tbuckley/cabot-search huggingface dataset:
Constitutive expression of interferon gamma-inducible protein 10 in lymphoid organs and inducible expression in T cells and thymocytes.
Authors: C R Gattass, L B King, A D Luster, J D Ashwell
Journal: The Journal of Experimental Medicine (1994)

Interferon gamma-inducible protein 10 (IP-10), a member of a family of small proinflammatory chemotactic polypeptides, is expressed in interferon gamma-stimulated keratinocytes, macrophages, fibroblasts, and endothelial cells. Here we report that IP-10 is also expressed by activated but not resting T hybridoma cells, normal T cells, and thymocytes. Although resting lymphocytes did not synthesize IP-10, surprisingly high levels of IP-10 transcripts were found in lymphoid organs (spleen, thymus, and lymph nodes). Thymic and splenic stromal cells were found to express constitutively high levels of both IP-10 mRNA and protein, accounting for the high level of spontaneous expression in lymphoid tissue. Therefore, in addition to its role as a proinflammatory cytokine, IP-10 may participate in T cell effector function and perhaps T cell development.
Role for protease activity in visceral pain in irritable bowel syndrome
Authors: Nicolas Cenac, Christopher N. Andrews, Marinella Holzhausen, Kevin Chapman, Graeme Cottrell, Patricia Andrade-Gordon, Martin Steinhoff, Giovanni Barbara, Paul Beck, Nigel W. Bunnett, Keith A. Sharkey, Jose Geraldo P. Ferraz, Eldon Shaffer, Nathalie Vergnolle
Journal: Journal of Clinical Investigation (2007)

Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-kappaB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor-2 (PAR2). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR2 antagonist and were absent in PAR2-deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2.
New <i>RAS</i>-Mutant Pancreatic Adenocarcinoma With Combined BRAF and MEK Inhibition for Metastatic Melanoma
Authors: Matteo S. Carlino, Vu Kwan, David K. Miller, Catherine A.B. Saunders, Desmond Yip, Adnan M. Nagrial, Jeanne Tomlinson, Sean M. Grimmond, Richard A. Scolyer, Richard F. Kefford, Andrew V. Biankin, Georgina V. Long
Journal: Journal of Clinical Oncology (2014)
Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model
Authors: Preeti J Khandelwal, Sonya B Dumanis, Li Rebekah Feng, Kathleen Maguire-Zeiss, GW Rebeck, Hilal A Lashuel, Charbel EH Moussa
Journal: Molecular Neurodegeneration (2010)

Abstract Background α-Synuclein aggregates in Lewy bodies and plays a central role in the pathogenesis of a group of neurodegenerative disorders, known as "Synucleinopathies", including Parkinson's disease. Parkin mutations result in loss of parkin E3-ubiquitin ligase activity and cause autosomal recessive early onset parkinsonism. Results We tested how these two genes interact by examining the effects of parkin on post-translational modification of α-Synuclein in gene transfer animal models, using a lentiviral gene delivery system into the striatum of 2-month old male Sprague Dawley rats. Viral expression of wild type α-Synuclein caused accumulation of α-Synuclein and was associated with increased cell death and inflammation. α-Synuclein increased PLK2 levels and GSK-3β activity and increased the levels of phosphorylated α-Synuclein and Tau. Parkin co-expression reduced the levels of phosphorylated α-Synuclein and attenuated cell death and inflammation. Parkin reduced PLK2 levels and increased PP2A activation. Conclusions These data suggest that parkin reduces α-Synuclein levels and alters the balance between phosphatase and kinase activities that affect the levels of phosphorylated α-Synuclein. These results indicate novel mechanisms for parkin protection against α-Synuclein-induced toxicity in PD.
Urinary Estrogens and Estrogen Metabolites and Subsequent Risk of Breast Cancer among Premenopausal Women
Authors: A. Heather Eliassen, Donna Spiegelman, Xia Xu, Larry K. Keefer, Timothy D. Veenstra, Robert L. Barbieri, Walter C. Willett, Susan E. Hankinson, Regina G. Ziegler
Journal: Cancer Research (2011)

Endogenous estrogens and estrogen metabolism are hypothesized to be associated with premenopausal breast cancer risk but evidence is limited. We examined 15 urinary estrogens/estrogen metabolites and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II (NHSII). From 1996 to 1999, urine was collected from 18,521 women during the mid-luteal menstrual phase. Breast cancer cases (N = 247) diagnosed between collection and June 2005 were matched to two controls each (N = 485). Urinary estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry and adjusted for creatinine level. Relative risks (RR) and 95% confidence intervals (CI) were estimated by multivariate conditional logistic regression. Higher urinary estrone and estradiol levels were strongly significantly associated with lower risk (top vs. bottom quartile RR: estrone = 0.52; 95% CI, 0.30-0.88; estradiol = 0.51; 95% CI, 0.30-0.86). Generally inverse, although nonsignificant, patterns also were observed with 2- and 4-hydroxylation pathway estrogen metabolites. Inverse associations generally were not observed with 16-pathway estrogen metabolites and a significant positive association was observed with 17-epiestriol (top vs. bottom quartile RR = 1.74; 95% CI, 1.08-2.81; P(trend) = 0.01). In addition, there was a significant increased risk with higher 16-pathway/parent estrogen metabolite ratio (comparable RR = 1.61; 95% CI, 0.99-2.62; P(trend) = 0.04). Other pathway ratios were not significantly associated with risk except parent estrogen metabolites/non-parent estrogen metabolites (comparable RR = 0.58; 95% CI, 0.35-0.96; P(trend) = 0.03). These data suggest that most mid-luteal urinary estrogen metabolite concentrations are not positively associated with breast cancer risk among premenopausal women. The inverse associations with parent estrogen metabolites and the parent estrogen metabolite/non-parent estrogen metabolite ratio suggest that women with higher urinary excretion of parent estrogens are at lower risk.
Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2)
Authors: Eranga N Vithana, Patricio Morgan, Periasamy Sundaresan, Neil D Ebenezer, Donald T H Tan, Moin D Mohamed, Seema Anand, Khin O Khine, Divya Venkataraman, Victor H K Yong, Manuel Salto-Tellez, Anandalakshmi Venkatraman, Ke Guo, Boomiraj Hemadevi, Muthiah Srinivasan, Venkatesh Prajna, Myint Khine, Joseph R Casey, Chris F Inglehearn, Tin Aung
Journal: Nature Genetics (2006)
Hemoglobin redondo [β 92(F8) His → Asn]: An unstable hemoglobin variant associated with heme loss which occurs in two forms
Authors: H. Wajcman, C. Vasseur, C. Poyart, Y. Blouquit, F. Galacteros, D. Esperito Santo, M. J. Peres, M. C. Martins
Journal: American Journal of Hematology (1991)

Abstract Hb Redondo [β92(F8) His→Asn] illustrates how post‐translational structural modifications may modify the phenotypic expression of an unstable hemoglobin. This variant was found in a Portuguese patient suffering from a chronic hemolytic anemia. The electrophoretic pattern demonstrated that it occurred in two forms, both being semi‐hemoglobins: the fastest one migrating like HbS and the other like HbA 2 ; after a few days of storage at 4°C the intensity of the slowest Hb fraction decreased while that of the other increased proportionally. In both cases, the RP‐HPLC analysis of the tryptic digest of the aminoethylated β chains demonstrated the presence of an abnormal βT10 peptide carrying a His→Asx substitution. Microsequence study of these two peptides demonstrated that the slowest abnormal Hb fraction had a β92 His → Asn substitution and the fastest a His → Asp at the same site. All these results suggest that the β92 His → Asn variant loses readily its heme group and that a deamidation occurs rapidly in vitro, yielding a β92 Asp semi‐hemoglobin. The oxygen affinity of the patient's red blood cells was increased, leading to a stimulation of erythropoiesis and to a macrocytic hemolytic disease.
Molecular and Geographic Patterns of Tuberculosis Transmission After 15 Years of Directly Observed Therapy
Authors: William R. Bishai
Journal: JAMA (1998)

Context.-Recent studies suggest that one third of tuberculosis cases in urban areas result from recent transmission.Improved tuberculosis control measures such as uniform implementation of directly observed therapy might reduce the proportion of cases resulting from recent transmission.Objective.-Todetermine patterns of tuberculosis transmission in Baltimore, Md, after 15 years of community-based directly observed therapy.Design.-A 30-month (January 1994-June 1996), prospective, city-wide study of all cases of tuberculosis using traditional contact investigations, geographic information systems data, and molecular epidemiologic comparison of Mycobacterium tuberculosis isolates with 2 DNA probes.Patients.-Onehundred eighty-two patients with culture-positive tuberculosis.Main Outcome Measures.-Proportion of disease defined as recently transmitted based on epidemiologic linkage by traditional contact tracing and molecular linkage by DNA fingerprint analysis of isolates; geographic foci of transmission based on linkage of residences by geographic information systems data.Results.-Of the 182 patients who had isolates of M tuberculosis available, 84 (46%) showed molecular clustering with 58 (32%) defined as being recently transmitted.Only 20 (24%) of 84 cases with clustered DNA fingerprints had epidemiologic evidence of recent contact.Geographic analysis showed significant spatial aggregation of the 20 clustered cases with epidemiologic links (PϽ.001), occurring in areas of low socioeconomic status and high drug use.The 64 cases with clustered DNA fingerprints but without epidemiologic links shared common risk factors and demographic features with the 20 clustered patients who did have epidemiologic links.Conclusions.-Recentlytransmitted tuberculosis accounts for a high proportion of tuberculosis cases in Baltimore.Recently transmitted cases occur in geographically distinct areas of Baltimore, and location-based control efforts may be more effective than contact tracing for the early identification of cases.
Fitting data to theory: The contribution of a comparative perspective
Authors: Steve Stewart-Williams
Journal: Behavioral and Brain Sciences (2005)

In this commentary, I consider Schmitt's cross-cultural investigation of sociosexuality from a comparative perspective. I argue that such a perspective lends support to an evolutionary explanation of a number of Schmitt's findings, including universal sex differences in sociosexuality and the sensitivity of mating behavior to contextual variables such as sex ratio.
Tim-3 expression in tumour-associated macrophages: a new player in HCC progression
Authors: Tobias Flecken, Pablo Sarobe
Journal: Gut (2015)

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide due to its emergence based on chronic liver disease. Thus, HCC can ultimately be caused by multiple factors, including chronic viral infection, alcohol abuse or obesity. Nevertheless, only a few therapeutic options are available, especially for patients in later stages of disease.1 Accordingly, prognosis of patients is often poor and HCC contributes disproportionately to cancer-related deaths worldwide. Thus, further research into HCC is required to inform the development of novel therapies as well as improvements to existing regimens. An important focus of current research into tumours in general, and HCC in particular, is the microenvironment in which development and progression of a tumour occurs. The tumour microenvironment comprises multiple cellular and non-cellular components and has been shown to be an important determinant of tumour progression, patient prognosis and thus also a determinant of therapeutic success in HCC and elsewhere.2 Indeed, some of the therapeutic effects of sorafenib, to date the only approved small-molecule inhibitor for treatment of advanced HCC, may be attributable to its effects on the tumour microenvironment.3 Among the different cell types found in the tumour microenvironment, macrophages, so-called tumour-associated macrophages (TAM), are among the most common. TAM typically differ from normal macrophages in their shift to an alternatively activated (M2) …
Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase, in Combination with High-Dose Cytarabine in Patients with Acute Myeloid Leukemia
Authors: Rebecca B. Klisovic, William Blum, Xiaohui Wei, Shujun Liu, Zhongfa Liu, Zhiliang Xie, Tamara Vukosavljevic, Cheryl Kefauver, LeNguyen Huynh, Jiuxia Pang, James A. Zwiebel, Steven Devine, John C. Byrd, Michael R. Grever, Kenneth Chan, Guido Marcucci
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Inhibition of ribonucleotide reductase reduces the availability of the endogenous pool of deoxycytidine and may increase cytarabine (AraC) cytotoxicity. We performed a phase I dose escalation trial of AraC combined with GTI-2040, a 20-mer antisense oligonucleotide shown in preclinical studies to decrease levels of the R2 subunit of ribonucleotide reductase, to determine the maximum tolerated dose in adults with relapsed/refractory acute myeloid leukemia. Experimental Design: Twenty-three adults (ages 18-59 years) were enrolled in this dose escalation phase I trial, receiving high-dose AraC twice daily combined with infusional GTI-2040. An ELISA-based assay measured plasma and intracellular concentrations of GTI-2040. R2 protein changes were evaluated by immunoblotting in pretreatment and post-treatment bone marrow samples. Results: The maximum tolerated dose was 5 mg/kg/d GTI-2040 (days 1-6) and 3 g/m2/dose AraC every 12 hours for 8 doses. Neurotoxicity was dose limiting. Eight patients (35%) achieved complete remission. Mean bone marrow intracellular concentration of GTI-2040 were higher at 120 hours than at 24 hours from the start of GTI-2040 (P = 0.002), suggesting intracellular drug accumulation over time. Reductions in bone marrow levels of R2 protein (&amp;gt;50%) were observed at 24 and 120 hours. Higher baseline R2 protein expression (P = 0.03) and reductions after 24 hours of GTI-2040 (P = 0.04) were associated with complete remission. Conclusions: GTI-2040 and high-dose AraC were coadministered safely with successful reduction of the intended R2 target and encouraging clinical results. The clinical efficacy of this combination will be tested in an upcoming phase II study.
Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles
Authors: Arif O. Khan, Dania S. Khalil, Latifa J. Al Sharif, Faisal E. Al-Ghadhfan, Nada A. Al Tassan
Journal: Ophthalmology (2009)
Epigenetic markers for early detection of nasopharyngeal carcinoma in a high risk population
Authors: Susanna H Hutajulu, Sagung R Indrasari, Luh PL Indrawati, Ahmad Harijadi, Sylvia Duin, Sofia M Haryana, Renske DM Steenbergen, Astrid E Greijer, Jaap M Middeldorp
Journal: Molecular Cancer (2011)

Abstract Background Undifferentiated nasopharyngeal carcinoma (NPC) is strongly related to Epstein-Barr virus (EBV) infection, allowing aberrant antibodies against EBV and viral DNA load as screening tools in high risk populations. Methylation analysis in the promoter of tumor suppressor genes (TSGs) may serve as a complementary marker for identifying early cases. This study determined methylation status of multiple TSGs and evaluated whether it may improve early detection. Methods Nasopharyngeal brushings were taken from 53 NPC patients, 22 high risk subjects and 25 healthy EBV carriers. Corresponding NPC paraffin tissue was included. DNA was bisulfite-modified preceding analysis by methylation-specific PCR (MSP). Ten TSGs were studied. Results NPC paraffin and brushing DNA revealed an 81.8% concordance so that MSP analysis was done using either one of both specimens. NPC samples showed methylation for individual TSGs (DAPK1 79.2%, CDH13 77.4%, DLC1 76.9%, RASSF1A 75.5%, CADM1 69.8%, p16 66.0%, WIF1 61.2%, CHFR 58.5%, RIZ1 56.6% and RASSF2A 29.2%). High risk individuals, having elevated EBV IgA and viral load, showed high frequency of methylation of CDH13, DAPK1, DLC1 and CADM1, but low frequency of methylation of p16 and WIF1 and undetectable methylation of RASSF1A, CHFR, RIZ1 and RASSF2A. Healthy subjects showed similar patterns as high risk individuals. A combination of RASSF1A and p16 gave good discrimination between NPC and non-NPC, but best results were combined analysis of five methylation markers (RASSF1A, p16, WIF1, CHFR and RIZ1) with detection rate of 98%. Conclusion Multiple marker MSP is proposed as a complementary test for NPC risk assessment in combination with EBV-based markers.
Primary sources and immunological prerequisites for sST2 secretion in humans
Authors: M. Mildner, A. Storka, M. Lichtenauer, V. Mlitz, M. Ghannadan, K. Hoetzenecker, S. Nickl, B. Dome, E. Tschachler, H. J. Ankersmit
Journal: Cardiovascular Research (2010)

AimsSerum levels of the soluble growth stimulation gene-2 (sST2) are elevated in heart and pulmonary diseases. However, the relationship of the sST2/interleukin (IL)-33 axis and its triggers as well as its organ distribution is still not known. This study was thus designed to investigate the cellular origin and regulation of sST2 and IL-33 in vitro and in vivo.
Antigen receptors on major histocompatibility complex-restricted T lymphocytes. I. Preparation and characterization of syngeneic antisera against trinitrophenyl-activated T cell blasts and demonstration of their specificity for idiotypes on cytotoxic T lymphocytes.
Authors: P H Krammer, R Rehberger, K Eichmann
Journal: The Journal of Experimental Medicine (1980)

This paper describes the specificity of AKR anti-(a) [AKR anti-trinitrophenylated AKR (AKR-TNP)] [AKRa (AKRaAKR TNP)] antisera raised in syngeneic AKR mice against AKRaAKR-TNP cell populations enriched for H-2-restricted aTNP cytotoxic lymphocytes (CTL) by blast-cell isolation. The activity of the antisera resided in the Ig fraction. All antisera were shown to reproducibly react with AKRaAKR-TNP-CTL-containing cell populations in indirect immunofluorescence and all removed the major fraction of CTL in complement-dependent lysis causing a considerable depression of cell-mediated lympholysis. The antisera were nonreactive with alloreactive AKRaC57BL/6 CTL and other H-2-restricted AKR CTL against fluorescein-isothiocyanate-conjugated AKR-target cells. It could be excluded that the antisera contained contaminating antibodies against TNP, TNP-neoantigenic determinants (NAD), or processed CTL-receptor-bound TNP-NAD, thus demonstrating specificity for determinants on T cell receptors of AKRaAKR-TNP CTL. These receptors were produced by the CTL themselves. These observations are interpreted to suggest that AKRa (AKRaAKR-TNP) antisera contain anti-idiotypic antibodies directed against specificity-associated determinants (idiotypes) on T cell receptors of H-2-restricted AKRaAKR-TNP CTL. The antisera provide a new tool to study the genetic control of idiotype expression on H-2-restricted CTL, the biochemistry of T cell receptors, and the regulation of the generation of H-2 restricted CTL on the idiotype level.
Risk of depression in women with psoriasis: a cohort study
Authors: E.D. Dommasch, T. Li, O.I. Okereke, Y. Li, A.A. Qureshi, E. Cho
Journal: British Journal of Dermatology (2015)

Psoriasis is a common, chronic and inflammatory disease of the skin, which has been associated with depression in cross‐sectional studies with limited adjustment for confounders. In this prospective cohort study, we investigated the risk of incident depression among individuals with psoriasis and psoriatic arthritis (PsA). We included 50 750 US female nurses from the Nurses' Health Study who were free of depression at baseline in 2000. Those participants who had ever self‐reported clinician‐diagnosed depression or regular use of antidepressants, or had a Mental Health Inventory score of ≤ 52 were excluded. In 2008, we retrospectively asked participants if they had ever received a physician's diagnosis of psoriasis or PsA. We defined depression as self‐report of clinician‐diagnosed depression or regular use of antidepressant medication. Time‐dependent Cox proportional hazard models were used to estimate age and multivariate‐adjusted relative risks (RRs) of clinical depression. After adjusting for covariates including body mass index, physical activity, smoking and the presence of major chronic conditions, the multivariate‐adjusted RRs of clinical depression were 1·29 [95% confidence interval (CI) 1·10–1·52] for women with psoriasis and 1·52 (95% CI 1·06–2·19) for women with psoriasis and concomitant PsA, compared with women without psoriasis. We found an increased risk of depression in US women with psoriasis compared with those without psoriasis. This risk was higher in those who reported concomitant PsA. Future studies are needed to confirm these findings in other populations and to identify pathophysiological mechanisms linking psoriasis to depression.
THE NATURE OF THE ACTION OF INTRAVENOUS ALDOSTERONE: EVIDENCE FOR A ROLE OF THE HORMONE IN URINARY DILUTION*
Authors: Edmund H. Sonnenblick, Paul J. Cannon, John H. Laragh
Journal: Journal of Clinical Investigation (1961)

This action takes place in the tubule at a locus distal to that of isosmotic reabsorption. Also, this effect of the hormone on sodium chloride reabsorption appears to be dissociated from the effect on potassium excretion.