Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and safety of single-agent pralatrexate for treatment of angioimmunoblastic T-cell lymphoma after failure of first line therapy: a pooled analysis

Abstract Angioimmunoblastic T-cell lymphoma (AITL) is a histological subtype of peripheral T-cell lymphoma associated with a poor prognosis. This post-hoc pooled analysis aims to provide insight about the efficacy of pralatrexate monotherapy in a subset of twenty-nine patients with relapsed or refractory (r/r) AITL drawn from two prospective registration trials completed in China and Japan. After a median of two prior lines of therapy, an overall response rate of 52% (15/29 patients; 95% CI 0.34, 0.70) was demonstrated. The estimated median duration of response, progression free survival (PFS) and overall survival (OS) were 6.4 months (196 days), 5.0 months (151 days), and 18.0 months (548 days), respectively. Grades 1–3 mucositis was observed in twenty-three patients (79.3%); and hemato-toxicity in twenty-six (89.7%) patients. Results of this analysis corroborate with data from two previously reported US retrospective cohorts, supporting the potential benefits of pralatrexate monotherapy in patients with r/r AITL.
Effect of Telehealth Extended Care for Maintenance of Weight Loss in Rural US Communities

Key Points Question Does extended care for obesity management delivered remotely via individual or group telephone counseling in rural communities improve the maintenance of weight loss compared with an education program about weight gain prevention? Findings In this randomized clinical trial of 445 participants who completed a lifestyle weight-loss intervention, extended care delivered remotely via individual telephone counseling decreased weight regain and increased the proportion of participants who achieved clinically meaningful weight losses compared with education alone. Meaning These findings suggest that extended care delivered remotely via individual telephone counseling may reduce weight regain and increase the proportion of participants who achieve long-term weight reductions of at least 10%.
Clinical implication and usefulness of de novo EGFR T790M mutation in lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutation

ABSTRACT Detection rate of de novo EGFR T790 M mutation was increased up to 80% through recent ultrasensitive detection methods. Here, we investigated the clinical significance and its usefulness of detecting de novo EGFR T790 M using ultrasensitive droplet-digital polymerase chain reaction (ddPCR) method. In total, 102 cases diagnosed as lung adenocarcinoma with EGFR-tyrosine kinase inhibitor (TKI) sensitizing mutations (mEGFR) and had been treated with 1st ~ 2nd generation EGFR-TKI alone were enrolled for this study. De novo T790 M status was tested using the tissues at the initial diagnosis and positivity was defined as the ratio of T790 M/wild-type copies over 0.00294 by ddPCR. Seventy patients (68.6%) harbored the de novo T790 M. De novo T790 M was more frequently detected in cases with EGFR L858 R mutation than those with EGFR exon 19 deletion (E19d) mutations (P = 0.024). Forty-three patients underwent rebiopsy due to disease progression. The cases who experienced progression due to acquired T790 M were more likely to have E19d at initial diagnosis and the presence of de novo T790 M and the ratio of T790 M/wild-type copies did not relate to the emergence of acquired T790 M. On the other hand, the cases with a longer duration of disease-control by EGFR-TKI had higher change to get acquired T790 M mutation (P-value = 0.040). The presence of de novo T790 M has limitation in predicting disease progression by acquired T790 M, suggesting that identifying de novo T790 M through the ultrasensitive methods may not be necessary identifying patients who would be beneficial by 3rd-generation EGFR-TKI as the 1st line treatment.
Duodenal eosinophils as predictors of symptoms in coeliac disease: a comparison of coeliac disease and non-coeliac dyspeptic patients with controls

Abstract Introduction: Duodenal eosinophilia is a key feature of functional dyspepsia, particularly in those with early satiety. Duodenal eosinophilia is also recognised in coeliac disease, although its relevance to symptoms is not understood. We aimed to determine if duodenal eosinophilia is present in patients with coeliac disease presenting with dyspepsia, and whether other histological characteristics were associated with clinical features on presentation. Methods: The coeliac study population comprised 61 patients with a new presentation of coeliac disease to a single centre from 2003 to 2013. A standard symptom assessment was documented for all patients. The control population (55 adults) presenting for endoscopy without coeliac disease was drawn from the same centre with similar demographics for age and gender. Duodenal biopsies from both groups were assessed for eosinophil counts and histological features. Results: Dyspepsia was present in 18.0% of coeliac patients and early satiety in 24.6%. The eosinophil counts were significantly higher in the stomach (12.1/mm2 vs. 4.0/mm2, p < .001) and duodenum (60.4/mm2 vs. 18.0/mm2, p < .001) of coeliac patients compared with controls. There was no significant difference in the mean duodenal eosinophil count in coeliac disease with and without early satiety (55.4/mm2 vs. 66.9/mm2, p = .51). Duodenal eosinophilia was not associated with the severity of coeliac enteropathy. The degree of villous atrophy was associated with iron deficiency at presentation (p = .01), but not symptoms. Conclusions: Although duodenal eosinophil counts are higher in coeliac disease than controls, we were not able to demonstrate an association with presenting symptoms or markers of disease severity.
ShakeDrop regularization

This paper proposes a powerful regularization method named \textit{ShakeDrop regularization}. ShakeDrop is inspired by Shake-Shake regularization that decreases error rates by disturbing learning. While Shake-Shake can be applied to only ResNeXt which has multiple branches, ShakeDrop can be applied to not only ResNeXt but also ResNet, Wide ResNet and PyramidNet in a memory efficient way. Important and interesting feature of ShakeDrop is that it strongly disturbs learning by multiplying even a negative factor to the output of a convolutional layer in the forward training pass. The effectiveness of ShakeDrop is confirmed by experiments on CIFAR-10/100 and Tiny ImageNet datasets.
Effect of salbutamol on neuromuscular junction function and structure in a mouse model of DOK7 congenital myasthenia

Abstract Congenital myasthenic syndromes (CMS) are characterized by fatigable muscle weakness resulting from impaired neuromuscular transmission. β2-adrenergic agonists are an effective treatment for DOK7-CMS. DOK7 is a component within the AGRN-LRP4-MUSK-DOK7 signalling pathway that is key for the formation and maintenance of the synaptic structure of the neuromuscular junction (NMJ). The precise mechanism of action of β2-adrenergic agonists at the NMJ is not fully understood. In this study, we investigated whether β2-adrenergic agonists improve both neurotransmission and structural integrity of the NMJ in a mouse model of DOK7-CMS. Ex-vivo electrophysiological techniques and microscopy of the NMJ were used to study the effect of salbutamol, a β2-adrenergic agonist, on synaptic structure and function. DOK7-CMS model mice displayed a severe phenotype with reduced weight gain and perinatal lethality. Salbutamol treatment improved weight gain and survival in DOK7 myasthenic mice. Model animals had fewer active NMJs, detectable by endplate recordings, compared with age-matched wild-type littermates. Salbutamol treatment increased the number of detectable NMJs during endplate recording. Correspondingly, model mice had fewer acetylcholine receptor-stained NMJs detected by fluorescent labelling, but following salbutamol treatment an increased number were detectable. The data demonstrate that salbutamol can prolong survival and increase NMJ number in a severe model of DOK7-CMS.
An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.

INTRODUCTION Multikinase inhibitors have clinical activity in radioactive iodine-refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. METHODS Assessment of responses and toxicities, and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy, were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining PR), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided =0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. RESULTS From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; anther was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included 1 death (thromboembolic) deemed possibly pazopanib-associated. Twenty two confirmed RECIST partial responses (PRs) resulted (36.7%, 95% CI: 24.6-50.1%); mean administered 4 week cycles was 10. Among 44 fully accessible patients, Tg nadir was greater among the 20 attaining PR (median: -86.8%; IQR: -90.7 to -70.9%) compared to the 28 who did not (median: -69.0%; IQR: -78.1 to -27.7%, Wilcoxon rank-sum test: p=0.002). However, the difference in the proportion of PRs among those whose Tg fell >50% after cycle 1 versus those that did not were not significantly correlated (-23.5%, 95%CI: -55.3% to 8.3%; Fisher's test p-value =0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. CONCLUSIONS This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status.
The association of schizotypal traits with Prepulse Inhibition: a double approach exploration

ABSTRACT Introduction: According to the fully-dimensional approach, schizotypy is a personality trait present in the population in a continuous manner while the quasi-dimensional approach emphasises its extreme presentations. In this study we examined the relationship between sensorimotor gating, a core risk-index of the schizophrenia-spectrum, and four schizotypal factors in a dimensional-wise and a dichotomising-wise approach. Methods: Two-hundred and eighty-three participants were assessed with the Schizotypal Personality Questionnaire and were tested for Prepulse Inhibition (PPI). Associations between the schizotypal factors and startle measures were examined with stepwise regressions (dimensional-wise approach). Individuals in the lower 20% or the upper 20% for each schizotypal factor were identified and between-group comparisons were conducted (dichotomising-wise approach). Results: We found that with both approaches, only high paranoid or negative schizotypy were associated with reduced PPI. The low negative schizotypy group had prolonged onset and peak latencies, indicating that prolonged stimulus detection accompanies superior sensorimotor gating in this group. Conclusions: The findings suggest that although differentiating the effects of the various schizotypal factors is primary, the approach employed is secondary. The study also adds evidence in the literature supporting PPI as a useful endophenotypic marker of the schizophrenia-spectrum and highlights the contribution of specific aspects of schizotypy.
Investigating class conversations with classtalk: a study with tangible object prototypes in a primary school

Interactive tangible objects can help orchestrate conversations in school classes. If such tangibles are created with a meta-design approach, for the specific context of their users, they evolve according to their usage. Specifically, tangible object prototypes are created; prototypes are adopted by their users in ecological studies; their usage is reflected over by users and designers to investigate design possibilities, which are rapidly prototyped and again adopted by users. This paper reports on the meta-design and latest evolution of ClassTalk, a tangible for conversations in primary school classes. It shows how new design ideas emerged by making users adopt ClassTalk prototypes, and by moving designers into users' context.
Pharmacokinetics and bioavailability of tildipirosin in rabbits following single-dose intravenous and intramuscular administration.

The objective of this study was to determine the pharmacokinetics of tildipirosin in rabbits after a single intravenous (i.v.) and intramuscular (i.m.) injection at a dose of 4 mg/kg. Twelve white New Zealand rabbits were assigned to a randomized, parallel trial design. Blood samples were collected prior to administration and up to 14 days postadministration. Plasma concentrations of tildipirosin were quantified using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The pharmacokinetic parameters were calculated using a noncompartmental model in WinNonlin 5.2 software. Following i.v. and i.m. administration, the elimination half-life (T1/2λ ) was 81.17 ± 9.28 and 96.68 ± 15.37 hr, respectively, and the mean residence time (MRTlast ) was 65.44 ± 10.89 and 67.06 ± 10.49 hr, respectively. After i.v. injection, the plasma clearance rate (Cl) and volume of distribution at steady state (Vdss ) were 0.28 ± 0.10 L kg-1 h-1 and 17.78 ± 5.15 L/kg, respectively. The maximum plasma concentration (Cmax ) and time to reach maximum plasma concentration (Tmax ) after i.m. administration were 836.2 ± 117.9 ng/ml and 0.33 ± 0.17 hr, respectively. The absolute bioavailability of i.m. administration was 105.4%. Tildipirosin shows favorable pharmacokinetic characteristics in rabbits, with fast absorption, extensive distribution, and high bioavailability. These findings suggest that tildipirosin might be a potential drug for the prevention and treatment of respiratory diseases in rabbits.
Correlation of serum BNP and ET-1 levels with cardiac pump function and ventricular remodeling in patients with heart failure.

This study aimed to explore the correlation of serum brain natriuretic peptide (BNP) and endothelin-1 (ET-1) levels with cardiac pump function and ventricular remodeling in patients with heart failure. Eighty-one patients with chronic heart failure admitted to our hospital from March 2016 to November 2018 were enrolled as the study group, and 80 healthy individuals as the control group. Immunofluorescence was used for the detection of serum BNP, ELISA for serum ET-1, and ultrasound for related indexes of cardiac pump function and ventricular remodeling. Moreover, correlation analysis and prognostic factors analysis were carried out. Both BNP and ET-1 were highly expressed in the serum of patients with heart failure. Cardiac pump function related indexes (left atrial ejection fraction (LAEF), left atrial passive ejection fraction (LAPEF), and left atrial active ejection fraction (LAAEF)) in the study group were significantly lower than those in the control group (P< 0.05). While ventricular remodeling related indexes (left ventricular end-diastolic diameter (LVEDD), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPM), and left ventricular mass index (LVMI) in the study group were significantly higher than those in the control group (P< 0.05). BNP and ET-1 were negatively correlated with LAEF, LAPEF and LAAEF (P< 0.05), and were positively correlated with LVEDD, IVST, LVPM and LVMI (P< 0.05). The expressions of serum BNP and ET-1 were higher in patients with cardiovascular events than those without cardiovascular events. Hypertension, hyponatremia, high BNP, high ET-1, NYHA classification, decreased LAEF and increased LVEDD were independent risk factors for cardiovascular adverse events. Serum BNP and ET-1 are closely related to cardiac pump function and ventricular remodeling in patients with heart failure and can be used as important reference indexes for prognosis evaluation.
Endostatin as a Mediator Between Endothelial Function and Cognitive Performance in Those at Risk for Vascular Cognitive Impairment

Background: Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium. Objective: The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients. Methods: In 50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment. Results: Endostatin, but not vascular endothelial growth factor, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment. Conclusion: These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease.
Nitrate reductase is required for salicylic acid-induced water stress tolerance of pepper by upraising the AsA-GSH pathway and glyoxalase system.

A trial was conducted to evaluate whether nitrate reductase (NR) participates in salicylic acid (SA)-improved water stress (WS) tolerance in pepper plants. Before starting WS treatment, 0.5 mM SA was applied to half of well-watered (WW) and WS-plants as a foliar spray once a day for a week. Soil water holding capacity was maintained at 40 and 80% of the full water storing capacity for WS and well-watered (WW) plants, respectively. Water stress caused substantial decreases in total plant dry weight, Fv/Fm, chlorophyll a and b, relative water content, leaf water potential (ΨI) by 53, 37, 49, 21, 36 and 33%, respectively relative to control, but significant increases in malondialdehyde (MDA), hydrogen peroxide (H2 O2 ), electrolyte leakage (EL), methylglyoxal (MG), proline, key antioxidant enzymes' activities, NO and NR activity. The SA reduced oxidative stress, but improved antioxidant defence system, ascorbate-glutathione (AsA-GSH) cycle enzymes, glyoxalase system-related enzymes, glyoxalase I (Gly I) and glyoxalase II (Gly II), plant growth, photosynthetic traits, NO, NR and proline. SA-induced WS tolerance was further improved by supplementation of sodium nitroprusside (SNP), a donor of NO. NR inhibitor, sodium tungstate (ST) was applied in conjunction with SA and SA+SNP to the WW and WS-plants to assess whether NR contributes to SA-improved WS tolerance. ST abolished the beneficial effects of SA by reducing NO and NR activity in WS-pepper, but the application of SNP along with SA+ST reversed negative effects of ST, showing that NO and NR are jointly needed for SA-induced WS tolerance of pepper plants. This article is protected by copyright. All rights reserved.
Poor Clinical Outcomes and Immunoevasive Contexture in Intratumoral IL-10-Producing Macrophages Enriched Gastric Cancer Patients

Objective: To investigate the clinical significance of IL-10+ tumor-associated macrophages (TAMs) in gastric cancer. Background: Due to the plasticity and diversity of TAMs, it is necessary to phenotypically and functionally classify subsets of TAMs to better understand the critical role of TAMs in cancer progression. TAMs expressing interleukin-10 (IL-10) have been found to facilitate immune evasion in many malignancies, but the role of IL-10+ TAMs in gastric cancer remains obscure. Methods: Four hundred and sixty-eight tumor tissue microarray specimens, 52 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, and data of 298 gastric cancer patients from the Cancer Genome Atlas (TCGA) were analyzed. IL-10+ TAM level and immune contexture were examined by CIBERSORT, immunohistochemistry, and flow cytometry. Clinical outcomes were analyzed by Kaplan–Meier curves and Cox model. Results: Gastric cancer patients with high IL-10+ TAM infiltration exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. IL-10+ TAM infiltration yielded an immunoevasive tumor microenvironment featured by regulatory T cell infiltration and CD8+ T cell dysfunction. The combinational analysis of IL-10+ TAM and CD8+ T cell infiltration stratified patients into distinct risk groups with different clinical outcomes. Moreover, IL-10+ TAM infiltration was correlated with tumor-intrinsic characteristics including EBV status, PD-L1 expression, and genome stability in gastric cancer. Conclusions: This study revealed that IL-10+ TAMs might drive an immunoevasive microenvironment and determine poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy, indicating IL-10+ TAMs could be applied as a potential target for immunotherapeutic approach in gastric cancer.