tbuckley/cabot-search huggingface dataset:
Response of Small Pulmonary Arteries to Unilobar Hypoxia and Hypercapnia
Authors: MIKIO KATO, NORMAN C. STAUB
Journal: Circulation Research (1966)

We measured the internal diameters of small muscular pulmonary arteries in the right and left lower lobes of lungs rapidly frozen in the anesthetized, open-thorax cat. In every cat the right lower lobe was ventilated with the test gas and all other lobes were ventilated with O 2 . In 4 cats, the test gas supplied to the right lower lobe was also O 2 (control experiments); in 6, it was 100% N 2 and in 6 it was 90% N 2 -10% CO 2 . In the 4 controls, there was no difference between the internal diameters of corresponding arteries in the right and left lower lobes. In the other 12 cats, there was a highly significant decrease in the diameter of arteries in the right lower lobe that correlated well with a large decrease in blood flow to that lobe, calculated using a shunt equation. Ventilation of the right lower lobe with 10% CO 2 in air (4 cats) did not affect the diameter of arteries and ligation of the pulmonary artery to the right lower lobe resulted in only a slight decrease in arterial dimensions in 3 of 4 cats. These data show that in regional alveolar hypoxia without systemic hypoxia the muscular pulmonary arteries of the terminal respiratory units in the hypoxic region actively constrict. The constriction occurs with or without alveolar hypercapnia.
Methylation level of the RASSF1A promoter is an independent prognostic factor for clear-cell renal cell carcinoma
Authors: Y. Kawai, S. Sakano, Y. Suehiro, T. Okada, Y. Korenaga, T. Hara, K. Naito, H. Matsuyama, Y. Hinoda
Journal: Annals of Oncology (2009)
Diabetes-Induced cholestasis in the rat: Possible role of hyperglycemia and hypoinsulinemia
Authors: Jose Juan Garcia-Marin, Gloria R. Villanueva, Alejandro Esteller
Journal: Hepatology (1988)

In one of our earlier studies, an impaired biliary function in diabetes was suggested. We studied bile formation in rats with streptozotocin-induced diabetes (60 mg per kg body weight). Diabetic rats showed hyperglycemia and hypoinsulinemia, but no significant changes in hematocrit, plasma protein concentration or plasma osmolality. Bile flow was significantly (p &lt; 0.05) reduced (-23%) as compared with control animals, despite a higher (p &lt; 0.05) bile acid secretion rate (+56%). The biliary responses to three choleretic compounds (taurocholate, ursodeoxycholate and insulin), acting in a very different way upon bile formation, were not impaired in diabetes. The study of the relationship between bile acid output and bile flow, after infusion of taurocholate at different doses (0.25 to 1.5 μmoles per min per 100 gm body weight) showed that diabetesinduced cholestasis in the rat is mainly related to a decreased bile acid-independent fraction of the bile flow. We tested the possible role of hyperglycemia and hypoinsulinemia as cholestatic factors in diabetes. Glucose infusion [300 mM, 150 μ per min (Group G)] induced a significant (p &lt; 0.05) reduction in bile flow (−0.33 μl per min per gm liver) as compared to the basal period. After acute pancreatectomy (P) or mannoheptulose treatment [0.14 mmole per 100 gm body weight (Group M)], similar cholestatic effects were observed (−0.29 and −0.27 μl per min per gm liver, respectively). However, plasma glucose and insulin concentrations were higher (p &lt; 0.01) in Group G than in P or M. Glucose infusion to acutely pancreatectomized (PG) or mannoheptulose-treated (MG) rats induced a similar and marked cholestasis (−0.46 and −0.51 μl per min per gm liver, respectively; both p &lt; 0.001). The plasma insulin concentration was not different among the P, M, PG and MG. Nevertheless, a lower (p &lt; 0.05) bile flow was observed in PG and MG, as compared to P and M, respectively. Plasma glucose concentrations were higher (p &lt; 0.001) in PG and MG as compared to P and M. Bile acid output and plasma osmolality were not significantly different in controls, P, M, PG and MG. In summary, our results indicate that diabetes induces cholestasis in the rat. They suggest that the decrease in bile formation is not due to general damage to the hepatic secretory system but rather to the presence of additive cholestatic factors, such as hyperglycemia and hypoinsulinemia, which specifically reduce the bile acid-independent fraction of bile flow.
<i>Salmonella</i>Typhimurium Infections Associated with Peanut Products
Authors: Elizabeth Cavallaro, Kashmira Date, Carlota Medus, Stephanie Meyer, Benjamin Miller, Clara Kim, Scott Nowicki, Shaun Cosgrove, David Sweat, Quyen Phan, James Flint, Elizabeth R. Daly, Jennifer Adams, Eija Hyytia-Trees, Peter Gerner-Smidt, Robert M. Hoekstra, Colin Schwensohn, Adam Langer, Samir V. Sodha, Michael C. Rogers, Frederick J. Angulo, Robert V. Tauxe, Ian T. Williams, Casey Barton Behravesh
Journal: New England Journal of Medicine (2011)

Contaminated food ingredients can affect multiple products, each distributed through various channels and consumed in multiple settings. Beginning in November 2008, we investigated a nationwide outbreak of salmonella infections.A case was defined as laboratory-confirmed infection with the outbreak strain of Salmonella Typhimurium occurring between September 1, 2008, and April 20, 2009. We conducted two case-control studies, product "trace-back," and environmental investigations.Among 714 case patients identified in 46 states, 166 (23%) were hospitalized and 9 (1%) died. In study 1, illness was associated with eating any peanut butter (matched odds ratio, 2.5; 95% confidence interval [CI], 1.3 to 5.3), peanut butter-containing products (matched odds ratio, 2.2; 95% CI, 1.1 to 4.7), and frozen chicken products (matched odds ratio, 4.6; 95% CI, 1.7 to 14.7). Investigations of focal clusters and single cases associated with nine institutions identified a single institutional brand of peanut butter (here called brand X) distributed to all facilities. In study 2, illness was associated with eating peanut butter outside the home (matched odds ratio, 3.9; 95% CI, 1.6 to 10.0) and two brands of peanut butter crackers (brand A: matched odds ratio, 17.2; 95% CI, 6.9 to 51.5; brand B: matched odds ratio, 3.6; 95% CI, 1.3 to 9.8). Both cracker brands were made from brand X peanut paste. The outbreak strain was isolated from brand X peanut butter, brand A crackers, and 15 other products. A total of 3918 peanut butter-containing products were recalled between January 10 and April 29, 2009.Contaminated peanut butter and peanut products caused a nationwide salmonellosis outbreak. Ingredient-driven outbreaks are challenging to detect and may lead to widespread contamination of numerous food products.
Feedback Control of Glomerular Vascular Tone in Neuronal Nitric Oxide Synthase Knockout Mice
Authors: VOLKER VALLON, TIMOTHY TRAYNOR, LUCIANO BARAJAS, YUNING G. HUANG, JOSIE P. BRIGGS, JU[Combining Diaeresis]RGEN SCHNERMANN
Journal: Journal of the American Society of Nephrology (2001)

For further elucidation of the role of neuronal nitric oxide synthase (nNOS) in macula densa (MD) cells, experiments were performed in anesthetized nNOS knockout mice (nNOS -/-). At comparable levels of arterial BP, renal blood flow was not significantly different between nNOS +/+ and nNOS -/- (1.7 +/- 0.2 versus 1.4 +/- 0.1 ml/min), and autoregulation of renal blood flow was maintained to a pressure level of approximately 85 mmHg in both groups of mice (n = 6 in each group). The fall in proximal tubular stop-flow pressure in response to an increase in loop of Henle perfusion rate from 0 to 30 nl/min was comparable in nNOS +/+ and -/- mice (40.7 +/- 1.6 to 32 +/- 2 mmHg versus 40.6 +/- 1.6 to 31.6 +/- 2 mmHg; not significant; n = 13 versus 18 nephrons). Luminal application of the nonselective NOS inhibitor nitro-L-arginine (10(-3) and 10(-2) M) enhanced the perfusion-dependent fall in stop-flow pressure in nNOS +/+ (7 +/- 1 to 13 +/- 2 mmHg; P < 0.05) but not in nNOS -/- (7 +/- 1 to 8 +/- 1 mmHg; not significant) mice. nNOS -/- mice exhibited a lower nephron filtration rate, compared with nNOS +/+, during free-flow collections from early distal tubules (influence of MD intact, 7 +/- 0.7 versus 10.9 +/- 1 nl/min; P = 0.002) but not from late proximal tubule (influence of MD minimized, 10.1 +/- 1 versus 11.7 +/- 1 nl/min; not significant; n = 16 nephrons). Distal Cl concentration and fractional absorption of fluid or chloride up to the early distal tubule was not different between nNOS -/- and +/+ mice. The data indicate that nNOS in MD tonically attenuates the GFR-lowering influence of ambient luminal NaCl, which may serve to increase the fluid and electrolyte load to the distal tubule, consistent with a role of MD nNOS in tubuloglomerular feedback resetting.
MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia
Authors: Steven P. Treon, Lian Xu, Guang Yang, Yangsheng Zhou, Xia Liu, Yang Cao, Patricia Sheehy, Robert J. Manning, Christopher J. Patterson, Christina Tripsas, Luca Arcaini, Geraldine S. Pinkus, Scott J. Rodig, Aliyah R. Sohani, Nancy Lee Harris, Jason M. Laramie, Donald A. Skifter, Stephen E. Lincoln, Zachary R. Hunter
Journal: New England Journal of Medicine (2012)

Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated.We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors.Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2.MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).
Pulmonary vascular resistance predicts early mortality in patients with diffuse fibrotic lung disease and suspected pulmonary hypertension
Authors: T J Corte, S J Wort, M A Gatzoulis, P Macdonald, D M Hansell, A U Wells
Journal: Thorax (2009)

<h3>Background:</h3> Pulmonary hypertension (PH) is associated with a poor prognosis in diffuse lung disease (DLD). A study was undertaken to compare the prognostic significance of invasive and non-invasive parameters in patients with DLD and suspected PH. <h3>Methods:</h3> Hospital records of consecutive patients with DLD undergoing right heart catheterisation (RHC) were reviewed (n = 66). Mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and non-invasive variables were examined against early (within 12 months) and overall mortality. A priori thresholds were examined against early mortality. Relationships between mPAP, PVR and non-invasive markers were assessed. <h3>Results:</h3> Fifty patients had PH on RHC (mean (SD) mPAP 33.5 (11.8) mm Hg, PVR 5.9 (4.3) Wood units (WU)). Raised PVR was strongly associated with early mortality (odds ratio (OR) 1.30; 95% confidence interval (CI) 1.11 to 1.52; p = 0.001), with PVR ⩾6.23 WU being the optimal threshold after adjustment for age, gender, composite physiological index (CPI) and diagnosis of idiopathic pulmonary fibrosis (OR 11.09; 95% CI 2.54 to 48.36; p = 0.001). Early mortality was linked, albeit less strongly, to right ventricular dilation at echocardiography, but not to other non-invasive variables or mPAP. Overall mortality was most strongly associated with increasing CPI levels. Correlations between PVR and non-invasive variables were moderate (R<sup>2</sup> &lt;0.32), improving little following construction of a multivariate index which did not itself predict mortality. <h3>Conclusion:</h3> In severe DLD, early mortality is strongly linked to increased PVR but not to other RHC or non-invasive variables. These findings suggest that the threshold for RHC in severe DLD should be low, enabling prioritisation of aggressive treatment including lung transplantation.
Tumor-Derived Autophagosome Vaccine: Mechanism of Cross-Presentation and Therapeutic Efficacy
Authors: Yuhuan Li, Li-Xin Wang, Puiyi Pang, Zhihua Cui, Sandra Aung, Daniel Haley, Bernard A. Fox, Walter J. Urba, Hong-Ming Hu
Journal: Clinical Cancer Research (2011)

Abstract Purpose: We previously reported that autophagy in tumor cells plays a critical role in cross-presentation of tumor antigens and that autophagosomes are efficient antigen carriers for cross-priming of tumor-reactive CD8+ T cells. Here, we sought to characterize further the autophagosome-enriched vaccine named DRibble (DRiPs-containing blebs), which is derived from tumor cells after inhibition of protein degradation, and to provide insights into the mechanisms responsible for their efficacy as a novel cancer immunotherapy. Experimental Design: DRibbles were characterized by Western blot and light or transmission electron microscopy. The efficiency of cross-presentation mediated by DRibbles was first compared with that of whole-tumor cells and pure proteins. The mechanisms of antigen cross-presentation by DRibbles were analyzed, and the antitumor efficacy of the DRibble vaccine was tested in 3LL Lewis lung tumors and B16F10 melanoma. Results: The DRibbles sequester both long-lived and short-lived proteins, including defective ribosomal products (DRiP), and damage-associated molecular pattern molecules exemplified by HSP90, HSP94, calreticulin, and HMGB1. DRibbles express ligands for CLEC9A, a newly described C-type lectin receptor expressed by a subset of conventional and plasmacytoid dendritic cells (DC), and cross-presentation was partially CLEC9A dependent. Furthermore, this autophagy-assisted antigen cross-presentation pathway involved both caveolae- and clathrin-mediated endocytosis and endoplasmic reticulum–associated degradation machinery. It depends on proteasome and TAP1, but not lysosome functions of antigen-presenting cells. Importantly, DCs loaded with autophagosome-enriched DRibbles can eradicate 3LL Lewis lung tumors and significantly delay the growth of B16F10 melanoma. Conclusions: These data documented the unique characteristics and potent antitumor efficacy of the autophagosome-based DRibble vaccine. The efficacy of DRibble cancer vaccine will be further tested in clinical trials. Clin Cancer Res; 17(22); 7047–57. ©2011 AACR.
Pro-hepcidin is unable to degrade the iron exporter ferroportin unless maturated by a furin-dependent process
Authors: Bruno Gagliardo, Nicole Kubat, Audrey Faye, Maryse Jaouen, Béatrice Durel, Jean-Christophe Deschemin, François Canonne-Hergaux, Marie-Agnès Sari, Sophie Vaulont
Journal: Journal of Hepatology (2008)
Integrins, myofibroblasts, and organ fibrosis
Authors: Michel Fausther, Jonathan A. Dranoff
Journal: Hepatology (2014)

Abstract Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α V integrin subunit because various α V -containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β3, β5 or β6 integrin or conditional loss of β8 integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the αV integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α V -containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α V integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
Role of CXCR4 in the Pathogenesis of Acute Myeloid Leukemia
Authors: Amnon Peled, Sigal Tavor
Journal: Theranostics (2013)

The Chemokine receptor CXCR4 and its ligand stromal derived factor-1 (SDF-1/CXCL12) are important players involved in cross-talk between leukemia cells and the bone marrow (BM) microenvironment.CXCR4 expression is associated with poor prognosis in AML patients with and without the mutated FLT3 gene.CXCL12 which is constrictively secreted from the BM stroma and AML cells is critical for the survival and retention of AML cells within the BM.In vitro, CXCR4 antagonists were shown to inhibit the migration of AML cells in response to CXCL12.In addition, such antagonists were shown to inhibit the survival and colony forming potential of AML cells and abrogate the protective effects of stromal cells on chemotherapy-induced apoptosis in AML cells.In vivo, using immune deficient mouse models, CXCR4 antagonists were found to induce the mobilization of AML cells and progenitor cells into the circulation and enhance anti leukemic effects of chemotherapy.The hypothesis that CXCL12/CXCR4 interactions contribute to the resistance of AML cells to signal transduction inhibitor-and chemotherapy-induced apoptosis is currently being tested in a series of Phase I/II studies in humans.
Maternal smoking during and after pregnancy and lung function in early adulthood: a prospective study
Authors: M R Hayatbakhsh, S Sadasivam, A A Mamun, J M Najman, G M Williams, M J O'Callaghan
Journal: Thorax (2009)

<h3>Background and aims:</h3> There is a paucity of evidence about whether exposure to antenatal smoking impacts on offspring’s lung function in early adulthood. This study aimed to examine whether (1) in utero exposure to maternal smoking is related to poorer respiratory functioning in early adulthood; (2) the impact of prenatal smoking is independent of postnatal maternal smoking; and (3) the link between prenatal smoking and a young adult’s lung function is explained by the child’s birth weight, smoking or history of asthma. <h3>Methods:</h3> Data were from a 21-year follow-up of mothers and their children recruited into the Mater–University of Queensland Study of Pregnancy, a longitudinal prebirth cohort. The study is based on 2409 young adults (1185 males and 1224 females) who had prospective data available on respiratory function at 21 years and maternal smoking during and after pregnancy. A Spirobank G spirometer system was used to measure forced vital capacity (FVC), forced expiratory volume in 1 s (FEV<sub>1</sub>) and forced expiratory flow between 25% and 75% of FVC (FEF<sub>25–75</sub>). <h3>Results:</h3> In utero exposure to maternal smoking was associated with a reduction in FEV<sub>1</sub> and FEF<sub>25–75</sub> in males (regression coefficient, −0.16; 95% CI, −0.30 to −0.02), after accounting for maternal smoking after pregnancy. At least part of the effect of in utero smoking on young adults’ lung function was explained by the child’s birth weight and subsequent asthma. <h3>Conclusions:</h3> Adverse effects of antenatal smoking on development of airway growth may persist into early adulthood. Gender differences noted in this longitudinal cohort need to be explored further.
Molecular Evolution of Rickettsia Surface Antigens: Evidence of Positive Selection
Authors: Guillaume Blanc, Maxime Ngwamidiba, Hiroyuki Ogata, Pierre-Edouard Fournier, Jean-Michel Claverie, Didier Raoult
Journal: Molecular Biology and Evolution (2005)

The Rickettsia genus is a group of obligate intracellular parasitic α-proteobacteria that includes human pathogens responsible for the typhus disease and various types of spotted fevers. rOmpA and rOmpB are two members of the “surface cell antigen” (Sca) autotransporter (AT) protein family that may play key roles in the adhesion of the Rickettsia cells to the host tissue. These molecules are likely determinants for the pathogenicity of the Rickettsia and represent good candidates for vaccine development. We identified the 17 members of this family of outer-membrane proteins in nine fully sequenced Rickettsia genomes. The typical architecture of the Sca proteins is composed of an N-terminal signal peptide and a C-terminal AT domain that promote the export of the central passenger domain to the outside of the bacteria. A characteristic of this family is the frequent degradation of the genes, which results in different subsets of the sca genes being expressed among Rickettsia species. Here, we present a detailed analysis of their phylogenetic relationships and evolution. We provide strong evidence that rOmpA and rOmpB as well as three other members of the Sca protein family—Sca1, Sca2, and Sca4—have evolved under positive selection. The exclusive distribution of the predicted positively selected sites within the passenger domains of these proteins argues that these regions are involved in the interaction with the host and may be locked in “arms race” coevolutionary conflicts.
Extensive deletions and insertions in different MHC supratypes detected by pusled field gel electrophoresis.
Authors: K Tokunaga, G Saueracker, P H Kay, F T Christiansen, R Anand, R L Dawkins
Journal: The Journal of Experimental Medicine (1988)

The genomic organization of the human MHC was examined in multiple examples of six different supratypes using pulsed field electrophoresis (PFGE) after digestion of genomic DNA with infrequency cutting restriction endonucleases. Differences in restriction fragment length and band intensity were shown to be specific for each supratype. Mapping of the MHC revealed that each supratype contains previously undescribed deletions and insertions between HLA B and DQ regions.
Anthropometric factors and endometrial cancer risk: a systematic review and dose–response meta-analysis of prospective studies
Authors: D. Aune, D.A. Navarro Rosenblatt, D.S.M. Chan, S. Vingeliene, L. Abar, A.R. Vieira, D.C. Greenwood, E.V. Bandera, T. Norat
Journal: Annals of Oncology (2015)