tbuckley/cabot-search huggingface dataset:
DNA polymerase β is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination
Authors: Xiaoming Wu, Janet Stavnezer
Journal: The Journal of Experimental Medicine (2007)

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID), which converts cytosines to uracils in switch (S) regions. Subsequent excision of dU by uracil DNA glycosylase (UNG) of the base excision repair (BER) pathway is required to obtain double-strand break (DSB) intermediates for CSR. Since UNG normally initiates faithful repair, it is unclear how the AID-instigated S region lesions are converted into DSBs rather than correctly repaired by BER. Normally, DNA polymerase beta (Polbeta) would replace the dC deaminated by AID, leading to correct repair of the single-strand break, thereby preventing CSR. We address the question of whether Polbeta might be specifically down-regulated during CSR or inhibited from accessing the AID-instigated lesions, or whether the numerous AID-initiated S region lesions might simply overwhelm the BER capacity. We find that nuclear Polbeta levels are induced upon activation of splenic B cells to undergo CSR. When Polbeta(-/-) B cells are activated to switch in culture, they switch slightly better to IgG2a, IgG2b, and IgG3 and have more S region DSBs and mutations than wild-type controls. We conclude that Polbeta attempts to faithfully repair S region lesions but fails to repair them all.
Rearrangement of Immunoglobulin Genes in Shark Germ Cells
Authors: Susan S. Lee, David Fitch, Martin F. Flajnik, Ellen Hsu
Journal: The Journal of Experimental Medicine (2000)

The variable (V), (diversity [D]), and joining (J) region recombinases (recombination activating genes [RAGs]) can perform like transposases and are thought to have initiated development of the adaptive immune system in early vertebrates by splitting archaic V genes with transposable elements. In cartilaginous fishes, the immunoglobulin (Ig) light chain genes are organized as multiple VJ-constant (C) clusters; some loci are capable of rearrangement while others contain fused VJ. The latter may be key to understanding the evolutionary role of RAG. Are they relics of the archaic genes, or are they results of rearrangement in germ cells? Our data suggest that some fused VJ genes are not only recently rearranged, but also resulted from RAG-like activity involving hairpin intermediates. Expression studies show that these, like some other germline-joined Ig sequences, are expressed at significant levels only early in ontogeny. We suggest that a rejoined Ig gene may not merely be a sequence restricting antibody diversity, but is potentially a novel receptor no longer tied to somatic RAG expression and rearrangement. From the combined data, we arrived at the unexpected conclusion that, in some vertebrates, RAG is still an active force in changing the genome.
Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction
Authors: Simon Schenk, Carrie E. McCurdy, Andrew Philp, Mark Z. Chen, Michael J. Holliday, Gautum K. Bandyopadhyay, Olivia Osborn, Keith Baar, Jerrold M. Olefsky
Journal: Journal of Clinical Investigation (2011)

Skeletal muscle insulin resistance is a key component of the etiology of type 2 diabetes. Caloric restriction (CR) enhances the sensitivity of skeletal muscle to insulin. However, the molecular signals within skeletal muscle linking CR to improved insulin action remain largely unknown. Recently, the mammalian ortholog of Sir2, sirtuin 1 (Sirt1), has been identified as a potential transducer of perturbations in cellular energy flux into subsequent metabolic adaptations, including modulation of skeletal muscle insulin action. Here, we have demonstrated that CR increases Sirt1 deacetylase activity in skeletal muscle in mice, in parallel with enhanced insulin-stimulated phosphoinositide 3-kinase (PI3K) signaling and glucose uptake. These adaptations in skeletal muscle insulin action were completely abrogated in mice lacking Sirt1 deacetylase activity. Mechanistically, Sirt1 was found to be required for the deacetylation and inactivation of the transcription factor Stat3 during CR, which resulted in decreased gene and protein expression of the p55α/p50α subunits of PI3K, thereby promoting more efficient PI3K signaling during insulin stimulation. Thus, these data demonstrate that Sirt1 is an integral signaling node in skeletal muscle linking CR to improved insulin action, primarily via modulation of PI3K signaling.
Absorption of vitamin E in children with biliary obstruction
Authors: J. T. Harries, D. P. R. Muller
Journal: Gut (1971)

Serum vitamin E levels and red cell haemolysis were measured in 17 children with biliary obstruction after oral and intramuscular loading tests, and during long-term oral administration of differing doses of a fat-soluble and water-miscible preparation of alpha-tocopheryl acetate. The results suggested a severe defect in the intestinal absorption of both preparations. In three of the children who were studied during periods of improving biliary obstruction, absorption was shown to have improved. Bile plays a major role in the absorption of vitamin E from the intestinal tract and the exact mechanism of its action requires further elucidation.
Effective use of cyclosporin in sarcoidosis: a treatment strategy based on computed tomography scanning
Authors: CA O'Callaghan, AU Wells, A Lalvani, PD Dhillon, DM Hansell, DN Mitchell
Journal: European Respiratory Journal (1994)

Cyclosporin was used successfully in a patient with severe pulmonary sarcoidosis, a poor response and unacceptable side-effects from corticosteroid therapy. Computed tomography (CT) scanning initially suggested reversible disease, and subsequently detected improvement earlier than other indices of disease activity. This information was critical in the decision to commence and to continue cyclosporin. The literature on the use of cyclosporin in sarcoidosis is reviewed.
Salivary gland scintigraphy in Sjogren's syndrome and patients with sicca symptoms but without Sjogren's syndrome: the psychological profiles and predictors for salivary gland dysfunction
Authors: E-K Tensing
Journal: Annals of the Rheumatic Diseases (2003)

To characterise the psychological profiles of Sjögren's syndrome (SS) and patients with sicca symptoms but without SS; to find predictors for salivary gland function; to evaluate salivary scintigraphy as a method to differentiate between SS and patients with sicca symptoms but without SS.Psychological tests (Medical Outcomes Study Short Form General Health Survey (SF-36), Jenkins Activity Survey, Toronto Alexithymia Scale, and Maastricht Questionnaire for vital exhaustion) were performed and assessment of the function of the salivary glands made in 26 patients with primary SS, 8 with secondary SS, and 9 with sicca symptoms but without SS. Data were analysed with BMDP new system version 1.0 statistical program.Psychological profiles were similar in all groups. Hb, RF, ANA, and SSA differentiated between the groups. Results of salivary scintigraphy were predicted to 51% by ANA, SSA, SSB, IgG, IgA, diagnosis, vitality, and role limitations due to emotional problems. No predictors were found for the resting salivary flow. Salivary scintigraphy was pathological in 21/26 (81%) and in 8/8 (100%) patients with secondary SS, but only in 2/9 (22%) patients with sicca symptoms without SS (p=0.002) (sensitivity 85.3%, specificity 77.8%).Patients with sicca symptoms but without SS have sickness behaviour similar to that of patients with SS. The results of salivary scintigraphy can be predicted by diagnosis and autoimmune findings; psychological characteristics added 20% to this predictive value. Distinction between SS and patients with sicca symptoms but without SS is difficult, but in addition to autoantibodies, salivary scintigraphy can be used for this purpose.
Human Papillomavirus Infection and Esophageal Cancer: a Nationwide Seroepidemiologic Case-Control Study in Sweden
Authors: J. Lagergren, Z. Wang, R. Bergstrom, J. Dillner, O. Nyren
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Infection with human papillomavirus (HPV) type 16 has been implicated as a risk factor for esophageal squamous cell carcinoma in three seroepidemiologic studies. We conducted a larger, population-based study to verify this association and to investigate possible confounding factors. METHODS: We performed a nationwide case-control study in Sweden of HPV16 or HPV18 infection and risk of esophageal squamous cell carcinoma or esophageal/gastroesophageal adenocarcinoma. Tumors were strictly classified by their location and histologic type. Case subjects with incident cancers and population-based control subjects donated blood samples and were interviewed in person about potential confounding factors. An enzyme-linked immunosorbent assay was used to detect HPV seropositivity. Multivariate analyses were conducted to study relationships between HPV seropositivity, level of education, smoking (all tobacco) status, alcohol consumption, and cancer risk. RESULTS: We compared 121 case subjects with esophageal squamous cell carcinoma and 173 case subjects with adenocarcinoma of the esophagus or gastroesophageal junction with 302 population-based control subjects. The age- and sex-adjusted odds ratios (ORs) for squamous cell carcinoma were 1.0 (95% confidence interval [CI] = 0.5-2.0) for persons seropositive for HPV16 and 0.5 (95% CI = 0.2-1.1) for persons seropositive for HPV18 in comparison with seronegative individuals. The corresponding ORs for adenocarcinoma were 1.2 (95% CI = 0.7-2.2) and 0.2 (95% CI = 0.1-0.7), respectively. Adjustments for smoking status, alcohol consumption, and level of education did not alter the results. CONCLUSIONS: We found no evidence of a positive association between HPV16 or HPV18 infection and either form of esophageal cancer. Our results do not support conclusions from previous studies.
Biology trumps statistics in the postgenomic era
Authors: Charles E. Glatt
Journal: Behavioral and Brain Sciences (2012)

Abstract Charney discusses the growing realization in the postgenomic era that genomic biology deviates from Mendelian assumptions at the heart of genetic heritability and association studies. Given the complexity of genomic biology, how are we to identify meaningful genetic factors that contribute to behavioral? One response is to make genetic variants the focus of biological rather than statistical analyses of behavior.
MIF Produced by Bone Marrow–Derived Macrophages Contributes to Teratoma Progression after Embryonic Stem Cell Transplantation
Authors: Xi Wang, Tianxiang Chen, Lin Leng, Jianqing Fan, Kai Cao, Zhaoxia Duan, Xijing Zhang, Changshun Shao, Mingmei Wu, Iman Tadmori, Tianyi Li, Li Liang, Dongming Sun, Shusen Zheng, Andreas Meinhardt, Wise Young, Richard Bucala, Yi Ren
Journal: Cancer Research (2012)

Although stem cell therapy holds promise as a potential treatment in a number of diseases, the tumorigenicity of embryonic stem cells (ESC) and induced pluripotent stem cells remains a major obstacle. In vitro predifferentiation of ESCs can help prevent the risk of teratoma formation, yet proliferating neural progenitors can generate tumors, especially in the presence of immunosuppressive therapy. In this study, we investigated the effects of the microenvironment on stem cell growth and teratoma development using undifferentiated ESCs. Syngeneic ESC transplantation triggered an inflammatory response that involved the recruitment of bone marrow (BM)-derived macrophages. These macrophages differentiated into an M2 or angiogenic phenotype that expressed multiple angiogenic growth factors and proteinases, such as macrophage migration inhibitory factor (MIF), VEGF, and matrix metalloproteinase 9, creating a microenvironment that supported the initiation of teratoma development. Genetic deletion of MIF from the host but not from ESCs specifically reduced angiogenesis and teratoma growth, and MIF inhibition effectively reduced teratoma development after ESC transplantation. Together, our findings show that syngeneic ESC transplantation provokes an inflammatory response that involves the rapid recruitment and activation of BM-derived macrophages, which may be a crucial driving force in the initiation and progression of teratomas.
Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle
Authors: Andrew P. Evan, James E. Lingeman, Fredric L. Coe, Joan H. Parks, Sharon B. Bledsoe, Youzhi Shao, Andre J. Sommer, Ryan F. Paterson, Ramsay L. Kuo, Marc Grynpas
Journal: Journal of Clinical Investigation (2003)

Our purpose here is to test the hypothesis that Randall’s plaques, calcium phosphate deposits in kidneys of patients with calcium renal stones, arise in unique anatomical regions of the kidney, their formation conditioned by specific stone-forming pathophysiologies. To test this hypothesis, we performed intraoperative biopsies of plaques in kidneys of idiopathic-calcium-stone formers and patients with stones due to obesity-related bypass procedures and obtained papillary specimens from non–stone formers after nephrectomy. Plaque originates in the basement membranes of the thin loops of Henle and spreads from there through the interstitium to beneath the urothelium. Patients who have undergone bypass surgery do not produce such plaque but instead form intratubular hydroxyapatite crystals in collecting ducts. Non–stone formers also do not form plaque. Plaque is specific to certain kinds of stone-forming patients and is initiated specifically in thin-limb basement membranes by mechanisms that remain to be elucidated.
COMBINED DRUG TREATMENT OF TUBERCULOSIS. II. STUDIES OF ANTIMICROBIALLY-ACTIVE ISONIAZID AND STREPTOMYCIN SERUM LEVELS IN ADULT TUBERCULOUS PATIENTS
Authors: William Mandel, Angeline D. Heaton, William F. Russell, Gardner Middlebrook
Journal: Journal of Clinical Investigation (1959)

The importance of achieving concentrations of both streptomycin and isoniazid adequate to sterilize all parent drug-susceptible organisms was empasized by in vitro studies on the prevention of emergence of mutants resistant to these drugs
Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer
Authors: Robert Dreicer, Daniel Petrylak, David Agus, Iain Webb, Bruce Roth
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent prostate cancer. Experimental Design: Two bortezomib doses (1.3 and 1.6 mg/m2/dose) in combination with four docetaxel doses (25-40 mg/m2/dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in Solid Tumors guidelines. Results: Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (≥50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for ≥4 weeks in 14 patients (21%). According to Response Evaluation Criteria in Solid Tumors guidelines, 11% achieved a partial response, and an additional 67% had stable disease. The degree of proteasome inhibition was similar to that reported with single-agent bortezomib. Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred. Conclusions: The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m2 bortezomib plus 40 mg/m2 docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.
Peripheral T cell activation and deletion induced by transfer of lymphocyte subsets expressing endogenous or exogenous mouse mammary tumor virus.
Authors: G A Waanders, A N Shakhov, W Held, O Karapetian, H Acha-Orbea, H R MacDonald
Journal: The Journal of Experimental Medicine (1993)

Murine T cell reactivity with products of the minor lymphocyte stimulatory (Mls) locus correlates with the expression of particular variable (V) domains of the T cell receptor (TCR) beta chain. It was recently demonstrated that Mls antigens are encoded by an open reading frame (ORF) in the 3' long terminal repeat of either endogenous or exogenous mouse mammary tumor virus (MMTV). Immature thymocytes expressing reactive TCR-V beta domains are clonally deleted upon exposure to endogenous Mtv's. Mature T cells proliferate vigorously in response to Mls-1a (Mtv-7) in vivo, but induction of specific anergy and deletion after exposure to Mtv-7-expressing cells in the periphery has also been described. We show here that B cells and CD8+ (but not CD4+) T cells from Mtv-7+ mice efficiently induce peripheral deletion of reactive T cells upon transfer to Mtv-7- recipients, whereas only B cells stimulate specific T cell proliferation in vivo. In contrast to endogenous Mtv-7, transfer of B, CD4+, or CD8+ lymphocyte subsets from mice maternally infected with MMTV(SW), an infectious homologue of Mtv-7, results in specific T cell deletion in the absence of a detectable proliferative response. Finally, we show by secondary transfers of infected cells that exogenous MMTV(SW) is transmitted multidirectionally between lymphocyte subsets and ultimately to the mammary gland. Collectively our data demonstrate heterogeneity in the expression and/or presentation of endogenous and exogenous MMTV ORF by lymphocyte subsets and emphasize the low threshold required for induction of peripheral T cell deletion by these gene products.
Drugs and Driving
Authors: J. G. Perry
Journal: JAMA (1966)

Our thesis is simple: Patients should be told by their physicians when drugs may decrease their driving skill. The physician's expert advice, coupled with the patient's common sense, may help to prevent accidents. The high incidence of death and injury from automobile accidents is a major public health problem. Although accident prevention may not be as clearly a medical responsibility as the treatment of accident victims, it is appropriate that physicians be concerned with prevention at least when iatrogenic factors may be involved. Such accidents undoubtedly represent only a small fraction of the total number, but this number is not specifically known. Moreover, our knowledge of the effect of drugs on driving is limited. The development of more factual information in these areas will help to define the physician's role in preventing motor vehicle accidents. <h3>Complexities of the Problem</h3> The motorist requires a variety of physical and mental skills in
Utility of cytopathology in diagnosis and molecular testing of lung cancer
Authors: S. A. Thiryayi, D. N. Rana, M. Woodhead
Journal: Thorax (2011)

We read with interest the editorial by Booton et al 1 on advances in the treatment and diagnosis of non-small cell lung cancer. Recently published best practice guidelines for pathology recommend the provision of as precise a diagnosis as possible, with optimisation of specimen use.2 We advocate the utility of cytopathology in this regard and share our experience of the diagnostic potential and the range of ancillary tests possible on respiratory-related cytology specimens.

During a 20-month period (1 September 2009 to 30 April 2011), 227 …
Longitudinal changes in the nature, severity and frequency of COPD exacerbations
Authors: G.C. Donaldson, T.A.R. Seemungal, I.S. Patel, S.J. Lloyd-Owen, T.M.A. Wilkinson, J.A. Wedzicha
Journal: European Respiratory Journal (2003)

Exacerbations are an important feature and outcome measure in chronic obstructive pulmonary disease (COPD), but little is known about changes in their severity, recovery, symptom composition or frequency over time. In this study 132 patients (91 male; median age 68.4 yrs and median forced expiratory volume in one second (FEV1) 38.4% predicted) recorded daily symptoms and morning peak expiratory flow. Patients were monitored for a median of 918 days and 1,111 exacerbations were identified. Patients with severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) category III, n=38) had an annual exacerbation frequency of 3.43 x yr(-1), 0.75 x yr(-1) higher than those with moderate COPD (GOLD II, n=94). Exacerbation frequency did not change significantly during the study. At exacerbation onset, symptom count increased to 2.23, relative to a baseline of 0.36 set 8-14 days previously, and this increase rose by 0.05 x yr(-1). Recovery to baseline levels in symptoms and FEV1 took longer (0.32 and 0.55 days x yr(-1)). Sputum purulence at exacerbation became more prevalent over time by 4.1% x yr(-1) from an initial value of 17%. The results of this study suggest that over time, individual patients have more symptoms during exacerbations, with an increased chance of sputum purulence and longer recovery times.
Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation
Authors: R. Luksch, A. Tienghi, K. Sundby Hall, F. Fagioli, P. Picci, E. Barbieri, L. Gandola, M. Eriksson, P. Ruggieri, P. Daolio, P. Lindholm, A. Prete, G. Bisogno, A. Tamburini, G. Grignani, M.E. Abate, M. Podda, S. Smeland, S. Ferrari
Journal: Annals of Oncology (2012)
Analysis of the T-cell receptor repertoire in human atherosclerosis
Authors: J Oksenberg
Journal: Cardiovascular Research (1997)

Objective: Analysis of T-cell receptor (TCR) β-chain gene expression in atherosclerotic lesions of human aorta. Methods: TCR diversity was studied using non-radioactive polymerase chain reaction for quantitative assessment of TCRBV gene transcripts, together with size and sequence analysis of the β-chain third complementarity-determining region (CDR3). Samples represent a wide range of atheromatous histology, allowing evaluation of the T-cell repertoire at different stages of disease. Results: Diverse TCRBV family usage was observed in the majority of the samples, as the 25 different TCRBV products were detected at levels exceeding background. The data also showed that TCRBV transcripts expressed in the diseased aorta tissue displayed considerable size heterogeneity and no repetition of CDR3 nucleotide motifs. Conclusions: The early presence of T-lymphocytes in the atheromatous blood vessel has been interpreted as an indication of specific immunological reactions operating during the course of the atherosclerotic process. Although a T-cell infiltrate characterized by limited usage of TCRAV genes cannot be excluded, the unrestricted usage of TCRBV genes argues against a local T-cell clonal expansion in atherogenesis.
250 μg or 500 μg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study
Authors: Paul O'Connor, Massimo Filippi, Barry Arnason, Giancarlo Comi, Stuart Cook, Douglas Goodin, Hans-Peter Hartung, Douglas Jeffery, Ludwig Kappos, Francis Boateng, Vitali Filippov, Maria Groth, Volker Knappertz, Christian Kraus, Rupert Sandbrink, Christoph Pohl, Timon Bogumil
Journal: The Lancet Neurology (2009)