Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312)

Purpose: Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors. Patients and Methods: Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day) delivered on days 1–5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed. Results: Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2–20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients. Conclusions: Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.
Prospective memory and working memory in comparison. New experimental paradigms

Abstract Aim of the study: Prospective memory (PM) is a cognitive high load activity. Two main models showed the relation between working memory (WM) and PM. The preparatory attentional and memory processes model (PAM) posits an interdependence between WM and PM; while, the multiprocess framework assumes independence between these two functions. Materials and methods: With the aim to investigate this relation, two tasks were administered to a sample of 21 healthy participants. The first task (arithmetic) required low cognitive and WM load together with a prospective task, the second (PASAT) required high cognitive and WM load together with a prospective switching task. The prospective task included two modalities of administration: based on a sound cue (event-based) or at a given moment (time-based). Results: PM accuracy was influenced by WM only when paired to complex tasks that require high cognitive load on WM and active PM self-retrieval processes (time-PASAT). Conclusions: These results support partial independence between these two mechanisms.
miR-324-5p inhibits gallbladder carcinoma cell metastatic behaviours by downregulation of transforming growth factor beta 2 expression

Abstract Increasing studies have demonstrated that microRNAs (miRNAs) are associated with the metastasis of gallbladder carcinoma (GBC). Recently, miR-324-5p has been reported to be a tumour-suppressive miRNA in many types of malignant cancer. However, the biological function and molecular mechanism of miR-324-5p in GBC still remain largely unknown. Here, we found that miR-324-5p expression was notably down-regulated in both GBC tissues and cells compared with that in normal controls. Downregulated miR-324-5p expression was negatively associated with the status of local invasion and lymph node metastasis and predicted a poor prognosis in GBC patients. Further functional assays revealed that restoration of miR-324-5p significantly suppressed GBC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and impeded the metastasis of GBC cells in vivo. Moreover, RNA immunoprecipitation (RIP) and dual-luciferase reporter assay confirmed that the transforming growth factor beta 2 (TGFB2) was a direct target gene of miR-324-5p in GBC cells. Mechanically, small interfering RNA (siRNA)-mediated knockdown of TGFB2 partially phenocopied the inhibitory effects of miR-324-5p overexpression on GBC cell metastatic phenotypes. In summary, our findings demonstrated that miR-324-5p targets TGFB2 expression to inhibit GBC cell metastatic behaviors, and implying miR-324-5p as a potential biomarker for diagnostic and therapeutic strategies in GBC.
A Set of Time-and-Frequency-Localized Short-Duration Speech-Like Stimuli for Assessing Hearing-Aid Performance via Cortical Auditory-Evoked Potentials

Short-duration speech-like stimuli, for example, excised from running speech, can be used in the clinical setting to assess the integrity of the human auditory pathway at the level of the cortex. Modeling of the cochlear response to these stimuli demonstrated an imprecision in the location of the spectrotemporal energy, giving rise to uncertainty as to what and when of a stimulus caused any evoked electrophysiological response. This article reports the development and assessment of four short-duration, limited-bandwidth stimuli centered at low, mid, mid-high, and high frequencies, suitable for free-field delivery and, in addition, reproduction via hearing aids. The durations were determined by the British Society of Audiology recommended procedure for measuring Cortical Auditory-Evoked Potentials. The levels and bandwidths were chosen via a computational model to produce uniform cochlear excitation over a width exceeding that likely in a worst-case hearing-impaired listener. These parameters produce robustness against errors in insertion gains, and variation in frequency responses, due to transducer imperfections, room modes, and age-related variation in meatal resonances. The parameter choice predicts large spectral separation between adjacent stimuli on the cochlea. Analysis of the signals processed by examples of recent digital hearing aids mostly show similar levels of gain applied to each stimulus, independent of whether the stimulus was presented in isolation, bursts, continuous, or embedded in continuous speech. These stimuli seem to be suitable for measuring hearing-aided Cortical Auditory-Evoked Potentials and have the potential to be of benefit in the clinical setting.
C-Reactive Protein, Metabolic Syndrome and Cardiovascular Disease

C-reactive protein (CRP) has been known to be highly associated with the occurrence of cardiovascular disease. However controversies were present among some clinical trials with regard to the role of CRP to be the cause or a bystander in cardiovascular disease [1-3]. Experimentally, CRP was found to cause vascular endothelial dysfunction, increase matrix metalloproteinase synthesis and impair fibrinolytic capacity, which involve the process of atherosclerosis resulting in an increased cardiovascular risk [4,5]. On the contrary, CRP could be produced from the inflamed adipocytes in pericardial and abdominal visceral fat tissues and it did not correlate well to the severity of vascular atherosclerosis [6]. Furthermore, CRP was related to the development of metabolic syndrome as well and it has been interpreted to be the underlying mediator [7]. As we know, there was no additive or multiplier hazardous effect of CRP to some classic risk factors for cardiovascular diseases such as hypertension, coronary calcium score, hyperlipidemia and metabolic syndrome on the basis of subgroup analyses from the JUPITER trial, the ASCOT trial and the Framingham offspring study [8-12]. Recent genetic analyses demonstrated that carriers of CRP polymorphisms with higher serum CRP levels were not associated with higher cardiovascular risk [13] Therefore, the controversies were still unresolved regarding the role of CRP in the pathogenesis of cardiovascular diseases.
Metaphors of the Challenges on Project Completion: Experiences of Block Release Students and their Supervisors at Midlands State University

This study examined challenges of block-release (University part-time students), post graduate and undergraduate students, with their research supervisors in the Faculty of Education at Midlands State University in Zimbabwe. The study also aimed to identify ways of improving the research project practice of the block-release students. The researchers chose a triangulated mixed methods design as the strategy for this study because of its flexibility in the use of both quantitative and qualitative approaches to research. The population comprised 103 block-release post diploma Bachelor of Education students (3 year programme), 52 block-release Postgraduate students (2 year programme), 3 research projects coordinators and 43 lecturers in the Faculty of Education. The sample comprised 35 lecturers, 50 block-release post-diploma Bachelor of Education students (3 year programme), 25 block-release Postgraduate students (2 year programme), and 3 research projects coordinators in the Faculty of Education. The study was carried out in the Faculty of Education at Midlands State University in Zimbabwe between January and December 2013.Stratified random sampling procedure was employed to select a sample of students and lecturers. The methods of data collection used were questionnaire and focus group discussions. The study found that both students and their supervisors were not satisfied with each otherâ€™s contribution in relation to research work. There were a number of challenges the students were facing such as, the distance and lack of supervisory support due to supervisorsâ€™ other work load. The study recommends training of supervisors in the following areas; research methodology, technical expertise and managing the supervision relationship
The Correlation between Cross-sectional Area of Lumbar Paraspinal Muscles and Sponylolisthesis; A Retrospective Study

Objectives To investigate correlation between slip percentage (SP) of spondylolisthesis and cross-sectional area (CSA) of lumbar paraspinal muscles; psoas major (PM), multifidus (MU) and erector spinae (ES). Methods A retrospective study was carried out in 120 spondylolisthesis patients who had visited the Spine center of Kyung Hee University Hospital at Gangdong and had taken lumbar MRI. CSA of lumbar paraspinal muscles was measured from axial T2-weighted MRI and divided by CSA of vertebral body to avoid weight`s influence. SP was also measured from sagittal MRI. Results SP increase has significant correlation with decreased CSA-MU (r
Enhancing the Identification of Commercial Sexual Exploitation Among a Population of High-Risk Youths Using Predictive Regularization Models

Despite an increasing awareness about the existence and harms of commercial sexual exploitation of children (CSEC), the identification of victims remains a challenge for practitioners, hindering their ability to provide appropriate services. Tools that gauge risk of CSEC support the identification of victims but are underdeveloped because most tools assess risk of CSEC within a general youth population. An understanding of what predicts actual CSEC victimizations among youths at higher risk of CSEC due to experiences of childhood adversities has been left unassessed. Research in this area is limited in part because traditional methods do not allow for an assessment of the unique impact of childhood adversities that tend to co-occur. To address these difficulties, the current study applied predictive regularization methods to identify the most decisive risk items for CSEC. Proximal risk of CSEC was assessed among 317 youths who were referred to a specialized program in the Northeast of the United States due to suspicion of CSEC. With an innovative methodological approach, this study seeks to prompt other scholars to examine risk utilizing novel techniques and provides a foundation for the development of concise tools that assess risk of CSEC among populations of youths at higher levels of risk.
Therapeutic Effect of Stereospermum suavelolens on Diabetic Nephropathy

Objective: In Indian traditional medicine, decoctions from different parts of Stereospermum suavelolens are used for the treatment of various human diseases including diabetes mellitus. The present study was aimed to evaluate ethyl acetate fraction of ethanol extract from Stereospermum suavelolens for nephroprotective effects in Streptozotocin (STZ)-induced diabetic rats by sub acute model. Methods: The STZ induced diabetic rats were treated once daily, orally with ethyl acetate fraction of Stereospermum suavelolens for 14 days at the doses of 200 and 400 mg/kg. The serum and urine renal function parameters-creatinine, urea, uric acid, albumin and total proteins were measured on 15 th day. The in vivo antioxidant activity of Stereospermum suavelolens was also evaluated in diabetic rats. Effects of the fraction treatments on the kidney histological profile in STZ nephrotoxic rats were also evaluated. Results: The present study investigation showed that the ethyl acetate fraction of Stereospermum suavelolens significantly (P<0.001) attenuated elevations in the serum levels of creatinine, urea, uric acid and total proteins in diabetic treated rats as compared with diabetic control rats. Significant (P<0.001) increase in Superoxide Dismutase (SOD), reduced Glutathione (GSH) and Catalase (CAT) levels and reduction in Thiobarbituric Acid Reactive Substances (TBARS) levels were also observed in ethyl acetate fraction treated rats kidney. The histopathological study of kidney in drug treated rats shows significant protective effect against STZ oxidative stress. Conclusion: Our study concludes that the ethyl acetate fractions of Stereospermum suavelolens possess potent nephroprotective effect against oxidative stress in STZ induced diabetic rats.
Motion verbs and memory for motion events

ABSTRACT Language is assumed to affect memory by offering an additional medium of encoding visual stimuli. Given that natural languages differ, cross-linguistic differences might impact memory processes. We investigate the role of motion verbs on memory for motion events in speakers of English, which preferentially encodes manner in motion verbs (e.g., driving), and Greek, which tends to encode path of motion in verbs (e.g., entering). Participants viewed a series of motion events and we later assessed their memory of the path and manner of the original events. There were no effects of language-specific biases on memory when participants watched events in silence; both English and Greek speakers remembered paths better than manners of motion. Moreover, even when motion verbs were available (either produced by or heard by the participants), they affected memory similarly regardless of the participants’ language: path verbs attenuated memory for manners of motion, but the reverse did not occur. We conclude that overt language affects motion memory, but these effects interact with underlying, shared biases in how viewers represent motion events.
Modulation of proliferation factors in lung adenocarcinoma with an analysis of the transcriptional consequences of genomic EGFR activation

Genes of the pre-replication, pre-initiation and replisome complexes duplicate the genome from many sites once in a normal cell cycle. This study examines complex components in lung adenocarcinoma (LUAD) closely, correlating changes in the genome and transcriptome with proliferation and overall survival. Molecular subtypes (The Cancer Genome Atlas (TCGA), 2014) based on copy number, DNA methylation, and mRNA expression had variable proliferation levels, the highest correlating with decreased survival. A pattern of increased expression typified by POLE2 and POLQ was found for multiple replication factors over thirty-seven tumor types. EGFR altered cases unanticipatedly inversely correlated with proliferation factor expression in LUAD, Colon adenocarcinoma, and Cancer Cell Line Encyclopedia cell lines, but not in glioblastoma or breast cancer. Activation mutations did not uniformly correlate with proliferation, most cases were pre-metastatic. A gene expression profile was identified, and pathway involvement considered. Significantly, results suggest EGFR over expression and activation are early alterations that likely stall the replication complex through PCNA phosphorylation creating replication stress responsible for DNA damage response and further mutation, but does not promote increased proliferation itself. An argument is presented that the mechanism driving lethality in this tumor cohort could differ from over proliferation seen in other LUAD.
Premature deaths by visceral leishmaniasis in Brazil investigated through a cohort study: A challenging opportunity?

Background Visceral Leishmaniasis (VL) is the most severe form of leishmaniasis because it can lead to death. In the Americas, 96% of cases are in Brazil, and despite efforts, the fatality rate has increased in the past years. We analyzed deaths associated to VL in Brazil and investigated the factors that could influence on the timeliness of fatal outcome with emphasis on time (tStoD). Methodology The registered deaths by VL were sourced from the Brazilian National Notification System from 2007–2014. Through a retrospective cohort study, univariate and multivariable Cox proportional hazards model analysis were performed and investigated the factors that could influence the time (tStoD). These factors were analyzed through survival models. Results Out of the 1,589 reported deaths, the median for onset of the symptoms and the case notification date (tStoN) is 25 days (10–61), and for date of case notification and death (tNotD) is 9 days (4–17). The time (tStoN) to event investigation for HIV non-infected individuals was 1.4 (1.16–1.68) greater than the HIV positive group. At the same time peri-urban and urban area were 0.83 (0.47–1.44) and 1.33 (1.16–1.52), respectively. The explorations revealed apparent differences between the time to event investigation (both for tStoN and tNotD) and the age at the onset of the symptoms. According to the tStoN the rate of notification is 1.73 times greater in patients under 5 years old at the onset of the clinical symptoms compared to older patients. Conclusion VL patients under 5 years old were diagnosed earlier and had shorter survival. It could mean that in younger population, although properly diagnosed, the fatality pattern might be related to the severity of the disease. Main host characteristics were evaluated, and age and co-infections seem to have an impact in the disease progression.
Diagnosing gaze and arrow cueing effects in unilateral spatial neglect

ABSTRACT Individuals with left unilateral spatial neglect (USN) following a right hemisphere lesion show difficulty in orienting their attention toward stimuli presented on the left. In normal cognition, others’ gaze direction and a pointing arrow naturally guide visual attention. Here, we explore a method to identify patients who may benefit from these skills as a base for compensation during rehabilitation. We tested gaze and arrow cueing effects in 26 healthy participants and in 13 patients with USN. Our data show that brain injuries causing USN do not affect gaze and arrow cueing in a consistent manner from one patient to another.
A cluster of Legionnaires' disease in Belgium linked to a cooling tower, August–September 2016: practical approach and challenges

Abstract A cluster of Legionnaires' disease (LD) with 10 confirmed, three probable and four possible cases occurred in August and September 2016 in Dendermonde, Belgium. The incidence in the district was 7 cases/100 000 population, exceeding the maximum annual incidence in the previous 5 years of 1.5/100 000. Epidemiological, environmental and geographical investigations identified a cooling tower (CT) as the most likely source. The case risk around the tower decreased with increasing distance and was highest within 5 km. Legionella pneumophila serogroup 1, ST48, was identified in a human respiratory sample but could not be matched with the environmental results. Public health authorities imposed measures to control the contamination of the CT and organised follow-up sampling. We identified obstacles encountered during the cluster investigation and formulated recommendations for improved LD cluster management, including faster coordination of teams through the outbreak control team, improved communication about clinical and environmental sample analysis, more detailed documentation of potential exposures obtained through the case questionnaire and earlier use of a geographical information tool to compare potential sources and for hypothesis generation.
Deubiquitinase Activity Profiling Identifies UCHL1 as a Candidate Oncoprotein That Promotes TGFβ-Induced Breast Cancer Metastasis

Purpose: Therapies directed to specific molecular targets are still unmet for patients with triple-negative breast cancer (TNBC). Deubiquitinases (DUB) are emerging drug targets. The identification of highly active DUBs in TNBC may lead to novel therapies. Experimental Design: Using DUB activity probes, we profiled global DUB activities in 52 breast cancer cell lines and 52 patients' tumor tissues. To validate our findings in vivo, we employed both zebrafish and murine breast cancer xenograft models. Cellular and molecular mechanisms were elucidated using in vivo and in vitro biochemical methods. A specific inhibitor was synthesized, and its biochemical and biological functions were assessed in a range of assays. Finally, we used patient sera samples to investigate clinical correlations. Results: Two DUB activity profiling approaches identified UCHL1 as being highly active in TNBC cell lines and aggressive tumors. Functionally, UCHL1 promoted metastasis in zebrafish and murine breast cancer xenograft models. Mechanistically, UCHL1 facilitates TGFβ signaling–induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination. We found that these responses are potently suppressed by the specific UCHL1 inhibitor, 6RK73. Furthermore, UCHL1 levels were significantly increased in sera of patients with TNBC, and highly enriched in sera exosomes as well as TNBC cell–conditioned media. UCHL1-enriched exosomes stimulated breast cancer migration and extravasation, suggesting that UCHL1 may act in a paracrine manner to promote tumor progression. Conclusions: Our DUB activity profiling identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis and may provide a potential target for TNBC treatment.
Single cell transcriptome analysis reveals disease-defining T cell subsets in the tumor microenvironment of classic Hodgkin lymphoma.

Hodgkin lymphoma (HL) is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of non-cancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding crosstalk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 HL tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the HL-specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel HL-associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class-II deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune checkpoint targeting in HL.