tbuckley/cabot-search huggingface dataset:
Differential expression of an equivalent clonotype among BALB/c and C57BL/6 mice
Authors: MP Cancro, NH Sigal, NR Klinman
Journal: The Journal of Experimental Medicine (1978)

The primary anti-phosphorylcholine (PC) response in BALB/c, C57BL/6, and congenic and recombinant inbred strains of these parental types has been examined in the splenic focus system. The frequencies of PC-specific precursors were shown to vary among these strains from 2 to 20 precursors per 10(6) splenic B cells. The distribution of these frequencies suggests that elements closely linked to or within the major histocompatibility complex may play a role in the determination of this parameter, although additional experiments are necessary to adequately assess this possibility. Moreover, all strains tested, regardless of immunoglobulin allotype, expressed monoclonal antibodies indistinguishable from the TEPC 15 myeloma protein (T15) clonotype. Further, the frequency of this clonotype in a given strain did not appear related to allotype, since both high and low T15 frequencies were found among strains of either the BALB/c (a(1)) or C57BL/6 (a(2)) allotype. The examination of normal serum for the T15 idiotype, however, revealed that only mice of the BALB/c allotype (a(1)) expressed the T15 idiotype in detectable quantities. After immunization with Diplococcus pneumoniae, sera from mice of the a(1) allotype consistently contained large quantities of the T15 idiotype, whereas sera from mice of the a(2) allotype exhibited various degrees of cross-reactivity with anti-T15 antibody. These results suggest that: (a) the allotype of an individual, although closely related to serum levels of an idiotype, is unrelated to the proportion of the precursor population which expresses that idiotype and; (b) the serum expression of a given idiotype may reflect regulatory processes, which act either during or before antigenic stimulation, rather than the actual clonotype representation in the repertoire. These findings indicate that distinctions must be made between the expression of idiotypic determinants within precursor B-cell populations and elements which regulate the subsequent appearance of those idiotypes in serum antibodies.
Consistent Etiology of Severe, Frequent Psychotic Experiences and Milder, Less Frequent Manifestations
Authors: Helena M. S. Zavos, Daniel Freeman, Claire M. A. Haworth, Philip McGuire, Robert Plomin, Alastair G. Cardno, Angelica Ronald
Journal: JAMA Psychiatry (2014)

<h3>Importance</h3> The onset of psychosis is usually preceded by psychotic experiences (PE). Little is known about the etiology of PE and whether the degree of genetic and environmental influences varies across different levels of severity. A recognized challenge is to identify individuals at high risk of developing psychotic disorders prior to disease onset. <h3>Objectives</h3> To investigate the degree of genetic and environmental influences on specific PE, assessed dimensionally, in adolescents in the community and in those who have many, frequent experiences (defined using quantitative cutoffs). We also assessed the degree of overlap in etiological influences between specific PE. <h3>Design, Setting, and Participants</h3> Structural equation model-fitting, including univariate and bivariate twin models, liability threshold models, DeFries-Fulker extremes analysis, and the Cherny method, was used to analyze a representative community sample of 5059 adolescent twin pairs (mean [SD] age, 16.31 [0.68] years) from England and Wales. <h3>Main Outcomes and Measures</h3> Psychotic experiences assessed as quantitative traits (self-rated paranoia, hallucinations, cognitive disorganization, grandiosity, and anhedonia, as well as parent-rated negative symptoms). <h3>Results</h3> Genetic influences were apparent for all PE (15%-59%), with modest shared environment for hallucinations and negative symptoms (17%-24%) and significant nonshared environment (49%-64%) for the self-rated scales and 17% for parent-rated negative symptoms. Three empirical approaches converged to suggest that the etiology in extreme-scoring groups (most extreme scoring: 5%, 10%, and 15%) did not differ significantly from that of the whole distribution. There was no linear change in heritability across the distribution of PE, with the exception of a modest increase in heritability for increasing severity of parent-rated negative symptoms. Of the PE that showed covariation, this appeared to be due to shared genetic influences (bivariate heritabilities, 0.54-0.71). <h3>Conclusions and Relevance</h3> These findings are consistent with the concept of a psychosis continuum, suggesting that the same genetic and environmental factors influence both extreme, frequent PE and milder, less frequent manifestations in adolescents. Individual PE in adolescence, assessed quantitatively, have lower heritability estimates and higher estimates of nonshared environment than those for the liability to schizophrenia. Heritability varies by type of PE, being highest for paranoia and parent-rated negative symptoms and lowest for hallucinations.
SEA-URCHIN SARCOIDAL GRANULOMA.
Authors: P.D.C. KINMONT
Journal: British Journal of Dermatology (1965)

Journal Article SEA‐URCHIN SARCOIDAL GRANULOMA. Get access P.D.C. KINMONT, M.B.E., M.D., F.R.C.P. P.D.C. KINMONT, M.B.E., M.D., F.R.C.P. Derbyshire Royal Infirmary, Derby Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 77, Issue 7, 1 July 1965, Pages 335–343, https://doi.org/10.1111/j.1365-2133.1965.tb14658.x Published: 01 July 1965
Preoperative Gemcitabine-Based Chemoradiation for Patients With Resectable Adenocarcinoma of the Pancreatic Head
Authors: Douglas B. Evans, Gauri R. Varadhachary, Christopher H. Crane, Charlotte C. Sun, Jeffrey E. Lee, Peter W.T. Pisters, Jean-Nicolas Vauthey, Huamin Wang, Karen R. Cleary, Gregg A. Staerkel, Chusilp Charnsangavej, Elizabeth A. Lano, Linus Ho, Renato Lenzi, James L. Abbruzzese, Robert A. Wolff
Journal: Journal of Clinical Oncology (2008)

We conducted a phase II trial to assess the outcomes of patients who received preoperative gemcitabine-based chemoradiation and pancreaticoduodenectomy (PD) for stage I/II pancreatic adenocarcinoma.Eligible patients with pancreatic head/uncinate process adenocarcinoma and radiographically defined potentially resectable disease received chemoradiation with 7 weekly intravenous (IV) infusions of gemcitabine (400 mg/m(2) IV over 30 minutes) plus radiation therapy (30 Gy in 10 fractions over 2 weeks). Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery.The study enrolled 86 patients. At the time of restaging, disease progression or a decline in performance status precluded 13 patients from surgery. Seventy-three (85%) of 86 patients were taken to surgery, extrapancreatic disease was found in nine, and 64 (74%) of 86 underwent a successful PD. Median overall survival (86 patients) was 22.7 months with a 27% 5-year survival. Median survival was 34 months for the 64 patients who underwent PD and 7 months for the 22 unresected patients (P < .001). The 5-year survival for those who did and did not undergo PD was 36% and 0%, respectively.Preoperative gemcitabine-based chemoradiation followed by restaging and evaluation for surgery separated the study population into two different subsets: patients likely to benefit from PD (n = 64) and those in whom surgery would be unlikely to provide clinical benefit (n = 22). Furthermore, the encouraging overall survival observed in this large trial supports the continued investigation of gemcitabine-based preoperative therapy in resectable pancreatic cancer.
Dissecting out crytogenic liver disease
Authors: J G C KINGHAM
Journal: Gut (2000)

See article on page 429 

The report from Pamplona in this issue of Gut 1 gives insight into the spectrum of liver disease in Southern Europe and emphasises the importance of careful laboratory evaluation (see page 429). A total of 1075 consecutive patients who had undergone liver biopsy because of elevated transaminases were assessed retrospectively. In 90% of cases the cause was clear on conventional clinical and serological criteria: most commonly chronic viral hepatitis was responsible with hepatitis C predominating. The study focuses on the remaining 10% in whom the cause was not obvious, in particular using polymerase chain reaction (PCR) on stored serum to detect hepatitis viral sequences, and careful review of the biopsy specimens. The histological review showed cirrhosis in 13, chronic hepatitis in 39, non-alcoholic steatohepatitis (NASH) in 16, and non-specific changes in 33 patients.

The most important finding was the high prevalence of hepatitis B and C sequences, albeit at low levels: 19 patients had hepatitis B virus (HBV) DNA and nine had hepatitis C virus (HCV) RNA in their serum (one had both). None had evidence of HBV or HCV infection by conventional antigen/antibody testing although 30 had evidence of …
A United Nations General Assembly Special Session for Mental, Neurological, and Substance Use Disorders: The Time Has Come
Authors: Judith K. Bass, Thomas H. Bornemann, Matthew Burkey, Sonia Chehil, Lenis Chen, John R. M. Copeland, William W. Eaton, Vijay Ganju, Erin Hayward, Rebecca S. Hock, Rubeena Kidwai, Kavitha Kolappa, Patrick T. Lee, Harry Minas, Flora Or, Giuseppe J. Raviola, Benedetto Saraceno, Vikram Patel
Journal: PLoS Medicine (2012)

Vikram Patel and other global mental health leaders call for a special session of the UN General Assembly to discuss and debate action needed on mental, neurological, and substance use disorders, which have been left off the international NCDs agenda.
Air Pollution and Health — Good News and Bad
Authors: C. Arden Pope
Journal: New England Journal of Medicine (2004)

Early concerns regarding the health-related effects of air pollution originated from severe episodes in Meuse Valley, Belgium, in 1930; Donora, Pennsylvania, in 1948; and London, in 1952. Although the overall effects of these episodes continue to be debated, well-documented, episode-related increases in morbidity and mortality from cardiopulmonary causes provided dramatic evidence that extremely high concentrations of air pollution can have serious adverse effects on health. Early public-policy efforts to improve air quality in the United States, Britain, and elsewhere were largely attempts to avert such “killer” episodes of air pollution. In the United States, a series of national legislative and . . .
CARPHENAZINE THERAPY OF ACUTELY PSYCHOTIC PATIENTS IN THE PSYCHIATRIC WARD OF A GENERAL HOSPITAL
Authors: IRVING BRONSKY
Journal: American Journal of Psychiatry (1965)

Twenty-eight patients who were acutely psychotic at the time of admission to the psychiatric ward of a general hospital were treated with carphenazine. Twenty-one patients (75%) were returned to the community as having recovered, after a median hospital stay of 25 days. This preliminary report indicates that carphenazine has a similar improvement rate to that of the more commonly used phenothiazines. Thus, it appears to have a wider range of activity than previously reported.
Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and inlivers of parabiotic mice
Authors: Thomas A. Lagace, David E. Curtis, Rita Garuti, Markey C. McNutt, Sahng Wook Park, Heidi B. Prather, Norma N. Anderson, Y.K. Ho, Robert E. Hammer, Jay D. Horton
Journal: Journal of Clinical Investigation (2006)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proteinase K subfamily of subtilases that reduces the number of LDL receptors (LDLRs) in liver through an undefined posttranscriptional mechanism. We show that purified PCSK9 added to the medium of HepG2 cells reduces the number of cell-surface LDLRs in a dose- and time-dependent manner. This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia. Binding and uptake of PCSK9 were largely dependent on the presence of LDLRs. Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. Purified PCSK9 had no effect on cell-surface LDLRs in hepatocytes lacking autosomal recessive hypercholesterolemia (ARH), an adaptor protein required for endocytosis of the receptor. Transgenic mice overexpressing human PCSK9 in liver secreted large amounts of the protein into plasma, which increased plasma LDL cholesterol concentrations to levels similar to those of LDLR-knockout mice. To determine whether PCSK9 was active in plasma, transgenic PCSK9 mice were parabiosed with wild-type littermates. After parabiosis, secreted PCSK9 was transferred to the circulation of wild-type mice and reduced the number of hepatic LDLRs to nearly undetectable levels. We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels.
Regulation of neural process growth, elaboration and structural plasticity by NF-κB
Authors: Humberto Gutierrez, Alun M. Davies
Journal: Trends in Neurosciences (2011)

The nuclear factor-kappa B (NF-κB) family of transcription factors has recently emerged as a major regulator of the growth and elaboration of neural processes. NF-κB signaling has been implicated in controlling axon initiation, elongation, guidance and branching and in regulating dendrite arbor size and complexity during development and dendritic spine density in the adult. NF-κB is activated by a variety of extracellular signals, and either promotes or inhibits growth depending on the phosphorylation status of the p65 NF-κB subunit. These novel roles for NF-κB, together with recent evidence implicating NF-κB in the regulation of neurogenesis in the embryo and adult, have important implications for neural development and for learning and memory in the mature nervous system.
Celecoxib, a Selective Cyclo-Oxygenase-2 Inhibitor, Enhances the Response to Preoperative Paclitaxel and Carboplatin in Early-Stage Non–Small-Cell Lung Cancer
Authors: N.K. Altorki, R.S. Keresztes, J.L. Port, D.M. Libby, R.J. Korst, D.B. Flieder, C.A. Ferrara, D.F. Yankelevitz, K. Subbaramaiah, M.W. Pasmantier, A.J. Dannenberg
Journal: Journal of Clinical Oncology (2003)

Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2).In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib.All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone.In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.
Clinical detection and characterization of bacterial pathogens in the genomics era
Authors: Pierre-Edouard Fournier, Gregory Dubourg, Didier Raoult
Journal: Genome Medicine (2014)

Abstract The availability of genome sequences obtained using next-generation sequencing (NGS) has revolutionized the field of infectious diseases. Indeed, more than 38,000 bacterial and 5,000 viral genomes have been sequenced to date, including representatives of all significant human pathogens. These tremendous amounts of data have not only enabled advances in fundamental biology, helping to understand the pathogenesis of microorganisms and their genomic evolution, but have also had implications for clinical microbiology. Here, we first review the current achievements of genomics in the development of improved diagnostic tools, including those that are now available in the clinic, such as the design of PCR assays for the detection of microbial pathogens, virulence factors or antibiotic-resistance determinants, or the design of optimized culture media for ‘unculturable’ pathogens. We then review the applications of genomics to the investigation of outbreaks, either through the design of genotyping assays or the direct sequencing of the causative strains. Finally, we discuss how genomics might change clinical microbiology in the future.
Abstract 384: CD14+S100A9 high monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer
Authors: Po-Hao Feng, Kang-Yun Lee, Ya-Ling Chang, Han-Pin Kuo
Journal: Cancer Research (2012)

Abstract Introduction: Myeloid-derived suppressor cells (MDSCs) are heterogeneous family of myeloid cells suppressing T cell immunity in tumor bearing hosts. We recently described an increased population of granulocyte-like CD11b+/CD14-/CD15+ MDSC in non-small cell lung cancer (NSCLC) patients. The role of CD11b+/CD14+ MDSC, being characterized as an inflammatory-type monocyte in mice, has not been well studied in human cancer. Methods: CD11b+/CD14- and CD11b+/CD14+ cells, determined and phenotyped by FACS analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naïve advanced NSCLC patients were correlated to clinical data. T cells activation in response to CD3/CD28 co-stimulation was determined by CFSE staining and ELISA analysis of IFN-γ. Cytokines and growth factors in the cultured supernatants were analyzed by ELISA. Results: NSCLC patients had significant higher ratio of CD11b+/CD14+ and CD11b+/CD14- cells than normal subjects. CD11b+/CD14+, but not CD11b+/CD11b- cells, correlated with poor performance and poor response to chemotherapy. Suppression of CD8+ and CD4+ T cells in NSCLC PBMCs was reversed by depleting either CD11b+ cells or CD14+ cells, an effect not seen in normal PBMCs. Both isolated CD11b+/CD14- and CD11b+/CD14+ cells suppressed CD8+ T cells proliferation and IFN-γ production in CD11b-depleted PBMC with equal ability. Enrichment of HLA-DR-/low cells decreased the suppressive ability of the CD14+ cells. CD11b+/CD14+ cells were monocyte-like expressing CD33+, CD15-/low, IL-4Rα+ and S100A9high and produced iNOS/arginase. The ratio of S100A9high cells positively correlated with the suppressive ability of the CD14+ cells and was associated with poor response to chemotherapy. CD11b+/CD14+ cell suppression of T cell proliferation was revered by the iNOS inhibitor aminoguanidine hydrochloride, the arginase inhibitor nor-NOHA, the STAT3 inhibitor AG490 and the blocking antibodies for IL-13, IL-4Rα+ and IL-10. CD11b+/CD14+ MDSCs secreted significant higher amounts of TNF-α, IL-8, IL-10, IL-13 and HGF than normal CD11b+/CD14+ cells. Conclusion: The CD11b+/CD14+ inflammatory monocyte in NSCLC patients is a distinct subset of MDSC with important clinical relevance, probably through secreting inflammatory cytokines and growth factors. These cells expressed IL-4Rα and high levels of S100A9. Among CD11b+/CD14+ monocytic MDSC, the expression of S100A9 protein seemd to be related to the immunosuppression activity and clinical response to chemotherapy. The role of S100A9 protein deserves further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 384. doi:1538-7445.AM2012-384
Widespread Failure of Hematolymphoid Differentiation Caused by a Recessive Niche-Filling Allele of the Ikaros Transcription Factor
Authors: Peter Papathanasiou, Andrew C. Perkins, Bradley S. Cobb, Roger Ferrini, Rupa Sridharan, Gerard F. Hoyne, Keats A. Nelms, Stephen T. Smale, Christopher C. Goodnow
Journal: Immunity (2003)
Inhaled corticosteroids in COPD: a light at the end of the tunnel?
Authors: J A Wedzicha
Journal: Thorax (2005)

Some promising findings on the effects of inhaled corticosteroids on mortality in COPD

Chronic obstructive pulmonary disease (COPD) is arguably the most common chronic disease of the lungs at present and, by 2020, it will be the third leading cause of death worldwide.1 COPD is associated with a relentless decline in forced expiratory volume in 1 second (FEV1) and, in the later stages, the condition progresses to pulmonary hypertension and hypoxic respiratory failure.

Few interventions have been shown to affect the outcome of COPD. The Lung Health Study-1 (LHS-1) showed that smoking cessation decreases the accelerated decline in FEV1 characteristic of this disease2 and, more recently, that smoking cessation is associated with decreases in cardiovascular and lung cancer mortality in patients with COPD.3 Furthermore, two randomised controlled studies of long term oxygen therapy (LTOT) showed that LTOT improves mortality in patients with COPD complicated by hypoxic respiratory failure.4,5

Because so few interventions have been shown to affect mortality and FEV1 decline in COPD, two further outcomes have been studied arising from the observed close association between exacerbation frequency and health related quality of life.6 In the ISOLDE study (Inhaled corticosteroids in Obstructive Lung Disease in Europe), inhaled corticosteroids were shown to slow the decline in health status over time and also to decrease exacerbation frequency.7 Further statistical modelling has shown that the effect of inhaled corticosteroids on quality of life is largely due to their effect on exacerbation frequency.8 Recent studies have closed the loop between exacerbation frequency, mortality, and lung function decline by showing that patients with a history of frequent exacerbations have an accelerated decline in FEV19,10 and increased mortality from COPD.11 From these data one would therefore expect that interventions that reduce …