Miracle-dz/UniFAR-FTUs huggingface dataset:
Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols

ABL-class fusions other than BCR-ABL1 characterize around 2–3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10−4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).
Prostate cancer incidence and mortality in the Baltic states, Belarus, the Russian Federation and Ukraine

Background Prostate cancer incidence varies internationally largely attributable to differences in prostate-specific antigen (PSA) use. The aim of this study was to provide the most recent detailed international epidemiological comparison of prostate cancer incidence and mortality in six north-eastern European countries (Belarus, Estonia, Latvia, Lithuania, the Russian Federation and Ukraine). Methods The number of incident prostate cancer cases was obtained from the countries national cancer registries. Prostate cancer mortality and corresponding population data were extracted from the WHO Mortality Database. Age-specific and age-standardised incidence and mortality rates were calculated (European Standard). The joinpoint regression model was used to provide an average annual percentage change and to detect points in time where significant changes in trends occurred. The observation period was between 13 (Ukraine) and 48 (Estonia) years regarding incidence and around 30 years regarding mortality. Results The comparison of prostate cancer incidence in six European countries showed almost sixfold differences in the age-adjusted rates in most recent years with highest incidence rates in Lithuania and Estonia. Through the observation period, overall a continuous rise was seen in incidence in all countries and a continuous rise in mortality, with a stabilisation in Estonia and a decrease in Lithuania in recent years. Data limitations included a descriptive design using ecological data. Conclusions A widespread use of PSA testing seems to be responsible for the changes in the epidemiology of the disease in north-eastern European countries. Substantial variation in the incidence of prostate cancer in the Baltic states suggests the possibility that PSA performance and utilisation spread have had a major influence on observed incidence trends, with a lack of effect on prostate cancer mortality.
Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity: a translational study.

AIMS Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood-brain barrier (BBB) is crucially involved in ischaemia/reperfusion (I/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke. METHODS AND RESULTS SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6-/-) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6-/- animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6-/- mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia/reoxygenation (H/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I/R. Further, SIRT6-silenced HBMVECs exposed to H/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome. CONCLUSION Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation.
Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial.

Importance To date, single-agent programmed cell death 1 protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint blockade has shown limited activity in recurrent epithelial ovarian cancer. Combination strategies of PD-1/PD-L1 inhibition with antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a potential therapeutic opportunity in this disease. Objective To evaluate the activity of combined nivolumab and bevacizumab in women with relapsed ovarian cancer. Design, Setting, and Participants A single-arm, phase 2 study enrolled patients between February 8, 2017, and December 29, 2017, at 2 sites in the United States; the primary data analysis was completed July 27, 2018. Thirty-eight women with relapsed epithelial ovarian cancer were enrolled in this study. Participants had disease recurrence within 12 months of their last platinum-based therapy and had received between 1 and 3 lines of prior therapy. Interventions Participants received intravenous nivolumab and intravenous bevacizumab once every 2 weeks. Main Outcome and Measures The primary end point was objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors 1.1. Secondary end points included evaluation of the ORR by platinum sensitivity, assessment of progression-free survival, assessment of safety data, and investigation of the association of tumor PD-L1 with response to therapy. Results Of the 38 women enrolled, 18 had platinum-resistant and 20 had platinum-sensitive disease; mean (SD) age was 63.0 (9.1) years. Eleven patients experienced a confirmed response to nivolumab with bevacizumab (ORR, 28.9%; 95% exact binomial CI, 15.4%-45.9%), with 1 additional unconfirmed response. The ORR was 40.0% (19.1%-64.0%) in platinum-sensitive and 16.7% (95% CI 3.6%-41.4%) in platinum-resistant participants. Thirty-four participants (89.5%) experienced at least 1 treatment-related adverse event; 9 participants (23.7%) experienced a grade 3 or higher treatment-related adverse event. Median progression-free survival was 8.1 months (95% CI, 6.3-14.7 months). In 36 histologic samples for which PD-L1 testing could be performed, 22 samples (61.1%) had a PD-L1 tumoral percentage less than 1, and 14 samples (38.9%) had a PD-L1 tumoral percentage of 1 or greater. Ten responses occurred in patients with PD-L1 tumor percentage less than 1, and 2 in patients with PD-L1 tumor percentages of 1 or greater. Conclusions and Relevance The nivolumab with bevacizumab combination appeared to show activity in patients with relapsed ovarian cancer, with greater activity in the platinum-sensitive setting. Alternative combinational strategies may be necessary in the platinum-resistant setting.
Effector mining from the Erysiphe pisi haustorial transcriptome identifies novel candidates involved in pea powdery mildew pathogenesis

Summary Pea powdery mildew (PM) is an important fungal disease caused by an obligate biotroph, Erysiphe pisi (Ep), which significantly impacts pea production worldwide. The phytopathogen secretes a plethora of effectors, primarily through specialized infection structures termed haustoria, to establish a dynamic relationship with its host. To identify Ep effector candidates, a cDNA library of enriched haustoria from Ep‐infected pea leaves was sequenced. The Ep transcriptome encodes 622 Ep candidate secreted proteins (CSPs), of which 167 were predicted to be candidate secreted effector proteins (CSEPs). Phylogenetic analysis indicates that Ep CSEPs are highly diverse, but, unlike cereal PM CSEPs, exhibit extensive sequence similarity with effectors from other PMs. Quantitative real‐time PCR of a subset of EpCSEP/CSPs revealed that the majority are preferentially expressed in haustoria and exhibit infection stage–specific expression patterns. The functional roles of EpCSEP001, EpCSEP009 and EpCSP083 were probed by host‐induced gene silencing (HIGS) via a double‐stranded (ds) RNA‐mediated RNAi approach. Foliar application of individual EpCSEP/CSP dsRNAs resulted in a marked reduction in PM disease symptoms. These findings were consistent with microscopic and molecular studies, suggesting that these Ep CSEP/CSPs play important roles in pea PM pathogenesis. Homology modelling revealed that EpCSEP001 and EpCSEP009 are analogous to fungal ribonucleases and belong to the RALPH family of effectors. This is the first study to identify and functionally validate candidate effectors from the agriculturally relevant pea PM, and highlights the utility of transcriptomics and HIGS to elucidate the key proteins associated with Ep pathogenesis.
Normalization of Early Isometric Force Production as a Percentage of Peak Force During Multijoint Isometric Assessment.

PURPOSE To determine the reliability of early force production (50, 100, 150, 200, and 250 ms) relative to peak force (PF) during an isometric mid-thigh pull and to assess the relationships between these variables. METHODS Male collegiate athletes (N = 29; age 21.1 [2.9] y, height 1.71 [0.07] m, body mass 71.3 [13.6] kg) performed isometric mid-thigh pulls during 2 separate testing sessions. Net PF and net force produced at each epoch were calculated. Within- and between-session reliabilities were determined using intraclass correlation coefficients and coefficient of variation percentages. In addition, Pearson correlation coefficients and coefficient of determination were calculated to examine the relationships between PF and time-specific force production. RESULTS Net PF and time-specific force demonstrated very high to almost perfect reliability both within and between sessions (intraclass correlation coefficients .82-.97; coefficient of variation percentages 0.35%-1.23%). Similarly, time-specific force expressed as a percentage of PF demonstrated very high to almost perfect reliability both within and between sessions (intraclass correlation coefficients .76-.86; coefficient of variation percentages 0.32%-2.51%). Strong to nearly perfect relationships (r = .615-.881) exist between net PF and time-specific net force, with relationships improving over longer epochs. CONCLUSION Based on the smallest detectable difference, a change in force at 50 milliseconds expressed relative to PF > 10% and early force production (100, 150, 200, and 250 ms) expressed relative to PF of >2% should be considered meaningful. Expressing early force production as a percentage of PF is reliable and may provide greater insight into the adaptations to the previous training phase than PF alone.
Reducing Health Care Disparities in Sickle Cell Disease: A Review

Sickle cell disease (SCD) is an inherited blood disorder most common among African American and Hispanic American persons. The disease can cause substantial, long-term, and costly health problems, including infections, stroke, and kidney failure, many of which can reduce life expectancy. Disparities in receiving health care among African Americans and other racial/ethnic minority groups in the United States are well known and directly related to poor outcomes associated with SCD. As an orphan disease—one that affects <200 000 persons nationwide—SCD does not receive the research funding and pharmaceutical investment directed to other orphan diseases. For example, cystic fibrosis affects fewer than half the number of persons but receives 3.5 times the funding from the National Institutes of Health and 440 times the funding from national foundations. In this review, we discuss the health inequities affecting persons with SCD, describe programs intended to improve their care, and identify actions that could be taken to further reduce these inequities, improve care, control treatment costs, and ease the burden of disease.
[Childhood trauma and its correlation with resilience among primary and middle school students in Wuhan city in 2015].

OBJECTIVE To investigate the prevalence of early trauma and resilience among adolescents in Wuhan, and explore the relationship between early trauma and resilience. METHODS Totally 4871 students aged 10-16 years were chosen by cluster sampling in Wuhan city from September to October 2015. All subjects completed self-report questionnaires, including general information, the Childhood Trauma Questionnaire( CTQ), and the Connor Davidson Resilience Scale( CD-RISC). RESULTS The mean score of CD-RISC of the total sample was( 64. 70 ± 18. 34). Statistical significance in different gender( t = 5. 373, P<0. 001), age( F = 49. 401, P<0. 001), single child( t = 3. 529, P<0. 001), levels of mother's education( F = 36. 129, P< 0. 001), relationship between parents( F = 89. 831, P < 0. 001), family economic status( F = 36. 547, P<0. 001). The rate of early trauma was 30. 1%. Male( χ~2= 42. 272, P < 0. 001), lower levels of mother 's education( χ~2= 44. 345, P < 0. 001), poorer relationship between parents( χ~2= 133. 045, P < 0. 001), and worse family economic status( χ~2= 31. 231, P<0. 001) were associated with increased risk of early trauma. The scores of emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect were negatively correlated with the scores of CD-RISC( r followed by-0. 256, -0. 107, -0. 053, -0. 355 and-0. 308, P<0. 01). Regression analysis implied female, older age, emotional abuse, emotional neglect, and physical neglect( B followed by-0. 156, -0. 117, -0. 109, -0. 214 and-0. 149, P < 0. 01) of primary and middle school students assumed predictive resilience. CONCLUSION Emotional abuse, emotional neglect, and physical neglect are negatively associated with resilience among children and adolescent. The result suggest that reducing emotional abuse, emotional neglect and physical neglect experience may contribute to child resilience.
Interactions of Streptococcus suis serotype 9 with host cells and role of the capsular polysaccharide: Comparison with serotypes 2 and 14

Streptococcus suis is an important porcine bacterial pathogen and a zoonotic agent responsible for sudden death, septic shock and meningitis, of which serotype 2 is the most widespread, with serotype 14 also causing infections in humans in South-East Asia. Knowledge of its pathogenesis and virulence are almost exclusively based on these two serotypes. Though serotype 9 is responsible for the greatest number of porcine cases in Spain, the Netherlands and Germany, very little information is currently available regarding this serotype. Of the different virulence factors, the capsular polysaccharide (CPS) is required for S. suis virulence as it promotes resistance to phagocytosis and killing and masks surface components responsible for host cell activation. However, these roles have been described for serotypes 2 and 14, whose CPSs are structurally and compositionally similar, both containing sialic acid. Consequently, we evaluated herein the interactions of serotype 9 with host cells and the role of its CPS, which greatly differs from those of serotypes 2 and 14. Results demonstrated that serotype 9 adhesion to but not invasion of respiratory epithelial cells was greater than that of serotypes 2 and 14. Furthermore serotype 9 was more internalized by macrophages but equally resistant to whole blood killing. Though recognition of serotypes 2, 9 and 14 by DCs required MyD88-dependent signaling, in vitro pro-inflammatory mediator production induced by serotype 9 was much lower. In vivo, however, serotype 9 causes an exacerbated inflammatory response, which combined with persistent bacterial presence, is probably responsible for host death during the systemic infection. Though presence of the serotype 9 CPS masks surface components less efficiently than those of serotypes 2 and 14, the serotype 9 CPS remains critical for virulence as it is required for survival in blood and development of clinical disease, and this regardless of its unique composition and structure.
The feasibility of using citizens to segment anatomy from medical images: Accuracy and motivation

The development of automatic methods for segmenting anatomy from medical images is an important goal for many medical and healthcare research areas. Datasets that can be used to train and test computer algorithms, however, are often small due to the difficulties in obtaining experts to segment enough examples. Citizen science provides a potential solution to this problem but the feasibility of using the public to identify and segment anatomy in a medical image has not been investigated. Our study therefore aimed to explore the feasibility, in terms of performance and motivation, of using citizens for such purposes. Public involvement was woven into the study design and evaluation. Twenty-nine citizens were recruited and, after brief training, asked to segment the spine from a dataset of 150 magnetic resonance images. Participants segmented as many images as they could within three one-hour sessions. Their accuracy was evaluated by comparing them, as individuals and as a combined consensus, to the segmentations of three experts. Questionnaires and a focus group were used to determine the citizens’ motivation for taking part and their experience of the study. Citizen segmentation accuracy, in terms of agreement with the expert consensus segmentation, varied considerably between individual citizens. The citizen consensus, however, was close to the expert consensus, indicating that when pooled, citizens may be able to replace or supplement experts for generating large image datasets. Personal interest and a desire to help were the two most common reasons for taking part in the study.
VDJbase: an adaptive immune receptor genotype and haplotype database

Abstract VDJbase is a publicly available database that offers easy searching of data describing the complete sets of gene sequences (genotypes and haplotypes) inferred from adaptive immune receptor repertoire sequencing datasets. VDJbase is designed to act as a resource that will allow the scientific community to explore the genetic variability of the immunoglobulin (Ig) and T cell receptor (TR) gene loci. It can also assist in the investigation of Ig- and TR-related genetic predispositions to diseases. Our database includes web-based query and online tools to assist in visualization and analysis of the genotype and haplotype data. It enables users to detect those alleles and genes that are significantly over-represented in a particular population, in terms of genotype, haplotype and gene expression. The database website can be freely accessed at https://www.vdjbase. org/, and no login is required. The data and code use creative common licenses and are freely downloadable from https://bitbucket.org/account/user/yaarilab/projects/GPHP.
Cell cycle-independent furrowing triggered by phosphomimetic mutations of the INCENP STD motif requires Plk1

ABSTRACT Timely and precise control of Aurora B kinase, the chromosomal passenger complex (CPC) catalytic subunit, is essential for accurate chromosome segregation and cytokinesis. Post-translational modifications of CPC subunits are directly involved in controlling Aurora B activity. Here, we identified a highly conserved acidic STD-rich motif of INCENP that is phosphorylated during mitosis in vivo and by Plk1 in vitro and is involved in controlling Aurora B activity. By using an INCENP conditional-knockout cell line, we show that impairing the phosphorylation status of this region disrupts chromosome congression and induces cytokinesis failure. In contrast, mimicking constitutive phosphorylation not only rescues cytokinesis but also induces ectopic furrows and contractile ring formation in a Plk1- and ROCK1-dependent manner independent of cell cycle and microtubule status. Our experiments identify the phospho-regulation of the INCENP STD motif as a novel mechanism that is key for chromosome alignment and cytokinesis. This article has an associated First Person interview with the first author of the paper. Highlighted Article: Phospho-regulation of the INCENP STD motif acts as a novel switch that is key to Aurora B activity modulation, chromosome alignment and cytokinesis.