Miracle-dz/UniFAR-FTUs huggingface dataset:
An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia

Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients. Experimental Design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n = 2,362, 65%) and validation set (n = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score. Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89–70.71, 95% confidence interval (CI)] and 64.76% (64.33–65.86, 95% CI) to 14.78% (10.91–17.41) and 18.11% (14.40–22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19–69.04, range) and 65.78 (65.20–66.28) for 2 years OS and LFS, respectively. Conclusions: The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. Clin Cancer Res; 23(21); 6478–86. ©2017 AACR.
The Frequency of Calcium Oscillations Induced by 5-HT, ACH, and KCl Determine the Contraction of Smooth Muscle Cells of Intrapulmonary Bronchioles

Increased resistance of airways or blood vessels within the lung is associated with asthma or pulmonary hypertension and results from contraction of smooth muscle cells (SMCs). To study the mechanisms regulating these contractions, we developed a mouse lung slice preparation containing bronchioles and arterioles and used phase-contrast and confocal microscopy to correlate the contractile responses with changes in [Ca2+]i of the SMCs. The airways are the focus of this study. The agonists, 5-hydroxytrypamine (5-HT) and acetylcholine (ACH) induced a concentration-dependent contraction of the airways. High concentrations of KCl induced twitching of the airway SMCs but had little effect on airway size. 5-HT and ACH induced asynchronous oscillations in [Ca2+]i that propagated as Ca2+ waves within the airway SMCs. The frequency of the Ca2+ oscillations was dependent on the agonist concentration and correlated with the extent of sustained airway contraction. In the absence of extracellular Ca2+ or in the presence of Ni2+, the frequency of the Ca2+ oscillations declined and the airway relaxed. By contrast, KCl induced low frequency Ca2+ oscillations that were associated with SMC twitching. Each KCl-induced Ca2+ oscillation consisted of a large Ca2+ wave that was preceded by multiple localized Ca2+ transients. KCl-induced responses were resistant to neurotransmitter blockers but were abolished by Ni2+ or nifedipine and the absence of extracellular Ca2+. Caffeine abolished the contractile effects of 5-HT, ACH, and KCl. These results indicate that (a) 5-HT and ACH induce airway SMC contraction by initiating Ca2+ oscillations, (b) KCl induces Ca2+ transients and twitching by overloading and releasing Ca2+ from intracellular stores, (c) a sustained, Ni2+-sensitive, influx of Ca2+ mediates the refilling of stores to maintain Ca2+ oscillations and, in turn, SMC contraction, and (d) the magnitude of sustained airway SMC contraction is regulated by the frequency of Ca2+ oscillations.
Ovine feto‐placental metabolism

Fetal growth depends on the transplacental nutrient supply, which, in turn, is determined partially by the consumption and production of nutrients by the uteroplacental tissues. In fetal sheep, the rates of growth and umbilical glucose uptake decline coincidently towards term in parallel with the normal prepartum rise in plasma cortisol. While cortisol is known to reduce growth in fetal sheep, its effects on the uteroplacental handling and delivery of nutrients remain unknown. Hence, this study, quantified the rates of umbilical uptake and uteroplacental consumption of nutrients in preterm fetuses infused with cortisol for 5 days to mimic the prepartum cortisol surge. Umbilical uptakes of glucose and lactate, but not oxygen, were significantly lower in cortisol‐ than saline‐infused fetuses, irrespective of whether values were expressed as absolute or weight‐specific rates. The rate of uteroplacental consumption of glucose, but not oxygen, was significantly higher in cortisol‐ than saline‐infused animals. Absolute rates of uteroplacental lactate production were lower in cortisol‐infused animals. When all data were combined, fetal plasma cortisol levels were positively correlated to uteroplacental glucose consumption and inversely related to umbilical glucose uptake. Cortisol treatment had no apparent effect on placental mRNA expression for the glucose transporters, GLUT‐1 and GLUT‐3. The results demonstrate that cortisol is physiological regulator of uteroplacental metabolism and nutrient delivery to the sheep fetus. These observations have important implications for fetal growth both in late gestation and during adverse intrauterine conditions, which raise fetal cortisol levels earlier in gestation.
Unlocking Patients with Mental Disorders Who Were in Restraints at Home: A National Follow-Up Study of China’s New Public Mental Health Initiatives

Background In 2005, China implemented a demonstration program known as “686” to scale-up nation-wide basic mental health services designed to improve access to evidence-based care and to promote human rights for people with severe mental disorders. As part of the 686 Program, teams “unlocked” and provided continuous mental health care to people with severe mental disorders who were found in restraints and largely untreated in their family homes. We implemented a nation-wide two-stage follow-up study to measure the effectiveness and sustainability of the “unlocking and treatment” intervention and its impact on the well-being of patients’ families. Methods 266 patients unlocked from 2005 in “686” demonstration sites across China were recruited in Stage One of the study in 2009. In 2012, 230 of the 266 cases were re-interviewed (the Stage Two study). Outcome measures included the patient medication adherence and social functioning, family burden ratings, and relocking rate. We utilized pre-post tests to analyze the changes over time following the unlocking efforts. Results 96% of patients were diagnosed with schizophrenia. Prior to unlocking, their total time locked ranged from two weeks to 28 years, with 32% having been locked multiple times. The number of persons regularly taking medicines increased from one person at the time of unlocking to 74% in 2009 and 76% in 2012. Pre-post tests showed sustained improvement in patient social functioning and significant reductions in family burden. Over 92% of patients remained free of restraints in 2012. Conclusion Practice-based evidence from our study suggests an important model for protecting the human rights of people with mental disorders and keeping them free of restraints can be achieved by providing accessible, community based mental health services with continuity of care. China’s “686” Program can inform similar efforts in low-resource settings where community locking of patients is practiced.
Attenuation of microRNA-16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy

Cyclins/retinoblastoma protein (pRb) pathway participates in cardiomyocyte hypertrophy. MicroRNAs (miRNAs), the endogenous small non‐coding RNAs, were recognized to play significant roles in cardiac hypertrophy. But, it remains unknown whether cyclin/Rb pathway is modulated by miRNAs during cardiac hypertrophy. This study investigates the potential role of microRNA‐16 (miR‐16) in modulating cyclin/Rb pathway during cardiomyocyte hypertrophy. An animal model of hypertrophy was established in a rat with abdominal aortic constriction (AAC), and in a mouse with transverse aortic constriction (TAC) and in a mouse with subcutaneous injection of phenylephrine (PE) respectively. In addition, a cell model of hypertrophy was also achieved based on PE‐promoted neonatal rat ventricular cardiomyocyte and based on Ang‐II‐induced neonatal mouse ventricular cardiomyocyte respectively. We demonstrated that miR‐16 expression was markedly decreased in hypertrophic myocardium and hypertrophic cardiomyocytes in rats and mice. Overexpression of miR‐16 suppressed rat cardiac hypertrophy and hypertrophic phenotype of cultured cardiomyocytes, and inhibition of miR‐16 induced a hypertrophic phenotype in cardiomyocytes. Expressions of cyclins D1, D2 and E1, and the phosphorylated pRb were increased in hypertrophic myocardium and hypertrophic cardiomyocytes, but could be reversed by enforced expression of miR‐16. Cyclins D1, D2 and E1, not pRb, were further validated to be modulated post‐transcriptionally by miR‐16. In addition, the signal transducer and activator of transcription‐3 and c‐Myc were activated during myocardial hypertrophy, and inhibitions of them prevented miR‐16 attenuation. Therefore, attenuation of miR‐16 provoke cardiomyocyte hypertrophy via derepressing the cyclins D1, D2 and E1, and activating cyclin/Rb pathway, revealing that miR‐16 might be a target to manage cardiac hypertrophy.
Reentrant Ventricular Arrhythmias in the Late Myocardial Infarction Period: 7. Effect of Verapamil and D‐600 and the Role of the “Slow Channel”

Reentrant ventricular arrhythmias (RVA) were analyzed in dogs 3–7 days after ligation of the anterior descending coronary artery using averaged “composite” recordings of electrical activity of reentrant pathways (RP) from the epicardial surface of the infarction zone (IZ). Verapamil (V) and D-600 (D) (0.2–0.5 mg/kg i.v.) resulted in slight-to-moderate improvement of conduction in RP with abolition of spontaneous RVA and RVA initiated by premature depolarizations. The effect of V was not blocked by pretreatment with propranolol (0.5 mg/kg i.v.). Using a standard microelectrode technique aad strips of epicardial muscle from the IZ, D (0.5–1 × 10−6 g/ml) slightly improved the upstroke velocity and membrane responses of depressed ischemic cells. In contrast, tetrodotoxin (5 × 10−7 g/ml) further depressed or abolished action potentials of ischemic cells. We conclude: 1) the moderate antiarrhythmic effect of V and D on RVA is the result of improved conduction in RP; 2) this action is partly explained by improvement of a depressed sodium channel and is not related to catecholamine release; 3) slow-response action potentials play no significant role in the genesis of ischemia-related RVA, which probably results from depression of the fast response.
Impact of donor and recipient CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus dosage requirements and rejection in Caucasian Spanish liver transplant patients

Studies of liver transplant (LT) patients, mainly in Asians, have evaluated the influence of the CYP3A5*1 allele and P‐glycoprotein gene ABCB1 on tacrolimus pharmacokinetics or biopsy‐proven acute rejection (BPAR) incidence, with no conclusive results. To investigate these issues, 98 Caucasian Spanish LT patients with tacrolimus, mycophenolate mofetil and steroids and 88 cadaveric donors were genotyped for the SNPs CYP3A5 6986G>A, ABCB1 1236C>T, ABCB1 2677G>A/T and ABCB1 3435C>T;. On day 7 post‐LT, patients with a native CYP3A5*1 allele had significantly lower tacrolimus trough concentrations C0 (P = .03) and dose‐adjusted concentrations C0/D (P = .02) than CYP3A5 *3/*3 homozygotes. Three months post‐LT, patients carrying a liver with CYP3A5*1 had significantly lower C0/D (P = .03) and took significantly higher tacrolimus doses (P = .03) than the corresponding *3/*3 homozygotes. ABCB1 SNPs showed no significant association with tacrolimus variables. The 3‐month incidence of BPAR was 10.2%, with no statistically significant differences related to CYP3A5 (14.3% in expresser vs. 9.5% in non‐expresser) or ABCB1 genotype of either patient or donor. We conclude that in Caucasian Spanish LT patients, a native or graft‐borne CYP3A5*1 allele tends to lower tacrolimus concentrations and increase dosage needs, but has no significant impact on the incidence of BPAR.
Estrogen receptor-mediated neuroprotection: The role of the Alzheimer’s disease-related gene seladin-1

Experimental evidence supports a protective role of estrogen in the brain. According to the fact that Alzheimer’s disease (AD) is more common in postmenopausal women, estrogen treatment has been proposed. However, there is no general consensus on the beneficial effect of estrogen or selective estrogen receptor modulators in preventing or treating AD. It has to be said that several factors may markedly affect the efficacy of the treatment. A few years ago, the seladin-1 gene (for selective Alzheimer’s disease indicator-1) has been isolated and found to be down-regulated in brain regions affected by AD. Seladin-1 has been found to be identical to the gene encoding the enzyme 3-beta-hydroxysterol delta-24-reductase, involved in the cholesterol biosynthetic pathway, which confers protection against β-amyloid-mediated toxicity and from oxidative stress, and is an effective inhibitor of caspase-3 activity, a key mediator of apoptosis. Interestingly, we found earlier that the expression of this gene is up-regulated by estrogen. Furthermore, our very recent data support the hypothesis that seladin-1 is a mediator of the neuroprotective effects of estrogen. This review will summarize the current knowledge regarding the neuroprotective effects of seladin-1 and the relationship between this protein and estrogen.
Overview of herd and CAEV status in dwarf goats in South Tyrol, Italy

Summary The analysis of the electronic data processing proved that 323 dwarf goats older than 6 months from 165 farms were kept in 63 of the 116 communes of South Tyrol. The number of dwarf goats maintained ranged from 1 to 19 animals, the average farm size revealed to be of 2 dwarf goats/farm. 47 animals were aged between 6 months and 1 year (AG1), 97 were between 1–2 years of age (AG2) and 179 were aged older than 2 years (AG3). The mean age amounted to 3.8 years, the age limit being 10 years. 235 animals were female and 88 animals were male (sex ratio 2.7:1). 187 animals (57.9%) were born between November and April and 136 animals (42.1%) were born between May and October. 13 animals (4.0%) proved to possess antibodies against CAEV in a serological examination performed with ELISA. The herd seroprevalence was 6.1% (10 positive farms). The seropositivity did not vary significantly in the different age groups (AG1: 4.3%; AG2: 4.1%; AG3: 3.9%). The seroprevalence of animals born outdoors between November and April (5.9%) did not differ significantly from those born indoors between May and October (1.5%). The seroprevalence of the female animals (3.4%) did not vary significantly from that of the male goats (5.7%). The low seroprevalence ascertained in the dwarf goats in South Tyrol is due to the non‐existing milk production, the marginal contact among each other as well as the sparse animal trade. This study should prompt adequate means of control to be established, so that the introduction of positive animals can be prevented. An eradication programme would be advisable, due to the low disease prevalence and its chances to be successfully implemented.
Regional Boundary Observability for Semi-Linear Systems Approach and Simulation

The paper aims at extending the notion of regional boundary observability developed for linear systems to the semilinear parabolic case. We give definitions and some properties of this notion and we show that under some hypothesis, the regional boundary observability guaranted.We describe two approaches where the first is based on HUM method combined with fixed point techniques and the second uses sectorial property. The obtained results are illustrated through numerical examples and simulations.
Clinical Significance of a Point Mutation in DNA Polymerase Beta (POLB) Gene in Gastric Cancer

Gastric cancer (GC) is a major cause of global cancer mortality. Genetic variations in DNA repair genes can modulate DNA repair capability and, consequently, have been associated with risk of developing cancer. We have previously identified a T to C point mutation at nucleotide 889 (T889C) in DNA polymerase beta (POLB) gene, a key enzyme involved in base excision repair in primary GCs. The purpose of this study was to evaluate the mutation and expression of POLB in a larger cohort and to identify possible prognostic roles of the POLB alterations in GC. Primary GC specimens and their matched normal adjacent tissues were collected at the time of surgery. DNA, RNA and protein samples were isolated from GC specimens and cell lines. Mutations were detected by PCR-RFLP/DHPLC and sequencing analysis. POLB gene expression was examined by RT-PCR, tissue microarray, Western blotting and immunofluorescence assays. The function of the mutation was evaluated by chemosensitivity, MTT, Transwell matrigel invasion and host cell reactivation assays. The T889C mutation was detected in 18 (10.17%) of 177 GC patients. And the T889C mutation was associated with POLB overexpression, lymph nodes metastases and poor tumor differentiation. In addition, patients with- the mutation had significantly shorter survival time than those without-, following postoperative chemotherapy. Furthermore, cell lines with T889C mutation in POLB gene were more resistant to the treatment of 5-fluorouracil, cisplatin and epirubicin than those with wild type POLB. Forced expression of POLB gene with T889C mutation resulted in enhanced cell proliferation, invasion and resistance to anticancer drugs, along with increased DNA repair capability. These results suggest that POLB gene with T889C mutation in surgically resected primary gastric tissues may be clinically useful for predicting responsiveness to chemotherapy in patients with GC. The POLB gene alteration may serve as a prognostic biomarker for GC.
Purinergic-independent Calcium Signaling Mediates Recovery from Hepatocellular Swelling

Swelling of hepatocytes and other epithelia activates volume-sensitive ion channels that facilitate fluid and electrolyte efflux to restore cell volume, but the responsible signaling pathways are incompletely defined. Previous work in model HTC rat hepatoma cells has indicated that swelling elicits ATP release, which stimulates P2 receptors and activates Cl− channels, and that this mechanism is essential for hepatocellular volume recovery. Since P2 receptors are generally coupled to Ca2+ signaling pathways, we determined whether hepatocellular swelling affected cytosolic [Ca2+], and if this involved a purinergic mechanism. Exposure of HTC cells to hypotonic media evoked an increase in cytosolic [Ca2+], which was followed by activation of K+ and Cl−currents. Maneuvers that interfered with swelling-induced increases in cytosolic [Ca2+], including extracellular Ca2+ removal and intracellular Ca2+ store depletion with thapsigargin, inhibited activation of membrane currents and volume recovery. However, the swelling-induced increases in cytosolic [Ca2+] were unaffected by either extracellular ATP depletion with apyrase or blockade of P2 receptors with suramin. These findings indicate that swelling elicits an increase in hepatocellular Ca2+, which is essential for ion channel activation and volume recovery, but that this increase does not stem from activation of volume-sensitive P2 receptors. Collectively, these observations imply that regulatory responses to hepatocellular swelling involve a dual requirement for a purinergic-independent Ca2+ signaling cascade and a Ca2+-independent purinergic signaling pathway.
Asymptotically Optimal Covering Designs

A (v,k,t)covering design, orcovering, is a family ofk-subsets, calledblocks, chosen from av-set, such that eacht-subset is contained in at least one of the blocks. The number of blocks is the covering'ssize, and the minimum size of such a covering is denoted byC(v,k,t). It is easy to see that a covering must contain at least (tv)/(tk) blocks, and in 1985 Rodl 5] proved a long-standing conjecture of Erdos and Hanani 3] that for fixedkandt, coverings of size (tv)/(tk)(1+o(1)) exist (asv? ∞). An earlier paper by the first three authors 4] gave new methods for constructing good coverings, and gave tables of upper bounds onC(v,k,t) for smallv,k, andt. The present paper shows that two of those constructions are asymptotically optimal: For fixedkandt, the size of the coverings constructed matches Rodl's bound. The paper also makes theo(1) error bound explicit, and gives some evidence for a much stronger bound.
Bagging and Boosting Classification Trees to Predict Churn

In this article, the authors explore the bagging and boosting classification techniques. They apply the two techniques to a customer database of an anonymous U.S. wireless telecommunications company, and both significantly improve accuracy in predicting churn. This higher predictive performance could ultimately lead to incremental profits for companies that use these methods. Furthermore, the results recommend the use of a balanced sampling scheme when predicting a rare event from large data sets, but this requires an appropriate bias correction.
CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart

ABSTRACT Cyclin dependent kinase (Cdk)9 acts through the positive transcription elongation factor-b (P-TEFb) complex to activate and expand transcription through RNA polymerase II. It has also been shown to regulate cardiomyocyte hypertrophy, with recent evidence linking it to cardiomyocyte proliferation. We hypothesised that modification of CDK9 activity could both impair and enhance the cardiac response to injury by modifying cardiomyocyte proliferation. Cdk9 expression and activity were inhibited in the zebrafish (Danio rerio) embryo. We show that dephosphorylation of residue Ser2 on the C-terminal domain of RNA polymerase II is associated with impaired cardiac structure and function, and cardiomyocyte proliferation and also results in impaired functional recovery following cardiac laser injury. In contrast, de-repression of Cdk9 activity, through knockdown of La-related protein (Larp7) increases phosphorylation of Ser2 in RNA polymerase II and increases cardiomyocyte proliferation. Larp7 knockdown rescued the structural and functional phenotype associated with knockdown of Cdk9. The balance of Cdk9 and Larp7 plays a key role in cardiomyocyte proliferation and response to injury. Larp7 represents a potentially novel therapeutic target to promote cardiomyocyte proliferation and recovery from injury. Summary: The balance of CDK9 and LARP7 plays a key role in cardiomyocyte proliferation and response to injury. LARP7 represents a potentially novel therapeutic target in promoting recovery from injury.