tbuckley/cabot-search huggingface dataset:
Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma
Authors: Heather Francis, Sharon DeMorrow, Julie Venter, Paolo Onori, Mellanie White, Eugenio Gaudio, Taylor Francis, John F Greene, Steve Tran, Cynthia J Meininger, Gianfranco Alpini
Journal: Gut (2011)

<h3>Background</h3> In several tumours the endogenous activity of histidine decarboxylase (HDC), the enzyme stimulating histamine synthesis, sustains the autocrine trophic effect of histamine on cancer progression. Cholangiocarcinoma is a biliary cancer with limited treatment options. Histamine interacts with four G-protein coupled receptors, H1–H4 histamine receptors (HRs). <h3>Objective</h3> To determine the effects of histamine stimulation and inhibition of histamine synthesis (by modulation of HDC) on cholangiocarcinoma growth. <h3>Methods</h3> In vitro studies were performed using multiple human cholangiocarcinoma lines. The expression levels of the histamine synthetic machinery and HRs were evaluated along with the effects of histamine stimulation and inhibition on cholangiocarcinoma proliferation. A xenograft tumour model was used to measure tumour volume after treatment with histamine or inhibition of histamine synthesis by manipulation of HDC. Vascular endothelial growth factor (VEGF) expression was measured in cholangiocarcinoma cells concomitant with the evaluation of the expression of CD31 in endothelial cells in the tumour microenvironment. <h3>Results</h3> Cholangiocarcinoma cells display (1) enhanced HDC and decreased monoamine oxidase B expression resulting in increased histamine secretion; and (2) increased expression of H1–H4 HRs. Inhibition of HDC and antagonising H1HR decreased histamine secretion in Mz-ChA-1 cells. Long-term treatment with histamine increased proliferation and VEGF expression in cholangiocarcinoma that was blocked by HDC inhibitor and the H1HR antagonist. In nude mice, histamine increased tumour growth (up to 25%) and VEGF expression whereas inhibition of histamine synthesis (by reduction of HDC) ablated the autocrine stimulation of histamine on tumour growth (∼80%) and VEGF expression. No changes in angiogenesis (evaluated by changes in CD31 immunoreactivity) were detected in the in vivo treatment groups. <h3>Conclusion</h3> The novel concept that an autocrine loop (consisting of enhanced histamine synthesis by HDC) sustains cholangiocarcinoma growth is proposed. Drug targeting of HDC may be important for treatment of patients with cholangiocarcinoma.
Partial Rescue of Glomerular Laminin α5 Mutations by Wild-Type Endothelia Produce Hybrid Glomeruli
Authors: Dale R. Abrahamson, Patricia L. St. John, Kathryn Isom, Barry Robert, Jeffrey H. Miner
Journal: Journal of the American Society of Nephrology (2007)

Both endothelial cells and podocytes are sources for laminin α1 at the inception of glomerulogenesis and then for laminin α5 during glomerular maturation. Why glomerular basement membranes (GBM) undergo laminin transitions is unknown, but this may dictate glomerular morphogenesis. In mice that genetically lack laminin α5, laminin α5β2γ1 is not assembled, vascularized glomeruli fail to form, and animals die at midgestation with neural tube closure and placental deficits. It was previously shown that renal cortices of newborn mice contain endothelial progenitors (angioblasts) and that when embryonic day 12 kidneys are transplanted into newborn kidney, hybrid glomeruli (host-derived endothelium and donor-derived podocytes) result. Reasoning that host endothelium may correct the glomerular phenotype that is seen in laminin α5 mutants, α5 null embryonic day 12 metanephroi were grafted into wild-type newborn kidney. Hybrid glomeruli were identified in grafts by expression of a host-specific LacZ lineage marker. Labeling of glomerular hybrid GBM with chain-specific antibodies showed a markedly stratified distribution of laminins: α5 was found only on the inner endothelial half of GBM, whereas α1 located to outer layers beneath mutant podocytes. For measurement of the contribution of host endothelium to hybrid GBM, immunofluorescent signals for laminin α5 were quantified: Hybrid GBM contained approximately 50% the normal α5 complement as wild-type GBM. Electron microscopy of glomerular hybrids showed vascularization, but podocyte foot processes were absent. It was concluded that (1) endothelial and podocyte-derived laminins remain tethered to their cellular origin, (2) developing endothelial cells contribute large amounts of GBM laminins, and (3) podocyte foot process differentiation may require direct exposure to laminin α5.
Effect of inhaled endotoxin on induced sputum in normal, atopic, and atopic asthmatic subjects
Authors: J. A Nightingale, D. F Rogers, L. A Hart, S. A Kharitonov, K F. Chung, P. J Barnes
Journal: Thorax (1998)

Inhalation of lipopolysaccharide (LPS) causes an inflammatory response in the lungs. To explore this response, inflammatory indices were measured in induced sputum from atopic asthmatic patients and compared with atopic and non-atopic subjects after inhalation of LPS.The effects of inhaled LPS (60 micrograms) or placebo (0.9% saline) were examined in a randomised, double blind, crossover trial in 11 non-atopic normal subjects, seven atopic, non-asthmatic individuals, and eight atopic, asthmatic patients. Sputum was induced by inhalation of 3.5% saline before the test inhalation and again at six hours and 24 hours. Spirometry (forced expiratory volume in one second (FEV1), forced vital capacity (FVC)), heart rate, blood pressure, and temperature were recorded before challenge and at intervals until eight hours, and at 24 hours after challenge.There was no change in cardiovascular parameters or spirometry with either exposure in any group. In the asthmatic patients only, inhalation of LPS caused a rise in temperature, with a peak of 0.6 degree C at seven hours, which was significantly higher than following placebo inhalation (p < 0.05). In normal subjects, LPS caused a significant rise in absolute neutrophil counts at 24 hours compared with placebo (median 1.1 x 10(6) cells/ml after LPS; median 0.2 x 10(6) cells/ml after placebo, p < 0.01), but no change in differential counts. In asthmatic patients, LPS caused a significant rise in differential neutrophil counts at six hours compared with placebo (median 88% after LPS; median 56% after placebo, p < 0.05), but no change in absolute cell counts at any time point. There was no change in neutrophil counts in the atopic subjects. There was a significant rise in sputum interleukin 8 (IL-8) concentrations in normal subjects at six hours compared with placebo (mean placebo 1.1 ng/ml; LPS 3.0 ng/ml, p < 0.05) and in asthmatics at 24 hours (mean placebo 2.0 ng/ml, LPS 6.9 ng/ml, p < 0.05). There were no changes in sputum concentrations of tumour necrosis factor alpha or granulocyte macrophage colony stimulating factor at any time.Inhalation of LPS causes a neutrophilic inflammation with increases in IL-8 in both normal and asthmatic subjects.
Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease
Authors: Alon Monsonego, Victor Zota, Arnon Karni, Jeffery I. Krieger, Amit Bar-Or, Gal Bitan, Andrew E. Budson, Reisa Sperling, Dennis J. Selkoe, Howard L. Weiner
Journal: Journal of Clinical Investigation (2003)

Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid beta protein (Abeta) in brain regions serving memory and cognition. In animal models of AD, immunization with Abeta results in the clearance of Abeta deposits from the brain. However, a trial of vaccination with synthetic human Abeta1-42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Abeta in middle-aged and elderly healthy subjects and in patients with AD. A significantly higher proportion of healthy elderly subjects and patients with AD had strong Abeta-reactive T cell responses than occurred in middle-aged adults. The immunodominant Abeta epitopes in humans resided in amino acids 16-33. Epitope mapping enabled the identification of MHC/T cell receptor (TCR) contact residues. The occurrence of intrinsic T cell reactivity to the self-antigen Abeta in humans has implications for the design of Abeta vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process.
In vitro model for the assessment of luminal factors on rectal mucosa.
Authors: A Allan, D P Jewell
Journal: Gut (1983)

An organ culture method for the maintenance of rectal biopsies over a period of 24 hours is described. Good preservation of histological architecture and continued crypt cell proliferation were shown over the culture period. The colonic enzyme alkaline phosphatase was found to rise over the period of culture. This rise was dependent upon continued protein synthesis by the cell. Changes in alkaline phosphatase activity during culture in biopsies from patients with ulcerative colitis and Crohn9s disease are reported. This organ culture system and the measurement of alkaline phosphatase activity during culture provides a new approach to the assessment of luminal antigens as possible effectors of colonic epithelial cell damage.
Aetiology and presentation of pulmonary disease in HAART-naive HIV-infected adults at a tertiary hospital in Lusaka, Zambia
Authors: Kondwelani Mateyo, Shabir Lakhi, Ben Chi, Brad Guffey, Ben Andrews, Aggrey Mweemba
Journal: European Respiratory Journal (2013)

Objectives: To determine the aetiology of pulmonary disease in HAART-naive, HIV-infected Zambian adults with severe immunosuppression  Design: A cross-section study.  Setting: University Teaching Hospital, Lusaka, Zambia.  Subjects: We conducted intensive TB screening for HAART-naive HIV-infected patients with CD4+ count less than 200/μL with pulmonary symptoms. Our algorithm comprised initial sputum screening with ZN stain. Patients unable to expectorate sputum and those in whom sputum smear for TB was negative underwent bronchoscopy. BAL was assessed for causative agents and correlated with clinical and radiological findings.  Results: Of 113 enrolled patients, 43 (38.1%) had TB on initial sputum screen. 53 (46.9%) had sputum smears negative for TB and 17 (15.0%) were unable to expectorate sputum; of these, 58 (82.9%) agreed to further screening with bronchoscopy. 7 (12.1%) of the BAL specimens had TB on smear, while 14 (24.1%) had TB on culture alone. Cumulatively, 63 (55.8%) patients were diagnosed with TB. 2 (3.5%) patients had Mycobacteria intracellulare and 1 (1.7%) Mycobacterium avium complex. Pneumocystis jirovecii was found in 5 (8.6%), Candida species in 6 (10.3%), Klebsiella in 5 (8.6%) and gram negative enteric bacteria in 2(3.5%). 1 (1.7%) each of Staphylococcus aureus, Streptococcus pneumonia and Proteus mirabilis were cultured. Kaposi’s sarcoma was diagnosed in 3 (5.2%) patients. 1(1.7%) had both TB and PJP. Cause was undetermined in 34 (30.1%).  Conclusion: TB was the major cause of pulmonary disease in this population. Clinical and immunological status did not distinguish the causes of pulmonary disease.
The Soviet "Doctors' Plot"---50 years on
Authors: A M. Clarfield
Journal: BMJ (2002)

A half century has passed since Stalin accused a group of doctors—most of them Jewish—of plotting against the state. The ramifications of this case continue to the present day 

Just under 50 years ago, on 4 April 1953, Pravda carried a prominent statement by Lavrenty Beria, Stalin's infamous head of secret police, exonerating nine Soviet doctors (seven of them Jews) who had previously been accused of “wrecking, espionage and terrorist activities against the active leaders of the Soviet Government.” The Soviet people, especially its Jews, were astounded to learn that just a month after Stalin's death the new leadership now admitted that the charges had been entirely invented by Stalin and his followers. Seven of the doctors were immediately released—two had already died at the hands of their jailers.

The infamous “Doctors' Plot” speaks volumes about Soviet politics, Stalin's role, the persistence of a medieval view of doctors as potential poisoners, and the survival of overt anti-Semitism in the Soviet Union, despite the known horrors of the recent Holocaust. 1 2 For Stalin, whose deeds easily matched those of Hitler and whose deceits had been evident throughout his life, the Doctors' Plot and intended show trial were meant to cleanse the Soviet Union of “foreign,” “cosmopolitan,” and “Zionist” (read Jewish) elements. In fact, it was the only one of Stalin's show trials that did not come off—only because he died just before the spectacle was to begin.3

#### Summary points

Stalin used show trials—as well as mass murder and forced migration—to terrify and silence citizens of the Soviet Union

In early 1953 Stalin planned to stage a show trial of several doctors, most of whom were Jewish and who were falsely accused of acting against the state—a trial that underlined Stalin's anti-Semitism

Despite the state's exoneration of the doctors immediately after Stalin's …
Neurobiology and linguistics are not yet unifiable
Authors: David Poeppel
Journal: Behavioral and Brain Sciences (1996)

Abstract Neurobiological models of language need a level of analysis that can account for the typical range of language phenomena. Because linguistically motivated models have been successful in explaining numerous language properties, it is premature to dismiss them as biologically irrelevant. Models attempting to unify neurobiology and linguistics need to be sensitive to both sources of evidence.
Evolution of Mouse Models for Studying CNS Cancer: a Decade of Progress
Authors: C. D. James
Journal: Neuro-Oncology (2011)

The first Mouse Models for Human Cancer Consortium (MMHCC) meeting for human nervous system cancer convened in New York City in November of 2000, with the proceedings of that meeting subsequently reported in Oncogene (1).The emphasis of the first meeting was on the comparative pathology of mouse models and corresponding human tumors. Recommendations from the meeting included the need to recapitulate human CNS tumor gene alterations in mouse model tumors, a need for increased emphasis on the molecular characterization of mouse model tumors for establishing consistency with corresponding human tumors, and the need to utilize mouse models in the preclinical evaluation of new therapies for treating CNS cancer. As indicated in the report ofthe 5th MMHCC meeting for nervous system cancer (Montreal, November 2010) in the current issue of Neuro-Oncology (2), these recommendations have proven influential, as most mouse models for CNS cancer are now 1) based on gene alterations suspected ofdriving corresponding human tumor development; 2) routinely subjected to extensive molecular characterization; and 3) are experiencingincreased use for therapeutic hypothesis testing.In addition, the sophistication of current models has increased substantially, with many utilizing information regarding potential cell of origin to regulate the expression or inactivation of genes in precursor cells thought to give rise to corresponding human tumors. Perhaps unforeseen at the 2000 MMHCC meeting was the revitalization of xenograft models for studying CNS cancer, which has been driven by the growing appreciation that histopathologically defined classes of CNS cancer, such as glioblastoma, consist of multiple distinct tumor subtypes, many of which can be propagated as xenografts, and the understanding that individual tumors are composed of distinct subpopulations of cells with distinct biologic properties.As a result of such understanding, human tumor xenografts, established either by direct transplantation from surgical specimens or by transplantation from primary cultures of surgical specimens, are viewed as model systems in their own right. Currently available genetically engineered mouse(GEM) models and human tumor xenografts now allow for detailed investigation of tumor initiation, progression, and response to therapy and have provided investigators with a resource armamentarium for the in-depthstudy of the molecular, cellular, and tumor biology of CNS cancer.It will be of interest to follow the progress during the next 10 years, as GEM modelers will undoubtedly utilize the rapidly growing base of information regarding developmental regulation of gene expression to further refine models for appropriate temporal, spatial, and cellular recapitulation of corresponding human tumor development.
Disease progression in young patients with COPD: rethinking the Fletcher and Peto model
Authors: Pablo Sanchez-Salcedo, Miguel Divo, Ciro Casanova, Victor Pinto-Plata, Juan P. de-Torres, Claudia Cote, Carlos Cabrera, Jorge Zagaceta, Roberto Rodriguez-Roisin, Javier J. Zulueta, Jose Maria Marin, Bartolome Celli
Journal: European Respiratory Journal (2014)

Chronic obstructive pulmonary disease (COPD), although frequent in older individuals, can also occur at younger age; this latter population has not been well described. We reviewed the functional progression of 1708 patients with COPD attending pulmonary clinics. Those with three or more annual spirometries were divided into those who, at enrolment, were ≤ 55 (n = 103) or ≥ 65 (n = 463) years of age (younger and older COPD, respectively). Baseline and annual changes in lung function (forced expiratory volume in 1 s (FEV1)) and BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) score were recorded and compared between both groups. Severity distribution by Global Initiative for Chronic Obstructive Lung Disease and BODE scores were similar in both groups, except for mild obstruction, which was higher in the younger group. Mean FEV1 decline was 38.8 and 40.6 mL · year(-1), while BODE scores increased 0.19 and 0.23 units per year, for younger and older COPD, respectively. Both groups had similar proportion of FEV1 rapid decliners (42% and 46%, respectively). The severity distribution and progression of disease in younger patients with COPD is similar to that of patients of older age. This observation suggests that younger individuals presenting with COPD develop the disease from an already compromised pulmonary and systemic status, complementing the model of steeper decline of lung function proposed by Fletcher and Peto.
Family History of Cancer and Cancer Risks in Women with BRCA1 or BRCA2 Mutations
Authors: K. Metcalfe, J. Lubinski, H. T. Lynch, P. Ghadirian, W. D. Foulkes, C. Kim-Sing, S. Neuhausen, N. Tung, B. Rosen, J. Gronwald, P. Ainsworth, K. Sweet, A. Eisen, P. Sun, S. A. Narod
Journal: JNCI Journal of the National Cancer Institute (2010)

Women who carry a deleterious mutation in BRCA1 or BRCA2 have high lifetime risks of breast and ovarian cancers. However, the influence of a family history of these cancers on these risks in women with BRCA mutations is unclear. We calculated cancer incidence rates for a multinational cohort comprising 3011 women with BRCA1 or BRCA2 mutations who were followed up for a mean of 3.9 years, during which time 243 incident breast or ovarian cancers were recorded. The 10-year cumulative risks of breast cancer were 18.1% (95% confidence interval [CI] = 13.3% to 22.8%) for women with a BRCA1 mutation and 15.2% (95% CI = 9.1% to 21.2%) for women with a BRCA2 mutation. Among women with a BRCA1 mutation, the risk of breast cancer increased by 1.2-fold for each first-degree relative with breast cancer before age 50 years (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.94 to 1.57) and the risk of ovarian cancer increased by 1.6 fold for each first- or second-degree relative with ovarian cancer (HR = 1.61; 95% CI = 1.21 to 2.14). Among women with a BRCA2 mutation, the risk of breast cancer increased by 1.7-fold for each first-degree relative younger than 50 years with breast cancer (HR = 1.67; 95% CI = 1.04 to 2.07)
Role of the Lysine-Specific Demethylase 1 in the Proinflammatory Phenotype of Vascular Smooth Muscle Cells of Diabetic Mice
Authors: Marpadga A. Reddy, Louisa M. Villeneuve, Mei Wang, Linda Lanting, Rama Natarajan
Journal: Circulation Research (2008)

Insulin resistance and type 2 diabetes are major risk factors for vascular complications. Vascular smooth muscle cells (VSMCs) derived from db/db mice, an established mouse model of type 2 diabetes, displayed enhanced inflammatory gene expression and proatherogenic responses. We examined the hypothesis that aberrant epigenetic chromatin events may the underlying mechanism for this persistent dysfunctional behavior and "memory" of the diabetic cells. Chromatin immunoprecipitation assays showed that levels of histone H3 lysine 4 dimethylation (H3K4me2), a key chromatin mark associated with active gene expression, were significantly elevated at the promoters of the inflammatory genes monocyte chemoattractant protein-1 and interleukin-6 in db/db VSMCs relative to db/+ cells. Tumor necrosis factor-alpha-induced inflammatory gene expression, H3K4me2 levels, and recruitment of RNA polymerase II at the gene promoters were also enhanced in db/db VSMCs, demonstrating the formation of open chromatin poised for transcriptional activation in diabetes. On the other hand, protein levels of lysine-specific demethylase1 (LSD1), which negatively regulates H3K4 methylation and its occupancy at these gene promoters, were significantly reduced in db/db VSMCs. High glucose (25 mmol/L) treatment of human VSMCs also increased inflammatory genes with parallel increases in promoter H3K4me2 levels and reduced LSD1 recruitment. LSD1 gene silencing with small interfering RNAs significantly increased inflammatory gene expression and enhanced VSMC-monocyte binding in nondiabetic VSMCs. In contrast, overexpression of LSD1 in diabetic db/db VSMCs inhibited their enhanced inflammatory gene expression. These results demonstrate novel functional roles for LSD1 and H3K4 methylation in VSMCs and inflammation. Dysregulation of their actions may be a major mechanism for vascular inflammation and metabolic memory associated with diabetic complications.
BINDING BETWEEN COMPONENTS OF THE TUBERCLE BACILLUS AND HUMORAL ANTIBODIES
Authors: Percy Minden, Richard S. Farr
Journal: The Journal of Experimental Medicine (1969)

Studies were undertaken to find a substance or substances for use in primary binding types of tests to detect humoral antibodies in rabbits and monkeys exposed to the tubercle bacillus that would distinguish between strains of mycobacteria. The antigen employed was a component of the 5159 strain of Mycobacterium tuberculosis that was obtained following sonification, ultracentrifugation, electrophoresis, and elution from a preparative polyacrylamide column. When the antigen was labeled with 131I, specific binding was observed in sera from immunized rabbits and BCG-protected rhesus monkeys by the radio-gel electrophoresis and ammonium sulfate tests. This component was partially characterized, and its major antigenic determinants were associated with anionic mucopolysaccharides. Electrophoretically at pH 8.3 it migrated anodally to albumin, its molecular weight was between 9,000 and 12,000, and it was soluble in 50% saturated ammonium sulfate. Binding to antibody was destroyed after treatment with Pronase, but not after DNase or RNase. Inhibition of the reaction, as measured by the ammonium sulfate test, between the 131I-labeled component and antisera from rabbits that had been immunized with sonicated 5159 organisms, was studied. These experiments demonstrated a capacity to define subtle similarities and differences among different mycobacteria and mycobacterial components. Some microorganisms not clearly related to mycobacteria also partially inhibited this reaction, suggesting that they shared antigenic groups with the component derived from 5159 organisms. The studies described suggested the advisability of using direct primary tests and purified components of mycobacteria to differentiate further the antigenic groups between individual pathogenic mycobacteria and between pathogenic and nonpathogenic organisms.