tbuckley/cabot-search huggingface dataset:
HDAC4-Regulated STAT1 Activation Mediates Platinum Resistance in Ovarian Cancer
Authors: Euan A. Stronach, Albandri Alfraidi, Nona Rama, Christoph Datler, James B. Studd, Roshan Agarwal, Tankut G. Guney, Charlie Gourley, Bryan T. Hennessy, Gordon B. Mills, Antonello Mai, Robert Brown, Roberto Dina, Hani Gabra
Journal: Cancer Research (2011)

Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests that resistant clones exist within a larger drug-sensitive cell population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically derived, intrapatient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 downregulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of histone deacetylase (HDAC) 4, FOLR2, PIK3R1, or STAT1 (P < 0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum-sensitive cells but not in HDAC4 overexpressing platinum-resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum-induced STAT1 activation, and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors [n = 7 of 16 (44%); P = 0.04]. Therefore, clinical selection of HDAC4-overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer.
First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia
Authors: Eric J. Feldman, Jeffrey E. Lancet, Jonathan E. Kolitz, Ellen K. Ritchie, Gail J. Roboz, Alan F. List, Steven L. Allen, Ekatherine Asatiani, Lawrence D. Mayer, Christine Swenson, Arthur C. Louie
Journal: Journal of Clinical Oncology (2011)

Purpose This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351. Patients and Methods CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m 2 with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred. Results The maximum-tolerated dose was 101 units/m 2 . DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m 2 . Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable &gt; 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours. Conclusion The recommended dose of CPX-351 for phase II study is 101 units/m 2 . Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.
Anti-inflammatory effects of inhaled beclomethasone dipropionate in nonatopic asthmatics
Authors: M Hoshino, Y Nakamura
Journal: European Respiratory Journal (1996)

The effects of inhaled beclomethasone dipropionate (BDP) on asthma symptoms and infiltration of the bronchial mucosa by inflammatory cells were investigated in an open study of 10 patients with mild-to-moderate nonatopic bronchial asthma. Asthma scores were recorded in an asthma diary. Peak expiratory flow (PEF), PEF diurnal variation (PEF%), forced expiratory volume in one second (FEV1%), methacholine airway hypersensitivity (minimum dose of methacholine) (Dmin) were measured. Biopsy of the bronchial mucosa was performed before and after 8 weeks of treatment with BDP (400 micrograms.day-1). The following inflammatory cells were immunostained: eosinophils with anti-EG2; mast cells with AA1; neutrophils with NP57; T-lymphocytes with anti-CD3, CD4, and CD8; and activated T-lymphocytes with anti-CD25. There was a significant improvement in the asthma symptom score, PEF%, FEV1%, and Dmin after BDP therapy and the number of EG2-, AA1-, CD3-, CD4-, and CD25-positive cells decreased significantly. We conclude that inhaled beclomethasone dipropionate inhibited inflammatory cell infiltration of airway tissue and that associated with this there was an improvement of symptoms in this open study of inhaled beclomethasone dipropionate in a group of nonatopic asthmatic subjects.
Rapid vascular regrowth in tumors after reversal of VEGF inhibition
Authors: M. R. Mancuso, R. Davis, S. M. Norberg, S. O'Brien, B. Sennino, T. Nakahara, V. J. Yao, T. Inai, P. Brooks, B. Freimark, D. R. Shalinsky, D. D. Hu-Lowe, D. M. McDonald
Journal: Journal of Clinical Investigation (2006)

Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%–60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less α–SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.
Glucocorticoid insensitive asthma: a one year clinical follow up pilot study
Authors: P. Demoly, D. Jaffuel, M. Mathieu, H. Sahla, P. Godard, F.-B. Michel, J. Bousquet
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Glucocorticoid resistant or insensitive asthmatic subjects are usually defined as patients whose baseline pre-bronchodilation forced expiratory volume in one second (FEV<sub>1</sub>) of less than 70–80% predicted improves significantly in response to β<sub>2</sub> agonists but by less than 15% following 1–2 weeks of 40 mg prednisolone daily. Since there is little long term clinical information on these patients, a one year prospective study was performed to assess whether glucocorticoid sensitivity may vary over time. <h3>METHODS</h3> Nineteen severe asthmatic subjects were studied and received 40 mg prednisolone daily for seven days. Prednisolone was given for a further seven days in glucocorticoid insensitive asthmatics and then stopped. Patients were followed up for one year and the glucocorticoid test was repeated on five patients in each group six months later. <h3>RESULTS</h3> Eleven patients were classified as glucocorticoid insensitive and eight as glucocorticoid sensitive on day 7. The demographic characteristics of the patients were similar in both groups. Four glucocorticoid insensitive patients became responsive after one further week of prednisolone treatment. Six months later, four of five glucocorticoid sensitive patients and three of five previously glucocorticoid insensitive patients were glucocorticoid sensitive. <h3>CONCLUSIONS</h3> Glucocorticoid sensitivity varies over time.
339 NAFLD LIVER FAT SCORE STRONGLY CORRELATES WITH HISTOLOGICAL SEVERITY OF NAFLD AND NASH IN A LARGE COHORT OF PROSPECTIVELY INCLUDED OVERWEIGHT PATIENTS
Authors: S. Francque, A. Verrijken, I. Mertens, G. Hubens, E. Van Marck, P. Michielsen, L. Van Gaal
Journal: Journal of Hepatology (2010)
iPLA2β: front and center in human monocyte chemotaxis to MCP-1
Authors: Ravi S. Mishra, Kevin A. Carnevale, Martha K. Cathcart
Journal: The Journal of Experimental Medicine (2008)

Monocyte chemoattractant protein-1 (MCP-1) directs migration of blood monocytes to inflamed tissues. Despite the central role of chemotaxis in immune responses, the regulation of chemotaxis by signal transduction pathways and their in vivo significance remain to be thoroughly deciphered. In this study, we examined the intracellular location and functions of two recently identified regulators of chemotaxis, Ca2+-independent phospholipase (iPLA2β) and cytosolic phospholipase (cPLA2α), and substantiate their in vivo importance. These enzymes are cytoplasmic in unstimulated monocytes. Upon MCP-1 stimulation, iPLA2β is recruited to the membrane-enriched pseudopod. In contrast, cPLA2α is recruited to the endoplasmic reticulum. Although iPLA2β or cPLA2α antisense oligodeoxyribonucleotide (ODN)–treated monocytes display reduced speed, iPLA2β also regulates directionality and actin polymerization. iPLA2β or cPLA2α antisense ODN–treated adoptively transferred mouse monocytes display a profound defect in migration to the peritoneum in vivo. These converging observations reveal that iPLA2β and cPLA2α regulate monocyte migration from different intracellular locations, with iPLA2β acting as a critical regulator of the cellular compass, and identify them as potential targets for antiinflammatory strategies.
Bovine serum albumin immunization: a new risk of allergy during protocols for <i>in vitro</i> fertilization
Authors: A. Moneret‐Vautrin, J.‐M. Wal, F. Guillet‐Rossof, H. Gérard, P. Boulard
Journal: Allergy (1991)

Three patients having undergone protocols for in vitro fertilization (IVF) showed an allergic reaction suggesting seric disease 6 to 10 days after follicle aspiration. The responsibilitty of bovine serum albumin, present in the follicle‐rinsing fluid and in the medium used for embryo culture was suspected. An immunological study was carried out, using two groups for comparison. Group 1: 7 controls. Group 2: 11 women having undergone IVF protocols without incident. Anti‐BSA antibodies were present in low quantities in one or two subclasses of IgG and IgA in Group 1, and in several subclasses at higher levels in nine of 11 subjects from Group 2. The IgG 4 response predominated 7 times out of 9. The antibody content gradually fell after the IVF attempt. An immune response predominated in the IgG 1 in two patients. Skin test for the two fluids and USA were positive only in the three patients. These results show the frequency of immunization to BSA induced through the ovarian and peritoneal pathways. Seric disease corresponds to a rise in IgG 1 . The association of a IgE‐dependent sensitization is suspected. The authors suggest the possibility of an interference of these immune processes with implantation and propose the elimination of heterologous proteins from fluids. They also suggest that LH‐RH analogues facilitate immune responses.
E Antigen: A Cell-Surface Antigen of C57BL Leukemias
Authors: Tadao Aoki, Burghard Stück, Lloyd J. Old, Ulrich Hämmerling, Etienne de Harven
Journal: Cancer Research (1970)

SUMMARY Antisera were prepared in (C3H/An X !)F! mice against a transplanted leukemia (E9SL2) that had arisen spontaneously in C57BL/6 mice. After removal of cytotoxic antibodies to normal alloantigens by absorption in vivo in C57BL/6 mice, the antisera detected an antigen, designated E, which is distinct from the four previously recognized cell-surface antigens (G, FMR, TL, and ML) associated with mouse leukemias. E antigen was detected on two other spontaneous leukemias of C57BL/6 origin and on the long-transplanted chemically induced leukemia, EL4. It was not found on any normal C57BL/6 tissues nor on radiation-induced or on virus-induced (Gross, Moloney, Rauscher) C57BL/6 leukemias. Thirty-nine solid tumors and leukemias from strains other than C57BL/6 lack E antigen. By the indirect immunoferritin technique, E antigen was seen to occupy discrete patches on the surface of E+ leukemia cells. Murine leukemia virus (type C or enveloped A) was not observed in E+ leukemias. Intracisternal A particles were present, but, as these are found also in Eâ€”leukemias and solid tumors, it is unlikely that they are related to E antigen. Thus, the origin of E antigen, whether from cellular genes or from viral genes, is unknown.
Bcl-2–dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis
Authors: Joseph A. Odin, Robert C. Huebert, Livia Casciola-Rosen, Nicholas F. LaRusso, Antony Rosen
Journal: Journal of Clinical Investigation (2001)

The close association between autoantibodies against pyruvate dehydrogenase-E2 (PDC-E2), a ubiquitous mitochondrial protein, and primary biliary cirrhosis (PBC) is unexplained. Many autoantigens are selectively modified during apoptosis, which has focused attention on apoptotic cells as a potential source of "neo-antigens" responsible for activating autoreactive lymphocytes. Since increased apoptosis of bile duct epithelial cells (cholangiocytes) is evident in patients with PBC, we evaluated the effect of apoptosis on PDC-E2. Autoantibody recognition of PDC-E2 by immunofluorescence persisted in apoptotic cholangiocytes and appeared unchanged by immunoblot analysis. PDC-E2 was neither cleaved by caspases nor concentrated into surface blebs in apoptotic cells. In other cell types, autoantibody recognition of PDC-E2, as assessed by immunofluorescence, was abrogated after apoptosis, although expression levels of PDC-E2 appeared unchanged when examined by immunoblot analysis. Both overexpression of Bcl-2 and depletion of glutathione before inducing apoptosis prevented this loss of autoantibody recognition, suggesting that glutathiolation, rather than degradation or loss, of PDC-E2 was responsible for the loss of immunofluorescence signal. We postulate that apoptotic cholangiocytes, unlike other apoptotic cell types, are a potential source of immunogenic PDC-E2 in patients with PBC.
Outcome of Patients With Early-Stage Breast Cancer Treated With Doxorubicin-Based Adjuvant Chemotherapy As a Function of <i>HER2</i> and <i>TOP2A</i> Status
Authors: Raymond Tubbs, William E. Barlow, G. Thomas Budd, Eric Swain, Peggy Porter, Allen Gown, I-Ten Yeh, George Sledge, Charles Shapiro, James Ingle, Charles Haskell, Kathy S. Albain, Robert Livingston, Daniel F. Hayes
Journal: Journal of Clinical Oncology (2009)

Amplification and deletion of the TOP2A gene have been reported as positive predictive markers of response to anthracycline-based therapy. We determined the status of the HER2 and TOP2A genes in a large cohort of breast cancer patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C).TOP2A/CEP17 and HER2/CEP17 fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) constructed from 2,123 of the 3,125 women with moderate-risk primary breast cancer who received equivalent doses of either concurrent adjuvant chemotherapy with A plus C (n = 1,592) or sequential A followed by C (n = 1,533).An abnormal TOP2A genotype was identified for 153 (9.4%) of 1,626 patients (4.0% amplified; 5.4% deleted). An abnormal HER2 genotype was identified for 303 (20.4%) of 1,483 patients (18.8% amplified; 1.6% deleted). No significant differences in either overall survival (OS) or disease-free survival (DFS) were identified for TOP2A. In univariate analysis, OS and DFS rates were strongly and adversely associated only with higher levels of HER2 amplification (ratio > or = 4.0). Survival was not associated with low-level HER2 amplification (ratio > or = 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio > or = 4 (OS HR, 1.45; P = .03; DFS HR, 1.38; P = .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size.In this population of patients with early-stage breast cancer who were treated with adjuvant AC chemotherapy, TOP2A abnormalities were not associated with outcome. HER2 high-level amplification was a prognostic marker in anthracycline-treated patients.
Enabling women to breast feed
Authors: M. Renfrew, D. Hall
Journal: BMJ (2008)

Is a challenge for the health professions

Breast feeding improves infant and maternal health and cognitive development in both developed and developing countries, and it is the single most important preventive approach for saving children’s lives.1 2 Yet most infants in developed countries are formula fed within the first three months of birth, either exclusively or partially,3 and in many developing countries exclusive breast feeding (no additional fluids, cereal, or other foods) is rare. In the United Kingdom, the women most likely to formula feed are young, white, and from low socioeconomic backgrounds. This poses a major public health and inequalities challenge.

Despite national and international policy initiatives, neither the duration of breast feeding nor the exclusivity of breast feeding up to six months of age have improved in the UK; 40% of women who start to breast feed discontinue by the time their baby is 6 weeks old, and only 20% of infants are exclusively breast fed at six weeks. The reasons women give for discontinuation are consistent over time and internationally; they think that they …
Left ventricular diverticulum and mitral incompetence in asymptomatic children.
Authors: M Gueron, M Hirsch, I Opschitzer, P Mogel
Journal: Circulation (1976)

Two children with congenital apical left ventricular diverticulum and significant mitral incompetence are reported. The angiographic and anatomic findings of the few previously reported patients with congenital diverticula and aneurysm were analyzed and a new classification differentiating between the two is proposed. The clinical data analyzed in apical diverticula and aneurysm are similar to those patients with anomalous origin of the left coronary artery from the pulmonary artery. Left ventriculography is the best diagnostic tool. The place of surgery in the treatment of the congenital apical diverticula with or without mitral incompetence in asymptomatic children is not clear. Further observations are needed to reveal its natural history.
The transcription factor X-box binding protein-1 in neurodegenerative diseases
Authors: Julie Dunys, Eric Duplan, Frédéric Checler
Journal: Molecular Neurodegeneration (2014)

Endoplasmic reticulum (ER) is the cellular compartment where secreted and integral membrane proteins are folded and matured. The accumulation of unfolded or misfolded proteins triggers a stress that is physiologically controlled by an adaptative protective response called Unfolded Protein Response (UPR). UPR is primordial to induce a quality control response and to restore ER homeostasis. When this adaptative response is defective, protein aggregates overwhelm cells and affect, among other mechanisms, synaptic function, signaling transduction and cell survival. Such dysfunction likely contributes to several neurodegenerative diseases that are indeed characterized by exacerbated protein aggregation, protein folding impairment, increased ER stress and UPR activation. This review briefly documents various aspects of the biology of the transcription factor XBP-1 (X-box Binding Protein-1) and summarizes recent findings concerning its putative contribution to the altered UPR response observed in various neurodegenerative disorders including Parkinson's and Alzheimer's diseases.
Rapid Declines in FEV<sub>1</sub> and Subsequent Respiratory Symptoms, Illnesses, and Mortality in Coal Miners in the United States
Authors: LU-ANN F. BEECKMAN, MEI-LIN WANG, EDWARD L. PETSONK, GREGORY R. WAGNER
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Coal mine dust exposure is associated with accelerated loss of lung function. We assessed long-term health outcomes in two groups of underground coal miners who during previous mine surveys had shown either high rates of FEV1 decline (cases, n = 310) or relatively stable lung function (referents, n = 324). Cases and referents were matched initially for age, height, smoking status, and FEV1. We determined vital status for 561 miners, and obtained a follow-up questionnaire for 121 cases and 143 referents. Responses on the follow-up questionnaire were compared with those on the last previous mine health survey questionnaire. Cases showed a greater incidence of symptoms than did referents for cough, phlegm production, Grades II and III dyspnea, and wheezing, and greater incidences than referents of chronic bronchitis and self- reported asthma and emphysema. More cases than referents (15% versus 4%) left mining before retirement because of chest illnesses. After controls were applied for age and smoking, cases had twice the risk of dying of cardiovascular and nonmalignant respiratory diseases and a 3.2-fold greater risk of dying of chronic obstructive pulmonary disease than did referents. Rapid declines in FEV1 experienced by some coal miners are associated with subsequent increases in respiratory symptoms, illnesses, and mortality from cardiovascular and nonmalignant respiratory diseases.