Miracle-dz/UniFAR-FTUs huggingface dataset:
ATM is activated by ATP depletion and modulates mitochondrial function through NRF1

We have uncovered new insights into the symptoms of ataxia-telangiectasia (A-T). Neurons with high physiological activity, particularly cerebellar Purkinje cells, have large and dynamic ATP demands. Depletion of ATP generates reactive oxygen species that activate ATM (the A-T Mutated gene product). Activated in this way, but not by DNA damage, ATM phosphorylates nuclear respiratory factor-1 (NRF1). This leads to NRF1 dimerization, nuclear translocation and the upregulation of nuclear-encoded mitochondrial genes, thus enhancing the capacity of the electron transport chain (ETC) and restoring mitochondrial function. In cells with ATM deficiency, resting ATP levels are normal, but cells replenish ATP poorly following surges in energy demand and chronic ATP insufficiency endangers cell survival. This is a particular problem for energy-intensive cells such as Purkinje cells, which degenerate in A-T. Our findings thus identify ATM as a guardian of mitochondrial output as well as genomic integrity, and suggest that alternate fuel sources may ameliorate A-T disease symptoms. Summary Oxidative stress, resulting from neuronal activity and depleted ATP levels, activates ATM, which phosphorylates NRF1, causing nuclear translocation and upregulation of mitochondrial gene expression. In ATM deficiency, ATP levels recover more slowly, particularly in active neurons with high energy demands.
The Cost of Osteoporosis, Osteopenia, and Associated Fractures in Australia in 2017

Osteoporosis and osteopenia are increasingly prevalent conditions among older adults. Not only do the fractures associated with poor bone health have significant health consequences for the individual, but also their economic impact is placing increasing financial burden on governments and society. This study aimed to determine the direct economic cost of osteoporosis, osteopenia, and fractures among Australians aged 50 years and older in 2017. This study uses previous Australian data on the incidence and prevalence of osteoporosis and osteopenia together with recent Australian data on health service utilization after fracture to provide an estimate of the economic burden of osteoporosis. A bottom‐up costing approach was used to determine the average direct health care and non‐health care total costs of a fracture, as well as the average community health service costs of managing individuals with osteoporosis or osteopenia. The total direct cost of osteoporosis in Australia in 2017 was estimated to be $3.44 billion (AUD 2017, USD 2.77 billion). Treatment of fractures accounted for 68% of total direct costs, and non‐fracture management of osteoporosis accounted for 32%. Hip fractures accounted for the highest proportion (43%) of the total direct cost of fractures, although fractures at “other” sites accounted for 38.5%. Fractures among individuals aged 70 years and older accounted for 74% of the direct costs (55% and 19% in women and men, respectively). Fracture costs in those with osteopenia accounted for 50% of direct fracture treatment costs. This up‐to‐date cost analysis estimated that costs in 2017 were three times higher than in 2007. These estimates will aid clinicians, policy makers, researchers, and health care organizations to acknowledge the economic importance of reducing osteoporosis‐related fractures and associated costs. This provides a strong public health case to promote bone health that will assist in reducing future fracture‐related costs. © 2018 American Society for Bone and Mineral Research.
Clinicopathological Pattern of Gastric Cancer of Yemeni Patients in Ibb Governorate

Objectives: To study the clinicopathological pattern of gastric cancer in-cluding the location of the tumor in the stomach and to compare our results with other studies. Design: Prospective study of patients confirmed with gastric malignancy during the period from July 2016 to July 2017. Setting: Specialized center of gastrointestinal and liver diseases in Ibb city, Yemen. Subjects: All patients with histopathological confirmation of gastric malig-nancy. Results: During the study period, we had 69 patients with gastric cancer; among them 48 were males and 21 were females, with male: Female ratio is 2.2:1. The age ranged between 35 years and 90 years and the mean age was 65.87 ± 12.79 years. Most of the patients presented with epigastric pain (87%), weight loss (72.5%), pallor (65.2%), dysphagia (47.8%), vomiting (42%), palpable epigastric mass (20.3%) and hematemesis/melena (18.8%). The cardiofundal location was encountered in 33 cases (47.8% ), 22 (45.8%) males and 11 (52.4%) females, the corpus location in 24 cases (26%), 20 (41.7%) males and 4 (19%) females, the antral location in 8 cases (11.6%), 4 (8.3%) males and 4 (19%) females and the whole stomach in 4 cases (5.8%), 2 (4.2%) males and 2 (9.5%) females. Adenocarcinoma constituted about 94.2%, of which the intestinal type was 87.5% and the diffuse type was 12.5%. The non-epithelial tumor was encounter 4.3%, of which 2.9% were lymphoma and 1.4% were GIST. Conclusion: In our studied patients, proximally located gastric cancer was the most common in both sexes.
Evaluation of aprepitant and fosaprepitant in pediatric patients

Single‐dose i.v. fosaprepitant has been approved as an alternative to 3 day oral aprepitant, a neurokinin‐1 receptor antagonist, and improves prevention of chemotherapy‐induced nausea and vomiting (CINV). Because fosaprepitant has shown similar efficacy to aprepitant in adult patients only, this study compared the efficacy and safety of aprepitant and fosaprepitant in pediatric patients.
Paclitaxel-loaded multifunctional nanoparticles for the targeted treatment of glioblastoma

Abstract Introduction: We hypothesised that the active targeting of αvβ3 integrin overexpressed in neoangiogenic blood vessels and glioblastoma (GBM) cells combined with magnetic targeting of paclitaxel- and SPIO-loaded PLGA-based nanoparticles could improve accumulation of nanoparticles in the tumour and therefore improve the treatment of GBM. Methods: PTX/SPIO PLGA nanoparticles with or without RGD-grafting were characterised. Their in vitro cellular uptake and cytotoxicity was evaluated by fluorospectroscopy and MTT assay. In vivo safety and anti-tumour efficacy of different targeting strategies were evaluated in orthotopic U87MG tumour model over multiple intravenous injections. Results: The nanoparticles of 250 nm were negatively charged. RGD targeted nanoparticles showed a specific and higher cellular uptake than untargeted nanoparticles by activated U87MG and HUVEC cells. In vitro IC50 of PTX after 48 h was ∼1 ng/mL for all the PTX-loaded nanoparticles. The median survival time of the mice treated with magnetic targeted nanoparticles was higher than the control (saline) mice or mice treated with other evaluated strategies. The 6 doses of PTX did not induce any detectable toxic effects on liver, kidney and heart when compared to Taxol. Conclusion: The magnetic targeting strategy resulted in a better therapeutic effect than the other targeting strategies (passive, active).
The effect of iodine deficiency during pregnancy on child development

It is well known that severe iodine deficiency during pregnancy may cause impaired brain development in the child, with effects on cognitive and motor function, hearing and speech. Whether mild-to-moderate deficiency also affects neurological development is less well known, but in the past decade a number of observational studies have been conducted to answer this question and these studies are reviewed in this article. The picture is now emerging that even mild-to-moderate iodine deficiency during pregnancy may be associated with subtle impairments in cognition and school performance, although the evidence from randomised controlled trials is still lacking. As global efforts to eradicate iodine deficiency in populations continue, it is more likely that mild-to-moderate, rather than severe, iodine deficiency will be the issue of concern in pregnancy, and therefore further research in regions of mild-to-moderate deficiency is required to strengthen the research base and to inform public-health policy.
Progressive Resistance Training to Impact Physical Fitness and Body Weight in Pancreatic Cancer Patients: A Randomized Controlled Trial

Objectives Maintaining or improving muscle mass and muscle strength is an important treatment goal in pancreatic cancer (PC) patients because of high risk of cachexia. Therefore, we assessed feasibility and effectivity of a 6-month progressive resistance training (RT) in PC patients within a randomized controlled trial. Methods Sixty-five PC patients were randomly assigned to either supervised progressive RT (RT1), home-based RT (RT2), or usual care control group (CON). Both exercise groups performed training 2 times per week for 6 months. Muscle strength for knee, elbow, and hip extensors and flexors and cardiorespiratory fitness and body weight were assessed before and after the intervention period. Results Of 65 patients, 43 patients were analyzed. Adherence rates were 64.1% (RT1) and 78.4% (RT2) of the prescribed training sessions. RT1 showed significant improvements in elbow flexor/extensor muscle strength and in maximal work load versus CON and RT2 (P < 0.05). Further, knee extensors were significantly improved for RT1 versus CON (P < 0.05). Body weight revealed no significant group differences over time. Conclusions Progressive RT was feasible in PC patients and improved muscle strength with significant results for some muscle groups. Supervised RT seemed to be more effective than home-based RT.
Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential

ABSTRACT Introduction: Chronic breathlessness is a common and distressing symptom of advanced disease with few effective treatments. Central nervous system mechanisms are important in respiratory sensation and control. Consequently, drugs which may modify processing and perception of afferent information in the brain may have a role. Antidepressants have been proposed; however, current evidence is limited. Of potentially suitable antidepressants, mirtazapine is an attractive option given its tolerability profile, low cost, and wide availability, along with additional potential benefits. Areas covered: The paper provides an overview of the physiology of breathlessness, with an emphasis on central mechanisms, particularly the role of fear circuits and the associated neurotransmitters. It provides a potential rationale for how mirtazapine may improve chronic breathlessness and quality of life in patients with advanced disease. The evidence was identified by a literature search performed in PubMed through to October 2018. Expert opinion: Currently, there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease. Mirtazapine is a promising candidate to pursue, with definitive randomized controlled trials required to determine its efficacy and safety in this setting.
Complex DNA structures trigger copy number variation across the Plasmodium falciparum genome

Abstract Antimalarial resistance is a major obstacle in the eradication of the human malaria parasite, Plasmodium falciparum. Genome amplifications, a type of DNA copy number variation (CNV), facilitate overexpression of drug targets and contribute to parasite survival. Long monomeric A/T tracks are found at the breakpoints of many Plasmodium resistance-conferring CNVs. We hypothesize that other proximal sequence features, such as DNA hairpins, act with A/T tracks to trigger CNV formation. By adapting a sequence analysis pipeline to investigate previously reported CNVs, we identified breakpoints in 35 parasite clones with near single base-pair resolution. Using parental genome sequence, we predicted the formation of stable hairpins within close proximity to all future breakpoint locations. Especially stable hairpins were predicted to form near five shared breakpoints, establishing that the initiating event could have occurred at these sites. Further in-depth analyses defined characteristics of these ‘trigger sites’ across the genome and detected signatures of error-prone repair pathways at the breakpoints. We propose that these two genomic signals form the initial lesion (hairpins) and facilitate microhomology-mediated repair (A/T tracks) that lead to CNV formation across this highly repetitive genome. Targeting these repair pathways in P. falciparum may be used to block adaptation to antimalarial drugs.
Mental Health Self-Directed Care Financing: Efficacy in Improving Outcomes and Controlling Costs for Adults With Serious Mental Illness.

OBJECTIVE: Self-directed care allows individuals with disabilities and elderly persons to control public funds to purchase goods and services that help them remain outside institutional settings. This study examined effects on outcomes, service costs, and user satisfaction among adults with serious mental illness. METHODS: Public mental health system clients were randomly assigned to self-directed care (N=114) versus services as usual (N=102) and assessed at baseline and 12 and 24 months. The primary outcome was self-perceived recovery. Secondary outcomes included psychosocial status, psychiatric symptom severity, and behavioral rehabilitation indicators. Mixed-effects random-regression analysis tested for longitudinal changes in outcomes between the two conditions. Differences in service costs were analyzed with negative binomial and zero-inflated negative binomial regression models. RESULTS: Compared with the control group, self-directed care participants had significantly greater improvement over time in recovery, self-esteem, coping mastery, autonomy support, somatic symptoms, employment, and education. No between-group differences were found in total per-person service costs in years 1 and 2 or both years combined. However, self-directed care participants were more likely than control group participants to have zero costs for six of 12 individual services and to have lower costs for four. The most frequent nontraditional purchases were for transportation (21%), communication (17%), medical care (15%), residential (14%), and health and wellness needs (11%). Client satisfaction with mental health services was significantly higher among intervention participants, compared with control participants, at both follow-ups. CONCLUSIONS: The budget-neutral self-directed care model achieved superior client outcomes and greater satisfaction with mental health care, compared with services as usual.
Risk of high‐grade malignancy in parotid gland tumors as classified by the Milan System for Reporting Salivary Gland Cytopathology

BACKGROUND The Milan System for Reporting Salivary Gland Cytopathology (Milan System) has previously shown its diagnostic utility by categorizing the seven cytology findings in salivary gland lesions. However, there has been lack of study about the risk of high-grade malignancy in the cytology diagnosis based on the Milan System. Thus, we tried to identify the diagnostic ability of the Milan System for high-grade malignancy and to suggest an improved diagnostic approach for preoperative estimation of high-grade malignancy using the Milan System. METHODS A total of 413 patients with parotid gland tumors, who had undergone surgical resection from 2011 to 2015 were included in the present study retrospectively. Cytopathology was reclassified according to the Milan System by two independent reviewers. The outcomes were risk of malignancy and risk of high-grade malignancy. The diagnostic performance of the Milan System category [Malignant] for detecting high-grade malignancy was calculated. RESULTS The risk of malignancy was 83.3% and 100% in the Milan System categories [Suspicious for Malignancy] and [Malignant], respectively. Meanwhile, the risk of high-grade malignancy was 16.7% and 55.9% in these two categories. Disease-free survival of patients with high-grade malignancy was significantly worse than those with low- and intermediate-grade malignancy. Union combining the Milan System category [Malignant] with the presence of nodal metastasis suggested high-grade malignancy with an acceptable diagnostic sensitivity (0.889-0.963) and negative predictive value (0.900-0.966). CONCLUSIONS The Milan System category [Malignant] with the presence of nodal metastasis suggested parotid gland tumors as high-grade malignancy in a pretreatment setting.
Factors affecting the accuracy of 18F-FDG PET/CT in evaluating axillary metastases in invasive breast cancer

Background and Aim: There are conflicting results of studies on accuracy of positron emission tomography (PET)/computed tomography (CT) for axillary staging. The aim of this study is to determine the factors affecting the efficacy of 18F-fluorodeoxyglucose (18F-FDG) PET/CT in detecting axillary metastases in invasive breast cancer. Materials and Methods: Data of 232 patients with invasive breast cancer who underwent 18F-FDG PET/CT examination before surgery between January 2013 and September 2017 were reviewed retrospectively. Histopathological examination of axillary lymph nodes (ALNs) was used as a reference to assess the efficacy of 18F-FDG PET/CT in detecting axillary metastases. Results: While 134 (57.8%) patients had axillary metastases as detected in 18F-FDG PET/CT scans, histopathologically axillary metastases were detected in 164 (70.7%) patients. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of 18F-FDG PET/CT in detection of axillary metastasis were 72.56%, 77.94%, 88.8%, 54%, and 74.1%, respectively. The false-negative and false-positive rates were 27.4% and 22%, respectively. In univariate analysis, patients' age, estrogen receptor positivity, higher ALN SUVmax, greater tumor size, and lymph node size determined by 18F-FDG PET/CT were all significantly associated with accuracy of 18F-FDG PET/CT for axillary metastasis. In multivariate analysis, tumor size determined by 18F-FDG PET/CT and ALN SUVmax were independent variables associated with axillary metastasis. The accuracy of 18F-FDG PET/CT for axillary metastasis was higher in patients with a larger tumor (≥19.5 mm) and a higher ALN SUVmax (≥3.2). Conclusion: 18F-FDG PET/CT should not be routinely used for axillary staging, especially in patients with small tumors. It cannot eliminiate the necessity of sentinel lymph node biopsy. When it is used, both visual information and optimal cut-off value of axillary node SUVmax should be taken into consideration.
The role of distractor inhibition in the attentional boost effect: evidence from the R/K paradigm

ABSTRACT Stimuli presented with targets in a detection task are later recognised more accurately than those presented with distractors, an unusual effect labelled the attentional boost effect (ABE). This effect may reflect an enhancement triggered by target detection, the inhibition of distractor rejection, or some combination of both. To test these possibilities, the present study adopted a baseline similar to that of Swallow and Jiang ([2014b]. The attentional boost effect really is a boost: evidence from a new baseline. Attention, Perception, & Psychophysics, 76(5), 1298–1307); the goal was to separate target-induced enhancements from distractor-induced inhibition. An R/K procedure was applied to further explore the kind of memory that might be affected by target detection or distractor rejection. The results show that the memory advantage for target-paired words was robust relative to that of baseline words; this advantage was mainly observed in R responses. More importantly, a memory reduction was also observed for distractor-paired words relative to baseline words, though this reduction was only observed in R responses. These data led us to conclude that the ABE was triggered by both processes: target-induced enhancement and distractor-induced inhibition. Moreover, both processes were more likely to affect recollection-based recognition.
Variation in the Caprine KAP24-1 Gene Affects Cashmere Fibre Diameter

Simple Summary The keratin-associated proteins (KAPs) are structural components of cashmere fibres. The human and sheep orthologous gene encoding high-sulphur (HS)-KAP24-1 is now described for the goat species. Our study identified the caprine KAP24-1 gene on goat chromosome 1, and we found that the gene was polymorphic and that variation in the gene affected cashmere fibre diameter. Abstract The keratin-associated proteins (KAPs) are structural components of cashmere fibres. The gene encoding the high-sulphur (HS)-KAP24-1 (KRTAP24-1) has been identified in humans and sheep, but it has not been described in goats. In this study, we report the identification of caprine KRTAP24-1, describe variation in this gene, and investigate the effect of this variation on cashmere traits. A search for sequences orthologous to the ovine gene in the goat genome revealed a 774 bp open reading frame on chromosome 1, which could encode an HS-KAP. Based on this goat genome sequence and comparison with ovine KRTAP24-1 sequences, polymerase chain reaction (PCR) primers were designed to amplify an 856 bp fragment that would contain the entire coding region of the putative caprine KRTAP24-1. Use of this PCR amplification with subsequent single-strand conformation polymorphism (SSCP) analysis of the amplicons identified four distinct patterns of DNA bands on gel electrophoresis, with these representing four different DNA sequences (A to D), in 340 Longdong cashmere goats reared in China. The variant sequences had the highest similarity to KRTAP24-1 sequences from sheep and humans, suggesting that they are variants of caprine KRTAP24-1. Nine single-nucleotide polymorphisms (SNPs) were detected in the gene, including four non-synonymous SNPs and an SNP in proximity to the ATG start codon. Of the three common genotypes (AA, AB, and BB) found in these Longdong cashmere goats, cashmere fibres from goats of genotype AA had lower mean fibre diameter (MFD) than did those of genotype AB, and cashmere fibres from goats of genotype AB had lower MFD than did those from goats of genotype BB.