snu-aidas/HVMap-dataset huggingface dataset:
Human T Cell Leukemia Virus Reactivation with Progression of Adult T-Cell Leukemia-Lymphoma

BACKGROUND Human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma (ATLL) has a very poor prognosis, despite trials of a variety of different treatment regimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and this has suggested that secondary genetic or epigenetic changes are important in disease pathogenesis. METHODS AND FINDINGS We prospectively investigated combination chemotherapy followed by antiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and 2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide, doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH) given for two to six cycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine, lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than one month due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objective response with median duration of response of thirteen months, and two complete remissions. During chemotherapy induction, viral RNA expression increased (median 190-fold), and virus replication occurred, coincident with development of disease progression. CONCLUSIONS EPOCH chemotherapy followed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma, but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternative therapies are sorely needed in this disease that simultaneously prevent virus expression, and are cytocidal for malignant cells.
Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial.

OBJECTIVES To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol. PARTICIPANTS Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for > or = 1 year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a beta agonist improvement of > or = 12% in FEV1. MAIN OUTCOME MEASURES The primary end point was the percentage of patients with at least one asthma exacerbation. RESULTS 20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to 5.0%). With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasone significantly increased FEV1 before a beta agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P < or = 0.001), whereas FEV1 after a beta agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated. CONCLUSION The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.
Asthma in United States Olympic athletes who participated in the 1996 Summer Games.

BACKGROUND Asthma prevalence appears to be increasing in the general population. We sought to determine whether asthma prevalence has also increased in highly competitive athletes. OBJECTIVE Our aim was to determine how many United States Olympic athletes who were chosen to participate in the 1996 Summer Olympic Games had a past history of asthma or symptoms that suggested asthma or took asthma medications. METHODS We analyzed responses to questions that asked about allergic and respiratory diseases on the United States Olympic Committee (USOC) Medical History Questionnaire that was completed by all athletes who were chosen to represent the US at the 1996 Summer Olympic Games in Atlanta. RESULTS Of the 699 athletes who completed the questionnaire, 107 (15.3%) had a previous diagnosis of asthma, and 97 (13.9%) recorded use of an asthma medication at some time in the past. One hundred seventeen (16.7%) reported use of an asthma medication, a diagnosis of asthma, or both (which was our basis for the diagnosis of asthma). Seventy-three (10. 4%) of the athletes were currently taking an asthma medication at the time that they were processed in Atlanta or noted that they took asthma medications on a permanent or semipermanent basis and were considered to have active asthma. Athletes who participated in cycling and mountain biking had the highest prevalence of having been told that they had asthma or had taken an asthma medication in the past (50%). Frequency of active asthma varied from 45% of cyclists and emountain bikers to none of the divers and weight lifters. Only about 11% of the athletes who participated in the 1984 Summer Olympic Games were reported to have had exercise-induced asthma on the basis of other criteria that may have been less restrictive. On the basis of these less restrictive criteria, more than 20% of the athletes who participated in the 1996 Olympic Games might have been considered to have had asthma. CONCLUSIONS Asthma appeared to have been more prevalent in athletes who participated in the 1996 Summer Games than in the general population or in those who participated in the 1984 Summer Games. This study also suggests that asthma may influence the sport that an athlete chooses.
Relapse specific mutations in NT5C2 in childhood acute lymphoblastic leukemia

Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.
Relationship between Sloan-Kettering virus expression and mouse follicular development

Sloan-Kettering virus gene product (Ski) is an unique nuclear pro-oncoprotein and belongs to the ski/sno proto-oncogene family. Ski plays multiple roles in a variety of cell types, it can induce both oncogenic transformation and terminal muscle differentiation when expressed at high levels. Ski/SnoN are important transcription regulators of the transforming growth factor-β (TGF-β) superfamily and function mainly through heterodimers. Since TGF-β superfamily are key regulators of follicle development and it has been previously shown that SnoN is also vital to follicle development, this research was conducted to clarify the relationship between Ski expression and mouse follicular development, in ovaries of neonatal and gonadotropin-induced immature mice by immunohistochemical and real-time PCR techniques. In postnatal mice, positive staining for Ski was highly detected in oocyte nuclei at postnatal day 1. With follicular development, the localization moved gradually from oocyte nuclei to perinuclear space and the total levels decreased. During the estrous cycle, Ski expression was apparent at proestrus and estrus, faint at metestrus, highest at diestrus. After injection of gonadotropin, Ski was found in perinuclear space and weak in oocyte nuclei. Following the initiation of luteinization, the expression of Ski was found in corpus luteum. Real-time PCR results also showed that Ski mRNA expression was opposite to ovulation-related genes during the cumulus expansion, with the development of the follicles, its expression level decreased. Ski is expressed in a specific manner during follicle development, ovulation and luteinization. So Ski might play essential roles in these processes especially during early follicular development.
Involvement of CB1 cannabinoid receptors in emotional behaviour

Rationale: Endogenous and exogenous cannabinoids acting through the CB1 cannabinoid receptors are implicated in the control of a variety of behavioural and neuroendocrine functions, including emotional responses, and learning and memory processes. Recently, knockout mice deficient in the CB1 cannabinoid receptor have been generated, and these animals result in an excellent tool to evaluate the neurophysiology of the endogenous cannabinoid system. Objectives: To establish the role of the CB1 cannabinoid receptor in several emotional-related behavioural responses, including aggressiveness, anxiety, depression and learning models, using CB1 knockout mice. Methods: We evaluated the spontaneous responses of CB1 knockout mice and wild-type controls under different behavioural paradigms, including the light/dark box, the chronic unpredictable mild stress, the resident–intruder test and the active avoidance paradigm. Results: Our findings showed that CB1 knockout mice presented an increase in the aggressive response measured in the resident–intruder test and an anxiogenic-like response in the light/dark box. Furthermore, a higher sensitivity to exhibit depressive-like responses in the chronic unpredictable mild stress procedure was observed in CB1 knockout mice, suggesting an increased susceptibility to develop an anhedonic state in these animals. Finally, CB1 knockout mice showed a significant increase in the conditioned responses produced in the active avoidance model, suggesting an improvement of learning and memory processes. Conclusions: Taken together these findings demonstrate that endogenous cannabinoids through the activation of CB1 receptors are implicated in the control of emotional behaviour and participate in the physiological processes of learning and memory.
Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients

Glioma is a most common type of primary brain tumors. Extracellular vesicles, in the form of exosomes, are known to mediate cell-cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we examined the cerebrospinal fluid (CSF) from patients with recurrent glioma for the levels of cancer-related miRNAs, and evaluated the values for prognosis by comparing the measures of CSF-, serum-, and exosome-contained miR-21 levels. Samples from seventy glioma patients following surgery were compared with those from brain trauma patients as a non-tumor control group. Exosomal miR-21 levels in the CSF of glioma patients were found significantly higher than in the controls; whereas no difference was detected in serum-derived exosomal miR-21 expression. The CSF-derived exosomal miR-21 levels correlated with tumor spinal/ventricle metastasis and the recurrence with anatomical site preference. From additional 198 glioma tissue samples, we verified that miR-21 levels associated with tumor grade of diagnosis and negatively correlated with the median values of patient overall survival time. We further used a lentiviral inhibitor to suppress miR-21 expression in U251 cells. The results showed that the levels of miR-21 target genes of PTEN, RECK and PDCD4 were up-regulated at protein levels. Therefore, we concluded that the exosomal miR-21 levels could be demonstrated as a promising indicator for glioma diagnosis and prognosis, particularly with values to predict tumor recurrence or metastasis.
Age‐associated microRNA expression in human peripheral blood is associated with all‐cause mortality and age‐related traits

Recent studies provide evidence of correlations of DNA methylation and expression of protein-coding genes with human aging. The relations of microRNA expression with age and age-related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole-blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 × 10-4 (Bonferroni-corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age-associated mRNA expression possibly driven by age-associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict 'microRNA age' that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Δage) and found that Δage was associated with all-cause mortality (hazards ratio 1.1 per year difference, P = 4.2 × 10-5 adjusted for sex and chronological age). Additionally, Δage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole-blood microRNA expression profiling. Age-associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age-related diseases.
Histone deacetylases (HDACs) in frontotemporal lobar degeneration.

AIMS Frontotemporal lobar degeneration (FTLD) is clinically and pathologically heterogeneous. Although associated with variations in MAPT, GRN and C9ORF72, the pathogenesis of these, and of other nongenetic, forms of FTLD, remains unknown. Epigenetic factors such as histone regulation by histone deacetylases (HDAC) may play a role in the dysregulation of transcriptional activity, thought to underpin the neurodegenerative process. METHODS The distribution and intensity of HDACs 4, 5 and 6 was assessed semi-quantitatively in immunostained sections of temporal cortex with hippocampus, and cerebellum, from 33 pathologically confirmed cases of FTLD and 27 controls. RESULTS We found a significantly greater intensity of cytoplasmic immunostaining for HDAC4 and HDAC6 in granule cells of the dentate gyrus in cases of FTLD overall compared with controls, and specifically in cases of FTLD tau-Picks compared with FTLD tau-MAPT and controls. No differences were noted between FTLD-TDP subtypes, or between the different genetic and nongenetic forms of FTLD. No changes were seen in HDAC5 in any FTLD or control cases. CONCLUSIONS Dysregulation of HDAC4 and/or HDAC6 could play a role in the pathogenesis of FTLD-tau associated with Pick bodies, although their lack of immunostaining implies that such changes do not contribute directly to the formation of Pick bodies.
The transcriptional program of sporulation in budding yeast

Diploid cells of budding yeast produce haploid cells through the developmental program of sporulation, which consists of meiosis and spore morphogenesis. DNA microarrays containing nearly every yeast gene were used to assay changes in gene expression during sporulation. At least seven distinct temporal patterns of induction were observed. The transcription factor Ndt80 appeared to be important for induction of a large group of genes at the end of meiotic prophase. Consensus sequences known or proposed to be responsible for temporal regulation could be identified solely from analysis of sequences of coordinately expressed genes. The temporal expression pattern provided clues to potential functions of hundreds of previously uncharacterized genes, some of which have vertebrate homologs that may function during gametogenesis.
Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity

Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (TH2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)–IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.
The behaviour change wheel: A new method for characterising and designing behaviour change interventions

BACKGROUND Improving the design and implementation of evidence-based practice depends on successful behaviour change interventions. This requires an appropriate method for characterising interventions and linking them to an analysis of the targeted behaviour. There exists a plethora of frameworks of behaviour change interventions, but it is not clear how well they serve this purpose. This paper evaluates these frameworks, and develops and evaluates a new framework aimed at overcoming their limitations. METHODS A systematic search of electronic databases and consultation with behaviour change experts were used to identify frameworks of behaviour change interventions. These were evaluated according to three criteria: comprehensiveness, coherence, and a clear link to an overarching model of behaviour. A new framework was developed to meet these criteria. The reliability with which it could be applied was examined in two domains of behaviour change: tobacco control and obesity. RESULTS Nineteen frameworks were identified covering nine intervention functions and seven policy categories that could enable those interventions. None of the frameworks reviewed covered the full range of intervention functions or policies, and only a minority met the criteria of coherence or linkage to a model of behaviour. At the centre of a proposed new framework is a 'behaviour system' involving three essential conditions: capability, opportunity, and motivation (what we term the 'COM-B system'). This forms the hub of a 'behaviour change wheel' (BCW) around which are positioned the nine intervention functions aimed at addressing deficits in one or more of these conditions; around this are placed seven categories of policy that could enable those interventions to occur. The BCW was used reliably to characterise interventions within the English Department of Health's 2010 tobacco control strategy and the National Institute of Health and Clinical Excellence's guidance on reducing obesity. CONCLUSIONS Interventions and policies to change behaviour can be usefully characterised by means of a BCW comprising: a 'behaviour system' at the hub, encircled by intervention functions and then by policy categories. Research is needed to establish how far the BCW can lead to more efficient design of effective interventions.
Pharmacological correction of a defect in PPARγ signaling ameliorates disease severity in Cftr-deficient mice

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.
Coding of Sweet, Bitter, and Umami Tastes Different Receptor Cells Sharing Similar Signaling Pathways

Mammals can taste a wide repertoire of chemosensory stimuli. Two unrelated families of receptors (T1Rs and T2Rs) mediate responses to sweet, amino acids, and bitter compounds. Here, we demonstrate that knockouts of TRPM5, a taste TRP ion channel, or PLCbeta2, a phospholipase C selectively expressed in taste tissue, abolish sweet, amino acid, and bitter taste reception, but do not impact sour or salty tastes. Therefore, despite relying on different receptors, sweet, amino acid, and bitter transduction converge on common signaling molecules. Using PLCbeta2 taste-blind animals, we then examined a fundamental question in taste perception: how taste modalities are encoded at the cellular level. Mice engineered to rescue PLCbeta2 function exclusively in bitter-receptor expressing cells respond normally to bitter tastants but do not taste sweet or amino acid stimuli. Thus, bitter is encoded independently of sweet and amino acids, and taste receptor cells are not broadly tuned across these modalities.