tbuckley/cabot-search huggingface dataset:
Flow-Dependent Regulation of Endothelial Toll-Like Receptor 2 Expression Through Inhibition of SP1 Activity
Authors: Stefan Dunzendorfer, Hyun-Ku Lee, Peter S. Tobias
Journal: Circulation Research (2004)

Innate immune system activation is associated with atherosclerotic lesion development. The specific sites of lesion development are believed to be defined by the shear stress of blood flow. Consequently, we investigated the responsiveness of human coronary artery endothelial cells (HCAECs) to Toll-like receptor (TLR) 2 and 4 agonists in an in vitro model of chronic laminar flow. HCAECs under chronic laminar flow were found to be normally responsive to lipopolysaccharide (and tumor necrosis factor) in terms of E-selectin expression but were found to be hyporesponsive to stimulation with the specific TLR2 ligands macrophage activating lipopeptide-2, PAM2-Cys, and Lip19; this was observed to be attributable to downregulation of TLR2 transcription and protein expression. We found that laminar flow induced SP1 serine phosphorylation by protein kinase CK2 and thereby blocked SP1 binding to the TLR2 promoter, which is required for TLR2 expression. This regulatory mechanism also blocked lipopolysaccharide- and tumor necrosis factor-induced TLR2 upregulation in HCAECs and could be important for suppression of other flow-sensitive endothelial proteins. These results extend the role of flow in controlling endothelial responsiveness. Given the current evidence that TLRs are proatherogenic, flow suppression of TLR2 expression may be atheroprotective.
Developing a Service Model That Integrates Palliative Care Throughout Cancer Care: The Time Is Now
Authors: Ann H. Partridge, Davinia S.E. Seah, Tari King, Natasha B. Leighl, Ralph Hauke, Dana S. Wollins, Jamie Hayden Von Roenn
Journal: Journal of Clinical Oncology (2014)

Palliative care is a fundamental component of cancer care. As part of the 2011 to 2012 Leadership Development Program (LDP) of the American Society of Clinical Oncology (ASCO), a group of participants was charged with advising ASCO on how to develop a service model integrating palliative care throughout the continuum of cancer care. This article presents the findings of the LDP group. The group focused on the process of palliative care delivery in the oncology setting. We identified key elements for models of palliative care in various settings to be potentially equitable, sustainable, feasible, and acceptable, and here we describe a dynamic model for the integrated, simultaneous implementation of palliative care into oncology practice. We also discuss critical considerations to better integrate palliative care into oncology, including raising consciousness and educating both providers and the public about the importance of palliative care; coordinating palliative care efforts through strengthening affiliations and/or developing new partnerships; prospectively evaluating the impact of palliative care on patient and provider satisfaction, quality improvement, and cost savings; and ensuring sustainability through adequate reimbursement and incentives, including linkage of performance data to quality indicators, and coordination with training efforts and maintenance of certification requirements for providers. In light of these findings, we believe the confluence of increasing importance of incorporation of palliative care education in oncology education, emphasis on value-based care, growing use of technology, and potential cost savings makes developing and incorporating palliative care into current service models a meaningful goal.
Response and tolerance to oral vasodilator up-titration after intravenous vasodilator therapy in advanced decompensated heart failure
Authors: Frederik H. Verbrugge, Matthias Dupont, Michael Finucan, Alaa Gabi, Nael Hawwa, Wilfried Mullens, David O. Taylor, James B. Young, Randall C. Starling, W.H. Wilson Tang
Journal: European Journal of Heart Failure (2015)
Childhood Size and Life Course Weight Characteristics in Association With the Risk of Incident Type 2 Diabetes
Authors: Edwina H. Yeung, Cuilin Zhang, Germaine M. Buck Louis, Walter C. Willett, Frank B. Hu
Journal: Diabetes Care (2010)

OBJECTIVE To determine how childhood overweight, in conjunction with other life course weight characteristics, relates to the development of type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS Among 109,172 women in the Nurses' Health Study II, body fatness at ages 5, 10, and 20 years was assessed by recall using 9-level pictorial diagrams (somatotypes) representing extreme thinness (category 1) to obesity (category 9). Recalled weights at age 18 years and adulthood were used to derive BMI. Self-reported cases of type 2 diabetes were confirmed by supplementary questionnaire. RESULTS Somatotypes at ages 5 and 10 years were positively associated with diabetes risk (Ptrend &amp;lt; 0.0001). The adjusted relative risk (RR) of women with somatotype ≥6 (vs. 2) at age 5 years was 2.19 (95% CI 1.79–2.67) and at age 10 years was 2.57 (2.20–3.01). Increases in size by somatotype or by weight gain since age 18 were associated with increased risk. Compared with women who were never overweight at any age, women who were overweight as an adult (BMI &amp;gt;25 kg/m2) but not previously had an adjusted RR of 8.23 (7.41–9.15). The adjusted RR was 15.10 (13.21–17.26) for women who were also overweight at age 10 (somatotype ≥5) and 18 (BMI &amp;gt;25 kg/m2). Increased childhood size was not associated with risk among women who did not continue to be overweight in adulthood. CONCLUSIONS Increased body size starting from childhood is associated with a greater risk of diabetes in adulthood. However, women who become lean in adulthood do not have an increased risk.
A Coregulatory Role for the Mediator Complex in Prostate Cancer Cell Proliferation and Gene Expression
Authors: Ravi Vijayvargia, Michael S. May, Joseph D. Fondell
Journal: Cancer Research (2007)

Abstract Androgen receptor (AR) signaling pathways are important for the survival and proliferation of prostate cancer cells. Because AR activity is facilitated by distinct coregulatory factors and complexes, it is conceivable that some of these proteins might also play a role in promoting prostate oncogenesis. The multisubunit Mediator complex is an important coactivator for a broad range of regulatory transcriptional factors including AR, yet its role in prostate cancer is unclear. Here, we used RNA interference to knock down the expression of two integral Mediator components, MED1/TRAP220 and MED17, in prostate cancer cells. MED1/TRAP220 plays a particularly important role in androgen signaling in that it serves as a direct binding target for AR. We found that the knockdown of either subunit markedly decreases transcription from transiently transfected androgen-responsive reporter genes, as well as inhibits androgen-dependent expression of endogenous AR target genes. We show for the first time that loss of either MED1/TRAP220 or MED17 in prostate cancer cells significantly decreases both androgen-dependent and -independent cellular proliferation, inhibits cell cycle progression, and increases apoptosis. Furthermore, we show that MED1/TRAP220 is overexpressed in both AR-positive and -negative prostate cancer cells lines, as well as in 50% (10 of 20) of the clinically localized human prostate cancers we examined, thus suggesting that MED1/TRAP220 hyperactivity may have implications in prostate oncogenesis. In sum, our data suggest that Mediator plays an important coregulatory role in prostate cancer cell proliferation and survival, and therefore, may represent a new target for therapeutic intervention. [Cancer Res 2007;67(9):4034–41]
Host-pathogen interactions: the seduction of molecular cross talk
Authors: P Sansonetti
Journal: Gut (2002)

Bacterial pathogens have evolved two major strategies to colonise the intestinal epithelium. Adherent microorganisms bind to the apical pole of the intestinal epithelium, whereas invasive microorganisms disrupt and invade the epithelium. Recognition of the genetic bases of bacterial pathogenicity and analysis of the molecular cross talks established between pathogens and their mammalian target cells have illuminated this diversity of interactions. We have compared the strategies of enteroinvasive pathogens, with emphasis on bacterial species such as <i>Shigella</i>, <i>Yersinia</i>, and <i>Salmonella</i>, that represent paradigms of interaction. Cross talks leading to alteration of the epithelial cell actin cytoskeleton appear as a recurrent theme during entry and dissemination into epithelial cells. Other cross talks alter the trafficking of cellular vesicles and induce changes in the intracellular compartment in which they reside, thus creating niches favourable to bacterial survival and growth. Finally, a variety of strategies also exist to deal with other components of the epithelial barrier, such as macrophages. Pro-phagocytic, anti-phagocytic, and pro-apoptotic processes appear to be of particular importance.
Aldosterone Production Is Activated in Failing Ventricle in Humans
Authors: Yuji Mizuno, Michihiro Yoshimura, Hirofumi Yasue, Tomohiro Sakamoto, Hisao Ogawa, Kiyotaka Kugiyama, Eisaku Harada, Masafumi Nakayama, Shota Nakamura, Teruhiko Ito, Yukio Shimasaki, Yoshihiko Saito, Kazuwa Nakao
Journal: Circulation (2001)

Background —Recent reports have indicated that aldosterone is produced in extra-adrenal tissues in animals. The present study was designed to examine whether aldosterone is produced in human heart. Methods and Results —Plasma levels of aldosterone, BNP, and angiotensin-converting enzyme were measured in anterior interventricular vein (AIV), coronary sinus (CS), and aortic root (Ao), respectively, in 20 patients with left ventricular systolic dysfunction (LVSD), 25 patients with LV diastolic dysfunction (LVDD), and 23 control subjects. Aldosterone levels were significantly higher in AIV and CS than Ao in LVSD (98±10 versus 72±9 pg/mL, P &lt;0.001, and 97±11 versus 72±9 pg/mL, P &lt;0.001, respectively) and LVDD (87±10 versus 71±9 pg/mL, P &lt;0.01, and 84±10 versus 71±9 pg/mL, P &lt;0.01, respectively) groups, but no differences were observed in levels for these sites in the control group. Levels of ACE activity and BNP also were higher in AIV than Ao in both LV dysfunction groups. The difference in aldosterone levels between AIV and Ao and those in BNP and angiotensin-converting enzyme had a significant positive correlation with LVEDP and a significant negative correlation with LV ejection fraction in the LVSD group. Conclusions —Production of aldosterone, angiotensin-converting enzyme, and BNP are activated in failing human ventricle in proportion to severity.
Chronic hypercapnia stimulates proximal bicarbonate reabsorption in the rat.
Authors: M G Cogan
Journal: Journal of Clinical Investigation (1984)

The hyperbicarbonatemia of chronic respiratory acidosis might be maintained by a reduction in filtration rate or an enhancement of tubular bicarbonate reabsorption. To investigate this question, 12 Munich-Wistar rats were exposed to a 10% CO2 atmosphere for 6-8 d. Chronic respiratory acidosis developed, with arterial pH 7.30 +/- 0.01, partial pressure of CO2 (pCO2) 80 +/- 2 mmHg, and total CO2 concentration 45 +/- 1 mM. Single nephron glomerular filtration rate was normal (42 +/- 1 nl/min). Chronic hypercapnia caused absolute proximal reabsorption to be significantly stimulated (1,449 +/- 26 pmol/min) as compared with reabsorption previously observed in normal animals (1,075 +/- 74 pmol/min) or in animals subjected to acute hypercapnia (1,200 +/- 59 pmol/min). This is the first demonstration that proximal bicarbonate reabsorption can be stimulated above normal euvolemic values. When eight animals were subsequently allowed to return toward a normocapnic state (arterial pCO2 46 +/- 1 mmHg) over the course of 1-1.5 h, bicarbonate reabsorption was still significantly higher (1,211 +/- 34 pmol/min) than in similarly alkalotic, normocapnic control groups (994 +/- 45 pmol/min). In conclusion, chronic, but not acute, hypercapnia stimulates absolute proximal bicarbonate reabsorption to exceed the level found in normal euvolemic rats.
Long-term follow-up results of no initial therapy for ocular adnexal MALT lymphoma
Authors: K. Tanimoto, A. Kaneko, S. Suzuki, N. Sekiguchi, D. Maruyama, S.W. Kim, T. Watanabe, Y. Kobayashi, Y. Kagami, A. Maeshima, Y. Matsuno, K. Tobinai
Journal: Annals of Oncology (2005)

The majority of lymphomas in the ocular adnexa are low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma). Although radiotherapy is the most frequently applied management, cataract and dry eye are problematic complications.Between 1973 and 2003, the clinical features of 36 patients with ocular adnexal MALT lymphoma with no symptoms who were managed with no initial therapy after biopsy or surgical resection were retrospectively analyzed.The median patient age was 63 years (range 22-84) and all patients had stage I disease, consisting of 31 unilateral cases and five bilateral cases. With a median follow-up of 7.1 years, 25 (69%) did not require treatment. The median time until the initiation of treatment in the remaining 11 patients (31%) was 4.8 years. Six patients (17%) died, and among them only two (6%) died due to progressive lymphoma. Seventeen patients (47%) progressed, but histologic transformation was recognized in only one (3%). The estimated overall survival rates of the 36 patients after 5, 10 and 15 years were 94%, 94% and 71%, respectively.In selected patients with ocular adnexal MALT lymphoma, no initial therapy might be an acceptable approach, because 70% of patients remained untreated at a median of 8.6 years, and their survival was comparable to that of reports on immediate therapy.
Measuring Social Class in US Public Health Research: Concepts, Methodologies, and Guidelines
Authors: N. Krieger, D. R. Williams, N. E. Moss
Journal: Annual Review of Public Health (1997)

Increasing social inequalities in health in the United States and elsewhere, coupled with growing inequalities in income and wealth, have refocused attention on social class as a key determinant of population health. Routine analysis using conceptually coherent and consistent measures of socioeconomic position in US public health research and surveillance, however, remains rare. This review discusses concepts and methodologies concerning, and guidelines for measuring, social class and other aspects of socioeconomic position (e.g. income, poverty, deprivation, wealth, education). These data should be collected at the individual, household, and neighborhood level, to characterize both childhood and adult socioeconomic position; fluctuations in economic resources during these time periods also merit consideration. Guidelines for linking census-based socioeconomic measures and health data are presented, as are recommendations for analyses involving social class, race/ethnicity, and gender. Suggestions for research on socioeconomic measures are provided, to aid monitoring steps toward social equity in health.
Wood Smoke Exposure and Gene Promoter Methylation Are Associated with Increased Risk for COPD in Smokers
Authors: Akshay Sood, Hans Petersen, Christopher M. Blanchette, Paula Meek, Maria A. Picchi, Steven A. Belinsky, Yohannes Tesfaigzi
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Wood smoke-associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.Our objective was to determine whether wood smoke exposure was a risk factor for COPD in a population of smokers in the United States and whether aberrant gene promoter methylation in sputum may modify this association.For this cross-sectional study, 1,827 subjects were drawn from the Lovelace Smokers' Cohort, a predominantly female cohort of smokers. Wood smoke exposure was self-reported. Postbronchodilator spirometry was obtained, and COPD outcomes studied included percent predicted FEV₁, airflow obstruction, and chronic bronchitis. Effect modification of wood smoke exposure with current cigarette smoke, ethnicity, sex, and promoter methylation of lung cancer-related genes in sputum on COPD outcomes were separately explored. Multivariable logistic and poisson regression models were used for binary and rate-based outcomes, respectively.Self-reported wood smoke exposure was independently associated with a lower percent predicted FEV₁ (point estimate [± SE] -0.03 ± 0.01) and a higher prevalence of airflow obstruction and chronic bronchitis (odds ratio, 1.96; 95% confidence interval, 1.52-2.52 and 1.64 (95% confidence interval, 1.31-2.06, respectively). These associations were stronger among current cigarette smokers, non-Hispanic whites, and men. Wood smoke exposure interacted in a multiplicative manner with aberrant promoter methylation of the p16 or GATA4 genes on lower percent predicted FEV₁.These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers.
A PATHOLOGICAL study of the lungs and heart in fatal and non-fatal chronic airways obstruction.
Authors: K W Scott
Journal: Thorax (1976)

<h3>Abstract</h3> Metabolic rate (MR) changes with body mass (BM) as MR = <i>a</i>BM<sup><i>b</i></sup>, where <i>a</i> is a normalisation constant (log–log intercept) and <i>b</i> the scaling exponent (log–log slope). This scaling relationship is fundamental to biology and widely applied, yet a century of research has provided little consensus on why and how steeply metabolic rate scales with body mass. I here show that ontogenetic (within-individual) <i>b</i> can be strongly and positively related to growth rates of juvenile fish when food availability is naturally restricted, with fast growing individuals having steep and near-isometric metabolic scaling (<i>b</i> ≈ 1). I suggest that the steep evolutionary (among-species) scaling also found for fishes (<i>b</i> also approaching 1) is a by-product of natural selection for these fast growing individuals early in ontogeny, and that a weaker relationship between metabolic scaling and growth later in life causes variation in <i>b</i> at lower taxonomic levels (within orders or species). I support these ideas by showing that <i>b</i> within fish orders is linked to natural mortality rates of fish larvae.
CNOT3 contributes to early B cell development by controlling <i>Igh</i> rearrangement and <i>p53</i> mRNA stability
Authors: Takeshi Inoue, Masahiro Morita, Atsushi Hijikata, Yoko Fukuda-Yuzawa, Shungo Adachi, Kyoichi Isono, Tomokatsu Ikawa, Hiroshi Kawamoto, Haruhiko Koseki, Tohru Natsume, Taro Fukao, Osamu Ohara, Tadashi Yamamoto, Tomohiro Kurosaki
Journal: The Journal of Experimental Medicine (2015)

The CCR4-NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mice lacking the CNOT3 subunit of this complex, specifically in B cells, have a developmental block at the pro- to pre-B cell transition. CNOT3 regulated generation of germline transcripts in the VH region of the immunoglobulin heavy chain (Igh) locus, compaction of the locus, and subsequent Igh gene rearrangement and destabilized tumor suppressor p53 mRNA. The developmental defect in the absence of CNOT3 could be partially rescued by ablation of p53 or introduction of a pre-rearranged Igh transgene. Thus, our data suggest that the CCR4-NOT complex regulates B cell differentiation by controlling Igh rearrangement and destabilizing p53 mRNA.
Prognosis of patients with COPD admitted to the ICU
Authors: J M Anon, A G. de Lorenzo
Journal: Thorax (2009)

Prognosis of patients with COPD admitted to the ICUWe read with interest the article by Wildman et al. 1 They have carried out an interesting study on patients with chronic obstructive pulmonary disease (COPD) or asthma admitted to the Intensive Care Unit (ICU).The authors in their discussion state that their overall results may be least applicable to patients on long-term oxygen (LTO) and/or with low functional scores.Intubated patients with COPD on LTO constitute 10.4% of 394 intubated patients in this study.Only mortality results relating to this population are shown in this article.It would have been interesting to show results such as quality of life at 180 days.If deciding to intubate is difficult in patients with exacerbated COPD, it is more difficult in those patients on LTO.Clinicians tend to be pessimistic about survival and quality of life and they are very selective when admitting these patients.In 1999 we reported on a study 2 which focused on patients with exacerbated COPD on LTO who were mechanically ventilated.Mortality was higher than that reported by Wildman et al in this subgroup of patients: 35% (in ICU), 50% (in hospital), 75% (at 1 year) and 85% (at 5 years).Patients who died in hospital and in the first year after discharge had a lower forced expiratory volume in 1 s (FEV 1 ) than survivors.Although the study was carried out in a University tertiary hospital, the sample size was small (20 patients recruited in 2 years).Our paper is, to date, the only one which focuses on patients with COPD on LTO.The small sample size of patients with COPD on LTO, both in the series of Wildman et al and in our series, supports the statement about the selective criteria considered when admitting these patients.Therefore, how many patients are not admitted who could survive with an acceptable quality of life?In our experience, of the five survivors at 1 year, two had a good functional level previously and both had a functional status similar to that prior to the ICU admission.The mean age of the three patients alive at 5 years was 63.3 years, and one of them was independent.The cost per quality-adjusted life year was US$44.602.Obviously, we have no predictors to help us in the daily decision making regarding these patients although we agree that functional status in the period of stability and FEV 1 before ICU admission can be helpful.However, our decisions can only be supported by the experiences of small studies or data from studies with different main objectives.Therefore, results regarding these patients with severe COPD would be very welcome.