tbuckley/cabot-search huggingface dataset:
Prognostic Value of Blood Pressure Variability and Average Blood Pressure Levels in Patients With Hypertension and Diabetes
Authors: Gianfranco Parati, Juan Eugenio Ochoa, Paolo Salvi, Carolina Lombardi, Grzegorz Bilo
Journal: Diabetes Care (2013)

Elevated blood pressure (BP) is a major risk factor for cardiovascular (CV) events and mortality (1) and a leading contributor to the global disease burden (2). Overwhelming evidence is now available showing that BP measured in the office shows a linear relationship with a number of CV and renal outcomes as well as with overall mortality and that lowering of office BP (OBP) with treatment is effective in reducing morbidity and mortality (3,4). However, application over the last 40 years of techniques for out-of-office BP monitoring including home BP monitoring (HBPM) and 24-h ambulatory BP monitoring (ABPM) has led to further important findings. In particular, 1 ) average BP measured in everyday life conditions may be an even better predictor of CV outcomes than isolated OBP readings and 2 ) the extent of fluctuations of BP over time may provide additional, independent prognostic information compared with both isolated office readings and average ambulatory BP (ABP) levels, respectively. These findings are of upmost relevance in the case of diabetic patients who are characterized by a significantly higher risk of CV events compared with nondiabetic individuals, with diabetes itself currently considered a CV disease equivalent (5,6). The aim of the present article is to review the available evidence on the prognostic importance of BP mean levels and of BP variability (BPV) estimates and to critically evaluate whether antihypertensive treatment strategies should be targeted at reducing not only average BP levels but also the degree of BPV in order to optimize CV protection in diabetic patients.

### Prognostic value of OBP values

Consistent evidence from observational studies has indicated that the risk of CV morbidity and mortality has a strong and continuous relationship with OBP levels (3), without any evidence of a threshold down to at least 115/75 mmHg (4). Furthermore, large meta-analyses of major interventional trials …
The country of residence affects the phenotype of familial Mediterranean fever: is it real or a selection bias?
Authors: Cengiz Korkmaz
Journal: Annals of the Rheumatic Diseases (2014)

The author estimates that statewide pension funds in the United States incur annual investment expenses averaging 1.3% of asset value. A sample of 24 of them underperformed passive investment during the past decade by an average of 1.4% a year. And yet, those same funds report that they outperformed benchmarks of their own devising by an average of +0.3% a year for the same period. This sharp disconnect raises questions about the usefulness of the funds’ performance reporting, as well as their heavy reliance on expensive active management.
Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers
Authors: Todd R. Mereniuk, Robert A. Maranchuk, Anja Schindler, Jonathan Penner-Chea, Gary K. Freschauf, Samar Hegazy, Raymond Lai, Edan Foley, Michael Weinfeld
Journal: Cancer Research (2012)

A genetic screen using a library of 6,961 siRNAs led to the identification of SHP-1 (PTPN6), a tumor suppressor frequently mutated in malignant lymphomas, leukemias, and prostate cancer, as a potential synthetic lethal partner of the DNA repair protein polynucleotide kinase/phosphatase (PNKP). After confirming the partnership with SHP-1, we observed that codepletion of PNKP and SHP-1 induced apoptosis. A T-cell lymphoma cell line that is SHP-1 deficient (Karpas 299) was shown to be sensitive to a chemical inhibitor of PNKP, but resistance was restored by expression of wild-type SHP-1 in these cells. We determined that while SHP-1 depletion does not significantly impact DNA strand-break repair, it does amplify the level of reactive oxygen species (ROS) and elevate endogenous DNA damage. The ROS scavenger WR1065 afforded protection to SHP-1-depleted cells treated with the PNKP inhibitor. We propose that codisruption of SHP-1 and PNKP leads to an increase in DNA damage that escapes repair, resulting in the accumulation of cytotoxic double-strand breaks and induction of apoptosis. This supports an alternative paradigm for synthetic lethal partnerships that could be exploited therapeutically.
Congenital nephrotic syndrome
Authors: M S Kim, W Primack, W E Harmon
Journal: Journal of the American Society of Nephrology (1992)

Congenital nephrotic syndrome (CNS) is a rare and uniformly fatal disease if it is not treated. Although renal transplantation has been a successful treatment, there remains a high mortality rate during the first year of life before transplantation. From 1979 to 1987, four patients with CNS, all of whom died before they could undergo renal transplantation were treated. On the basis of this clinical experience, early elective bilateral nephrectomy and dialysis for infants with CNS were initiated to improve overall outcome. From 1987 to 1989, this protocol has been used on four consecutive patients with CNS. In these patients, bilateral nephrectomy was performed only after patients suffered a serious CNS-related complication that occurred between 4 and 6 months of age. Despite nephrectomy and the need for chronic dialysis, all patients grew at normal or accelerated rates. By 16 months of age, all patients underwent successful renal transplantation.
Juvenile pityriasis rubra pilaris: Report of 28 cases in Taiwan
Authors: Chao-Chun Yang, I-Hsin Shih, Wan-Lung Lin, Yi-Sheng Yu, Hsien-Ching Chiu, Po-Han Huang, Yu-Wen Cheng, Julia Yu-Yun Lee, WenChieh Chen
Journal: Journal of the American Academy of Dermatology (2008)
Adefovir dipivoxil (ADV) alone and in combination with lamivudine (LAM) suppresses LAM-resistant hepatitis B virus (HBV) replication: 16 week interim analysis
Authors: Marion Peters, H.W. Hann, Paul Martin, Elizabeth Heathcote, P. Buggisch, A.E. Moorat, Mark Sullivan, Kristin Kleber, Ramin Ebrahimi, Shelly Xiong, Carol Brosgart
Journal: Journal of Hepatology (2002)
Dual Inhibition of mTOR and Estrogen Receptor Signaling<i>In vitro</i>Induces Cell Death in Models of Breast Cancer
Authors: Anne Boulay, Joelle Rudloff, Jingjing Ye, Sabine Zumstein-Mecker, Terence O'Reilly, Dean B. Evans, Shiuan Chen, Heidi A. Lane
Journal: Clinical Cancer Research (2005)

RAD001 (everolimus), a mammalian target of rapamycin (mTOR) pathway inhibitor in phase II clinical trials in oncology, exerts potent antiproliferative/antitumor activities. Many breast cancers are dependent for proliferation on estrogens synthesized from androgens (i.e., androstenedione) by aromatase. Letrozole (Femara) is an aromatase inhibitor used for treatment of postmenopausal women with hormone-dependent breast cancers. The role of the mTOR pathway in estrogen-driven proliferation and effects of combining RAD001 and letrozole were examined in vitro in two breast cancer models.The role of the mTOR pathway in estrogen response was evaluated in aromatase-expressing MCF7/Aro breast cancer cells by immunoblotting. Effects of RAD001 and letrozole (alone and in combination) on the proliferation and survival of MCF7/Aro and T47D/Aro cells were evaluated using proliferation assays, flow cytometry, immunoblotting, and apoptosis analyses.Treatment of MCF7/Aro cells with estradiol or androstenedione caused modulation of the mTOR pathway, a phenomenon reversed by letrozole or RAD001. In MCF7/Aro and T47D/Aro cells, both agents inhibited androstenedione-induced proliferation; however, in combination, this was significantly augmented (P < 0.001, two-way ANOVA, synergy by isobologram analysis). Increased activity of the combination correlated with more profound effects on G1 progression and a significant decrease in cell viability (P < 0.01, two-way ANOVA) defined as apoptosis (P < 0.05, Friedman test). Increased cell death was particularly evident with optimal drug concentrations.mTOR signaling is required for estrogen-induced breast tumor cell proliferation. Moreover, RAD001-letrozole combinations can act in a synergistic manner to inhibit proliferation and trigger apoptotic cell death. This combination holds promise for the treatment of hormone-dependent breast cancers.
Peritonitis Treated With Prolonged, Intermittent Peritoneal Lavage
Authors: A. Condon Dalton
Journal: JAMA (1969)

Generalized peritonitis developed following colectomy in a patient with ulcerative colitis. A catheter inserted into the peritoneal cavity 13 days postoperatively yielded 2 liters of purulent fluid containing Escherichia coli and Pseudomonas aeruginosa . When fever and purulent drainage persisted despite antibiotic therapy, repeated peritoneal lavage was done through the catheter for 15 days. The patient recovered. Repeated lavage may be of value in severe peritonitis poorly responsive to standard therapy.
Functional brain imaging in respiratory medicine
Authors: Kyle Pattinson
Journal: Thorax (2015)

Discordance of clinical symptoms with markers of disease severity remains a conundrum in a variety of respiratory conditions. The breathlessness of chronic lung disease correlates poorly with spirometry, yet is a better predictor of mortality. In chronic cough, symptoms are often evident without clear physical cause. In asthma, the terms 'over perceivers' and 'under perceivers' are common parlance. In all these examples, aberrant brain mechanisms may explain the mismatch between symptoms and pathology. Functional MRI is a non-invasive method of measuring brain function. It has recently become significantly advanced enough to be useful in clinical research and to address these potential mechanisms. This article explains how FMRI works, current understanding from FMRI in breathlessness, cough and asthma and suggests possibilities for future research.
A Lecture on Chronic Rhinitis and its Sequelae
Authors: G. H. MacKenzie
Journal: BMJ (1888)

SiNCE Voltolini first (lemonstrated the causal relationshlip between nasal polypi and asthlma, the stu(ly of nasal diseases hlas become of increased importance, not only from their direct effects, but also from their secondary or reflex results upon the organs of respiration.In discussing the symptoms and results of nasal disease, not
Targeting Cancer Cell Metabolism: The Combination of Metformin and 2-Deoxyglucose Induces p53-Dependent Apoptosis in Prostate Cancer Cells
Authors: Issam Ben Sahra, Kathiane Laurent, Sandy Giuliano, Frédéric Larbret, Gilles Ponzio, Pierre Gounon, Yannick Le Marchand-Brustel, Sophie Giorgetti-Peraldi, Mireille Cormont, Corine Bertolotto, Marcel Deckert, Patrick Auberger, Jean-François Tanti, Frédéric Bost
Journal: Cancer Research (2010)

Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, exerts antitumoral and antiproliferative action. In this study, the addition of metformin to 2-deoxyglucose (2DG) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP. The combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone, leading to 96% inhibition of cell viability in LNCaP prostate cancer cells. In contrast, a moderate effect on cell viability was observed in normal prostate epithelial cells. At the cellular level, the combination of metformin and 2DG induced p53-dependent apoptosis via the energy sensor pathway AMP kinase, and the reexpression of a functional p53 in p53-deficient prostate cancer cells restored caspase-3 activity. In addition to apoptosis, the combination of metformin and 2DG arrested prostate cancer cells in G(2)-M. This G(2)-M arrest was independent of p53 and correlated with a stronger decrease in cell viability than obtained with either drug. Finally, metformin inhibited 2DG-induced autophagy, decreased beclin 1 expression, and triggered a switch from a survival process to cell death. Our study reinforces the growing interest of metabolic perturbators in cancer therapy and highlights the potential use of the combination of metformin and 2DG as an anticancerous treatment.
Targeting the HGF/c-MET Pathway in Hepatocellular Carcinoma
Authors: Lipika Goyal, Mandar D. Muzumdar, Andrew X. Zhu
Journal: Clinical Cancer Research (2013)

Hepatocellular carcinoma (HCC) is a significant cause of cancer-related morbidity and mortality worldwide. Despite improvements in local therapies, including surgical resection, liver transplantation, and transarterial embolization, the prognosis remains poor for the majority of patients who develop recurrence or present with advanced disease. Systemic therapy with the tyrosine kinase inhibitor sorafenib represents a milestone in advanced HCC but provides a limited survival benefit. Ongoing efforts to study hepatocarcinogenesis have identified an important role for c-MET signaling in the promotion of tumor growth, angiogenesis, and metastasis. In this review, we summarize the preclinical data from human tissue, cell lines, and animal models that implicate c-MET in the pathogenesis of HCC. We also evaluate potential biomarkers that may estimate prognosis or predict response to c-MET inhibitors for more rational clinical trial design. Finally, we discuss the latest clinical trials of c-MET inhibitors in advanced HCC.
Early Metabolic Response Evaluation by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Allows <i>In vivo</i> Testing of Chemosensitivity in Gastric Cancer: Long-term Results of a Prospective Study
Authors: Katja Ott, Ken Herrmann, Florian Lordick, Hinrich Wieder, Wolfgang A. Weber, Karen Becker, Andreas K. Buck, Martin Dobritz, Ulrich Fink, Kurt Ulm, Tibor Schuster, Markus Schwaiger, Jörg-Rüdiger Siewert, Bernd J. Krause
Journal: Clinical Cancer Research (2008)

We prospectively evaluated the predictive value of positron emission tomography using fluorine-18 fluorodeoxyglucose (FDG-PET) for in vivo testing of chemosensitivity in locally advanced gastric cancer using an a priori definition of metabolic response (a decrease of >35% of the standard uptake value). The goal of the study was the definition of biologically different groups of patients prior to or early during induction therapy, with special emphasis on FDG non-avid tumors.Based on our data, which was published in 2003, at least 36 patients with metabolic response or FDG non-avid tumors had to be recruited for an analysis of the group of FDG non-avid tumors with sufficient statistical power. Seventy-one patients (32 metabolic nonresponders, 17 metabolic responders, and 22 patients with FDG non-avid tumors) underwent FDG-PET at baseline. In FDG-avid tumors, FDG-PET was repeated 14 days after the initiation of chemotherapy.Metabolic responders (17 of 49) showed a high histopathologic response rate (69%) and a favorable prognosis (median survival not reached), whereas metabolic nonresponders (32 of 49) had a poor prognosis (median survival, 24.1 months) and showed a histopathologic response in 17%. The histopathologic response rate (24%) for FDG-PET non-avid patients showed no significant difference compared with FDG-avid nonresponders (P=0.72). Survival of FDG non-avid patients was 36.7 months (not significantly different from FDG-avid nonresponders, 24.1 months, P=0.46).In locally advanced gastric cancer, three different metabolic groups exist. Response and survival was predicted by PET in FDG-avid tumors. Metabolic response assessment was not possible in FDG non-avid tumors; however, due to unfavorable outcome, therapy modification might also be considered in FDG non-avid tumors.
An Angiogenic Switch in Breast Cancer Involves Estrogen and Soluble Vascular Endothelial Growth Factor Receptor 1
Authors: M. Elkin, A. Orgel, H. K. Kleinman
Journal: JNCI Journal of the National Cancer Institute (2004)

Estrogen is involved in breast tumorigenesis, but the precise mechanisms for its oncogenic and angiogenic actions are poorly understood. Angiogenesis is regulated, in part, by these critical components: vascular endothelial growth factor (VEGF) and its two receptors (VEGFR-1 and VEGFR-2). VEGFR-2 is a positive angiogenic signal transducer, whereas VEGFR-1, especially its soluble form (soluble VEGFR-1), is a negative regulator of VEGF availability. We found that breast epithelial cells express soluble VEGFR-1 and hypothesized that because estrogen can regulate expression of members of the VEGF family, it might stimulate angiogenesis in breast cancer by decreasing expression of soluble VEGFR-1. Soluble VEGFR-1 expression decreased in estrogen receptor (ER)–positive but not in ER-negative breast cancer cell lines treated with estrogen. Pretreatment of the cells with the ER antagonist ICI 182,780 blocked the effect. The estrogen-mediated decrease in soluble VEGFR-1 expression was accompanied by a statistically significant increase in angiogenesis in vivo. Our data suggest that inhibition of soluble VEGFR-1 expression represents a novel mechanism—an estrogen-driven angiogenic switch—possibly responsible for breast carcinoma progression.
Facilitating Role of Preprotachykinin-I Gene in the Integration of Breast Cancer Cells within the Stromal Compartment of the Bone Marrow
Authors: Gayatri Rao, Prem S. Patel, Suji P. Idler, Paul Maloof, Pedro Gascon, Julius A. Potian, Pranela Rameshwar
Journal: Cancer Research (2004)

Abstract Despite early detection of breast cancer, patients’ survival may be compromised if the breast cancer cells (BCCs) enter the bone marrow (BM). It is highly probable that BCCs enter the BM long before clinical detection. An in vitro coculture model with BM stroma and BCCs (cell lines; primary cells from stage III BC, n = 7, and stage M0, n = 3) mimicked early entry of BCCs into the BM. In coculture, BCCs exhibit contact inhibition and do not require otherwise needed growth supplements. Stromal growth rate was increased 2-fold in coculture. The inclusion of BCCs in stromal support of long-term culture-initiating cell assay frequencies show no difference (38 ± 3 versus 36 ± 6). Nontumorigenic breast cells (patients and cell lines) did not survive in coculture, suggesting that the model could select for malignant population in surgical breast tissues. Cocultures were able to select cells with 73 ± 7% cloning efficiencies and with the ability to form cocultures with BM stroma. Preprotachykinin-I (PPT-I), a gene that is conserved by evolution, facilitates BCC integration as part of the stromal compartment. This was deduced as follows: (a) nontumorigenic breast cells (n = 4) genetically engineered to express PPT-I and led to anchorage-independent growth, foci formation, and formation of cocultures; and (b) suppression of PPT-I in BCCs (n = 5) with pPMSKH1-PPT-I small interfering RNA reverted the cells to nontumorigenic phenotypes and was undetectable in the BM nude mice. The evidence supports that the PPT-I gene facilitates the integration of BCCs in the stromal compartment during a period before clinical detection, without disrupting hematopoietic activity.
Lung function estimates in idiopathic pulmonary fibrosis: the potential for a simple classification
Authors: J J Egan, F J Martinez, A U Wells, Trevor John Williams
Journal: Thorax (2005)

Application of a classification based on simple lung function testing in IPF

For many years the idiopathic pulmonary fibrosis (IPF) community has debated the merits of the histopathological classification of idiopathic interstitial pneumonia (IIP).1 The ATS/ERS consensus statement identifies the importance of histological categories of usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). Furthermore, it emphasises that IPF is the clinical correlate of UIP. Despite the recognition of the importance of histological characterisation, surgical biopsy rates vary considerably.2 Most clinicians do not subject their patients to surgical biopsy, despite the potential prognostic benefit of detailed histological evaluation, because many patients are elderly and have significantly impaired lung function and other medical co-morbidities resulting in a potentially high mortality rate.3 In addition, HRCT scanning provides diagnostic data of high sensitivity and specificity for the diagnosis of IPF with acceptable interobserver variability.4,5

Meanwhile, the chronic obstructive pulmonary disease (COPD) and lung transplantation communities have applied simple but pragmatically useful classifications. Bronchiolitis obliterans syndrome (BOS), for example, has been subject to a clinical grading system reflecting the degree of impairment of lung function following lung transplantation. The emergence of a classification based on simple lung function testing occurred because of the difficulties in obtaining adequate tissue for the diagnosis of obliterative bronchiolitis. This is comparable to the situation in IPF where tissue is also difficult to obtain. The success of the classification of BOS is reflected by the publication of an updated version.6

The global initiative for COPD (GOLD) is another example of a consensus classification based on simple lung function testing. GOLD provides a staging system ranging from an “at risk” category to a severe disease category.7 Based on simple lung function testing, it is reproducible and has facilitated the identification of patients with …
Cdc42 is a key regulator of B cell differentiation and is required for antiviral humoral immunity
Authors: Marianne Burbage, Selina J. Keppler, Francesca Gasparrini, Nuria Martínez-Martín, Mauro Gaya, Christoph Feest, Marie-Charlotte Domart, Cord Brakebusch, Lucy Collinson, Andreas Bruckbauer, Facundo D. Batista
Journal: The Journal of Experimental Medicine (2014)

The small Rho GTPase Cdc42, known to interact with Wiskott–Aldrich syndrome (WAS) protein, is an important regulator of actin remodeling. Here, we show that genetic ablation of Cdc42 exclusively in the B cell lineage is sufficient to render mice unable to mount antibody responses. Indeed Cdc42-deficient mice are incapable of forming germinal centers or generating plasma B cells upon either viral infection or immunization. Such severe immune deficiency is caused by multiple and profound B cell abnormalities, including early blocks during B cell development; impaired antigen-driven BCR signaling and actin remodeling; defective antigen presentation and in vivo interaction with T cells; and a severe B cell–intrinsic block in plasma cell differentiation. Thus, our study presents a new perspective on Cdc42 as key regulator of B cell physiology.
Regulation of Ligands for the NKG2D Activating Receptor
Authors: David H. Raulet, Stephan Gasser, Benjamin G. Gowen, Weiwen Deng, Heiyoun Jung
Journal: Annual Review of Immunology (2013)

NKG2D is an activating receptor expressed by all NK cells and subsets of T cells. It serves as a major recognition receptor for detection and elimination of transformed and infected cells and participates in the genesis of several inflammatory diseases. The ligands for NKG2D are self-proteins that are induced by pathways that are active in certain pathophysiological states. NKG2D ligands are regulated transcriptionally, at the level of mRNA and protein stability, and by cleavage from the cell surface. In some cases, ligand induction can be attributed to pathways that are activated specifically in cancer cells or infected cells. We review the numerous pathways that have been implicated in the regulation of NKG2D ligands, discuss the pathologic states in which those pathways are likely to act, and attempt to synthesize the findings into general schemes of NKG2D ligand regulation in NK cell responses to cancer and infection.
Chronic Kidney Disease and Cardiovascular Risk
Authors: Donal N. Reddan, Preston S. Klassen
Journal: Journal of the American Society of Nephrology (2002)

Using a robust statistical analysis of a selected population of patients older than 60 years of age with isolated systolic hypertension, the article by de Leeuw et al. ([1][1]) in this issue of JASN demonstrates that renal impairment and proteinuria are independent predictors of cardiovascular risk