tbuckley/cabot-search huggingface dataset:
A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency
Authors: Haifa H Jabara, Steven E Boyden, Janet Chou, Narayanaswamy Ramesh, Michel J Massaad, Halli Benson, Wayne Bainter, David Fraulino, Fedik Rahimov, Colin Sieff, Zhi-Jian Liu, Salem H Alshemmari, Basel K Al-Ramadi, Hasan Al-Dhekri, Rand Arnaout, Mohammad Abu-Shukair, Anant Vatsayan, Eli Silver, Sanjay Ahuja, E Graham Davies, Martha Sola-Visner, Toshiro K Ohsumi, Nancy C Andrews, Luigi D Notarangelo, Mark D Fleming, Waleed Al-Herz, Louis M Kunkel, Raif S Geha
Journal: Nature Genetics (2015)
Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation
Authors: Anna R. Cliffe, Jesse H. Arbuckle, Jodi L. Vogel, Matthew J. Geden, Scott B. Rothbart, Corey L. Cusack, Brian D. Strahl, Thomas M. Kristie, Mohanish Deshmukh
Journal: Cell Host & Microbe (2015)
Changes in Diet Quality Scores and Risk of Cardiovascular Disease Among US Men and Women
Authors: Mercedes Sotos-Prieto, Shilpa N. Bhupathiraju, Josiemer Mattei, Teresa T. Fung, Yanping Li, An Pan, Walter C. Willett, Eric B. Rimm, Frank B. Hu
Journal: Circulation (2015)

Background— Adherence to several diet quality scores, including the Alternative Healthy Eating Index, Alternative Mediterranean Diet score, and Dietary Approach to Stop Hypertension, has been associated with lower risk of cardiovascular disease (CVD), but little is known about how changes in these scores over time influence subsequent CVD risk. Methods and Results— We analyzed the association between 4-year changes in the 3 diet quality scores (Alternative Healthy Eating Index, Alternative Mediterranean Diet score, and Dietary Approach to Stop Hypertension) and subsequent cardiovascular disease (CVD) risk among 29 343 men in the Health Professionals Follow-up Study and 51 195 women in the Nurses’ Health Study (1986–2010). During 1 394 702 person-years of follow-up, we documented 11 793 CVD cases. Compared with participants whose diet quality remained relatively stable in each 4-year period, those with the greatest improvement in diet quality scores had a 7% to 8% lower CVD risk in the subsequent 4-year period (pooled hazard ratio, 0.92 [95% confidence interval (CI), 0.87–0.99] for the Alternative Healthy Eating Index; 0.93 [95% CI, 0.85–1.02] for the Alternative Mediterranean Diet score; and 0.93 [95% CI, 0.87–0.99] for the Dietary Approach to Stop Hypertension; all P for trend &lt;0.05). In the long term, increasing the diet scores from baseline to the first 4-year follow-up was associated with lower CVD risk during the next 20 years (7% [95% CI, 1–12] for the Alternative Healthy Eating Index, and 9% [95% CI, 3–14] for the Alternative Mediterranean Diet score). A decrease in diet quality scores was associated with significantly elevated risk of CVD in subsequent time periods. Conclusions— Improving adherence to diet quality scores over time is associated with significantly lower CVD risk in both the short term and long term.
G9a is essential for epigenetic silencing of K+ channel genes in acute-to-chronic pain transition
Authors: Geoffroy Laumet, Judit Garriga, Shao-Rui Chen, Yuhao Zhang, De-Pei Li, Trevor M Smith, Yingchun Dong, Jaroslav Jelinek, Matteo Cesaroni, Jean-Pierre Issa, Hui-Lin Pan
Journal: Nature Neuroscience (2015)
Mood as Representation of Momentum
Authors: Eran Eldar, Robb B. Rutledge, Raymond J. Dolan, Yael Niv
Journal: Trends in Cognitive Sciences (2015)

TrendsWith increasing use of computational models to understand human behavior, scientists have begun to model the dynamics of subjective states such as mood.Recent data suggest that mood reflects the cumulative impact of differences between reward outcomes and expectations.Behavioral and neural findings suggest that mood biases the perception of reward outcomes such that outcomes are perceived as better when one is in a good mood relative to when one is in a bad mood.These two lines of research establish a bidirectional interaction between mood and reinforcement learning, which may play an important adaptive role in healthy behavior, and whose dysfunction might contribute to psychiatric disorders.AbstractExperiences affect mood, which in turn affects subsequent experiences. Recent studies suggest two specific principles. First, mood depends on how recent reward outcomes differ from expectations. Second, mood biases the way we perceive outcomes (e.g., rewards), and this bias affects learning about those outcomes. We propose that this two-way interaction serves to mitigate inefficiencies in the application of reinforcement learning to real-world problems. Specifically, we propose that mood represents the overall momentum of recent outcomes, and its biasing influence on the perception of outcomes 'corrects' learning to account for environmental dependencies. We describe potential dysfunctions of this adaptive mechanism that might contribute to the symptoms of mood disorders.
Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells
Authors: Junya Ohtake, Shun Kaneumi, Mishie Tanino, Takuto Kishikawa, Satoshi Terada, Kentaro Sumida, Kazutaka Masuko, Yosuke Ohno, Toshiyuki Kita, Sadahiro Iwabuchi, Toshiya Shinohara, Yoshinori Tanino, Tamiko Takemura, Shinya Tanaka, Hiroya Kobayashi, Hidemitsu Kitamura
Journal: Journal of Allergy and Clinical Immunology (2015)
Is It Finally Time for a Personalized Medicine Approach for Fluorouracil-Based Therapies?
Authors: Steven M. Offer, Robert B. Diasio
Journal: Journal of Clinical Oncology (2015)

At present, implementation of pretreatment genotypic tests to individualize fluorouracil (5-FU)-based chemotherapy is limited despite a wealth of evidence demonstrating that individuals who carry certain variants of the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) are at significantly greater risk of experiencing severe and potentially lethal adverse toxicity (grade $ 3) when receiving treatment with standard dosages of 5-FU. The DPYD *2A variant—also known as rs3918290, NM_000110.3:c.190511G.A, and DPYD: IVS14_1G.A—has been reproducibly shown to result in a catalytic inactive form of DPD using a variety of methods, including the study of patient-derived clinical specimens 1 and through direct invitro study of the variant form of the protein. 2 Despite strong evidence linking this varianttotoxicity,andthemountingevidencelinkingadditionalDPYD variants to toxicity, the US Food and Drug Administration and the European Medicines Agency do not currently require pharmacogenomics testing before 5-FU administration. 3 Both agencies, however, do recommend the use of alternative drugs in individuals with known DPD deficiency. Scientific groups, such as the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group, provide regularly updated gene and drug clinical practice guidelines to help to translate research results into actionable treatment decisions for various drugs, including 5-FU, on the basis of peer-reviewed pharmacogenetic information. 4-6 Much of the information from these groups is disseminated by the Pharmacogenomics Knowledgebase, an actively updated, online resource for dosing guidelines, drug labels, and potentially actionable gene-drug and genotype-phenotype relationships. 7 However, it should be noted that the goal of these groups and online tools is not to direct which tests should be ordered, but, rather, to assist with the integration of test results into the decision-making process.
Expansion of Noncanonical V-Arm-Containing tRNAs in Eukaryotes
Authors: Kiyofumi Hamashima, Masaru Tomita, Akio Kanai
Journal: Molecular Biology and Evolution (2015)

Transfer RNA (tRNA) is essential for the translation of genetic information into proteins, and understanding its molecular evolution is important if we are to understand the genetic code. In general, long variable-arm (V-arm) structures form in tRNALeu, tRNASer, and bacterial and organellar tRNATyr. However, as we have previously reported, noncanonical V-arms occur in nematode tRNAGly and tRNAIle, and potentially affect translational fidelity. Here, we comprehensively analyzed 69 eukaryotic genome sequences and examined the evolutionary divergence of the V-arm-containing tRNAs. In total, 253 V-arm-containing tRNAs, with neither leucine nor serine anticodons, were identified in organisms ranging from nematodes to fungi, plants, and vertebrates. We defined them as "noncanonical V-arm-containing tRNAs" (nov-tRNAs). Moreover, 2,415 nov-tRNA-like sequences lacking some of the conserved features of tRNAs were also identified, largely in vertebrate genomes. These nov-tRNA/nov-tRNA-like sequences can be categorized into three types, based on differences in their possible evolutionary origins. The type A nov-tRNAs in nematodes probably evolved not only from tRNALeu but also from tRNASer and other isotypes on several independent occasions. The type B nov-tRNAs are dispersed abundantly throughout vertebrate genomes, and seem to have originated from retrotransposable elements. The type C nov-tRNAs may have been acquired from plant chloroplasts or from bacteria through horizontal transfer. Our findings provide unexpected insight into the evolution of the tRNA molecule, which was diverse and occurred independently in nematodes, vertebrates, and plants.
Serum amyloid A impairs the antiinflammatory properties of HDL
Authors: Chang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O’Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. de Beer, Frederick C. de Beer, William R. Osborne, Keith B. Elkon, Alan Chait
Journal: Journal of Clinical Investigation (2015)

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface–associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA-containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane.
Thigh Muscle Strength Predicts Knee Replacement Risk Independent of Radiographic Disease and Pain in Women: Data From the Osteoarthritis Initiative
Authors: Adam G. Culvenor, Wolfgang Wirth, Anja Ruhdorfer, Felix Eckstein
Journal: Arthritis & Rheumatology (2015)

To determine whether thigh muscle strength predicts the risk of undergoing knee replacement surgery, independent of radiographic severity of osteoarthritis and pain.Participants in the Osteoarthritis Initiative study who had received a knee replacement between the 12-month and 60-month follow-up visits (cases) were each matched with 1 control subject (who did not receive a knee replacement over 60 months) for age, sex, height, body mass index, baseline radiographic stage, and location of joint space narrowing. Isometric knee extensor and flexor strength was recorded biennially. The strength examination prior to knee replacement (≤2 years) was termed time 0, that 2 years prior to time 0 was termed time -2, and that 4 years prior to time 0 was termed time -4. Muscle strength in patients and controls was compared using paired t-tests and conditional logistic regression analysis adjusted for pain.One hundred thirty-six participants (60% women, mean ± SD age 65 ± 9 years, body mass index 29 ± 4 kg/m(2) ) received a knee replacement during follow-up, had strength data for at least time 0, and had a matched control. Knee extensor strength at time 0 (primary outcome measure) was significantly lower in female patients compared with controls (P < 0.001, pain-adjusted odds ratio [ORadj ] 1.72, 95% confidence interval 1.16-2.56), but no significant difference was observed in men. Results were similar for knee flexor strength at time 0 and for longitudinal change in extensor and flexor strength between time -2 and time 0. Thigh muscle strength at time -2 or time -4, or change between time -4 and time -2, did not predict the risk of undergoing knee replacement surgery in men or women.Thigh muscle strength predicted the risk of undergoing knee replacement surgery in women, but not in men. The results of this study may identify a window during which the risk of undergoing knee replacement surgery in women can be modified.
Are Most Cancers Caused by Specific Risk Factors Acting on Tissues With High Underlying Stem Cell Divisions?
Authors: E. L. Giovannucci
Journal: JNCI Journal of the National Cancer Institute (2015)

A recent paper by Tomasetti and Vogelstein demonstrated a high correlation coefficient of 0.81 between estimated lifetime normal renewing cell (stem cell) divisions among tissues in the body and the lifetime cancer risk in that organ. This finding has been interpreted frequently to suggest that if two-thirds of cancers arise primarily through normal proliferation then environmental and hereditary factors combined could explain only one-third of cancers. Yet, the pool of dividing stem cells is what risk factors act upon; it is unlikely that risk factors and proliferation act completely independently and are simply additive; thus, there is no constraint that stem cell proliferation and environmental/genetic attributable risk sum to 100%. The cancers illustrated to represent lifetime risk in the paper by Tomasetti and Vogelstein all implicitly incorporate risk factors common in the United States (example, obesity, physical inactivity, tobacco, alcohol, diet, infectious agents). In fact, there is little evidence that a cancer would exceed a substantial rate, such as greater than 1% lifetime risk, in the absence of an important risk factor. Relatively high rates of cancer (eg, > 1% lifetime risk) only seem to occur in organs when strong risk factors (example, 10- to 20-fold) are superimposed on relatively high stem cell division. In organs with low stem cell divisions, the lifetime cancer risk will typically be very low. The major types and most abundant cancers in a given population will arise from tissues that have relatively high stem cell division rates and that have a high prevalence of strong relevant risk factors.
Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer
Authors: Mariangela Russo, Sandra Misale, Ge Wei, Giulia Siravegna, Giovanni Crisafulli, Luca Lazzari, Giorgio Corti, Giuseppe Rospo, Luca Novara, Benedetta Mussolin, Alice Bartolini, Nicholas Cam, Roopal Patel, Shunqi Yan, Robert Shoemaker, Robert Wild, Federica Di Nicolantonio, Andrea Sartore Bianchi, Gang Li, Salvatore Siena, Alberto Bardelli
Journal: Cancer Discovery (2015)

Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA-NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors.We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identification of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the first time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements.
Effectiveness of azacitidine for the treatment of higher-risk myelodysplastic syndromes in daily practice: results from the Dutch population-based PHAROS MDS registry
Authors: A G Dinmohamed, Y van Norden, O Visser, E F M Posthuma, P C Huijgens, P Sonneveld, A A van de Loosdrecht, M Jongen-Lavrencic
Journal: Leukemia (2015)
ACR–ASNR Practice Parameter for Brain PET/CT Imaging Dementia
Authors: Kirk A. Frey, Martin A. Lodge, Carolyn Cidis Meltzer, Patrick J. Peller, Terence Z. Wong, Christopher P. Hess, Jeffrey R. Petrella, Haris I. Sair, Rathan M. Subramaniam
Journal: Clinical Nuclear Medicine (2015)

This practice parameter is for both FDG and amyloid brain PET or PET/computed tomography (CT) for patients with cognitive decline, and has been developed collaboratively by the American College of Radiology (ACR) and the American Society for Neuroradiology (ASNR). It is estimated that the number of people with dementia, 36.5 million worldwide in 2010, will increase to 65.7 million in 2030 and to 115 million in 2050. Four primary neurodegenerative etiologies of dementia have been defined: Alzheimer disease (AD), vascular dementia, frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Alzheimer disease is the most common form of dementia, accounting for approximately 60%-80% of all cases. Indications for FDG and amyloid brain PET and qualifications for personnel are discussed in this practice parameter.
cis elements of the human CDX2 gene regulate expression of transgenes in mouse colonic epithelial cells
Authors: Takao Hinoi, Aytekin Akyol, Eric R. Fearon
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

1975 

BACKGROUND: CDX2 is a caudal -related homeobox transcription factor that is expressed at high levels in epithelial cells of adult small intestine and colon in human and mouse. Previously, we found transcriptional activity of a reporter gene construct containing a 9.5-kb fragment from the 5’ region of the human CDX2 gene was well correlated with endogenous CDX2 expression in colon cancer cell lines (Hinoi T et al. , J. Biol. Chem . 278, 44608-16, 2003). This finding motivated us to assess the activity of the elements in an in vivo model. METHODS: Recombinant DNA constructs, containing 9.5-kb and 0.5-kb fragments from the 5’ region of the human CDX2 gene were cloned upstream of sequences for a nuclear localization signal and a LacZ (β-galactosidase) gene (CDX2P-9.5kb/NLSLacZ and CDX2P-0.5kb/NLSLacZ, respectively), were used to generate transgenic founders. Transgenic mice carrying the CDX2-9.5kb fragment upstream of sequences encoding a nuclear localization signal-Cre recombinase (CDX2P/NLSCre) fusion protein were also generated. β-galactosidase (β-gal) activity was measured by standard methods, and Cre expression/activity was analyzed by generating mice carrying the CDX2P/NLSCre transgene and Gtrosa26tm1Sor targeted mutation, which is a reporter for cells in which Cre recombinase has been active. RESULTS: In mice carrying the CDX2P-9.5kb/NLSLacZ construct, i n situ assays demonstrated strong β-gal expression in essentially all epithelial cells in appendix, colon, and rectal tissues, while minimal β-gal expression was seen in mice carrying CDX2P-0.5kb/NLSLacZ construct. The expression data from adult CDX2P-9.5kb/NLSLacZ transgenic mice contrast with data showing strong endogenous CDX2 expression throughout small intestine and colonic epithelium. Analysis in CDX2P-9.5kb/NLSLacZ staged embryos indicated β-gal expression largely mirrors the expression of CDX2 during development. Cre expression from mice carrying the CDX2P/NLSCre and Gtrosa26tm1Sor mutation was restricted in the gastrointestinal tract to distal ileum, appendix, colon, and rectum. Studies in various adult tissues indicated Cre expression is activated during development in caudal and posterior cells, which normally express CDX2 during development. CONCLUSIONS: A 9.5-kb 5’-flanking region from the human CDX2 gene contains key cis elements for regulating transcription predominantly in colonic epithelium of adult mice. Our studies with CDX2P/NLSCre mice suggest the mice may be very useful for somatic targeting of genes containing lox P sites preferentially in colonic epithelial cells of the adult mouse, perhaps allowing generation of new mouse colon cancer progression models.
Conference on the care of patients with severe chronic pain in terminal illness
Authors: E. N. Brandt
Journal: JAMA (1984)

Millions of Americans with arthritis, back disorders, coronary disease, traumatic injury, and other chronic conditions wage a daily war against pain. In many instances, the pain is severe enough to cause partial or total disability and prevent participation in routine activities. While most patients with severe pain are, in fact, being treated adequately with a wide range of effective analgesics, there continue to be deficiencies in current pain therapy created by voids in our knowledge about pain and its mechanisms as well as by the inadequate or improper application of available knowledge. This situation is particularly true for the terminally ill patient. The impact that pain can have on the patient's life can range from tolerable discomfort to crippling defeat. In spite of great advances in biomedical knowledge and technology, there remain problems with the development, dissemination, and application of knowledge, as well as with misguided attitudes among health professionals.
Lipocalin 2 drives neutrophilic inflammation in alcoholic liver disease
Authors: Verena Wieser, Piotr Tymoszuk, Timon Erik Adolph, Christoph Grander, Felix Grabherr, Barbara Enrich, Alexandra Pfister, Lisa Lichtmanegger, Romana Gerner, Mathias Drach, Patrizia Moser, Heinz Zoller, Günter Weiss, Alexander Rupert Moschen, Igor Theurl, Herbert Tilg
Journal: Journal of Hepatology (2015)