bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cap-dependent Endonuclease Inhibitor S-033188 for the Treatment of Influenza: Results from a Phase 3, Randomized, Double-Blind, Placebo- and Active-Controlled Study in Otherwise Healthy Adolescents and Adults with Seasonal Influenza
Authors: Portsmouth Simon , Kawaguchi Keiko , Arai Masatsugu , Tsuchiya Kenji , Uehara Takeki 
Published: October 2017

Abstract

Background
Cap-dependent endonuclease (CEN) resides in the PA subunit of influenza virus polymerase and mediates the “cap-snatching” process during viral mRNA biosynthesis. S-033188 is a potent, selective, small molecule inhibitor of CEN. Here we report clinical and virologic outcomes from a global Phase 3 study CAPSTONE-1.

Method
This was a multicenter, randomized, double-blind, placebo- and active-controlled study. Key eligibility criteria included 12–64 years of age, fever (axillary temperature ≥38.0°C), ≥1 general symptom and ≥1 respiratory symptom (moderate to severe), and ≤48 hours from symptom onset. Patients between 20 and 64 years of age were randomized in 2:2:1 ratio to receive a single oral administration of S-033188, placebo, or 75 mg oseltamivir BID for 5 days. Patients between 12 and 19 years of age were randomized in 2:1 ratio to receive either a single oral administration of S-033188 or placebo. The primary efficacy endpoint was time to alleviation of influenza symptoms (TTAS) in the infected intent to treat population. Viral titer and RNA content were determined from pre- and postdose nasal/throat swabs.

Result
A total of 1436 patients were randomized. TTAS was significantly shorter in the S-033188 group than that in the placebo group (median TTAS: 53.7 hours vs. 80.2 hours, P &lt; 0.0001). Median time to cessation of viral shedding was 24 hours in patients treated with S-033188, compared with 72 hours in those treated with oseltamivir (P &lt; 0.0001) and 96 hours for placebo (P &lt; 0.0001). Patients in the S-033188 group had significantly greater reductions from baseline in both viral titer and RNA content than those in oseltamivir or placebo groups at all time-points until Day 3 (compared with oseltamivir) or Day 5 (compared with placebo). S-033188 was generally well tolerated, with overall incidence of treatment-emergent adverse events lower than that seen with oseltamivir.

Conclusion
Treatment with S-033188 was superior to placebo in alleviating influenza symptoms, and superior to both oseltamivir and placebo in virologic outcomes. Safety profile of S-033188 compared favorably with that of oseltamivir.

Disclosures
S. Portsmouth, Shionogi Inc.: Employee, Salary. K. Kawaguchi, Shionogi & Co., Ltd.: Employee, Salary. M. Arai, Shionogi & Co Ltd: Employee, Salary. K. Tsuchiya, Shionogi & Co., Ltd.: Employee, Salary. T. Uehara, Shionogi & Co., Ltd.: Employee, Salary.
Ethanol Lock Treatment and Secondary Prophylaxis for Central Line-Associated Bloodstream Infection in Pediatric Hematology and Oncology: A Randomized, Double-Blind, Placebo-Controlled, Intervention Trial
Authors: Wolf Joshua , Connell Tom , Allison Kim J , Tang Li , Richardson Julie , Branum Kristen , Borello Eloise , Gaur Aditya , Hakim Hana , Su Yin , Mechinaud Francoise , Hayden Randall , Monagle Paul , Worth Leon , Curtis Nigel , Flynn Patricia M 
Published: October 2017

Abstract

Background
Central line-associated bloodstream infection (CLABSI) commonly affects children with cancer and hematological disorders, with significant attributable costs and morbidity. Treatment failure, comprising persistent infection, infection relapse or new infection, occurs in ~50% of cases. Adjunctive ethanol lock therapy (ELT) has been proposed to prevent failure, but has never been tested in a prospective controlled study.

Methods
A prospective, dual-center, double-blind, block-randomized, placebo-controlled trial of ELT (70% ethanol in water) for CLABSI, given as treatment (2 hours per lumen per day) for 5 days, followed by secondary prophylaxis (2 hours per lumen up to 3 days per week) for 24 weeks, in children with oncologic or hematologic disorders (NCT01472965). Risk of treatment failure was compared between intervention and control groups according to proportional and cumulative incidence models, using intention-to-treat and per-protocol analyses. The study was discontinued at a pre-specified futility analysis.

Results
Of 94 evaluable participants, 48 were randomized to ELT and 46 to placebo; groups were similar at baseline for all measured variables. Forty-one (43.6%) participants had treatment failure (11 early failure, 9 relapse, and 21 reinfection). There was no difference between patients receiving ELT or placebo for risk of treatment failure (43.8% vs. 43.5%; P = 0.9) or for cumulative incidence of treatment failure in intention to treat (Figure 1) and per-protocol analyses (Figure 2). Catheter occlusion was significantly more common in participants receiving ethanol (58.3% vs. 32.6%, P = 0.01) but other adverse events, including LFT elevations (14.6% vs. 26.1%) and infusion reactions (18.8% vs. 8.7%), were not significantly different between groups.

Conclusion
Although observational studies suggested ELT might be effective for treatment of CLABSI in pediatric oncology, we found no benefit in treatment outcome and an increase in adverse effects. These results may not apply to patients receiving dialysis or with fungal CLABSI as these were not well-represented. Routine use of ELT for CLABSI in children with oncologic or hematologic disorders is not recommended.

Disclosures
All authors: No reported disclosures.
Low-dose Aspirin Inhibits Cardiac Sympathetic Activation and Vagal Withdrawal Response to Morning Rising
Authors: Yasumasu Tomiya , Takahara Kazuo , Otsuji Yutaka 
Published: October 2017

Abstract:
Aspirin is known to interfere with platelet function and can protect individuals at risk of sudden death. However, this property of aspirin is less defined for cardiac autonomic activity. We assessed pulse rate variability by spectral analysis and measured plasma eicosanoid levels before and after administration of 81-mg aspirin to 12 healthy subjects over a 60-degree head-up tilt test in the morning. In upright posture, low-dose aspirin decreased both the normalized unit value of low-frequency (normalized LF) power (mean ± SD, 82.5 ± 4.5 vs. 77.5 ± 6.5 nu, P = 0.01) and LF/HF ratio (6.0 ± 2.1 vs. 4.7 ± 2.7, P = 0.02) and augmented the normalized unit value of high-frequency power (15.0 ± 4.4 vs. 19.8 ± 6.4 nu, P = 0.004). It simultaneously upregulated plasma 6-keto-PGF1α level (13.4 ± 6.8 vs. 19.7 ± 12.8 pg/mL, P = 0.04) and inhibited plasma thromboxane B2 (TXB2) level (11.6 ± 7.3 vs. 6.3 ± 4.2 pg/mL, P = 0.003). In the upright posture, both before and after aspirin, there was a significant direct correlation between plasma TXB2 levels and the normalized LF power (r = 0.42, P = 0.04) as well as between the plasma TXB2/6-keto-PGF1α ratio and the normalized LF power (r = 0.50, P = 0.01). Administration of low-dose aspirin in healthy people inhibits cardiac sympathetic activation and vagal withdrawal response to morning rising through an alternation of the TXA2/PGI2 balance.
Isolated Testicular Recurrence of AML in Patients With Chronic GVHD >1 Year Following Allogeneic Stem Cell Transplant
Authors: Dang Brian N. , De Oliveira Satiro , Bowles LaVette , Moore Theodore B. 
Published: October 2017

Background:
Patients with chronic graft-versus-host disease (cGVHD) following allogeneic transplant for myeloid leukemias seem to experience a reduced risk of relapse than comparable patients without cGVHD. It is unclear to what extent extramedullary sites are impacted by a graft-versus-leukemia effect.

Design/Method:
Case Series and review of the literature.

Results:
We present 2 cases of pediatric patients with Acute Myelogenous Leukemia who developed isolated testicular relapse more than a year following hematopoietic stem cell transplantation despite having had extensive cGVHD. Both patients were off immunosuppression and cGVHD medications when testicular relapse occurred. At time of relapse, these patients were negative for minimal residual disease in the marrow and the marrow contained all donor cells by engraftment studies. No evidence was found for lymphocyte infiltration into the affected testicle in either patient.

Conclusions:
Although a reduction of marrow relapse can be appreciated in patients with myeloid leukemias and chronic GVHD, this graft-versus-leukemia process may be less robust in extramedullary sites and careful surveillance should be maintained to allow early intervention before overt marrow involvement.
Decisional Informatics for Psychosocial Rehabilitation
Authors: Choi Jimmy , Lysaker Paul H. , Bell Morris D. , Dixon Lisa , Margolies Paul , Gold Matthew , Golden-Roose Elizabeth , Thime Warren , Haber Lawrence C. , Dewberry Michael J. , Stevens Michael , Pearlson Godfrey D. , Fiszdon Joanna M. 
Published: October 2017

Abstract
This study introduces a computerized clinical decision-support tool, the Fluid Outpatient Rehabilitation Treatment (FORT), that incorporates individual and ever-evolving patient needs to guide clinicians in developing and updating treatment decisions in real-time. In this proof-of-concept feasibility pilot, FORT was compared against traditional treatment planning using similar behavioral therapies in 52 adults with severe mental illness attending community-based day treatment. At posttreatment and follow-up, group differences and moderate-to-large effect sizes favoring FORT were detected in social function, work readiness, self-esteem, working memory, processing speed, and mental flexibility. Of participants who identified obtaining a General Education Diploma as their goal, 73% in FORT passed the examination compared with 18% in traditional treatment planning. FORT was also associated with higher agency cost-effectiveness and a better average benefit-cost ratio, even when considering diagnosis, baseline symptoms, and education. Although the comparison groups were not completely equivalent, the findings suggest computerized decision support systems that collaborate with human decision-makers to personalize psychiatric rehabilitation and address critical decisions may have a role in improving treatment effectiveness and efficiency.
Long-term Oncologic Outcome After Laparoscopic Converted or Primary Open Resection for Colorectal Cancer: A Systematic Review of the Literature
Authors: Furnée Edgar J.B. , Allaix Marco E. , Morino Mario 
Published: October 2017

Purpose:
The aim of this study was to critically review the current evidence regarding the oncologic outcomes after laparoscopic converted or open resection for colorectal cancer.

Materials and Methods:
A literature search was performed in Pubmed. Study selection and data acquisition were independently performed by 2 reviewers.

Results:
The search strategy yielded a total of 746 articles, resulting in 7 studies eligible for inclusion. A total of 9190 (57 to 8307) patients were included in the open and 238 (17 to 56) in the converted group. In none of the studies, differences were found in disease stage between both groups. There were no significant differences between both groups with regard to overall survival, local recurrence and distant metastasis rate.

Conclusions:
There is currently insufficient evidence that patients who had a laparoscopic resection for colorectal cancer converted to open surgery have a worse oncologic outcome than patients who were primarily treated by an open approach.
Modelling wave-induced sea ice break-up in the marginal ice zone
Authors: Montiel F. , Squire V. A. 
Published: October 2017

A model of ice floe break-up under ocean wave forcing in the marginal ice zone (MIZ) is proposed to investigate how floe size distribution (FSD) evolves under repeated wave break-up events. A three-dimensional linear model of ocean wave scattering by a finite array of compliant circular ice floes is coupled to a flexural failure model, which breaks a floe into two floes provided the two-dimensional stress field satisfies a break-up criterion. A closed-feedback loop algorithm is devised, which (i) solves the wave-scattering problem for a given FSD under time-harmonic plane wave forcing, (ii) computes the stress field in all the floes, (iii) fractures the floes satisfying the break-up criterion, and (iv) generates an updated FSD, initializing the geometry for the next iteration of the loop. The FSD after 50 break-up events is unimodal and near normal, or bimodal, suggesting waves alone do not govern the power law observed in some field studies. Multiple scattering is found to enhance break-up for long waves and thin ice, but to reduce break-up for short waves and thick ice. A break-up front marches forward in the latter regime, as wave-induced fracture weakens the ice cover, allowing waves to travel deeper into the MIZ.
Chromatin organization by an interplay of loop extrusion and compartmental segregation
Authors: Nuebler Johannes , Fudenberg Geoffrey , Imakaev Maxim , Abdennur Nezar , Mirny Leonid 
Published: October 2017

AbstractMammalian chromatin is organized on length scales ranging from individual nucleosomes to chromosomal territories. At intermediate scales two dominant features emerge in interphase: (i) alternating regions (<5Mb) of active and inactive chromatin that spatially segregate into different compartments, and (ii) domains (<1Mb), i.e. regions that preferentially interact internally, which are also termed topologically associating domains (TADs) and are central to gene regulation. There is growing evidence that TADs are formed by active extrusion of chromatin loops by cohesin, whereas compartments are established by a phase separation process according to local chromatin states. Here we use polymer simulations to examine how the two processes, loop extrusion and compartmental segregation, work collectively and potentially interfere in shaping global chromosome organization. Our integrated model faithfully reproduces Hi-C data from previously puzzling experimental observations, where targeting of the TAD-forming machinery led to changes in compartmentalization. Specifically, depletion of chromatin-associated cohesin reduced TADs and revealed hidden, finer compartments, while increased processivity of cohesin led to stronger TADs and reduced compartmentalization, and depletion of the TAD boundary protein, CTCF, weakened TADs while leaving compartments unaffected. We reveal that these experimental perturbations are special cases of a general polymer phenomenon of active mixing by loop extrusion. This also predicts that interference with chromatin epigenetic states or nuclear volume would affect compartments but not TADs. Our results suggest that chromatin organization on the megabase scale emerges from competition of non-equilibrium active loop extrusion and epigenetically defined compartment structure.
Comparative Transcriptomics of Mango (Mangifera indica L.) Cultivars Provide Insights of Biochemical Pathways Involved in Flavor and Color
Authors: Khan Waqasuddin , Razzak Safina Abdul , Kamran Azim M. 
Published: October 2017

AbstractMango is an economically important fruit crop of many tropical and subtropical countries. Recently, leaf and fruit transcriptomes of mango cultivars grown in different geographical regions have characterized. Here, we presented comparative transcriptome analysis of four mango cultivars i.e. cv. Langra, cv. Zill, cv. Shelly and cv. Kent from Pakistan, China, Israel and Mexico respectively. De-novo sequence assembly generated 30,953-85,036 unigenes from RNASeq datasets of mango cultivars. KEGG pathway mapping of mango unigenes identified terpenoids, flavonoids and carotenoids biosynthetic pathways involved in flavor and color. The analysis revealed linalool as major monoterpenoid found in all cultivars studied whereas, monoterpene α-terpineol was specifically found in cv. Shelly. Ditepene gibberellin biosynthesis pathway was found in all cultivars whereas, homoterpene synthase involved in biosynthesis of 4,8,12-trimethyltrideca-1,3,7,11-tetraene (TMTT; an insect induced diterpene) was found in cv. Kent. Among sesquiterpenes and triterpenes, biosynthetic pathway of Germacrene-D, an antibacterial and anti-insecticidal metabolite was found in cv. Zill and cv. Shelly. Two bioactive triterpenes, lupeol and β-amyrin were found in cv. Langra and cv. Zill. Unigenes involved in biosynthesis of carotenoids, β-carotene and lycopene, were found in cultivars studied. Many unigenes involved in flavonoid biosynthesis were also found. Comparative transcriptomics revealed naringenin (an anti-inflammatory and antioxidant metabolite) as ‘central’ flavanone responsible for biosynthesis of an array of flavonoids. The present study provided insights on genetic resources responsible for flavor and color of mango fruit.
IRF4 haploinsufficiency in a family with Whipple’s disease
Authors: Guérin Antoine , Kerner Gaspard , Marr Nico , Markle Janet G. , Fenollar Florence , Wong Natalie , Boughorbel Sabri , Avery Danielle T. , Ma Cindy S. , Bougarn Salim , Bouaziz Matthieu , Beziat Vivien , Della Mina Erika , Lazarovt Tomi , Worley Lisa , Nguyen Tina , Patin Etienne , Deswarte Caroline , Martinez-Barricarte Rubén , Boucherit Soraya , Ayral Xavier , Edouard Sophie , Boisson-Dupuis Stéphanie , Rattina Vimel , Bigio Benedetta , Vogt Guillaume , Geissmann Frédéric , Quintana-Murci Lluis , Chaussabel Damien , Tangye Stuart G. , Raoult Didier , Abel Laurent , Bustamante Jacinta , Casanova Jean-Laurent 
Published: October 2017

AbstractThe pathogenesis of Whipple’s disease (WD) remains largely unknown, as WD strikes only a very small minority of the individuals infected withTropheryma whipplei(Tw). Asymptomatic carriage of Tw is less rare. We studied a large multiplex French kindred, containing four otherwise healthy WD patients (mean age: 76.7 years) and five healthy carriers of Tw (mean age: 55 years). We used a strategy combining genome-wide linkage analysis and whole-exome sequencing to test the hypothesis that WD is inherited in an autosomal dominant (AD) manner, with age-dependent incomplete penetrance. WD was linked to 12 genomic regions covering 27 megabases in the four patients. These regions contained only one very rare non-synonymous variation: the R98W variant ofIRF4. The five Tw carriers were heterozygous for R98W. Interferon regulatory factor 4 (IRF4) is a transcription factor with pleiotropic roles in immunity. We showed that R98W was a loss-of-function allele, like only five other exceedingly rareIRF4alleles of a total of 39 rare and common non-synonymous alleles tested. Furthermore, heterozygosity for R98W led to a distinctive pattern of transcription in leukocytes following stimulation with BCG or Tw. Finally, we found thatIRF4had evolved under purifying selection and that R98W was not dominant-negative, suggesting that the IRF4 deficiency in this kindred was due to haploinsufficiency. Overall, haploinsufficiency at theIRF4locus selectively underlies WD in this multiplex kindred. This deficiency displays AD inheritance with incomplete penetrance, and chronic carriage probably precedes WD by several decades in Tw-infected heterozygotes.
Structural Basis for Katanin Self-Assembly
Authors: Nithiananatham Stanley , McNally Francis J. , Al-Bassam Jawdat 
Published: October 2017

SUMMARYThe reorganization of microtubules in mitosis, meiosis and development requires the microtubule-severing activity of katanin. Katanin is composed of a AAA ATPase subunit and a regulatory subunit. Microtubule severing requires ATP hydrolysis by katanin’s conserved AAA ATPase domains. Whereas other AAA ATPases form stable hexamers, we show that wild-type katanin only forms heterodimers and heterotetramers. Heterododecamers were only observed for an ATP hydrolysis deficient mutant in the presence of ATP, suggesting an auto-inhibition mechanism that prevents oligomerization. X-ray structures of katanin’s AAA ATPase in monomeric nucleotide-free and pseudo-oligomeric ADP-bound states reveal conformational changes in AAA subdomains and N and C-terminal expansion segments that explain this auto-inhibition of assembly. These data lead to a model in which self-inhibited heterodimers bind to a microtubule, then transition into an assembly-competent conformation upon ATP binding. Microtubule-bound heterododecamers then promote tubulin extraction from the microtubule prior to oligomer dissociation.
Classification and Mutation Prediction from Non-Small Cell Lung Cancer Histopathology Images using Deep Learning
Authors: Coudray Nicolas , Moreira Andre L. , Sakellaropoulos Theodore , Fenyö David , Razavian Narges , Tsirigos Aristotelis 
Published: October 2017

AbstractVisual analysis of histopathology slides of lung cell tissues is one of the main methods used by pathologists to assess the stage, types and sub-types of lung cancers. Adenocarcinoma and squamous cell carcinoma are two most prevalent sub-types of lung cancer, but their distinction can be challenging and time-consuming even for the expert eye. In this study, we trained a deep learning convolutional neural network (CNN) model (inception v3) on histopathology images obtained from The Cancer Genome Atlas (TCGA) to accurately classify whole-slide pathology images into adenocarcinoma, squamous cell carcinoma or normal lung tissue. Our method slightly outperforms a human pathologist, achieving better sensitivity and specificity, with ∼0.97 average Area Under the Curve (AUC) on a held-out population of whole-slide scans. Furthermore, we trained the neural network to predict the ten most commonly mutated genes in lung adenocarcinoma. We found that six of these genes – STK11, EGFR, FAT1, SETBP1, KRAS and TP53 – can be predicted from pathology images with an accuracy ranging from 0.733 to 0.856, as measured by the AUC on the held-out population. These findings suggest that deep learning models can offer both specialists and patients a fast, accurate and inexpensive detection of cancer types or gene mutations, and thus have a significant impact on cancer treatment.
Mitochondrial Methylation Two-Peak Profile Absent in Parkinson’s Disease Patient
Authors: Valente André X. C. N. , Liao Qiwen , Rohkin Guy , Bouça-Machado Raquel , Guedes Leonor Correia , Ferreira Joaquim J. , Lee Simon Ming-Yuen 
Published: October 2017

ABSTRACTWhole-mitochondrial genome methylation profiles were obtained for mitochondrial DNA (mtDNA) from blood samples of one sporadic Parkinson’s Disease (PD) patient and one healthy control donor, via Whole-Genome Next-Generation Bisulfite Sequencing. Methylation frequency was determined at 836 CpG sites out of the 1146 CpG sites in mtDNA (73% of the total). The control mtDNA methylation profile exhibited a two-peak frequency distribution, with most CpG sites showing either no methylation, or a methylation above 7%. Instead, the sporadic PD mtDNA methylation profile exhibited a generic bell-shaped frequency distribution. The data is suggestive of the bell-shaped methylation profile arising via a degradation towards randomness of the healthy sample two-peak methylation pattern. Overall, this finding provides a possible explanation for the repeated observation of PD-phenotypic characteristics in cybrid cell lines where solely the mtDNA originates from a PD patient. We discuss the finding in terms of the sporadic PD Hematopoietic Origin Theory (HOT).