Miracle-dz/UniFAR-FTUs huggingface dataset:
The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications

Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage. Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation. Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid β-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair–related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies. Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. Clin Cancer Res; 24(21); 5433–44. ©2018 AACR.
Design of novel quinoline-aminopiperidine derivatives as Mycobacterium tuberculosis (MTB) GyrB inhibitors: an in silico study

Abstract Tuberculosis (TB) is an infectious disease that causes a number of deaths, and the development of new, safer and more adequate TB inhibitors/drugs has become a necessity as well as a great challenge. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of anti-tubercular drug discovery. To design the novel and potent Mycobacterium tuberculosis (MTB) inhibitors, we performed molecular modeling studies that combined the 3D-QSAR, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. Forty eight quinoline-aminopiperidine inhibitors which act on DNA gyrase B subunit were used for constructing 3D-QSAR models. The results showed that the best CoMFA model had the high performance with q2 = 0.643, r2 = 0.947, while the best CoMSIA model yielded q2 = 0.536, r2 = 0.948. The contour map was in good agreement with the docking and MD simulations which strongly demonstrated that the molecular modeling was reliable. Based on this information, several potential compounds were designed and their inhibitory activities were also verified by the accomplished models and ADME/T predictions. We hope that our research could bring new ideas to facilitate the development of novel inhibitors with higher inhibitory activity for TB. Communicated by Ramaswamy H. Sarma
Selection of an ASIC1a-blocking combinatorial antibody that protects cells from ischemic death

Significance Unfortunately, the need for ideal medical treatment of acute ischemic stroke is still largely unmet. One of the contributing factors to the deleterious neuronal death is the opening of acid-sensing ion channels (ASICs) at reduced pH, which in turn, activates other calcium-permeable channels that initiate the catastrophic cascade. Here, we report the discovery of an antibody that blocks the ASIC1a with high specificity and potency. Infusion of this antibody reduces the damaged area from brain ischemia in the murine stroke model. We hypothesize that using antibodies to target ASIC1a is a valid approach for future stroke therapy. The antibody that we report here has the potential to be further developed as drug candidate. Acid-sensing ion channels (ASICs) have emerged as important, albeit challenging therapeutic targets for pain, stroke, etc. One approach to developing therapeutic agents could involve the generation of functional antibodies against these channels. To select such antibodies, we used channels assembled in nanodiscs, such that the target ASIC1a has a configuration as close as possible to its natural state in the plasma membrane. This methodology allowed selection of functional antibodies that inhibit acid-induced opening of the channel in a dose-dependent way. In addition to regulation of pH, these antibodies block the transport of cations, including calcium, thereby preventing acid-induced cell death in vitro and in vivo. As proof of concept for the use of these antibodies to modulate ion channels in vivo, we showed that they potently protect brain cells from death after an ischemic stroke. Thus, the methodology described here should be general, thereby allowing selection of antibodies to other important ASICs, such as those involved in pain, neurodegeneration, and other conditions.
Evaluation of the Relationship Between Attention Deficit Hyperactivity Disorder Symptoms and Chronotype cycle, sleep habits, circadian preference

Introduction: The aim of the study is to investigate the relationship between circadian characteristics and behavioral problems in children with Attention Deficit Hyperactivity Disorder (ADHD) (n=53), and to compare this group with healthy controls (n=38). Method: Fifty-three medication-free children with ADHD, aged 6–12 years, and 38 healthy children, age and sex matched, participated. Parents completed the Conners’ Parent Rating Scale-Revised, the Children’s Chronotype Questionnaire (CCTQ), and the Children’s Sleep Habits Questionnaire (CSHQ) to assess sleep variables. Results: ADHD children had more sleep-onset problems and parasomnias (in CSHQ) compared to healthy controls. However, circadian preferences did not differ between the groups in CCTQ scores. Another important finding was a mild correlation between parasomnia, bedtime on schooldays, and ADHD symptoms. Conclusion: Our study showed that children with ADHD showed more resistance to going to bed than did controls on school days. However, in contrast to our hypothesis, morningness/eveningness preference did not differ from controls in ADHD children. ABSTRACT (n=53) ve ve daha önce yaş arası 53 çocuk ile yaş ve cinsiyet açısından benzer özellikte olan 38 sağlıklı çocuk çalışmaya alınmıştır. Uyku ile ilgili değişkenlerin incelenmesi için ebeveynler Conners Anababa Dereceleme Ölçeği Yenilenmiş Uzun Formu, Çocuk Kronotip Ölçeği (CKÖ) ve Çocuk Uyku Alışkanlıkları Ölçeklerini (ÇUAÖ) doldurmuştur. Bulgular: DEHB tanılı çocuklarında sağlıklı kontrollere göre daha fazla uykuya dalma ve parasomni şikayetleri vardır. Ancak, CKÖ’ye this to investigate circadian preferences, sleep habits (such as bedtime resistance and sleep-onset insomnia), and ADHD symptoms in children with ADHD. In our study, we assumed that children with ADHD who were eveningness types had more inattention problems.
Dysbiosis in Children Born by Caesarean Section

The rate of Caesarean-section delivery in the United States has increased by 60% from 1996 through to 2013 and now accounts for > 30% of births [CDC, 2017]. The purpose of this review is to present the current understanding of both the microbial risk factors that increase the likelihood of a Caesarean-section delivery and the microbial dysbiosis that is thought to result from the Caesarean section. We provide examples of research into the impact of early-life microbial dysbiosis on infant development and long-term health outcomes, as well as consider the efficacy and the long-term implications of microbiome-based therapies to mitigate this dysbiosis. The steep rise in the Caesarean-section delivery rate makes it imperative to understand the potential of microbiota modulation for the treatment of dysbiosis.
A Synergistic Formulation of Plant Extracts Decreases Postprandial Glucose and Insulin Peaks: Results from Two Randomized, Controlled, Cross-Over Studies Using Real-World Meals

This study investigated the efficacy of a plant-derived dietary supplement with respect to decreasing postprandial glucose and insulin peaks after the intake of real-world meals. Two randomized, double-blind, placebo-controlled, cross-over experiments were conducted on healthy subjects who received a supplement containing extracts of white mulberry, white bean, and green coffee or one containing the three extracts with added fibre before consuming high-GI/GL (glycaemic index/glycaemic load) meals. In study one, 32 subjects received an investigational product/placebo before a standardized meal at two visits. In study two, 150 subjects received an investigational product/placebo before five different standardized meals. Postprandial glucose and insulin concentrations were lower 20–35 min after meal intake among subjects taking the investigational product, and fewer episodes of postprandial reactive hypoglycaemia were noted. For example, after consuming breakfast cereal with milk, lower glucose peaks were observed for the investigational product (vs. placebo) after 20 min (100.2 ± 1.97 vs. 112.5 ± 3.12 mg/dL, respectively; p < 0.01); lower insulin peaks were noted at the same time point (45.9 ± 4.02 IU/mL vs. 68.2 ± 5.53 IU/mL, respectively, p < 0.01). The combined formulation decreases the adverse consequences of high-GI/GL meal consumption. It can be an effective dietary supplement for the management of metabolic syndrome and type 2 diabetes mellitus.
Comorbidities, Complications and Non-Pharmacologic Treatment in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal disease. The treatment is challenging and nowadays a comprehensive approach based not only in pharmacological strategies is necessary. Identification and control of comorbidities, non-pharmacological treatment, prevention and management of exacerbations as well as other areas of care (social, psychological) are fundamental for a holistic management of IPF. Gastroesophageal reflux, pulmonary hypertension, obstructive sleep apnea, combined with emphysema, lung cancer and cardiovascular involvement are the main comorbidities associated with IPF. Non-pharmacological treatment includes the use of oxygen in patients with rest or nocturnal hypoxemia and other support therapies such as non-invasive ventilation or even a high-flow nasal cannula to improve dyspnea. In some patients, lung transplant should be considered as this enhances survival. Pulmonary rehabilitation can add benefits in outcomes such control of dyspnea, exercise capacity distance and, overall, improve the quality of life; therefore it should be considered in patients with IPF. Also, multidisciplinary palliative care programs could help with symptom control and psychological support, with the aim of maintaining quality of life during the whole process of the disease. This review intends to provide clear information to help those involved in IPF follow up to improve patients’ daily care.
Extracellular Vesicles Secreted by Human Urine-Derived Stem Cells Promote Ischemia Repair in a Mouse Model of Hind-Limb Ischemia

Background/Aims: Our previous studies have shown that human urine-derived stem cells (USCs) have great potential as a cell source for cytotherapy and tissue engineering and that extracellular vesicles (EVs) secreted by USCs (USCs-EVs) can prevent diabetes-induced kidney injury in an animal model. The present study was designed to evaluate the effects of USCs-EVs on ischemia repair. Methods: USCs-EVs were isolated and purified by a battery of centrifugation and filtration steps. The USCs-EVs were then characterized by transmission electron microscopy, western blot and tunable resistive pulse sensing techniques. After intramuscularly transplanting USCs-EVs into an ischemic mouse hind-limb, we observed the therapeutic effects of USCs-EVs on perfusion by laser doppler perfusion imaging, angiogenesis and muscle regeneration by histology and immunohistochemistry techniques over 21 days. We subsequently tested whether USCs-EVs can induce the proliferation of a human microvascular endothelial cell line HMEC-1 and a mouse myoblast cell line C2C12 by cell counting kit 8 assay in vitro. Meanwhile, the potential growth factors in the USCs-EVs and supernatants of the USCs cultures were detected by enzyme-linked immunosorbent assay. Results: The USCs-EVs were spherical vesicles with a diameter of 30–150 nm and expressed exosomal markers, such as CD9, CD63 and Tsg101. Ischemic limb perfusion and function were markedly increased in the hind-limb ischemia (HLI) model after USCs-EVs administration. Moreover, angiogenesis and muscle regeneration levels were significantly higher in the USCs-EVs treatment group than in the PBS group. The in vitro experiments showed that USCs-EVs facilitated HMEC-1 and C2C12 cell proliferation in a dose-dependent manner. Conclusions: These results revealed for the first time that USCs-EVs efficiently attenuate severe hind-limb ischemic injury and represent a novel therapy for HLI.
Topical photodynamic therapy with 5-aminolevulinic acid in Chinese patients with Rosacea

ABSTRACT Background: Rosacea is difficult to cure and frequently recurs. Topical photodynamic therapy (PDT) has been tentatively used, with only preliminary results reported. Objective: To evaluate the efficacy and safety of topical PDT in Chinese patients with rosacea. Methods & Materials: Seventeen participants with rosacea were treated three times using 5-aminolevulinic acid (ALA)-PDT at intervals of 7–10 days. Papule and pustule numbers, erythema severity, telangiectasia severity, physician’s global assessment (PGA) score (1 [best]–6), and patient satisfaction score (0–3 [highest]) were assessed. Rosacea improvement and the total effective rate were calculated. Stratum corneum hydration and sebum levels, and the melanin index (MI) and erythema index (EI) were measured non-invasively. Results: After three treatments with ALA-PDT, the total effective rate (≥50% improvement) was 64.71%, mean PGA score was 2.88 ± 0.93, and mean patient satisfaction score was 1.71 ± 0.69. The EI significantly decreased 1 month after the final treatment (from 468 ± 80.61 to 439 ± 77.78 for the forehead and from 507.65 ± 92.51 to 483.27 ± 78.32 for the nasal ala). Four participants received three additional treatments. They achieved 50–74% improvement after three treatments and ≥75% improvement after six treatments. Conclusion: ALA-PDT is safe and effective for treating rosacea.
Multiple Resolution Residually Connected Feature Streams for Automatic Lung Tumor Segmentation From CT Images

Volumetric lung tumor segmentation and accurate longitudinal tracking of tumor volume changes from computed tomography images are essential for monitoring tumor response to therapy. Hence, we developed two multiple resolution residually connected network (MRRN) formulations called incremental-MRRN and dense-MRRN. Our networks simultaneously combine features across multiple image resolution and feature levels through residual connections to detect and segment the lung tumors. We evaluated our method on a total of 1210 non-small cell (NSCLC) lung tumors and nodules from three data sets consisting of 377 tumors from the open-source Cancer Imaging Archive (TCIA), 304 advanced stage NSCLC treated with anti- PD-1 checkpoint immunotherapy from internal institution MSKCC data set, and 529 lung nodules from the Lung Image Database Consortium (LIDC). The algorithm was trained using 377 tumors from the TCIA data set and validated on the MSKCC and tested on LIDC data sets. The segmentation accuracy compared to expert delineations was evaluated by computing the dice similarity coefficient, Hausdorff distances, sensitivity, and precision metrics. Our best performing incremental-MRRN method produced the highest DSC of 0.74 ± 0.13 for TCIA, 0.75±0.12 for MSKCC, and 0.68±0.23 for the LIDC data sets. There was no significant difference in the estimations of volumetric tumor changes computed using the incremental-MRRN method compared with the expert segmentation. In summary, we have developed a multi-scale CNN approach for volumetrically segmenting lung tumors which enables accurate, automated identification of and serial measurement of tumor volumes in the lung.
Chronic effects of lead exposure on topsmelt fish (Atherinops affinis): Influence of salinity, organism age, and relative sensitivity to other marine species

The aim of the present study was to determine the influence of salinity and organism age on the chronic toxicity of waterborne lead (Pb) to Atherinops affinis and to compare the relative Pb sensitivity of A. affinis with other marine species. Chronic Pb exposure experiments were conducted in a water flow‐through testing system. Survival, standard length, dry weight, and tissue Pb concentration were measured and lethal concentrations (LCs), effect concentrations (ECs), and bioconcentration factors (BCFs) were calculated. In general, increasing salinity and organism age decreased Pb toxicity. The LC50s for larval fish at 14 and 28 ppt salinity were 15.1 and 79.8 μg/L dissolved Pb, respectively; whereas, the LC50 for juvenile fish was 167.6 μg/L dissolved Pb at 28 ppt salinity. Using standard length data, the EC10 values for larval fish were 16.4 and 82.4 μg/L dissolved Pb at 14 and 28 ppt salinity, respectively. The dry weight EC25s for low and high salinity were 15.6 and 61.84 μg/L dissolved Pb, respectively. The BCFs were higher with the lower salinity study (1703) in comparison to the higher salinity study (654). Results of Pb speciation calculation showed higher fraction of Pb2+ in water with lower salinity, explaining the higher observed toxicity of Pb in lower salinity water than higher salinity water. Atherinops affinis is more sensitive to Pb than several other marine species. Evidence of abnormal swimming and skeletal deformities were observed in Pb exposure treatments. Results of the present study are useful for marine biotic ligand modeling and support ecological risk assessment and deriving Pb environmental quality criteria for marine environments. Environ Toxicol Chem 2018;37:2705–2713. © 2018 SETAC
Acute Reduction in Spirometry Values After Prolonged Exercise Among Recreational Runners

BACKGROUND: Prolonged endurance running may acutely reduce spirometric lung values. This study examined changes in spirometry before and immediately after prolonged endurance exercise (running and/or walking). Specifically, we examined potential factors that predict the presence of at least a 10% postexercise reduction in FEV1. METHODS: After institutional review board approval, recruitment occurred at a pre-race exposition, where informed consent was obtained. Pre-and post-race spirometry measurements were taken from 79 study subjects who competed in a half-marathon (n = 66) or a marathon (n = 13). Spirometry was performed 1–2 days before the marathon or half-marathon and 25 min after finish the race. RESULTS: We identified a subgroup of 23 subjects with a postexercise decrease in FEV1 of ≥10%. In this subgroup, the mean post-race values for FEV1, FVC, and peak expiratory flow were 19–24% lower than the pre-race values. In the 56 subjects with a change in FEV1 of <10%, the mean post-race changes in spirometry values were not >6%. There was no difference between the 2 groups in sex distribution or between subjects who completed the half-marathon or the full marathon. For every 1-y increase in age, the likelihood of developing a postexercise reduction in FEV1 of at least 10% decreased by nearly 10% (R2 = 0.15, P = .003). CONCLUSIONS: Exercise-induced bronchoconstriction (EIB) is the most probable explanation for the reduction in post-race FEV1. Prolonged endurance exercise reduced spirometric lung function by ∼20% in those with EIB. Age was the only predictor for EIB, and EIB did not affect the finish times among recreational runners and/or walkers.
Obesity bias among preclinical and clinical chiropractic students and faculty at an integrative health care institution: A cross-sectional study.

OBJECTIVE: The purpose of this study was to assess the prevalence of obesity bias among preclinical and clinical chiropractic students and faculty at an integrative health care academic institution. METHODS: This was a cross-sectional quantitative, single-method survey with group comparison using the Beliefs About Obese Persons scale (BAOP) and the Attitudes Toward Obese Persons scale. Both instruments were administered as a single 28 question survey via email to 450 students and 46 faculty members in a doctor of chiropractic (DC) program. Differences were determined by 2 tailed t tests. RESULTS: The response rate for faculty and students was 31% and 65%, respectively. One hundred forty-three DC students, preclinical ( n = 65) and clinical ( n = 78), and 30 DC faculty, preclinical ( n = 15) and clinical ( n = 15) completed the survey. Both students and faculty harbored antiobesity attitudes and moderate antiobesity beliefs. Students demonstrated slightly more positive attitudes toward obese persons than did preclinical faculty. Although preclinical faculty did not demonstrate more biased attitudes than did preclinical students ( p = .057), they were more biased than clinical students ( p = .26). On the BAOP, preclinical faculty scored significantly lower than both preclinical students and clinical students ( p = .013 and .017, respectively). CONCLUSION: Obesity bias was common among clinical and preclinical chiropractic students and faculty at our institution. A cultural shift that reduces bias may require changes in both the curriculum and cocurriculum.
Understanding Adolescents’ Experiences of Self-Harm: Secondary Analysis of Family Therapy Sessions from the SHIFT Trial

The objective of this study was to explore, using first-hand accounts, adolescents’ understandings of why they self-harmed, what their responses to self-harm were, and how they resisted or ceased self-harm. Secondary analysis was conducted of video-recorded family therapy sessions from the Self-harm Intervention: Family Therapy (SHIFT Trial). Recordings of 22 participants, approximately 170 hours of footage, formed the dataset. The study developed 5 core themes: (1) Distress can be difficult to convey; (2) Self-harm and suicidal ideation: a complex relationship; (3) Self-harm as a form of communication; (4) Self-harm to manage emotions; and (5) Moving forward. Self-harm was a means of communicating distress as well as managing emotions. Accounts highlighted the complex interplay between self-harm and suicidal intent. Encouragingly, many participants described being able to resist self-harm.