Miracle-dz/UniFAR-FTUs huggingface dataset:
Seed-driven Document Ranking for Systematic Reviews in Evidence-Based Medicine

Systematic review (SR) in evidence-based medicine is a literature review which provides a conclusion to a specific clinical question. To assure credible and reproducible conclusions, SRs are conducted by well-defined steps. One of the key steps, the screening step, is to identify relevant documents from a pool of candidate documents. Typically about 2000 candidate documents will be retrieved from databases using keyword queries for a SR. From which, about 20 relevant documents are manually identified by SR experts, based on detailed relevance conditions or eligibility criteria. Recent studies show that document ranking, or screening prioritization, is a promising way to improve the manual screening process. In this paper, we propose a seed-driven document ranking (SDR) model for effective screening, with the assumption that one relevant document is known, i.e., the seed document. Based on a detailed analysis of characteristics of relevant documents, SDR represents documents using bag of clinical terms, rather than the commonly used bag of words. More importantly, we propose a method to estimate the importance of the clinical terms based on their distribution in candidate documents. On benchmark dataset released by CLEF'17 eHealth Task 2, we show that the proposed SDR outperforms state-of-the-art solutions. Interestingly, we also observe that ranking based on word embedding representation of documents well complements SDR. The best ranking is achieved by combining the relevances estimated by SDR and by word embedding. Additionally, we report results of simulating the manual screening process with SDR.
Stratum recruits Rab8 at Golgi exit sites to regulate the basolateral sorting of Notch and Sanpodo

ABSTRACT In Drosophila, the sensory organ precursor (SOP or pI cell) divides asymmetrically to give birth to daughter cells, the fates of which are governed by the differential activation of the Notch pathway. Proteolytic activation of Notch induced by ligand is based on the correct polarized sorting and localization of the Notch ligand Delta, the Notch receptor and its trafficking partner Sanpodo (Spdo). Here, we have identified Stratum (Strat), a presumptive guanine nucleotide exchange factor for Rab GTPases, as a regulator of Notch activation. Loss of Strat causes cell fate transformations associated with an accumulation of Notch, Delta and Spdo in the trans-Golgi network (TGN), and an apical accumulation of Spdo. The strat mutant phenotype is rescued by the catalytically active as well as the wild-type form of Rab8, suggesting a chaperone function for Strat rather than that of exchange factor. Strat is required to localize Rab8 at the TGN, and rab8 phenocopies strat. We propose that Strat and Rab8 act at the exit of the Golgi apparatus to regulate the sorting and the polarized distribution of Notch, Delta and Spdo. Summary: Stratum, the putative guanine nucleotide exchange factor for Rab GTPases, is involved in restricting the apical delivery of Sanpodo to control spatiotemporal Notch activation following asymmetric cell division in Drosophila sensory organs.
Training working memory updating in Parkinson’s disease: A randomised controlled trial

ABSTRACT Frontostriatal dysfunction in Parkinson’s disease (PD) increases the risk for working memory (WM) impairment and depression, calling for counteractive measures. Computerised cognitive rehabilitation is a promising option, but targeted training protocols are lacking and lab-based training can be demanding due to the repeated visits. This study tested the feasibility and efficacy of home-based computerised training targeting mainly WM updating in PD. Fifty-two cognitively well-preserved PD patients were randomised to a WM training group and an active control group for five weeks of training (three 30-min sessions per week). WM training included three computerised adaptive WM tasks (two updating, one maintenance). The outcomes were examined pre- and post-training with trained and untrained WM tasks, tasks tapping other cognitive domains, and self-ratings of executive functioning and depression. Home-based training was feasible for the patients. The training group improved particularly on the updating training tasks, and showed posttest improvement on untrained WM tasks structurally similar to the trained ones. Moreover, their depression scores decreased compared to the controls. Our study indicates that patients with mild-to-moderate PD can self-administer home-based computerised WM training, and that they yield a similar transfer pattern to untrained WM tasks as has been observed in healthy older adults.
First fully automated planning solution for robotic radiosurgery – comparison with automatically planned volumetric arc therapy for prostate cancer

Abstract Background: For conventional radiotherapy treatment units, automated planning can significantly improve plan quality. For robotic radiosurgery, systems for automatic generation of clinically deliverable plans do not yet exist. For prostate stereotactic body radiation therapy (SBRT), few studies have systematically compared VMAT with robotic treatment. Material and methods: The multi-criteria autoplanning optimizer, developed at our institute, was coupled to the commercial treatment planning system of our robotic treatment unit, for fully automated generation of clinically deliverable plans (autoROBOT). The system was then validated by comparing autoROBOT plans with manually generated plans. Next, the autoROBOT system was used for systematic comparisons between autoROBOT plans and VMAT plans, that were also automatically generated (autoVMAT). CTV-PTV margins of 3 mm were used for autoROBOT (clinical routine) and autoVMAT plan generation. For autoVMAT, an extra plan was generated with 5 mm margin (often applied for VMAT). Plans were generated for a 4 × 9.5 Gy fractionation scheme. Results: Compared to manual planning, autoROBOT improved rectum D (16%), V (75%) and D (41%), and bladder D (37%) (all p .002), with equal PTV coverage. In the autoROBOT and autoVMAT comparison, both with 3 mm margin, rectum doses were lower for autoROBOT by 5% for rectum D (p=.002), 33% for V (p=.001) and 4% for D (p=.05), with comparable PTV coverage and other OAR sparing. With 5 mm margin for VMAT, 18/20 plans had a PTV coverage lower than requested (<95%) and all plans had higher rectum doses than autoROBOT (mean percentage differences of 13% for D, 69% for V and 32% for D (all p<.001)). Conclusions: The first system for fully automated generation of clinically deliverable robotic plans was built. Autoplanning did largely enhance robotic plan quality, compared to manual planning. Using autoplanning for both the robotic system and VMAT, superiority of non-coplanar robotic treatment compared to coplanar VMAT for prostate SBRT was demonstrated.
Secreted Phosphatase and Deoxyribonuclease Are Required by Pseudomonas aeruginosa To Defend against Neutrophil Extracellular Traps

Neutrophil extracellular traps (NETs) are produced by neutrophils as an innate immune defense mechanism to trap and kill microbial pathogens. NETs are comprised of ejected chromatin that forms a lattice structure enmeshed with numerous antimicrobial proteins. ABSTRACT Neutrophil extracellular traps (NETs) are produced by neutrophils as an innate immune defense mechanism to trap and kill microbial pathogens. NETs are comprised of ejected chromatin that forms a lattice structure enmeshed with numerous antimicrobial proteins. In addition to forming the structural backbone of NETs, extracellular DNA (eDNA) has membrane-disrupting antimicrobial activity that contributes to NET killing. Many pathogens produce secreted extracellular DNases to evade the antimicrobial activity of NETs. Pseudomonas aeruginosa encodes an operon of two secreted enzymes, a predicted alkaline phosphatase and a DNase. The DNase (eddB) degrades eDNA to use as a nutrient source. Here we report that both eDNA and NETs are potent inducers of this DNase-phosphatase operon. Furthermore, the secreted DNase contributes to degrading NET DNA and defends P. aeruginosa against NET-mediated killing. We demonstrate that EddA has both alkaline phosphatase and phosphodiesterase (PDase) activities and also protects against the antimicrobial activity of NETs. Although the phosphatase does not cause DNA degradation similar to that of the DNase, its protective function is likely a result of removing the cation-chelating phosphates from the eDNA phosphodiester backbone. Therefore, both the DNase and PDase contribute to defense against NET killing of P. aeruginosa, highlighting the role of DNA-manipulating enzymes in targeting the eDNA in neutrophil extracellular traps.
Induction of oligoclonal CD8 T cell responses against pulmonary metastatic cancer by a phospholipid-conjugated TLR7 agonist

Significance A major goal of cancer immunotherapy is the expansion and/or reactivation of cytotoxic CD8+ T cell responses against malignant cells. We previously showed that the direct injection of toll-like receptor 7 (TLR7) agonists into primary tumors can induce tumor-specific oligoclonal T cell responses whose magnitude correlates with therapeutic efficacy. However, tumors are not always accessible to local therapy. Here, we demonstrate in murine lung metastasis models that single systemic administration of a phospholipid conjugated TLR7 agonist can also expand tumor-specific cytotoxic T cells that are shared by different animals. The expansion can be achieved without causing apparent toxicity. Similar technology combining immune repertoire analysis and immunomodulatory drugs can help to guide the development of optimal immunotherapeutic regimens in cancer patients. Recent advances in cancer immunotherapy have improved patient survival. However, only a minority of patients with pulmonary metastatic disease respond to treatment with checkpoint inhibitors. As an alternate approach, we have tested the ability of systemically administered 1V270, a toll-like receptor 7 (TLR7) agonist conjugated to a phospholipid, to inhibit lung metastases in two variant murine 4T1 breast cancer models, as well as in B16 melanoma, and Lewis lung carcinoma models. In the 4T1 breast cancer models, 1V270 therapy inhibited lung metastases if given up to a week after primary tumor initiation. The treatment protocol was facilitated by the minimal toxic effects exerted by the phospholipid TLR7 agonist compared with the unconjugated agonist. 1V270 exhibited a wide therapeutic window and minimal off-target receptor binding. The 1V270 therapy inhibited colonization by tumor cells in the lungs in an NK cell dependent manner. Additional experiments revealed that single administration of 1V270 led to tumor-specific CD8+ cell-dependent adaptive immune responses that suppressed late-stage metastatic tumor growth in the lungs. T cell receptor (TCR) repertoire analyses showed that 1V270 therapy induced oligoclonal T cells in the lungs and mediastinal lymph nodes. Different animals displayed commonly shared TCR clones following 1V270 therapy. Intranasal administration of 1V270 also suppressed lung metastasis and induced tumor-specific adaptive immune responses. These results indicate that systemic 1V270 therapy can induce tumor-specific cytotoxic T cell responses to pulmonary metastatic cancers and that TCR repertoire analyses can be used to monitor, and to predict, the response to therapy.
Augmented anticancer activity of naringenin-loaded TPGS polymeric nanosuspension for drug resistive MCF-7 human breast cancer cells

Abstract Naringenin (NAR) is a naturally occurring plant flavonoid, found predominantly in citrus fruits, possesses a wide range of pharmacological properties. However, despite the therapeutic potential of NAR, its clinical development has been hindered due to low aqueous solubility and inefficient transport across biological membranes resulting in low bioavailability at tumor sites. In our previous studies, nanosuspension of naringenin (NARNS) was prepared using high pressure homogenization method using different polymers. D-α-Tocopheryl polyethylene glycol succinate 1000 (TPGS) was added as a co-stabilizer. All formulation characterization studies were performed. As a continuation of our previous research, current study has further evaluated the ability of the TPGS-coated NARNS, to reverse drug-resistance of P-gp-over expressing MCF-7 human breast adenocarcinoma cell line and animal model. MTT-based colorimetric assay revealed higher cytotoxic efficacy of NARNS than free NAR in MCF-7 cells. NARNS treatment significantly increased intracellular ROS level, mitochondrial membrane potential, caspase-3 activity, lipid peroxidation status (TBARS) and decreased GSH levels when compared to free NAR treatment in MCF-7 cells. It has been also noticed that the presence of apoptotic indices (membrane blebbing, nuclear fragmentation) in NARNS treated cancer cells. Further, NARNS exhibited dose-dependent in vitro antitumor activity with DLA cells. A significant increase in the life span and a decrease in the cancer cell number and tumor weight were noted in the tumor-induced mice after treatment with NARNS.
The prevalence of mental health problems in adults with intellectual disabilities in Japan, associated factors and mental health service use

BACKGROUND People with intellectual disabilities are more likely than people in the general population to experience life events associated with an increased risk of mental health problems. However, there has been little research in Japan on the prevalence of mental health problems in adults with intellectual disability (ID) or on associated factors and access to relevant services. METHODS Informants completed the Japanese version of the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist, and questions on the use of mental health services, for 126 adults with ID living in Tokyo. RESULTS A total of 23.8% of adults with ID had scores above the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist threshold score. Mental health problems were associated with age, gender and life events and not associated with the level of ID or living environment. Approximately 60% of participants with mental health problems were treated by psychiatrists and 6% of them received psychotherapy. CONCLUSION In the present study, mental health problems occurred in adults with ID at similar frequencies as in previous studies. Adults with ID who experienced mental health problems tended to receive less psychological therapy than the general Japanese population experiencing such problems. This result may indicate poor provision of psychological services for people with intellectual disabilities in Japan.
Does the architectural layout of a NICU affect alarm pressure? A comparative clinical audit of a single-family room and an open bay area NICU using a retrospective study design

Objectives To determine differences in alarm pressure between two otherwise comparable neonatal intensive care units (NICUs) differing in architectural layout—one of a single-family room (SFR) design and the other of an open bay area (OBA) design. Design Retrospective audit of more than 2000 patient days from each NICU cataloguing the differences in the number and duration of alarms for critical and alerting alarms, as well as the interaction of clinicians with the patient monitor. Setting Two level 3 NICUs. Results A total of more than 150 000 critical and 1.2 million alerting alarms were acquired from the two NICUs. The number of audible alarms and the associated noise pollution varied considerably with the OBA NICU generating 44% more alarms per infant per day even though the SFR NICU generated 2.5 as many critical desaturation alarms per infant per day. Conclusion Differences in the architectural layout of NICUs and the consequent differences in delays, thresholds and distribution systems for alarms are associated with differences in alarm pressure.
Antioxidant intake in relation to serum C-reactive protein in mid-life and older African Americans

ABSTRACT Objective: African Americans (AAs) experience greater prevalence of cardiovascular disease (CVD) compared to other ethnic/racial groups. Low-grade chronic inflammation (often quantified by serum C-reactive protein CRP) is a well-documented risk factor for CVD. A healthy diet is plentiful in antioxidant nutrients and is associated with a lower inflammatory status and CVD risk. Our objective was to examine the relationship between dietary intake of antioxidants (carotenoids, vitamins A, C, E, and selenium) and serum CRP concentrations in mid-life and older AAs, while controlling for confounders. Methods: Data were from the baseline phase of a longitudinal church-based intervention study to reduce CVD risk in AAs. Anthropometrics were measured in a standard manner. Fasting serum samples were analyzed with ELISA for CRP. Multiple-pass 24-hour dietary recalls were used to assess intake; self-reported questionnaires were used to collect demographics. Statistical analyses were performed using SPSS Statistics 21 with the level of significance set at p < 0.05. Results: A total of n = 73 participants (n = 51 females) were included in the analyses. The females and males, respectively were 58.9 ± 10.3 and 59.4 ± 9.7 years old, with BMI of 34.6 ± 8.3 and 35.6 ± 9.3 kg/m2 (Mean ± SD). The mean serum CRP was above 0.6 mg/dL, although slightly lower in males. Males consumed more energy (kcal) and met RDA for selenium, whereas females met RDA for vitamin C. Both groups met RDA for vitamin A. All other dietary variables fell below the RDA or had no RDA established. Results from the binary logistic regression did not show significant association between dietary antioxidants and serum CRP in males or females. However, among females, for every unit increase in BMI, there was a 15% increase in serum CRP (OR = 1.15, p = 0.04). Conclusions: Our study does not support the inverse relationship between antioxidants intake and CRP, but does support the evidence for obesity-induced inflammation and suggests the association can be applied to AA women.
On the Developmental Timing of Stress: Delineating Sex-Specific Effects of Stress across Development on Adult Behavior

Stress, and the chronic overactivation of major stress hormones, is associated with several neuropsychiatric disorders. However, clinical literature on the exact role of stress either as a causative, triggering, or modulatory factor to mental illness remains unclear. We suggest that the impact of stress on the brain and behavior is heavily dependent on the developmental timing at which the stress has occurred, and as such, this may contribute to the overall variability reported on the association of stress and mental illness. Here, animal models provide a way to comprehensively assess the temporal impact of stress on behavior in a controlled manner. This review particularly focuses on the long-term impact of stress on behavior in various rodent stress models at three major developmental time points: early life, adolescence, and adulthood. We characterize the various stressor paradigms into physical, social, and pharmacological, and discuss commonalities and differences observed across these various stress-inducing methods. In addition, we discuss here how sex can influence the impact of stress at various developmental time points. We conclude here that early postnatal life and adolescence represent particular periods of vulnerability, but that stress exposure during early life can sometimes lead to resilience, particularly to fear-potentiated memories. In the adult brain, while shorter periods of stress tended to enhance spatial memory, longer periods caused impairments. Overall, males tended to be more vulnerable to the long-term effects of early life and adolescent stress, albeit very few studies incorporate both sexes, and further well-powered sex comparisons are needed.
High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

Purpose: The advent of next-generation sequencing technologies has enabled the identification of several activating mutations of Erb-B2 receptor tyrosine kinase 2 (ERBB2) among various cancers. However, the significance of infrequent mutations has not been fully investigated. Herein, we comprehensively assessed the functional significance of the ERBB2 mutations in a high-throughput manner. Experimental Design: We evaluated the transforming activities and drug sensitivities of 55 nonsynonymous ERBB2 mutations using the mixed-all-nominated-in-one (MANO) method. Results: G776V, G778_S779insG, and L841V were newly revealed to be activating mutations. Although afatinib, neratinib, and osimertinib were shown to be effective against most of the ERBB2 mutations, only osimertinib demonstrated good efficacy against L755P and L755S mutations, the most common mutations in breast cancer. In contrast, afatinib and neratinib were predicted to be more effective than other inhibitors for the A775_776insYVMA mutation, the most frequent ERBB2 mutation in lung cancer. We surveyed the prevalence of concurrent ERBB2 mutation with gene amplification and found that approximately 30% of ERBB2-amplified urothelial carcinomas simultaneously carried ERBB2 mutations, altering their sensitivity to trastuzumab, an mAb against ERBB2. Furthermore, the MANO method was applied to evaluate the functional significance of 17 compound mutations within ERBB2 reported in the COSMIC database, revealing that compound mutations involving L755S were sensitive to osimertinib but insensitive to afatinib and neratinib. Conclusions: Several ERBB2 mutations showed varying sensitivities to ERBB2-targeted inhibitors. Our comprehensive assessment of ERBB2 mutations offers a fundamental database to help customize therapy for ERBB2-driven cancers. We identified several ERBB2 mutations as activating mutations related to tumorigenesis. In addition, our comprehensive evaluation revealed that several ERBB2 mutations showed varying sensitivities to ERBB2-targeted inhibitors, and thus, the functional significance of each variant should be interpreted precisely to design the best treatment for each patient. Clin Cancer Res; 24(20); 5112–22. ©2018 AACR.