tbuckley/cabot-search huggingface dataset:
Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide
Authors: Martin Hülsmeyer, Maria Teresa Fiorillo, Francesca Bettosini, Rosa Sorrentino, Wolfram Saenger, Andreas Ziegler, Barbara Uchanska-Ziegler
Journal: The Journal of Experimental Medicine (2004)

The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.
HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma
Authors: Netanya I. Pollock, Jennifer R. Grandis
Journal: Clinical Cancer Research (2014)

Abstract The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with advanced-stage disease. The current standard of care is surgery followed by adjuvant radiotherapy with or without chemotherapy or chemoradiation alone. The addition of cetuximab for the treatment of patients with locally advanced or recurrent/metastatic HNSCC has improved overall survival and locoregional control; however, responses are often modest, and treatment resistance is common. A variety of therapeutic strategies are being explored to overcome cetuximab resistance by blocking candidate proteins implicated in resistance mechanisms such as HER2. Several HER2 inhibitors are in clinical development for HNSCC, and HER2-targeted therapy has been approved for several cancers. This review focuses on the biology of HER2, its role in cancer development, and the rationale for clinical investigation of HER2 targeting in HNSCC. Clin Cancer Res; 21(3); 526–33. ©2014 AACR.
Signaling-Mediated Regulation of MicroRNA Processing
Authors: Jia Shen, Mien-Chie Hung
Journal: Cancer Research (2015)

miRNAs are important regulatory elements for gene expression that are involved in diverse physiologic and pathologic processes. Canonical miRNA biogenesis consists of a two-step processing, from primary transcripts (pri-miRNA) to precursor miRNAs (pre-miRNA) mediated by Drosha in the nucleus and from pre-miRNAs to mature miRNAs mediated by Dicer in the cytoplasm. Various routes of miRNA maturation that are tightly regulated by signaling cascades and specific to an individual or a subclass of miRNAs have been recently identified. Here, we review the current findings in signaling-mediated miRNA processing as well as their potential clinical relevance in cancer.
The Toll-like receptor 4 agonist MRP8/14 protein complex is a sensitive indicator for disease activity and predicts relapses in systemic-onset juvenile idiopathic arthritis
Authors: Dirk Holzinger, Michael Frosch, Astrid Kastrup, Femke H M Prince, Marieke H Otten, Lisette W A Van Suijlekom-Smit, Rebecca ten Cate, Esther P A H Hoppenreijs, Sandra Hansmann, Halima Moncrieffe, Simona Ursu, Lucy R Wedderburn, Johannes Roth, Dirk Foell, Helmut Wittkowski
Journal: Annals of the Rheumatic Diseases (2012)

Analysis of myeloid-related protein 8 and 14 complex (MRP8/14) serum concentrations is a potential new tool to support the diagnosis of systemic-onset juvenile idiopathic arthritis (SJIA) in the presence of fever of unknown origin.To test the ability of MRP8/14 serum concentrations to monitor disease activity in patients with SJIA and stratify patients at risk of relapse.Serum concentrations of MRP8/14 in 52 patients with SJIA were determined by a sandwich ELISA. The monitoring of therapeutic regimens targeting interleukin 1 and tumour necrosis factor α, and methotrexate treatment was analysed and diagnostic power to predict flares was tested.MRP8/14 levels were clearly raised in active disease and decreased significantly in response to successful treatments. Serum concentrations of MRP8/14 increased significantly (p<0.001) (mean±95% CI 12.030±3.090 ng/ml) during disease flares compared with patients with inactive disease (864±86 ng/ml). During clinical remission MRP8/14 serum levels of >740 ng/ml predicted disease flares accurately (sensitivity 92%, specificity 88%). MRP8/14 levels correlated well with clinical disease activity, as assessed by physician's global assessment of disease activity (r=0.62), Childhood Health Assessment Questionnaire (r=0.56), active joint count (r=0.46) and with C-reactive protein (r=0.71) and erythrocyte sedimentation rate (r=0.72) (for all p<0.001).MRP8/14 serum concentrations correlate closely with response to drug treatment and disease activity and therefore might be an additional measurement for monitoring anti-inflammatory treatment of individual patients with SJIA. MRP8/14 serum concentrations are the first predictive biomarker indicating subclinical disease activity and stratifying patients at risk of relapse during times of clinically inactive disease.
The HER4/4ICD Estrogen Receptor Coactivator and BH3-Only Protein Is an Effector of Tamoxifen-Induced Apoptosis
Authors: Anjali Naresh, Ann D. Thor, Susan M. Edgerton, Kathleen C. Torkko, Rakesh Kumar, Frank E. Jones
Journal: Cancer Research (2008)

Abstract Greater than 40% of breast cancer patients treated with tamoxifen exhibit de novo or acquired tumor resistance. Recent clinical evidence indicates that loss of expression of HER4 is an independent marker for tamoxifen resistance. In direct corroboration with clinical observations, suppression of HER4 expression in the tamoxifen-sensitive MCF-7 and T47D breast tumor cell lines resulted in resistance to tamoxifen-induced apoptosis. Furthermore, HER4 expression was lost in three independent MCF-7 models of acquired tamoxifen resistance. The HER4 intracellular domain (4ICD) is an independently signaling nuclear protein that functions as a potent ERα coactivator. In addition, mitochondrial 4ICD functions as a proapoptotic BH3-only protein. Tamoxifen disrupts an estrogen-driven interaction between ERα and 4ICD while promoting mitochondrial accumulation of the 4ICD BH3-only protein. BCL-2 inhibition of tamoxifen-induced apoptosis and tamoxifen activation of BAK, independent of BAX, further supports a role for 4ICD during tamoxifen-induced apoptosis. Finally, reintroduction of HER4, but not HER4 with a mutated BH3 domain, restores tamoxifen sensitivity to tamoxifen-resistant TamR cells in a xenograft model. Clinically, breast cancer patients with tumor expression of nuclear 4ICD responded to tamoxifen therapy with no clinical failures reported after 14 years of follow-up, whereas 20% of patients lacking nuclear 4ICD expression succumbed to their disease within 10 years of diagnosis. Our identification of the HER4/4ICD BH3-only protein as a critical mediator of tamoxifen action provides a clinically important role for 4ICD in human cancer and reveals a potential tumor marker to predict patient response to tamoxifen therapy. [Cancer Res 2008;68(15):6387–95]
PLASMA PREKALLIKREIN: ISOLATION, CHARACTERIZATION, AND MECHANISM OF ACTIVATION
Authors: Kirk D. Wuepper, Charles G. Cochrane
Journal: The Journal of Experimental Medicine (1972)

The precursor of the kinin-forming enzyme, prekallikrein, was isolated from rabbit plasma protected from activation during preparatory procedures. Prekallikrein was shown to be a 4.5S γ1-glycoprotein with an isoelectric point of 5.9 and a mol wt of 99,900. The proenzyme was activated at neutral pH by an enzyme from rabbit or human plasma we have termed prekallikrein activator (PKA) or by trypsin. Prekallikrein was activated by PKA by a process of enzymatic scission. This resulted in the appearance of two fragments; the larger of these possessed kallikrein activity.
NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease
Authors: Wing-Kin Syn, Kolade M Agboola, Marzena Swiderska, Gregory A Michelotti, Evaggelia Liaskou, Herbert Pang, Guanhua Xie, George Philips, Isaac S Chan, Gamze F Karaca, Thiago de Almeida Pereira, Yuping Chen, Zhiyong Mi, Paul C Kuo, Steve S Choi, Cynthia D Guy, Manal F Abdelmalek, Anna Mae Diehl
Journal: Gut (2012)

<h3>Objective</h3> Immune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells. <h3>Design</h3> The hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans. <h3>Results</h3> When fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH-fibrosis. Ja18‒/‒ and CD1d‒/‒ mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity. <h3>Conclusion</h3> Hepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis.
Upper lobe infiltrate with cough, fever, fatigue
Authors: A Biglino, G De Rosa, F Lipani
Journal: European Respiratory Journal (1992)

Case historyA 41 yr old housewife, orig ina lly from Sicily, presented in June 1990 with a fever of five months duration, dry cough and fatigue.She denied present or previous occupational risks as we.ll as travel outside ftaly during the previous J 0 yrs.The patient appeared in good condition; physical examination was negative for superficial lymphadenopathy.hepatosplenomegaly and pulmonary findings.A left upper lobe pulmonary opacity was detected at another hospital on r outine chest roentgenogram; a fi ne-needle aspiration-biopsy was not diagnostic.Laboratory tests were within nom1al range with the exception of erythrocyte sedimentation rate (ESR) (43 mm•h• 1 ) and of a mild hypochromic microcytic anaemia (Hb= 95 g•/' 1 ; mean corpuscular volume (MCV)=74 J.l.~; blood iron= 230 J.l.g•/• 1 ).Anti-human immunodeficiency virus-I (HIV -I) specific antibodies were repeatedly negative by enzyme immuneassays .Circulating CD4+ cells were normal in number (1, li5•J.l.l• 1 ) and CD4/CD 8 ratio was 2.18.
TdT activity in acute myeloid leukemias defined by monoclonal antibodies
Authors: J. F. San Miguel, M. Gonzalez, M. C. Cañizo, J. P. Anta, J. A. Portero, A. Lopez‐Borrasca
Journal: American Journal of Hematology (1986)

Blast cells from eight out of 71 patients diagnosed with acute myeloid leukemia (AML) by morphological, cytochemical, and immunological criteria showed TdT activity. Their distribution according to the FAB classification was one M1, one M2, one M4, two M5a, one M5b, one M6, and one undifferentiated case. The TdT+ AML cases did not show major clinical and hematological differences when compared with the classical TdT- AML patients. Other phenotypical aberrations in the expression of membrane antigens, apart from the presence of nuclear TdT, were not observed in these TdT+ cases after study with a large panel of monoclonal antibodies. A higher incidence of TdT+ cases was found among the monocytic variants of AML (M4 and M5)--four cases--than in the granulocytic variants (M1, M2, and M3)--2 cases. These TdT+ cases should be distinguished from mixed leukemias by double labeling techniques, assessing in the TdT+ AML the coexpression of TdT and myeloid markers in individual cells as shown in four of our cases.
Cough {middle dot} 3: Chronic cough and gastro-oesophageal reflux
Authors: G A Fontana
Journal: Thorax (2003)

The pathogenesis and clinical features of gastro-oesophageal reflux related cough are complex and the diagnostic tests available are of limited reliability. Treatment needs to be tailored to the specific needs of individual patients and other possible causes of chronic cough should be investigated. Treatment should only be considered to have failed when cough persists after administration of proton pump inhibitors at an adequate dosage for a sufficient length of time.
Effectiveness of third-generation chemotherapy on the survival of patients with advanced non-small cell lung cancer in Norway: a national study
Authors: C von Plessen, T-E Strand, T Wentzel-Larsen, E Omenaas, N Wilking, S Sundstrom, S Sorenson
Journal: Thorax (2008)

<h3>Background:</h3> To investigate whether the introduction of modern third-generation chemotherapy was associated with survival benefits in a national population of patients with advanced non-small cell lung cancer (ANSCLC) and to explore geographical and temporary variations in the utilisation of chemotherapy. <h3>Methods:</h3> All patients with ANSCLC in the Cancer Registry of Norway during 1994–2005 were included. Using sales of vinorelbine as an indicator for chemotherapy, annual county utilisation rates were calculated. Survival before and after the general introduction of vinorelbine and associations between survival and variations in utilisation in counties were investigated. In a subgroup, the predictors of having received chemotherapy were explored. <h3>Results:</h3> Of 24 875 registered patients with lung cancer, 13 757 had ANSCLC. The annual utilisation of the indicator drug in Norway increased from 3.7 to 184.2 g (1998–2005). Median survival increased from 149 to176 days (p&lt;0.001). The adjusted hazard ratio (HR) for a diagnosis after the introduction was 0.93 (95% CI 0.88 to 0.99). County utilisation rates of vinorelbine (increments of 100 mg/1000 inhabitants) were inversely associated with the risk of death (HR 0.84, 95% CI 0.73 to 0.98). County of residence predicted chemotherapy utilisation with odds ratios in the range 0.13 (95% CI 0.1 to 0.19) to 1.04 (95% CI 0.64 to 1.69), a county with traditionally high utilisation as reference. <h3>Conclusion:</h3> Utilisation of third-generation chemotherapy was associated with slightly increased survival of patients with ANSCLC. Geographical and temporal differences in utilisation indicate variable quality of delivered care.
Negative impacts of unreported COPD exacerbations on health-related quality of life at 1 year
Authors: W. Xu, J-P. Collet, S. Shapiro, Y. Lin, T. Yang, C. Wang, J. Bourbeau
Journal: European Respiratory Journal (2009)

Unreported chronic obstructive pulmonary disease (COPD) exacerbations are common, but their intermediate-to-long-term impacts on health-related quality of life (HRQoL) are unknown. The aim of the present study was to examine the impact of unreported exacerbations on HRQoL at 1 yr. A multicentric prospective cohort study in 491 COPD patients was conducted in China. HRQoL was measured using the St George's Respiratory Questionnaire (SGRQ). Other measurements included sociodemographic, clinical, psychosocial and treatment profiles. Patients were monitored monthly for 12 months to document exacerbations (at least one symptom worsening for > or =48 h). Patients were categorised into six groups: no exacerbation, one unreported exacerbation only, more than one unreported exacerbation only, one reported exacerbation only, more than one reported exacerbation only, and both unreported and reported exacerbations. Generalised estimating equations were used to estimate the adjusted associations between exacerbations and HRQoL change. A total of 466 unreported and 410 reported exacerbations were recorded. Compared with patients with no exacerbations, the change in SGRQ total score was similar amongst patients with one unreported exacerbation (adjusted mean change 1.22 points (95% CI -4.05-6.48)), but significantly worse among patients with more than one unreported exacerbation (4.61 (95% CI 0.09-9.13)). Development and evaluation of self-management programmes emphasising early recognition of exacerbations and consequent action appear to be warranted.
Gating Properties of <i>SCN5A</i> Mutations and the Response to Mexiletine in Long-QT Syndrome Type 3 Patients
Authors: Yanfei Ruan, Nian Liu, Raffaella Bloise, Carlo Napolitano, Silvia G. Priori
Journal: Circulation (2007)

Background— Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene ( SCN5A ). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations. Methods and Results— We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg · kg −1 · d −1 ). We classified the mutations as sensitive to Mex (P1332L, R1626P; ≥10% of QTc shortening and QTc &lt;500 ms or no arrhythmias) or insensitive to Mex (S941N, M1652R; negligible or no QTc shortening and sudden death). We measured Na + current from HEK 293 cells transfected with wild-type (WT) or mutant Nav1.5. All mutations showed impaired inactivation of Na + current, but the mutations identified in patient responders to Mex (P1332L, R1626P) showed a hyperpolarizing shift of V 1/2 of steady-state inactivation. Furthermore, Mex produced use-dependent block with the order R1626P=P1332L&gt;S941N=WT&gt;M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block. Conclusions— We propose that voltage dependence of channel availability and shifts of V 1/2 of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3.
A Dual Role of EGFR Protein Tyrosine Kinase Signaling in Ubiquitination of AAV2 Capsids and Viral Second-strand DNA Synthesis
Authors: Li Zhong, Weihong Zhao, Jianqing Wu, Baozheng Li, Sergei Zolotukhin, Lakshmanan Govindasamy, Mavis Agbandje-McKenna, Arun Srivastava
Journal: Molecular Therapy (2007)

A 52 kd cellular protein, FK506-binding protein (FKBP52), phosphorylated at tyrosine residues by epidermal growth factor receptor protein tyrosine kinase (EGFR-PTK), inhibits adeno-associated virus 2 (AAV2) second-strand DNA synthesis and transgene expression. FKBP52 is dephosphorylated at tyrosine residues by T-cell protein tyrosine phosphatase (TC-PTP), and TC-PTP over-expression leads to improved viral second-strand DNA synthesis and improved transgene expression. In these studies, we observed that perturbation of EGFR-PTK signaling by a specific inhibitor, Tyrphostin 23 (Tyr23), augmented the transduction efficiency of the single-stranded AAV (ssAAV) vector as well as the self-complementary AAV (scAAV) vector. Similarly, tyrosine-dephosphorylation of FKBP52 by TC-PTP resulted in increased transduction by both vectors. These data suggested that EGFR-PTK signaling also affects aspects of AAV transduction other than viral second-strand DNA synthesis. We document that inhibition of EGFR-PTK signaling leads to decreased ubiquitination of AAV2 capsids which, in turn, facilitates nuclear transport by limiting proteasome-mediated degradation of AAV vectors. We also document that Tyr23-mediated increase in AAV2 transduction efficiency is not further enhanced by a specific proteasome inhibitor, MG132. Thus, EGFR-PTK signaling modulates ubiquitin (Ub)/proteasome pathway-mediated intracellular trafficking as well as FKBP52-mediated second-strand DNA synthesis of AAV2 vectors. This has implications in the optimal use of AAV vectors in gene therapy.
Pharmacy Compounding Guidance
Authors: Lester M. Crawford, Jr
Journal: JAMA (2002)

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Health effects of housing improvement: systematic review of intervention studies
Authors: H. Thomson, M. Petticrew, D. Morrison
Journal: BMJ (2001)

<h3>Objectives</h3> This article aims to measure the willingness of the Swiss public to participate in personalised health research, and their preferences regarding data management and governance. <h3>Setting</h3> Results are presented from a nationwide survey of members of the Swiss public. <h3>Participants</h3> 15 106 randomly selected Swiss residents received the survey in September 2019. The response rate was 34.1% (n=5156). Respondent age ranged from 18 to 79 years, with fairly uniform spread across sex and age categories between 25 and 64 years. <h3>Primary and secondary outcome measures</h3> Willingness to participate in personalised health research and opinions regarding data management and governance. <h3>Results</h3> Most respondents preferred to be contacted and reconsented for each new project using their data (39%, 95% CI: 37.4% to 40.7%), or stated that their preference depends on the project type (29.4%, 95% CI: 27.9% to 31%). Additionally, a majority (52%, 95% CI: 50.3% to 53.8%) preferred their data or samples be stored anonymously or in coded form (43.4%, 95% CI: 41.7% to 45.1%). Of those who preferred that their data be anonymised, most also indicated a wish to be recontacted for each new project (36.8%, 95% CI: 34.5% to 39.2%); however, these preferences are in conflict. Most respondents desired to personally own their data. Finally, most Swiss respondents trust their doctors, along with researchers at universities, to protect their data. <h3>Conclusion</h3> Insight into public preference can enable Swiss biobanks and research institutions to create management and governance strategies that match the expectations and preferences of potential participants. Models allowing participants to choose how to interact with the process, while more complex, may increase individual willingness to provide data to biobanks.