wilk Berend J. , Noordman Bo J. , Neijenhuis Lisanne K. A. , Nieboer Daan , Nieuwenhuijzen Grard A. P. , Sosef Meindert N. , van Berge Henegouwen Mark I. , Lagarde Sjoerd M. , Spaander Manon C. W. , Valkema Roelf , Biermann Katharina , Wijnhoven Bas P. L. , van der Gaast Ate , van Lanschot J. Jan B. , Doukas Michael , Nikkessen Suzan , Luyer Misha , Schoon Erik J. , Roef Mark J. , van Lijnschoten Ineke , Oostenbrug Liekele E. , Riedl Robert G. , Gisbertz Suzanne S. , Krishnadath Kausilia K. , Bennink Roel J. , Meijer Sybren L. 
Published: October 2019

Objective:
This study compared outcomes of patients with esophageal cancer and clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) undergoing active surveillance or immediate surgery.

Background:
Since nearly one-third of patients with esophageal cancer show pathologically complete response after nCRT according to CROSS regimen, the oncological benefit of immediate surgery in cCR is topic of debate.

Methods:
Patients with cCR based on endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration initially declining or accepting immediate surgery after nCRT were identified between 2011 and 2018. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), rate and timing of distant dissemination, and postoperative outcomes.

Results:
Some 98 patients with cCR were identified: 31 in the active surveillance- and 67 in the immediate surgery group with median followup of survivors of 27.7 and 34.8 months, respectively. Propensity score matching resulted in 2 comparable groups (n = 29 in both groups). Patients undergoing active surveillance or immediate surgery had a 3-year OS of 77% and 55% (HR 0.41; 95% CI 0.14–1.20, P = 0.104), respectively. The 3-year PFS was 60% and 54% (HR 1.08; 95% CI 0.44–2.67, P = 0.871), respectively. Patients undergoing active surveillance or immediate surgery had a comparable distant dissemination rate (both groups 28%), radical resection rate (both groups 100%), and severity of postoperative complications (Clav- ien-Dindo grade ≥ 3: 43% vs 45%, respectively).

Conclusion:
In this retrospective study, OS and PFS in patients with cCR undergoing active surveillance or immediate surgery were not significantly different. Active surveillance with postponed surgery for recurrent disease was not associated with a higher distant dissemination rate or more severe adverse postoperative outcomes.
Meta-analysis, Meta-regression, and GRADE Assessment of Randomized and Nonrandomized Studies of Incisional Negative Pressure Wound Therapy Versus Control Dressings for the Prevention of Postoperative Wound Complications
Authors: Zwanenburg Pieter R. , Tol Berend T. , Obdeijn Miryam C. , Lapid Oren , Gans Sarah L. , Boermeester Marja A. 
Published: October 2019

Objective:
The aim of this study was to evaluate the efficacy of iNPWT for the prevention of postoperative wound complications such as SSI.

Summary of Background Data:
The 2016 WHO recommendation on the use of iNPWT for the prevention of SSI is based on low-level evidence, and many trials have been published since. Preclinical evidence suggests that iNPWT may also prevent wound dehiscence, skin necrosis, seroma, and hematoma.

Methods:
PubMed, EMBASE, CINAHL, and CENTRAL were searched for randomized and nonrandomized studies that compared iNPWT with control dressings. The evidence was assessed using the Cochrane Risk of Bias Tool, the Newcastle-Ottawa scale, and GRADE. Meta-analyses were performed using random-effects models.

Results:
High level evidence indicated that iNPWT reduced SSI [28 RCTs, n = 4398, relative risk (RR) 0.61, 95% confidence interval [CI]: 0.49–0.76, P < 0.0001, I
2 = 27%] with a number needed to treat of 19. Low level evidence indicated that iNPWT reduced wound dehiscence (16 RCTs, n = 3058, RR 0.78, 95% CI: 0.64–0.94). Very low-level evidence indicated that iNPWT also reduced skin necrosis (RR 0.49, 95% CI: 0.33–0.74), seroma (RR 0.43, 95% CI: 0.32–0.59), and length of stay (pooled mean difference −2.01, 95% CI: −2.99 to 1.14).

Conclusions:
High-level evidence indicates that incisional iNPWT reduces the risk of SSI with limited heterogeneity. Low to very low-level evidence indicates that iNPWT also reduces the risk of wound dehiscence, skin necrosis, and seroma.
Molecular profiling of primary central nervous system lymphomas – predictive and prognostic value?
Authors: Ho K. Grace , Grommes Christian 
Published: October 2019

Purpose of review
Primary central nervous system lymphoma (PCNSL) is a rare but aggressive variant of non-Hodgkin lymphoma. The diagnostic gold standard remains the pathologic review of tumor tissue mainly collected though biopsies. The majority of PCNSL are diffuse large B cell lymphoma (DLBCL). Biopsies are invasive procedures, and there have been efforts to develop minimally invasive diagnostic testing using serum and cerebral spinal fluid. This article reviews multiple markers that could potentially serve as future diagnostic tools and predictors of treatment response.

Recent findings
Many studies have attempted to classify DLBCL into different subtypes for prognostic purposes using methods such as immunohistochemistry. PCNSL often falls under the activated B-cell-like subgroup, and further genomic sequencing has identified alterations in genes within the B-cell receptor signaling axis at increased frequencies. Two such genes, MYD88 and CD79B, implicate the involvement of the NF-kB (nuclear factor kappa-light-chain enhancer of activated B cells) pathway, and targeted agents to this pathway are currently being used in the treatment of relapsed/refractory PCNSL.

Summary
Although recent genomic profiling of PCNSL has increased the understanding of drivers in this disease and has also led to the introduction of targeted inhibitors, these markers have not yet been used for diagnostic and/or prognostic purposes. Further studies will need to evaluate if they hold great diagnostic potential.
Reconstruction of protein domain evolution using single-cell amplified genomes of uncultured choanoflagellates sheds light on the origin of animals
Authors: López-Escardó David , Grau-Bové Xavier , Guillaumet-Adkins Amy , Gut Marta , Sieracki Michael E. , Ruiz-Trillo Iñaki 
Published: October 2019

Understanding the origins of animal multicellularity is a fundamental biological question. Recent genome data have unravelled the role that co-option of pre-existing genes played in the origin of animals. However, there were also some important genetic novelties at the onset of Metazoa. To have a clear understanding of the specific genetic innovations and how they appeared, we need the broadest taxon sampling possible, especially among early-branching animals and their unicellular relatives. Here, we take advantage of single-cell genomics to expand our understanding of the genomic diversity of choanoflagellates, the sister-group to animals. With these genomes, we have performed an updated and taxon-rich reconstruction of protein evolution from the Last Eukaryotic Common Ancestor (LECA) to animals. Our novel data re-defines the origin of some genes previously thought to be metazoan-specific, like the POU transcription factor, which we show appeared earlier in evolution. Moreover, our data indicate that the acquisition of new genes at the stem of Metazoa was mainly driven by duplications and protein domain rearrangement processes at the stem of Metazoa. Furthermore, our analysis allowed us to reveal protein domains that are essential to the maintenance of animal multicellularity. Our analyses also demonstrate the utility of single-cell genomics from uncultured taxa to address evolutionary questions.
This article is part of a discussion meeting issue ‘Single cell ecology’.
Realizing the potential of full-length transcriptome sequencing
Authors: Byrne Ashley , Cole Charles , Volden Roger , Vollmers Christopher 
Published: October 2019

Long-read sequencing holds great potential for transcriptome analysis because it offers researchers an affordable method to annotate the transcriptomes of non-model organisms. This, in turn, will greatly benefit future work on less-researched organisms like unicellular eukaryotes that cannot rely on large consortia to generate these transcriptome annotations. However, to realize this potential, several remaining molecular and computational challenges will have to be overcome. In this review, we have outlined the limitations of short-read sequencing technology and how long-read sequencing technology overcomes these limitations. We have also highlighted the unique challenges still present for long-read sequencing technology and provided some suggestions on how to overcome these challenges going forward.
This article is part of a discussion meeting issue ‘Single cell ecology’.
ATR16 Syndrome: Mechanisms Linking Monosomy to Phenotype
Authors: Babbs Christian , Brown Jill , Horsley Sharon W. , Slater Joanne , Maifoshie Evie , Kumar Shiwangini , Ooijevaar Paul , Kriek Marjolein , Dixon-McIver Amanda , Harteveld Cornelis L. , Traeger-Synodinos Joanne , Higgs Douglas , Buckle Veronica 
Published: October 2019

AbstractBackgroundSporadic deletions removing 100s-1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual’s clinical phenotype is challenging.MethodsHere, as an example of this common phenomenon, we analysed 34 patients with simple deletions of ∼177 to ∼2000 kb affecting one allele of the well characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised precise deletion extent and screened for genetic background effects, telomere position effect and compensatory up regulation of hemizygous genes.ResultsWe find the risk of developmental and neurological abnormalities arises from much smaller terminal chromosome 16 deletions (∼400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes, however, genetic background effects substantially modify phenotypic abnormalities.ConclusionsUsing ATR-16 as a general model of disorders caused by sporadic copy number variations, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but also depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling.
Bioinformatic analysis of brain-specific miRNAs for identification of candidate traumatic brain injury blood biomarkers
Authors: Smothers Christine , Winkelman Chris , O’Connell Grant C. 
Published: October 2019

AbstractBackgroundDetection of brain-specific miRNAs in the peripheral blood could serve as a surrogate marker of traumatic brain injury (TBI). Here, we systematically identified brain-enriched miRNAs, and tested their utility for use as TBI biomarkers in the acute phase of care.MethodsPublically-available microarray data generated from 31 postmortem human tissues was used to rank 1,364 miRNAs in terms of their degree of brain-specific expression. Levels of the top five ranked miRNAs were then prospectively measured in serum samples collected from 10 TBI patients at hospital admission, as well as from 10 controls.ResultsThe top five miRNAs identified in our analysis (miR-137, miR-219a-5p, miR-128-3p, miR-124-3p, and miR-138-5p) exhibited 31 to 74-fold higher expression in brain relative to other tissues. Furthermore, their levels were elevated in serum from TBI patients compared to controls, and were collectively able to discriminate between groups with 90% sensitivity and 80% specificity. Subsequent informatic pathway analysis revealed that their target transcripts were significantly enriched for components of signaling pathways which are active in peripheral organs such as the heart.ConclusionsThe five candidate miRNAs identified in this study have promise as blood biomarkers of TBI, and could also be molecular contributors to systemic physiologic changes commonly observed post-injury.A FINAL PEER REVIEWED VERSION OF THIS ARTICLE HAS BEEN PUBLISHED IN BRAIN INJURY AT THE FOLLOWING DOI: 10.1080/02699052.2020.1764102There are some notable differences between the analysis presented in this preprint and our final peer-reviewed article. There was a single tissue sample originating from spinal cord that we had classified as a non-brain tissue in our original analysis outlined in this preprint. Because the composition of spinal cord and brain are highly similar in terms of gene expression, classifying this sample as a non-brain tissue dramatically reduced the levels of brain enrichment observed in the analysis. Because brain and spinal cord are molecularly highly similar, but technically distinct anatomical structures, we simply decided to exclude this sample from our final analysis published in Brain Injury to avoid confounds. The top 5 miRNAs identified in our original analysis still fell within the top 7 of this final analysis. In addition, the final analysis identified two additional miRNAs which could be candidate biomarkers based on levels of brain enrichment.The final article published in Brain Injury also reports an additional confirmatory tissue specificity analysis performed in a second independent dataset, as well as additional analysis examining the brain specificity of several notable previously proposed miRNA TBI biomarkers, which is not described in this preprint.
Optimizing a human fecal assay that elicits bacterial swarming
Authors: Byju Arjun , Patel Deeti , Chen Weijie , Mani Sridhar 
Published: October 2019

AbstractA distinct property of many bacteria is swarming: swift movement across a surface through flagella propulsion. Early research indicates that bacterial swarming can be a protective host response to intestinal inflammation. Central to the further study of bacterial swarming in human health is an effective and replicable assay for swarming that can accommodate complex material, such as fecal matter. To date, nearly all swarming assays described in the literature are specific for bacteria grown in culture, most often Pseudomonas. In this paper, we describe a protocol for discerning swarming of bacteria from frozen human fecal samples. Moreover, we tested 4 variables that may influence the effectiveness of the assay: the method by which frozen samples were thawed, the concentration of agar used in the Lysogenic broth (LB) agar plate, the volume of LB agar poured in the plate, and the volume of sample inoculated. We found that while the type of thaw and volume of LB agar had little to no effect on swarming, greater concentrations of agar were negatively correlated with swarming and greater volumes of the sample were positively correlated with swarming.
Assessing a causal relationship between circulating lipids and breast cancer risk: Mendelian randomization study
Authors: Johnson Kelsey E. , Siewert Katherine M. , Klarin Derek , Damrauer Scott M. ,   the VA Million Veteran Program, Chang Kyong-Mi , Tsao Philip S. , Assimes Themistocles L. , Maxwell Kara N. , Voight Benjamin F. 
Published: October 2019

AbstractObjectiveTo assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein cholesterol, HDL; low-density lipoprotein cholesterol, LDL; triglycerides, TG) with risk for breast cancer.DesignMendelian randomization (MR) study.Setting and ParticipantsData from genome-wide association studies in up to 215,551 subjects from the Million Veterans Project were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on breast cancer risk was evaluated using genetic data from the BCAC consortium based on 122,977 breast cancer cases and 105,974 controls.ExposuresGenetically modified plasma levels of LDL, HDL, or TG.Main Outcomes and MeasuresOdds ratio (OR) for breast cancer risk per standard-deviation increase in HDL, LDL, or TG.ResultsWe observed that a 1-SD genetically determined increase in HDL levels is associated with an increased risk for all breast cancers (HDL: OR=1.08, 95% CI=1.04-1.13, P=7.4×10−5).Multivariable MR analysis, which adjusted for the effects of LDL, TG, body mass index, and age at menarche, corroborated this observation for HDL (OR=1.06, 95% CI=1.03-1.10, P=4.9×10−4) and also a relationship between LDL and breast cancer risk (OR=1.03, 95% CI=1.01-1.07, P=0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for breast cancers (OR=1.11, 95% CI=1.06–1.16, P=1.5×10−6), including gene-specific associations at ABCA1, APOE-APOC1-APOC4-APOC2 and CETP. In addition, we find evidence that genetic variation at the ABO locus affects both lipid levels and breast cancer.ConclusionsGenetically elevated plasma HDL levels appear to increase breast cancer risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal to develop potential therapeutic strategies aimed at altering the HDL-mediated effect on breast cancer risk.
New North American isolates of Venturia inaequalis can overcome apple scab resistance of Malus floribunda 821
Authors: Papp David , Singh Jugpreet , Gadoury David , Khan Awais 
Published: October 2019

AbstractApple scab, caused by Venturia inaequalis (Cke.) Wint., is a destructive fungal disease of major apple cultivars worldwide, most of which are moderately to highly susceptible. Thus, development of scab resistant cultivars is one of the highest priorities of apple breeding programs. The principal source of resistance for breeding programs has been the scab resistance gene Rvi6 that originated from the Japanese crabapple Malus floribunda (Sieb.) sel. 821. Isolates of V. inaequalis able to overcome Rvi6 have been identified in Europe, but have not yet been reported on the American continents. We recently discovered scab infection on M. floribunda 821 trees in a research orchard at Geneva, New York, USA, where approximately 10% of the leaves bore profusely sporulating apple scab lesions, many of which had coalesced to cover entire leaves. Chlorosis and pinpoint pitting symptoms typical of failed infections by V. inaequalis on hosts bearing the Rvi6 and Rvi7 genes were also observed. We assessed genetic diversity and population genetic structure of six V. inaequalis isolates collected from M. floribunda 821, one isolate from ‘Nova Easygro’, one isolate from ‘Golden Delicious’ and two isolates from Europe (11 isolates in total) using 16,321 genome-wide SNPs. Population genetic structure and PCA separated the isolates into distinct European and USA groups. The forgoing suggests that the new Rvi6 virulent isolates emerged within USA populations, rather than being transported from Europe. The overcoming of resistance in M. floribunda 821 but not in descendant cultivars suggests that durable resistance to apple scab will require a more comprehensive understanding of Rvi6 mediated resistance in diverse genetic backgrounds.
Choosing to view morbid information involves reward circuitry
Authors: Oosterwijk Suzanne , Snoek Lukas , Tekoppele Jurriaan , Engelbert Lara , Scholte H. Steven 
Published: October 2019

AbstractPeople often seek out stories, videos or images that detail death, violence or harm. Considering the ubiquity of this behavior, it is surprising that we know very little about the neural circuits involved in choosing negative information. Here we show that choosing intensely negative stimuli engages similar brain regions as those that support extrinsic incentives and “regular” curiosity. Participants made choices to view negative and positive images, based on negative (e.g., a soldier kicks a civilian against his head) and positive (e.g., children throw flower petals at a wedding) verbal cues. We hypothesized that the conflicting, but relatively informative act of choosing to view a negative image, resulted in stronger activation of reward circuitry as opposed to the relatively uncomplicated act of choosing to view a positive stimulus. Indeed, as preregistered, we found that choosing negative cues was associated with activation of the striatum, inferior frontal gyrus, anterior insula, and anterior cingulate cortex, both when contrasting against a passive viewing condition, and when contrasting against positive cues. These findings nuance models of decision-making, valuation and curiosity, and are an important starting point when considering the value of seeking out negative content.
CaBLAM for chiropraxis in cryoEM, UnDowser to rethink “waters”, and NGL Viewer to recapture online 3D graphics in MolProbity validation
Authors: Prisant Michael G. , Williams Christopher J. , Chen Vincent B. , Richardson Jane S. , Richardson David C. 
Published: October 2019

AbstractThe MolProbity web service provides macromolecular model validation to help correct local errors, for the structural biology community worldwide. Here we highlight new validation features, and also describe how we are fighting back against recent outside changes that degrade or endanger that mission. Sophisticated hacking of the MolProbity server has required continual monitoring and various security measures short of restricting user access. Refinement software now increasingly restrains validation criteria in order to supplement the sparser experimental data at 3-4Å resolutions typical of modern cryoEM. But unfortunately the broad density allows optimization without fixing underlying problems, which means these structures often score much better than they really are. CaBLAM, our first new tool designed for this regime, was described in the previous Tools issue, and here we demonstrate its effectiveness in diagnosing local errors even when other validation outliers have been artificially removed. The deprecation of Java applets now prevents KiNG interactive online display of outliers on the 3D model during a MolProbity run, but that important functionality is now recaptured with a modified version of the Javascript NGL Viewer. Other new changes are more straightforwardly good. We are moving to the Neo4j database (graphical rather than relational), and will soon have cleaner as well as much larger reference datasets. In addition to several minor new features, we have developed a tool called UnDowser that analyzes the properties and context of modeled but clashing HOH “waters” to diagnose what they might actually represent. A dozen distinct scenarios are illustrated and described.