Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuroprotective effect of chondroitin sulfate on SH-SY5Y cells overexpressing wild-type or A53T mutant α-synuclein

Accumulation of α-synuclein (α-SYN) is a common pathology for Parkinson's disease (PD). There is abundant evidence that the toxic-gain-of-function of α-SYN's is associated with aggregation and consequent effects. To assess the potential of chondroitin sulfate (CS) in this regard, the present study investigated its neuroprotective on SH-SY5Y cells overexpressing wild-type (WT) or A53T mutant α-SYN. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential were detected by flow cytometry. The protein expression levels of total α-SYN, phosphorylated Ser129 α-SYN, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and cytochrome-c (Cyt-c) were analyzed by western blotting. It was observed that CS reduced the expression levels of total α-SYN and phosphorylated Ser129 α-SYN, prevented cell loss and inhibited apoptosis. The subsequent mechanism study indicated that CS inhibited ROS overproduction. CS also significantly attenuated WT and A53T mutant α-SYN-induced dysfunction, including decrease of mitochondrial membrane potential, decrease of Bcl-2 expression, and increase of Bax expression, release of Cyt-c from the mitochondria and activation of caspase-3 and caspase-9, which demonstrated that CS suppressed α-SYN-induced apoptosis possibly through mitochondria protection. These results suggested that CS protects SH-SY5Y cells overexpressing WT or A53T mutant α-SYN by inhibiting the expression and phosphorylation of α-SYN, and ROS overproduction and mitochondrial apoptosis. These results implicate CS as a potential therapeutic agent for the treatment of PD.
Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial

Importance Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes. Objective To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival. Design, Setting, and Participants Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014. Interventions After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia. Main Outcomes and Measures The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up. Results A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98; P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%). Conclusions and Relevance Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted. Trial Registration clinicaltrials.gov Identifier: NCT00003052
Diagnostic Inferencing via Improving Clinical Concept Extraction with Deep Reinforcement Learning: A Preliminary Study

Clinical diagnostic inferencing is a complex task, which often requires significant medical research and investigation based on an underlying clinical scenario. This paper proposes a novel approach by formulating the task as a reinforcement learning problem such that the system can infer the most probable diagnoses by optimizing clinical concept extraction from a free text case narrative via leveraging relevant external evidence. Such a formulation is deemed to be suitable due to the inherent complexity of the task and unavailability of sufficient annotated data. During training, the agent tries to learn the optimal policy through iterative search and consolidation of the most relevant clinical concepts that best describe a correct diagnosis. A deep Q-network architecture is trained to optimize a reward function that measures the accuracy of the candidate diagnoses and clinical concepts. Our preliminary experiments on the TREC CDS dataset demonstrate the effectiveness of our system over non-reinforcement learning-based strong baselines.
Dyslexia: Investigating Self-Harm and Suicidal Thoughts/Attempts as a Coping Strategy

Purpose: This study aims to investigate the emotional perspective of having Dyslexia, a specific learning difficulty that not only affects literacy but many aspects of an individual’s life, from childhood into adulthood. This paper investigates negative emotional coping which took place, which included self-harming with: alcohol, food, body injury, suicide thoughts and suicidal attempts. Method: The sample of N=29 diagnosed developmental dyslexics (N=22 with prior diagnosis of depression) were interviewed with a semi-structured script with a wide ranging script spanning childhood and adulthood experience. Interpretative Phenomenological Analysis (IPA) was used to analyse the data into themes. Results: Self-harm was greater in the depressive to non-depressive sample; however, the type of self-harm varied. Males and non-depressives tended to predominantly self-harm with alcohol, followed by food and then rarely with bodily harm, whereas females in general, tended to predominantly self-harm with food, then bodily harm and lastly alcohol. Overall depressives self-harmed predominantly with food and then equally between alcohol and bodily-harm. Conclusion: Each group had their own profile and suggests that self-harm is a complex issue, with self-harm activities happening both in child and adulthood.
Synthesis of filigrees for digital fabrication

Filigrees are thin patterns found in jewelry, ornaments and lace fabrics. They are often formed of repeated base elements manually composed into larger, delicate patterns. Digital fabrication simplifies the process of turning a virtual model of a filigree into a physical object. However, designing a virtual model of a filigree remains a time consuming and challenging task. The difficulty lies in tightly packing together the base elements while covering a target surface. In addition, the filigree has to be well connected and sufficiently robust to be fabricated. We propose a novel approach automating this task. Our technique covers a target surface with a set of input base elements, forming a filigree strong enough to be fabricated. We exploit two properties of filigrees to make this possible. First, as filigrees form delicate traceries they are well captured by their skeleton. This affords for a simpler definition of operators such as matching and deformation. Second, instead of seeking for a perfect packing of the base elements we relax the problem by allowing appearance preserving partial overlaps. We optimize a filigree by a stochastic search, further improved by a novel boosting algorithm that records and reuses good configurations discovered during the process. We illustrate our technique on a number of challenging examples reproducing filigrees on large objects, which we manufacture by 3D printing. Our technique affords for several user controls, such as the scale and orientation of the elements.
Environmental control on the occurrence of high-coercivity magnetic minerals and formation of iron sulfides in a 640 ka sediment sequence from Lake Ohrid (Balkans)

Abstract. The bulk magnetic mineral record from Lake Ohrid, spanning the past 637 kyr, reflects large-scale shifts in hydrological conditions, and, superimposed, a strong signal of environmental conditions on glacial–interglacial and millennial timescales. A shift in the formation of early diagenetic ferrimagnetic iron sulfides to siderites is observed around 320 ka. This change is probably associated with variable availability of sulfide in the pore water. We propose that sulfate concentrations were significantly higher before ∼ 320 ka, due to either a higher sulfate flux or lower dilution of lake sulfate due to a smaller water volume. Diagenetic iron minerals appear more abundant during glacials, which are generally characterized by higher Fe / Ca ratios in the sediments. While in the lower part of the core the ferrimagnetic sulfide signal overprints the primary detrital magnetic signal, the upper part of the core is dominated by variable proportions of high- to low-coercivity iron oxides. Glacial sediments are characterized by high concentration of high-coercivity magnetic minerals (hematite, goethite), which relate to enhanced erosion of soils that had formed during preceding interglacials. Superimposed on the glacial–interglacial behavior are millennial-scale oscillations in the magnetic mineral composition that parallel variations in summer insolation. Like the processes on glacial–interglacial timescales, low summer insolation and a retreat in vegetation resulted in enhanced erosion of soil material. Our study highlights that rock-magnetic studies, in concert with geochemical and sedimentological investigations, provide a multi-level contribution to environmental reconstructions, since the magnetic properties can mirror both environmental conditions on land and intra-lake processes.
Weekly Versus Daily Dipeptidyl Peptidase 4 Inhibitor Therapy for Type 2 Diabetes: Systematic Review and Meta-analysis

Once-weekly dipeptidyl peptidase 4 inhibitors (weekly DPP-4is) were recently developed in addition to the once-daily agents (1), and weekly DPP-4is may improve compliance by reducing the burden of medication. Omarigliptin and trelagliptin are the weekly DPP-4is currently available in Japan. We performed a meta-analysis to assess the efficacy and safety of weekly DPP-4is compared with daily DPP-4is and placebo for type 2 diabetes. This research was carried out according to a predetermined protocol (CRD42017069004) and followed the standard guidelines for conduct and reporting of systematic reviews and meta-analyses (Supplementary Appendices 1 and 2). We searched MEDLINE, EMBASE, and the Cochrane Library up to 16 September 2017. Prospective randomized double-blind trials of weekly DPP-4is performed in adults with type 2 diabetes using an intervention period of at least 12 weeks were identified. Studies were excluded if other aspects of treatment were targeted, if not double-blind (e.g., open-label or crossover), or if the follow-up period was <12 weeks. Studies of children and observational studies were also ineligible. We checked the reference lists of the original studies, review articles, and meta-analyses identified by our searches to find other eligible trials. There were no language restrictions. Two reviewers independently assessed the studies and extracted data. Bias was analyzed with the Cochrane Collaboration tool. Meta-analysis was performed by a …
Mechanisms underlying elevated SBP differ with adiposity in young adults: the Enigma study

Objectives: The positive association between adiposity and hypertension is well recognized. However, not all overweight individuals have elevated blood pressure (BP). Moreover, different factors may be associated with high BP in normal-weight versus overweight individuals. The aim of the current study was to examine the influence of adiposity on the relationship between SBP and underlying haemodynamic mechanisms in young adults. Method: Data from 2502 patients were available from the Enigma study. Detailed demographic, biochemical, and haemodynamic data were obtained in all individuals. Data were analysed between lower and upper tertiles of BMI and SBP, separately for each sex. Results: In normal-weight individuals, cardiac output (CO) was elevated in those with higher SBP, independently of body size. Moreover, higher CO was associated with an increased stroke volume in men (P < 0.001), but an increased heart rate in women (P = 0.002). In contrast, in overweight individuals, peripheral vascular resistance (PVR) was elevated in men with higher SBP (P = 0.02) and those with lower SBP had the lowest PVR of all groups. In linear regression analyses, there was a stronger association between SBP and CO in normal-weight individuals, but a stronger association between SBP and PVR in overweight individuals. Conclusion: Different haemodynamic mechanisms are associated with elevated SBP in young adults, depending on body size and sex. These data suggest the need for differential approaches to the identification and management of young adults with elevated BP.
Gender Differences in White Matter Microstructure

Background Sexual dimorphism in human brain structure is well recognised, but little is known about gender differences in white matter microstructure. We used diffusion tensor imaging to explore differences in fractional anisotropy (FA), an index of microstructural integrity. Methods A whole brain analysis of 135 matched subjects (90 men and 45 women) using a 1.5 T scanner. A region of interest (ROI) analysis was used to confirm those results where proximity to CSF raised the possibility of partial-volume artefact. Results Men had higher fractional anisotropy (FA) in cerebellar white matter and in the left superior longitudinal fasciculus; women had higher FA in the corpus callosum, confirmed by ROI. Discussion The size of the differences was substantial - of the same order as that attributed to some pathology – suggesting gender may be a potentially significant confound in unbalanced clinical studies. There are several previous reports of difference in the corpus callosum, though they disagree on the direction of difference; our findings in the cerebellum and the superior longitudinal fasciculus have not previously been noted. The higher FA in women may reflect greater efficiency of a smaller corpus callosum. The relatively increased superior longitudinal fasciculus and cerebellar FA in men may reflect their increased language lateralisation and enhanced motor development, respectively.
Learning to Search with MCTSnets

Planning problems are among the most important and well-studied problems in artificial intelligence. They are most typically solved by tree search algorithms that simulate ahead into the future, evaluate future states, and back-up those evaluations to the root of a search tree. Among these algorithms, Monte-Carlo tree search (MCTS) is one of the most general, powerful and widely used. A typical implementation of MCTS uses cleverly designed rules, optimized to the particular characteristics of the domain. These rules control where the simulation traverses, what to evaluate in the states that are reached, and how to back-up those evaluations. In this paper we instead learn where, what and how to search. Our architecture, which we call an MCTSnet, incorporates simulation-based search inside a neural network, by expanding, evaluating and backing-up a vector embedding. The parameters of the network are trained end-to-end using gradient-based optimisation. When applied to small searches in the well known planning problem Sokoban, the learned search algorithm significantly outperformed MCTS baselines.
A Stretch of Negatively Charged Amino Acids of Linker for Activation of T-Cell Adaptor Has a Dual Role in T-Cell Antigen Receptor Intracellular Signaling

The adaptor protein linker for activation of T cells (LAT) has an essential role transducing activatory intracellular signals coming from the TCR/CD3 complex. Previous reports have shown that upon T-cell activation, LAT interacts with the tyrosine kinase Lck, leading to the inhibition of its kinase activity. LAT–Lck interaction seemed to depend on a stretch of negatively charged amino acids in LAT. Here, we have substituted this segment of LAT between amino acids 113 and 126 with a non-charged segment and expressed the mutant LAT (LAT-NIL) in J.CaM2 cells in order to analyze TCR signaling. Substitution of this segment in LAT prevented the activation-induced interaction with Lck. Moreover, cells expressing this mutant form of LAT showed a statistically significant increase of proximal intracellular signals such as phosphorylation of LAT in tyrosine residues 171 and 191, and also enhanced ZAP70 phosphorylation approaching borderline statistical significance (p = 0.051). Nevertheless, downstream signals such as Ca2+ influx or MAPK pathways were partially inhibited. Overall, our data reveal that LAT–Lck interaction constitutes a key element regulating proximal intracellular signals coming from the TCR/CD3 complex.
Severe and irreversible myelopathy after concurrent systemic and intrathecal nucleoside analogue treatment for refractory diffuse large B-cell lymphoma: A case report and review of the literature

We report a patient with refractory diffuse large B-cell lymphoma who developed irreversible, severe spinal neurotoxicity after concurrent treatment with intrathecal and systemic cytarabine. Shortly after concomitant administration of intrathecal triple therapy (MTX, dexamethasone and cytarabine) and high-dose systemic cytarabin (R-DHAP protocol) the patient lost control of bowel and bladder function and developed an ascending, irreversible paraplegia. Infectious or neoplastic diseases of the spinal cord were ruled out. A magnetic resonance imaging scan of the spine resulted in a diagnosis of toxic myelitis. Previously observed cases of spinal neurotoxicity after cytarabine treatment are reviewed as well as current guidelines for the use of intrathecal chemotherapy in high-grade non-Hodgkin lymphoma. In summary, severe spinal neurotoxicity of intrathecal chemotherapy is a rare side-effect, however several studies suggest that the neurotoxicity of cytarabine is significantly enhanced by concurrent intrathecal and high-dose systemic administration. Simultaneous high-dose systemic and intrathecal chemotherapy with cytarabine should therefore be avoided.
Randomized, Open-Label, Parallel Group Study to Evaluate the Effect of Internet-Based Glucose Management System on Subjects with Diabetes in China.

OBJECTIVE Large amounts of time and effort are needed to implement an Internet-based glucose monitoring system (IBGMS) in the clinical setting. This study was designed using research experience that was developed while implementing an IBGMS in Korea, and the research platform was modified to evaluate the efficacy of an IBGMS in controlling blood sugar in the Chinese population. METHODS A randomized, open-label, parallel group design was used to evaluate the efficacy of an IBGMS among Chinese subjects with type 2 diabetes. Over a 6-month period, 182 subjects were evaluated in the IBGMS (n = 92) or control (n = 90) groups. RESULTS After 3 months, the control group's HbA1c levels were reduced from 8.0% ± 0.8% to 7.3% ± 1.2% (p < 0.001) and the IBGMS group experienced a reduction from 7.9% ± 0.8% to 6.9% ± 0.7% (p < 0.001); the IBGMS group's end value was significantly lower (p = 0.014). The intragroup changes in the control and IBGMS groups were significant at the 3-month (p = 0.002) and 6-month (p < 0.01) follow-ups. Over this period, the HbA1c levels in the control group increased slightly (7.3% ± 1.1% to 7.4% ± 1.3%, p = 0.605), and the HbA1c levels in the IBGMS group decreased slightly (6.9% ± 0.7% to 6.7% ± 0.7%, p = 0.081). CONCLUSIONS The IBGMS was effective in improving blood sugar levels among patients with diabetes. Therefore, IBGMS experience can be effectively transferred between institutions and countries.
Investigation of Al2O3‐ and SSiC‐ceramic under lubricated, reciprocating sliding contact and cavitation erosion

Tribological performance of alumina and silicon carbide ceramics as well as of the hardened steel 100Cr6 for reference was studied during reciprocating sliding and cavitation erosion in isooctane as substitute of gasoline and in distilled water. It was the aim to characterize effects of surface finish of the specimens and the liquid media on friction, resistance to sliding wear and cavitation erosion. Sliding wear tests were run on the self‐mated ceramics and ceramic/steel pairs under conditions of boundary lubrication using a laboratory tribometer with cylinder‐on‐plate geometry. Vibratory cavitation erosion tests were conducted according to ASTM G 32‐92.
Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions

The hope of selectively targeting cancer cells by therapy and eradicating definitively malignancies is based on the identification of pathways or metabolisms that clearly distinguish “normal” from “transformed” phenotypes. Some tyrosine kinase activities, specifically unregulated and potently activated in malignant cells, might represent important targets of therapy. Consequently, tyrosine kinase inhibitors (TKIs) might be thought as the “vanguard” of molecularly targeted therapy for human neoplasias. Imatinib and the successive generations of inhibitors of Bcr-Abl1 kinase, represent the major successful examples of TKI use in cancer treatment. Other tyrosine kinases have been selected as targets of therapy, but the efficacy of their inhibition, although evident, is less definite. Two major negative effects exist in this therapeutic strategy and are linked to the specificity of the drugs and to the role of the targeted kinase in non-malignant cells. In this review, we will discuss the data available on the TKIs effects on the metabolism and functions of mesenchymal stromal cells (MSCs). MSCs are widely distributed in human tissues and play key physiological roles; nevertheless, they might be responsible for important pathologies. At present, bone marrow (BM) MSCs have been studied in greater detail, for both embryological origins and functions. The available data are evocative of an unexpected degree of complexity and heterogeneity of BM-MSCs. It is conceivable that this grade of intricacy occurs also in MSCs of other organs. Therefore, in perspective, the negative effects of TKIs on MSCs might represent a critical problem in long-term cancer therapies based on such inhibitors.