tbuckley/cabot-search huggingface dataset:
がん:10,000人の患者の前向き臨床研究で行われた塩基配列解読から明らかになった転移がんの変異の全体像
Authors: Zehir Ahmet, Benayed Ryma, Shah Ronak H, Syed Aijazuddin, Middha Sumit, Kim Hyunjae R, Srinivasan Preethi, Hameed Meera, Dogan Snjezana, Ross Dara S, Hechtman Jaclyn F, Delair Deborah F, Yao JinJuan, Mandelker Diana L, Cheng Donavan T, Chandramohan Raghu, Mohanty Abhinita S, Ptashkin Ryan N, Jayakumaran Gowtham, Prasad Meera, Syed Mustafa H, Rema Anoop Balakrishnan, Liu Zhen Y, Nafa Khedoudja, Borsu Laetitia, Sadowska Justyna, Casanova Jacklyn, Bacares Ruben, Kiecka Iwona J, Razumova Anna, Son Julie B, Stewart Lisa, Baldi Tessara, Mullaney Kerry A, Al‐Ahmadie Hikmat, Vakiani Efsevia, Camacho Niedzica, Won Helen H, Klimstra David S, Arcila Maria E, Ladanyi Marc, Berger Michael F, Gao Jianjiong, Chakravarty Debyani, Gross Benjamin E, Kundra Ritika, Heins Zachary J, Chen Hsiao‐Wei, Phillips Sarah, Zhang Hongxin, Wang Jiaojiao, Ochoa Angelica, Taylor Barry S, Schultz Nikolaus, Solit David B, Devlin Sean M, Abeshouse Adam A, Penson Alexander, Jonsson Philip, Chang Matthew T, Hellmann Matthew D, Schram Alison M, Abida Wassim, Cercek Andrea, Feldman Darren R, Gounder Mrinal M, Harding James J, Iyer Gopa, Janjigian Yelena Y, Jordan Emmet J, Kelly Ciara M, Lowery Maeve A, Raj Nitya, Razavi Pedram, Shoushtari Alexander N, Soumerai Tara E, Varghese Anna M, Yaeger Rona, Riely Gregory J, Saltz Leonard B, Scher Howard I, Sabbatini Paul J, Robson Mark E, Baselga Jose, Hyman David M, Barron David A, Wills Jonathan, Eubank Michael, Thomas Stacy B, Gardos Stuart M, Reales Dalicia N, Galle Jesse, Durany Robert, Cambria Roy, Coleman Jonathan, Bochner Bernard, Hakimi A Ari, Morris Luc G T, Omuro Antonio M, Shukla Neerav
Journal: Nature Medicine (2017)
Abstract 324: Analysis of Transcriptome Profiles Identifies Novel Genes in Pathological Cardiac Hypertrophy
Authors: Jennifer Chyu, Yiqiang Zhang, Robb MacLellan
Journal: Circulation Research (2013)

Both the underlying cause and resulting consequence of many cardiovascular diseases is the permanent loss of contractile cardiac myocytes (CMs). Because the vertebrate heart has no innate ability to regenerate, the response to disease stimuli is limited to hypertrophy, an initial response to preserve cardiac function. However, sustained hypertrophy can turn the growth response of myocytes to one of cell death leading to pathological ventricular remodeling and decreased cardiac function. In this study, we are interested in identifying novel therapeutic gene targets that play a role in cardiac hypertrophic progression. To identify differentially expressed genes in hypertrophy, we utilized trans-aortic constriction (TAC) to induce hypertrophy in mice and performed whole transcriptome profiling on isolated CMs and compared to wild-type adult and embryonic CMs. Globally, the correlation coefficients between adult or TAC CM samples ranged from 0.955 to 0.991, suggesting limited early response of CMs in hearts subjected to TAC. However, pathway and ontology analysis revealed that embryonic CMs are far different from both adult and TAC in global gene expression profile. Through bioinformatic analysis, we identified a panel of 12 genes that are differentially expressed between TAC and adult CMs. Pathway and ontology analysis implicated the genes to participate in either oxidative stress pathways or cardiac remodeling processes. Selective validation of the gene panel revealed MMP23 to have increased expression in an in vitro model of HF and in patients with end-stage heart failure (HF) suggesting a previously undescribed link to human HF disease progression. Together, this work identifies individual genes that contribute to pathological hypertrophy and can serve as novel targets for HF interventional therapies.
02.45 Enhanced bruton’s tyrosine kinase activity in peripheral blood b lymphocytes of autoimmune disease patients
Authors: Odilia B.J. Corneth, Gwenny M.P. Verstappen, Sandra M.J. Paulissen, Marjolein J.W. de Bruijn, Jasper Rip, Melanie Lukkes, Jan Piet van Hamburg, Erik Lubberts, Hendrika Bootsma, Frans G.M. Kroese, Rudi W. Hendriks
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objective</h3> Bruton's tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacological BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity and, conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We investigated BTK expression and activity in human B cells in the context of autoimmune disease. <h3>Methods</h3> Using intracellular flow cytometry, we quantified BTK expression and phosphorylation in peripheral blood B cell subsets and activation and presence of T cell subsets in patients with rheumatoid arthritis (RA; n=30) and primary Sjogren's Syndrome (pSS; n=26) and matched healthy controls. <h3>Results</h3> In circulating B cells BTK protein expression levels correlated with BTK phosphorylation. BTK expression was upregulated upon BCR stimulation <i>in vitro</i> and significantly higher in CD27+ memory B cells than in CD27-IgD+ naive B cells. Importantly, BTK protein and phosphorylated-BTK were significantly increased in B cells from RA patients expressing anti-citrullinated protein antibodies (ACPA<sup>+</sup>) but not in ACPA<sup>-</sup> patients. BTK was increased both in naïve and memory B cells and correlated with the frequencies of circulating CCR6<sup>+</sup> T helper-17 cells. Likewise, BTK protein was increased in B cells from a major fraction of pSS patients and correlated with B cell activation, serum rheumatoid factor levels and parotid gland T cell infiltration. Interestingly, targeting T cell activation in pSS patients by abatacept (CTLA4-Ig) treatment restored BTK protein expression in B cells to normal levels. <h3>Conclusions</h3> These data indicate that human autoimmune disease is characterised by enhanced BTK activity, which is not only linked to autoantibody formation but also to T cell activity.
Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide
Authors: Claire N. Harrison, Adam J. Mead, Anesh Panchal, Sonia Fox, Christina Yap, Emmanouela Gbandi, Aimee Houlton, Samah Alimam, Joanne Ewing, Marion Wood, Frederick Chen, Jason Coppell, Nicki Panoskaltsis, Steven Knapper, Sahra Ali, Angela Hamblin, Robyn Scherber, Amylou C. Dueck, Nicholas C. P. Cross, Ruben Mesa, Mary Frances McMullin
Journal: Blood (2017)
Preclinical rationale leading to clinical benefit: Multiple myeloma as a poster child
Authors: Sagar Lonial
Journal: Clinical Cancer Research (2008)

CN02-03   For many years the clinical advances for patients with myeloma were limited. The recent approval of the proteasome inhibitor bortezomib and immunomodulatory agent lenalidomide has revolutionized patient care and outcomes for patients at all phases of their disease. Preclinical investigations have led to clinical trials that seek to optimally combine emerging agents with approved agents, as well as to define which new agents are best suited for Phase I/II trials in myeloma. Targets such as HSP-90, HDACs, monoclonal antibodies, CDK inhibitors, and many others were interrogated in preclinical models, and have now yielded clinical benefit for patients with relapsed or refractory myeloma. Further preclinical evaluation is critical to designing rational clinical trials and to developing appropriate correlative studies for these innovative clinical trials.
Abstract 5451: Coronary Spatial Distribution of Non-ST Elevation Myocardial Infarction is Non-Uniform and Clustered in the Proximal Portion of the Coronary Tree
Authors: M Faisal Khan, Susana C Candia, Cathy Jeon, John C Wang, Richard Kuntz, Laura Mauri
Journal: Circulation (2009)

Introduction: We hypothesized that plaque rupture leading to NSTEMI is a non-uniform process with variable risk for different anatomic locations within each coronary artery. It is not known whether this distribution is similar to that in STEMI, where we have previously observed proximal clustering of lesions. Methods: We used quantitative angiographic analysis (QCA) to compare the spatial location of lesions in NSTEMI to STEMI in consecutive patients undergoing coronary angiography at the Brigham and Women’s Hospital over a 24-month period for NSTEMI and STEMI (N= 200 and 208 respectively). The segment lengths of the culprit vessel and its side branches were measured. The Wilcoxon rank sum test was used to compare the distribution of culprit lesions in NSTEMI vs. STEMI. Results: NSTEMI patients were older and had a higher prevalence of prior infarction, diabetes mellitus, hypertension, dyslipidemia, and renal insufficiency. Despite these differences, lesions in both NSTEMI and STEMI were clustered in the proximal third of each of the coronary arteries. There was no significant difference in the spatial distribution of the lesions in NSTEMI as compared to STEMI in the LAD, p=0.36 (Fig 1a &amp; b ), LCx, p=0.13 or RCA, p=0.22.) Conclusion: We conclude that NSTEMI plaque ruptures are not uniformly distributed but proximally clustered similar to STEMI lesions. This suggests that the anatomic zones at risk for acute thrombosis are independent of the type of acute coronary syndrome and that the proximal segments are at highest risk. Figure 1a &amp; b. LAD Absolute Distance Analysis and Cumulative Frequency Distribution. 50% of NSTEMI lesions occurred within the first 35mm of the vessel (proximal 1/3 rd
LONG-TERM CONSEQUENCES OF INTERPERSONAL VIOLENCE AGAINST CHILDREN IN SPORT
Authors: Tine Vertommen, Jarl Kampen, Nicolette Schipper-van Veldhoven, Filip Van Den Eede
Journal: British Journal of Sports Medicine (2017)

Background A recent prevalence study in the Netherlands and Belgium showed that 38% of children in sport experienced psychological violence, 11% physical violence, and 14% sexual violence. Ethnic minority, lesbian/gay/bisexual (LGB) and disabled athletes, and those competing at the international level reported significantly more experiences with interpersonal violence in sport. Objective While general literature has repeatedly shown that exposure to interpersonal violence in childhood is associated with adverse psychological outcomes in adulthood, this relationship has not yet been demonstrated in athletes. This study aims to explore the long-term consequences of these experiences on adult psychopathology and quality of life. Design A cross-sectional, retrospective design, using an online survey, provides a prevalence estimate of interpersonal violence in sport in a representative sample of adults, prescreened on having participated in organized sport before the age of 18 ( N=4043 ). In this sample, psychopathology (depression, anxiety and somatic problems) was assessed using the Brief Symptom Inventory. Quality of life was measured with the World Health Organization Quality of Life questionnaire (WHOQOL BREF). Using Poisson and ordinal logistic regression, the impact on psychopathology and quality of life was investigated, while controlling for demographics, as well as disability, sexual orientation and adverse childhood experiences outside sport. Results Moderate and severe experiences with interpersonal violence in sport (psychological, physical and sexual) proved to have a significant negative impact on psychopathology and quality of life in adulthood. Conclusions This study shows that interpersonal violence against children in sport is related to mental health problems and lower quality of life in adulthood. With its Consensus Statement on non-accidental violence in sport, the IOC gives a strong impetus to prioritize athlete welfare and implement prevention policies. Sport medicine practitioners can actively contribute to a safer sports climate by being attentive to signs of violence against athletes and effectively respond to disclosures.
Distrust in the End-of-Life Care Provided to a Parent and Long-Term Negative Outcomes Among Bereaved Adolescents: A Population-Based Survey Study
Authors: Kim Beernaert, Ulrika Kreicbergs, Carl Johan Fürst, Tommy Nyberg, Gunnar Steineck, Tove Bylund-Grenklo
Journal: Journal of Clinical Oncology (2017)

Purpose Previous research shows that the death of a parent places children at risk for a number of negative outcomes. The role of trust in health care at the end of life has been acknowledged as crucial for patients and adult family members. However, the consequences of children's distrust in the care provided to their parents remain unknown. Therefore, we investigated the negative long-term outcomes of cancer-bereaved sons' and daughters' distrust in the care that was provided to a dying parent. Methods We used a population-based nationwide survey to investigate self-reported distrust in the care provided and possible negative outcomes in 622 (73%) participants who had lost a parent as a result of cancer 6 to 9 years earlier, at ages 13 to 16 years. All participants were 18 years or older at the time of the survey. Results In those who reported no or little trust (ie, distrust) in the health care provided to their dying parents, we found statistically significantly higher risks of various negative outcomes at the time of survey: bitterness toward health care professionals for not having done everything that was possible (crude risk ratio [RR], 3.5; 95% CI, 2.3 to 5.1) and for having stopped treatment (RR, 3.4; 95% CI, 2.1 to 6.0), self-destructiveness (eg, self-injury [RR, 1.7; 95% CI, 1.2 to 2.4]), and psychological problems (eg, moderate to severe depression according to the Patient Health Questionnaire-9 [RR, 2.3; 95% CI, 1.5 to 3.5]). Conclusion In cancer-bereaved former adolescents, distrust in the health care provided to the dying parent is associated with a higher risk of negative long-term outcomes. The health care professionals involved in this care might play an important role in safeguarding the trust of adolescents.
02.50 Intestinal overexpression of human tnf triggers sacro-iliitis
Authors: Karlijn Debusschere, Heleen Cypers, Peggy Jacques, Filip Van den Bosch, Donald Souza, Maryanne Brown, Gerald Nabozny, Devan Dove, Alexander Klimowicz, Dirk Elewaut
Journal: Annals of the Rheumatic Diseases (2017)

<h3></h3> An intriguing link exists between gut and joint inflammation in spondyloarthritis (SpA). About 50% of patients has subclinical (eg, microscopic) gut inflammation, which represents a risk factor for development of Crohn's disease, sacroiliac inflammation and evolution in to ankylosing spondylitis. However, the underlying mechanisms are still relatively poorly understood. Our goal was to examine the relationship between TNF, microscopic gut inflammation and axial inflammation. Therefore, we examined <i>in situ</i> expression of TNF, TNFR1 and TNFR2 using triple <i>in situ</i> hybridisation in gut biopsies of human SpA patients and found marked upregulation of TNF in inflamed versus non-inflamed biopsies. We also noted a predominant upregulation of TNFR1 on intestinal epithelium and TNFR2 in lamina propria respectively. Of interest, IL-17 and IL-23 were also markedly increased while IL-22 was most abundant in chronically inflamed samples. In line with this, we found that patients with gut inflammation had a higher need for anti-TNF therapy and their degree of clinical response after anti-TNF was also markedly higher. We speculated that TNF in the gut represents an important risk factor for disease severity and progression in SpA. To investigate this further we generated intestinal specific human TNF transgenic mice, in which hTNF is under control of a rat iFABP (fatty acid binding protein) promoter, generating a mouse-model over-expressing human TNF in the ileum. These mice, together with wild type littermates, were evaluated for the development of arthritis up until the age of 13 weeks after which they were euthanized and ankle and sacroiliac joints as well as ileum were processed for histology. Transgenic mice exhibit a runt phenotype and hallmarks of inflammatory bowel disease, including increased intestinal permeability and inflammation compared to their wild-type littermates. While in peripheral joints no clear signs of arthritis were observed, the sacroiliac joints in transgenic mice, by contrast, showed marked signs of inflammation as well as bone erosion and destruction. These data propose a new paradigm that gut-derived TNF is sufficient to trigger sacroiliitis and provide an alternate explanation on the relationship between gut inflammation, evolution to inflammatory bowel disease and axial inflammation in SpA.
Assessment of eosinophilic airway inflammation as a contribution to the diagnosis of occupational asthma
Authors: C. Beretta, C. Rifflart, G. Evrard, J. Jamart, J. Thimpont, O. Vandenplas
Journal: Allergy (2017)

Abstract Background Ascertaining the presence of asthma through the assessment of nonspecific bronchial hyperresponsiveness ( NSBH ) is a key step in the diagnosis of occupational asthma ( OA ). We aimed at investigating whether indices of airway inflammation including fractional exhaled nitric oxide (Fe NO ) and sputum eosinophils would be useful adjuncts to the measurement of NSBH in diagnosing OA defined as a positive specific inhalation challenge ( SIC ). Methods The study included 240 consecutive subjects with a suspicion of OA who completed a SIC , of whom 133 showed a positive response. The sensitivity, specificity, and predictive values of NSBH , and Fe NO , as well as sputum eosinophil counts assessed at baseline of the SIC were determined. Results A concentration of histamine inducing a 20% decline in FEV 1 ( PC 20 ) ≤16 mg/mL showed a sensitivity of 87% and a specificity of 36%. A Fe NO level ≥25 ppb and a sputum eosinophil count ≥2% provided lower sensitivity rates (47% and 39%, respectively) than the PC 20 value. Eight of the 17 subjects without baseline NSBH despite a positive SIC showed a sputum eosinophil count ≥2%, a Fe NO level ≥25 ppb, or both outcomes. Combining either a PC 20 value ≤16 mg/ mL or a Fe NO ≥25 ppb increased the sensitivity to 91%. Using either a PC 20 ≤16 mg/ mL or a sputum eosinophil count ≥1% increased the sensitivity to 94%. Conclusion Adding the assessment of Fe NO level and sputum eosinophils to NSBH improves the identification of subjects who may have OA and require further objective testing before excluding the possibility of OA .
KNEE VALGUS ANGLE AND LOADING ACROSS COMMON ATHLETIC TASKS; REFERENCE VALUES AND GENDER DIFFERENCES IN A HEALTHY POPULATION
Authors: Faisal Alenezi, Lee Herrington, Paul Jones, Richard Jones
Journal: British Journal of Sports Medicine (2017)

Background Abnormal lower-limb mechanics during functional activities have been reported as being associated with several knee injuries. Hence it is important to develop screening tests to identify healthy individuals who may be susceptible to knee injury and then to design individual intervention programs. Objective To established reference values for knee valgus angle and moment during single leg squat (SLS), single leg landing (SLL), running (RUN), and cutting (CUT) tasks. Moreover, assessing gender differences in knee biomechanics during these tasks. Design An observational study. Setting Undertaken in the human performance laboratory at the University of Salford. Participants 90 healthy individuals, 55 males and 35 females, (age 25.2±5.1 years; height 1.6±7.38 m; and mass 67.6 ±10.93 kg) were recruited. Assessment of Risk Factors Qualisys motion analysis system (10 Cameras) connected to an AMTI force platform were used to collect knee biomechanical variables. Then, Visual 3D software (C-Motion, USA) was used to process all data. Main Outcome Measurements Knee valgus angles and moments during SLS, SLL, RUN and CUT tasks. Results Knee valgus angle values were: SLS (−1.5°±4.1), SLL (−4.2°±4.9), RUN (−5.2°±4.3), and CUT (−8.3°±6.1). Knee valgus moment values for SLS, SLL, RUN and CUT were (0.01±0.1; 0.49±0.3; 0.31±0.1; 1.2±0.6, Nm/kg), respectively. Females demonstrated significantly higher knee valgus angles across all tasks. Knee-valgus moments were significantly different between the genders during RUN and CUT tasks (p=0.007 and 0.001, respectively). Discussion Finding reference values for knee valgus angles and loading during commonly assessed screening tasks in non-injured individuals may help to find ways of identifying at-risk individuals for non-contact knee injuries associated with misalignment, such ACL and PFPS. However, more research is required to discover the underlying causes of poor mechanics when performing these tasks, this would help in devising more efficient injury-prevention protocols.
Zika virus and reproduction: facts, questions and current management
Authors: Sylvie Epelboin, Emmanuel Dulioust, Loïc Epelboin, Alexandra Benachi, Françoise Merlet, Catherine Patrat
Journal: Human Reproduction Update (2017)

Zika virus (ZIKV) is an arthropod-borne virus of the family Flaviviridae, genus Flavivirus. ZIKV is currently the focus of an ongoing pandemic and worldwide public health emergency. Although originally isolated in 1947, its pathogenesis was poorly known and very few documented infections were published until recently. Its route of transmission and its impact on reproduction and pregnancy have only recently begun to be disclosed.This review summarizes the most recent knowledge about ZIKV infection and pathogenesis and focuses on its impacts on male and female genital tracts, including the risks of sexual transmission and to pregnancy. The consequences of ZIKV infection for pregnancy planning and ART are also discussed.The PubMed and EMBASE databases were inter-rogated using specific terms, such as 'ZIKV', 'transmission', 'male', 'female', fertility', 'pregnancy, 'semen', 'testis', 'ovary' and 'genital tract', up to 17 March 2017.ZIKV has long been considered a harmless virus, but increasing evidence suggests that it has adverse effects on the neurological system and on pregnancy outcomes. In mice, ZIKV slows foetal growth and damages the foetal brain. In humans, the virus is able to cross the placental barrier and to induce foetal death and major anomalies, such as microcephaly, brain defects and long-term neurologic sequelae, i.e. the 'congenital Zika syndrome'. In addition to its transmission by mosquitoes, ZIKV may be transmitted sexually. Currently available data indicate that ZIKV RNA can remain detectable in semen for several months, whereas shedding in the female genital tract appears to be rare and of short duration. Current guidance on preventing the sexual transmission of ZIKV is based on the assumption that transmission occurs from a male partner to a receptive partner. Furthermore, in mouse models, the virus can actively replicate in male genital organs and induce severe orchitis, which raises concerns about its possible impact on human male fertility.These new and relevant findings have led many countries and institutions to release updated and regular guidance for preconception counselling and ART to prevent the sexual transmission of ZIKV. Progress in understanding the sexual transmission of ZIKV and its dissemination to genital systems would also help to better anticipate and control outbreaks of potentially sexually transmissible infectious agents.