tbuckley/cabot-search huggingface dataset:
Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer
Authors: Sao Jiralerspong, Shana L. Palla, Sharon H. Giordano, Funda Meric-Bernstam, Cornelia Liedtke, Chad M. Barnett, Limin Hsu, Mien-Chie Hung, Gabriel N. Hortobagyi, Ana M. Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2009)

Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy.We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using chi(2) tests of independence and compared pair- wise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model.The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use.Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.
The effect of estrogen on the lipoprotein lipase activity of rat adipose tissue.
Authors: M Hamosh, P Hamosh
Journal: Journal of Clinical Investigation (1975)

The effect of 17beta-estradiol or progesterone administration on adipose tissue lipoprotein lipase activity was studied in male and ovariectomized female rats. Lipoprotein lipase activity was measured in acetone-ether-extracted preparations of adipose tissue with doubly labeled (14C-fatty acid, 3H-glyceryl) chylomicron triglyceride as substrate. Administration of 17beta-estradiol to male rats lowered adipose tissue lipoprotein lipase activity from 8.22 plus or minus 1.8 U/g (1 U = 1 mumol triglyceride hydrolyzed per h) to 4.96 plus or minus 0.5 U/g in the treated group. Ovariectomy increased adipose tissue lipoprotein lipase activity from 10.4 plus or minus 1.8 U/g in controls to 22.7 plus or minus 4.3 U/g. 17beta-Estradiol administration to ovariectomized rats cuased a marked fall in adipose tissue lipoprotein lipase activity: 17beta-estradiol (2.5 mug/day) lowered the enzyme activity to 9.00 plus or minus 1.2 U/g, whereas 25 mug/day further decreased lipoprotein lipase activity to 3.2 plus or minus 0.6 U/g. Blood triglyceride levels increased from 0.8 plus or minus 0.05 mumol/ml in ovariectomized rats to 1.4 plus or minus 0.09 mumol/ml in 25 mug/day 17beta-estradiol-treated rats. Progesterone administration did not affect adipose tissue lipoprotein lipase activity in either male or ovariectomized rats. Heart and lung lipoprotein lipase activity was unaffected by hormone treatment. We suggest that the rise in blood triglyceride concentrations, which accompanies high palsma estrogen levels, could be due to the marked inhibition of adipose tissue lipoprotein lipase activity.
Membrane Type 1-Matrix Metalloproteinase Cleaves Off the NH2-Terminal Portion of Heparin-Binding Epidermal Growth Factor and Converts It into a Heparin-Independent Growth Factor
Authors: Naohiko Koshikawa, Hiroto Mizushima, Tomoko Minegishi, Ryo Iwamoto, Eisuke Mekada, Motoharu Seiki
Journal: Cancer Research (2010)

Epidermal growth factor (EGF) receptors (ErbB) and EGF family members represent promising targets for cancer therapy. Heparin-binding EGF (HB-EGF) is a member of the EGF family and is an important target for therapy in some types of human cancers. Processing of HB-EGF by proprotein convertases, and successively, by ADAM family proteases, generates a soluble growth factor that requires heparin as a cofactor. Although heparin potentiates HB-EGF activity in vitro, it is not clear how the heparin-binding activity of HB-EGF is regulated. Here, we show that membrane type 1-matrix metalloproteinase (MT1-MMP; MMP14), a potent invasion-promoting protease, markedly enhances HB-EGF-dependent tumor formation in mice. MT1-MMP additionally cleaves HB-EGF and removes the NH(2)-terminal 20 amino acids that are important for binding heparin. Consequently, the processing of HB-EGF by MT1-MMP converts HB-EGF into a heparin-independent growth factor with enhanced mitogenic activity, and thereby, expression of both proteins costimulates tumor cell growth in vitro and in vivo. The ErbB family of receptors expressed in human gastric carcinoma cells play a role in mediating enhanced HB-EGF activity by MT1-MMP during invasive cell growth in collagen. Thus, we shed light on a new mechanism whereby HB-EGF activity is regulated that should be considered when designing HB-EGF-targeted cancer therapy.
Circulatory reflexes from carotid and extracarotid baroreceptor areas in man.
Authors: G Mancia, A Ferrari, L Gregorini, R Valentini, J Ludbrook, A Zanchetti
Journal: Circulation Research (1977)

The carotid sinus baroreceptor reflex was studied in 11 normotensive subjects, using a variable pressure neck chamber and correcting for imperfect pressure transmission to the carotid sinus. Decreased carotid baroreceptor stimulation caused a sustaineded rise in arterial pressure, and increased carotid baroreceptor stimulation caused a sustain fall. The responses were in linear relation to the stimulus, and, after reaching the steady state, greater for the reduced than for the increased baroreceptor stimulation. Thus the carotid sinus baroreceptor reflex of the normotensive man is an effective antihypotensive and antihypertensive feedback system, though the former function may have more sensitivity. The increased and decreased baroreceptor stimulation by the neck chamber also caused bradycardia and tachycardia which were modest in magnitude and often transient. In eight subjects the reflex changes in heart rate induced by the neck chamber were compared with those induced by altering transmural pressure not merely at the carotid sinus but throughout the arterial tree (injection of phenylephrine and trinitroglycerin). The slopes of these relations were 3 times as great in the latter circumstance. Thus the carotid baroreceptors play a lesser role in heart rate control than do extracarotid baroreceptors.
Invasive Procedures in Acute Myocardial Infarction
Authors: K. Lance Gould
Journal: JAMA (1994)

The article entitled "Does More Intensive Treatment of Acute Myocardial Infarction in the Elderly Reduce Mortality? Analysis Using Instrumental Variables" by McClellan et al<sup>1</sup>in this issue ofThe Journalis important for several reasons. The authors describe a new method in medical outcomes research called instrumental variables estimation. In principle, this approach eliminates the bias of patient selection on mortality in the Medicare population receiving varying intensities of treatment for acute myocardial infarction, particularly cardiac catheterization and associated coronary revascularization. The authors argue that this approach has the same effect as prospective randomization in eliminating unrecognized biases of patient selection on outcomes of differing treatment intensities. The article makes the following conclusions for the Medicare population: (1) after acute myocardial infarction, cardiac catheterization and associated revascularization are performed less frequently in women and black men than in white men; (2) cardiac catheterization and associated revascularization have a marginal
The Spontaneous CD8+ T-Cell Response to HLA-A2-Restricted NY-ESO-1b Peptide in Hepatocellular Carcinoma Patients
Authors: Xiao-Ying Shang, Hong-Song Chen, Hua-Gang Zhang, Xue-Wen Pang, Huan Qiao, Ji-Run Peng, Li-Ling Qin, Ran Fei, Ming-Hui Mei, Xi-Sheng Leng, Sacha Gnjatic, Gerd Ritter, Andrew J. G. Simpson, Lloyd J. Old, Wei-Feng Chen
Journal: Clinical Cancer Research (2004)

Hepatocellular carcinoma (HCC) can express various cancer-testis antigens including NY-ESO-1, members of the SSX family, members of the MAGE family, SCP-1, and CTP11. Immunotherapy directed against these antigens is a potential alternative treatment for HCC. To date, it remains unclear whether HCC patients have spontaneous immune responses to these tumor antigens. The objectives of this study were to measure immune responses to NY-ESO-1, a promising cancer vaccine candidate, in HCC patients using the HLA-A2-restricted NY-ESO-1b peptide (p157-165) to measure cellular responses and whole protein to measure antibody responses.In HLA-A2(+) patients with NY-ESO-1(+) HCC, we analyzed T-cell antigen-dependent interferon (IFN)-gamma and/or Granzyme B release by enzyme-linked immunospot (ELISPOT) assay and IFN-gamma-producing intracellular cytokine flow cytometry (CytoSpot). As an assay independent of T-cell function, we performed tetramer staining. Antibodies to whole NY-ESO-1 were assayed by enzyme-linked immunosorbent assay.The frequency of specific CD8(+) T-cell responses to NY-ESO-1b in 28 NY-ESO-1 mRNA(+)HLA-A2(+) HCC patients was 35.7% (10 of 28). The average magnitude of effector CD8(+) T cells was 0.3% (89 +/- 59 per 2.5 x 10(4) CD8(+) cells) and 1.2% as measured by IFN-gamma release ELISPOT and CytoSpot assays, respectively. These in vitro induced NY-ESO-1b-specific CD8(+) T cells can also recognize HepG2 cells transfected with pcDNA3.1-NY-ESO-1 in both IFN-gamma and Granzyme B ELISPOT assays. Frequencies of NY-ESO-1b-specific T cells in several patients were confirmed by tetramer staining. Nonfunctional tetramer(+)CD8(+) T cells were also present. The CD8(+) T-cell response was apparently increased in patients with late-stage HCC. A discordance between antibody and CD8(+) T-cell responses in HCC patients was observed.The elevated frequency of specific CD8(+) T-cell responses to NY-ESO-1b in NY-ESO-1 mRNA(+)HLA-A2(+) HCC patients suggests that NY-ESO-1 is appropriate for use in the immunotherapy of HCC patients.
Targeted Disruption of Heparan Sulfate Interaction with Hepatocyte and Vascular Endothelial Growth Factors Blocks Normal and Oncogenic Signaling
Authors: Fabiola Cecchi, Deborah Pajalunga, C. Andrew Fowler, Aykut Üren, Daniel C. Rabe, Benedetta Peruzzi, Nicholas J. MacDonald, Davida K. Blackman, Stephen J. Stahl, R. Andrew Byrd, Donald P. Bottaro
Journal: Cancer Cell (2012)
Cell Surface Tetraspanin CD9 Mediates Chemoresistance in Small Cell Lung Cancer
Authors: Satoshi Kohmo, Takashi Kijima, Yasushi Otani, Masahide Mori, Toshiyuki Minami, Ryo Takahashi, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Sho Goya, Mitsuhiro Yoshida, Toru Kumagai, Isao Tachibana, Soichiro Yokota, Ichiro Kawase
Journal: Cancer Research (2010)

Abstract Small cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearance of widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial therapy. A theory of cell adhesion–mediated drug resistance is thought to be a principal mechanism in which extracellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found that the tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from three of seven relapsed patients, whereas chemonaïve primary tumors from 16 patients were CD9 negative with only one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisplatin or etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to either of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via β1 integrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of the chemoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreover, selective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering RNA triggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell adhesion–mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC. Cancer Res; 70(20); 8025–35. ©2010 AACR.
TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways
Authors: Sandra B. Haudek, George E. Taffet, Michael D. Schneider, Douglas L. Mann
Journal: Journal of Clinical Investigation (2007)

Transgenic mice with cardiac-restricted overexpression of secretable TNF (MHCsTNF) develop progressive LV wall thinning and dilation accompanied by an increase in cardiomyocyte apoptosis and a progressive loss of cytoprotective Bcl-2. To test whether cardiac-restricted overexpression of Bcl-2 would prevent adverse cardiac remodeling, we crossed MHCsTNF mice with transgenic mice harboring cardiac-restricted overexpression of Bcl-2. Sustained TNF signaling resulted in activation of the intrinsic cell death pathway, leading to increased cytosolic levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9. Cardiac-restricted overexpression of Bcl-2 blunted activation of the intrinsic pathway and prevented LV wall thinning; however, Bcl-2 only partially attenuated cardiomyocyte apoptosis. Subsequent studies showed that c-FLIP was degraded, that caspase-8 was activated, and that Bid was cleaved to t-Bid, suggesting that the extrinsic pathway was activated concurrently in MHCsTNF hearts. As expected, cardiac Bcl-2 overexpression had no effect on extrinsic signaling. Thus, our results suggest that sustained inflammation leads to activation of multiple cell death pathways that contribute to progressive cardiomyocyte apoptosis; hence the extent of such programmed myocyte cell death is a critical determinant of adverse cardiac remodeling.
Evaluation of methacholine dose-response curves by linear and exponential mathematical models: goodness-of-fit and validity of extrapolation
Authors: G Verlato, I Cerveri, A Villani, M Pasquetto, M Ferrari, F Fanfulla, E Zanolin, B Rijcken, R de Marco
Journal: European Respiratory Journal (1996)

Several models have been proposed to analyse dose-response curves recorded in bronchoprovocation challenge tests. The aims of the present work were: 1) to investigate which model (linear vs exponential) and which minimization method (trials and errors vs Levenberg-Marquardt) gives better results in terms of data interpolation (goodness-of-fit); and 2) to verify the validity of extrapolation by comparing forced expiratory volume in one second (FEV1) observed after 4 mg methacholine with values extrapolated after truncation of the curves at 2 mg. For these purposes, methacholine dose-response curves were obtained in 832 subjects from a random population sample, as part of the European Community Respiratory Health Survey (ECRHS) in Italy. Methacholine was inhaled up to a maximum dose of 6 mg by dosimeter technique. The coefficient of determination (r2) was significantly higher with the exponential model (0.81 +/- 0.22; mean +/- SD) than with the linear model (0.69 +/- 0.27). With both models, extrapolated values were usually lower than observed values. As a consequence, a 20% fall in FEV1 with respect to postsaline FEV1 was observed in only 24% and 21% of the tests, where a 20% fall had been predicted, respectively, according to the linear and exponential model. In conclusion, exponential models are better than linear models with respect to data interpolation of methacholine dose-response curves. However, they are worse with respect to extrapolation to higher doses. With any model, extrapolation of dose-response curves by one doubling-dose should be avoided.
Apolipoprotein 3 allele is associated with persistent hepatitis C virus infection
Authors: D A Price
Journal: Gut (2005)

<b>Background:</b> Host genetic factors may significantly influence the ability to clear hepatitis C virus (HCV) following infection. HCV is associated with very low density lipoproteins (VLDL) and low density lipoproteins (LDL) in the host's circulation. Apolipoprotein E (APOE) is found in VLDL and binds to potential receptors involved in HCV entry into cells, the LDL receptor, and the scavenger receptor protein SR-B1. The <i>APOE</i> gene is polymorphic with three alleles coding for three isoforms: Apo-ε2, Apo-ε3, and Apo-ε4. The aim of this study was to assess if these functional polymorphisms determine disease outcome in HCV infected individuals. <b>Methods:</b> The <i>APOE</i> genotype was determined in 420 Northern European patients with evidence of exposure to HCV. Genotype and allele distribution were compared with those of 288 healthy controls and progression of liver disease and viral clearance were analysed according to <i>APOE</i> allele status. <b>Results:</b> The <i>APOE*E2 and APOE*E4</i> alleles were both associated with a reduced likelihood of chronic infection (odds ratio (OR) 0.39 (95% confidence interval (CI) 0.211–0.728), p = 0.003; and OR 0.6 (95% CI 0.38–0.96), p = 0.032) and there was a notable absence of the <i>E2E2</i> genotype in the HCV antibody positive group compared with the control population (p = 0.0067). Overall the genotypes carrying the E2 allele (<i>E2,E3</i> and <i>E2,E4</i>) were associated with the equivalent of a 3–5-fold reduction in the risk of chronic HCV infection (genotype relative risk 0.36 and 0.20, respectively). <b>Conclusion:</b> This study indicates that functional <i>APOE</i> gene polymorphisms may be a determinant of outcome in HCV infection. We hypothesise that the <i>E2</i> allele may protect against viral persistence via defective binding of HCV lipoviral particles to the cellular receptors involved in entry of these infectious particles.
RETRACTED ARTICLE: α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway
Authors: Sarita Saraswati, Shakti Kumar, Abdulqader A Alhaider
Journal: Molecular Cancer (2013)

Abstract Background VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, recently, most of these anticancer drugs have some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed. Methods We used α-santalol and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVECs) and Prostate tumor cells (PC-3 or LNCaP) in vitro . Tumor xenografts in nude mice were used to examine the in vivo activity of α-santalol. Results α-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that α-santalol inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including AKT, ERK, FAK, Src, mTOR, and pS6K in HUVEC, PC-3 and LNCaP cells. α-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. α-santalol significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model. The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Molecular docking simulation indicated that α-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. Conclusion α-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.
Increased 8-Isoprostane, a Marker of Oxidative Stress, in Exhaled Condensate of Asthma Patients
Authors: PAOLO MONTUSCHI, MASSIMO CORRADI, GIOVANNI CIABATTONI, JULIA NIGHTINGALE, SERGEI A. KHARITONOV, PETER J. BARNES
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Oxidative stress has an important role in the pathogenesis of asthma. 8-Isoprostane is a prostaglandin (PG)-F2–like compound belonging to the F2 isoprostane class that is produced in vivo by the free radical-catalyzed peroxidation of arachidonic acid. 8-Isoprostane is a biomarker of oxidative stress, and its concentration is increased in the bronchoalveolar lavage fluid of patients with interstitial lung diseases. We measured 8-isoprostane concentrations in exhaled breath condensate in healthy subjects and in patients with mild (steroid naive, n = 12), moderate (inhaled steroid treatment, n = 17), and severe asthma (oral steroid treatment, n = 15). We also measured exhaled carbon monoxide (CO) and nitric oxide (NO), which may also reflect oxidative stress in the airways. 8-Isoprostane was detectable in breath condensate of normal subjects (15.8 ± 1.6 pg/ml), and was increased in the breath condensate of patients with mild (33.7 ± 2.8, p < 0.001), moderate (38.3 ± 3.7 pg/ml, p < 0.001), and severe asthma (48.9 ± 5.0 pg/ml, p < 0.001). There was a positive correlation (r = 0.68, p < 0.05) of 8-isoprostane with NO, but not with CO, in the exhaled air of patients with mild asthma, but not in that of patients with moderate or severe asthma. There was no correlation between 8-isoprostane and lung function tests in any group of patients. Our study shows that oxidative stress is increased in asthmatic subjects as reflected by 8-isoprostane concentrations in breath condensate.
High Incidence of Sudden Cardiac Death With Conduction Disturbances and Atrial Cardiomyopathy Caused by a Nonsense Mutation in the <i>STA</i> Gene
Authors: Kenji Sakata, Masami Shimizu, Hidekazu Ino, Masato Yamaguchi, Hidenobu Terai, Noboru Fujino, Kenshi Hayashi, Tomoya Kaneda, Masaru Inoue, Yoshio Oda, Takashi Fujita, Bunji Kaku, Hounin Kanaya, Hiroshi Mabuchi
Journal: Circulation (2005)

The STA gene encodes emerin and is one of the genes that is affected in Emery-Dreifuss muscular dystrophy (EDMD). Although it has been reported that EDMD caused by the STA gene mutation is associated with X-linked recessive inheritance, the genotype-phenotype correlations, with special reference to cardiac manifestations, are not well defined.We identified 16 carriers (7 male and 9 female) with a nonsense mutation in exon 6 of the STA gene in 2 EDMD families. Pacemakers were required for treatment of bradyarrhythmias in all 7 male carriers and in 2 of the 9 female carriers. In addition, 2 of the 9 female carriers displayed atrial fibrillation. In these 2 families, 3 males without pacemaker implantation, who were not tested genetically, had died suddenly. In these family members, the majority of carriers with the mutation had not been clinically diagnosed as having EDMD before genetic testing because of extremely mild or nonexistent skeletal myopathy.EDMD caused by this mutation is characterized by atypical clinical features and incomplete penetrance of the clinical phenotype and may result in serious cardiac complications, including sudden death. Approaches to preventing possible sudden death in carriers with the STA gene mutation require further study.