tbuckley/cabot-search huggingface dataset:
The A/G Allele of Rs16906252 Predicts for <i>MGMT</i> Methylation and Is Selectively Silenced in Premalignant Lesions from Smokers and in Lung Adenocarcinomas
Authors: Shuguang Leng, Amanda M. Bernauer, Chibo Hong, Kieu C. Do, Christin M. Yingling, Kristina G. Flores, Mathewos Tessema, Carmen S. Tellez, Randall P. Willink, Elizabeth A. Burki, Maria A. Picchi, Christine A. Stidley, Michael D. Prados, Joseph F. Costello, Frank D. Gilliland, Richard E. Crowell, Steven A. Belinsky
Journal: Clinical Cancer Research (2011)

To address the association between sequence variants within the MGMT (O(6)-methylguanine-DNA methyltransferase) promoter-enhancer region and methylation of MGMT in premalignant lesions from smokers and lung adenocarcinomas, their biological effects on gene regulation, and targeting MGMT for therapy.Single nucleotide polymorphisms (SNP) identified through sequencing a 1.9 kb fragment 5' of MGMT were examined in relation to MGMT methylation in 169 lung adenocarcinomas and 1,731 sputum samples from smokers. The effect of promoter haplotypes on MGMT expression was tested using a luciferase reporter assay and cDNA expression analysis along with allele-specific sequencing for methylation. The response of MGMT methylated lung cancer cell lines to the alkylating agent temozolomide (TMZ) was assessed.The A allele of rs16906252 and the haplotype containing this SNP were strongly associated with increased risk for MGMT methylation in adenocarcinomas (ORs ≥ 94). This association was observed to a lesser extent in sputum samples in both smoker cohorts. The A allele was selectively methylated in primary lung tumors and cell lines heterozygous for rs16906252. With the most common haplotype as the reference, a 20 to 41% reduction in promoter activity was seen for the haplotype carrying the A allele that correlated with lower MGMT expression. The sensitivity of lung cancer cell lines to TMZ was strongly correlated with levels of MGMT methylation and expression.These studies provide strong evidence that the A allele of a MGMT promoter-enhancer SNP is a key determinant for MGMT methylation in lung carcinogenesis. Moreover, TMZ treatment may benefit a subset of lung cancer patients methylated for MGMT.
Oral contraceptives, depression, and libido.
Authors: W F O'Dwyer
Journal: BMJ (1971)

For women with 3 or more pregnancies complicated by reno-hypertensive abnormalities oral contraception is the only available method.  These women strongly motivated to avoid pregnancy do not abandon the pills nor do they experience common side effects of depression headaches or loss of libido.  From his experience in treating these patients Dr. ODwyer concludes that most pill side effects and failures are psychogenic in origin.  He does not give the number of women he has treated.
Simultaneous or Delayed Administration of Hepatocyte Growth Factor Equally Represses the Fibrotic Changes in Murine Lung Injury Induced by Bleomycin
Authors: MASAHIRO YAEKASHIWA, SHOICHI NAKAYAMA, KAZUYA OHNUMA, TOSHIHIKO SAKAI, TATSUYA ABE, KEN SATOH, KUNIO MATSUMOTO, TOSHIKAZU NAKAMURA, TOHRU TAKAHASHI, TOSHIHIRO NUKIWA
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Hepatocyte growth factor (HGF) is a humoral mediator of epithelial-mesenchymal interactions, acting on a variety of epithelial cells as mitogen, motogen, and morphogen. Exogenous HGF acts as a hepatotrophic factor and a renotrophic factor during experimental injury. To investigate whether HGF has a pulmotrophic function, human recombinant HGF was administered to C57BL/6 mice with severe lung injury by bleomycin (BLM). Low dose simultaneous and continuous administration of HGF (50 μ g/mouse/7 d) with BLM (100 mg/mouse/7 d) repressed fibrotic morphological changes at 2 and 4 wk. Ashcroft score showed a significant difference in lung fibrosis with and without HGF at 4 wk (3.7 ± 0.4 versus 4.9 ± 0.3, p < 0.05). Furthermore, either simultaneous or delayed administration of high dose HGF (280 μ g/mouse/14 d) equally repressed fibrotic changes by BLM when examined at 4 wk (Ashcroft score: 2.6 ± 0.4 and 2.4 ± 0.2 versus 4.1 ± 0.2, p < 0.01). Hydroxyproline content in the lungs was significantly lower in mice with either simultaneous or delayed administration of high dose HGF as compared to those administered BLM alone (121.8 ± 8.1% and 113.2 ± 6.2% versus 162.7 ± 4.6%, p < 0.001). These findings indicate that exogenous HGF acts as a pulmotrophic factor in vivo and prevents the progression of BLM-induced lung injury when administered in either a simultaneous or delayed fashion. HGF may be a potent candidate to prevent or treat lung fibrosis.
Exaggerated Hyperglycemia After A Pizza Meal in Well-Controlled Diabetes
Authors: Jo Ann Ahern, Patricia M Gatcomb, NANcy A Held, William A Petit, William V Tamborlane
Journal: Diabetes Care (1993)

OBJECTIVE To examine whether the postprandial hyperglycemic effect of pizza in well-controlled IDDM patients is related to overeating or to unique properties of this popular food. RESEARCH DESIGN AND METHODS On two evenings, each patient (n = 8) consumed a meal that was similar in macronutrient composition except that one consisted of pizza and the other was a control meal that included high glycemic index foods. The insulin regimen was held constant. RESULTS Postprandial glucose levels were within the target range (&amp;lt; or = 10 mM) after the control meal. Although the initial glucose increase was similar for the two meals, plasma glucose continued to rise and was significantly increased from 4 to 9 h after ingestion of pizza compared with the control meal (P &amp;lt; 0.05). This increase occurred even though free insulin, glucagon, and free fatty acid levels did not differ significantly. CONCLUSIONS Our data suggest that pizza has properties that accentuate and sustain postprandial hyperglycemia.
Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen.
Authors: H Hochster, L Liebes, J Speyer, J Sorich, B Taubes, R Oratz, J Wernz, A Chachoua, B Raphael, R Z Vinci
Journal: Journal of Clinical Oncology (1994)

PURPOSE The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer. PATIENTS AND METHODS Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation. RESULTS The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions). CONCLUSION Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer.
Activity and Phenotype of Natural Killer Cells in Peptide Transporter (TAP)-deficient Patients (Type I Bare Lymphocyte Syndrome)
Authors: Jacques Zimmer, Lionel Donato, Daniel Hanau, Jean-Pierre Cazenave, Marie-Marthe Tongio, Alessandro Moretta, Henri de la Salle
Journal: The Journal of Experimental Medicine (1998)

In this paper we describe the function and phenotype of natural killer (NK) lymphocytes from HLA class I–deficient patients. These cells are, as has been previously reported, unable to lyse HLA class I− K562 cells, but are able to perform antibody-dependent cellular cytotoxicity (ADCC), although with lower efficiency as compared to NK cells from normal individuals. Transporter associated to antigen processing (TAP)− NK cells proliferate when cultured in the presence of lymphoblastoid B cells (B-LCs) and interleukin 2 and develop a spectrum of cytotoxicity similar to that of activated normal NK cells. Importantly, activation of the TAP− NK cells induces strong cytotoxicity to autologous B-LCs. Analysis of the phenotype of circulating TAP− NK lymphocytes showed them to display a normal diverse repertoire of HLA class I–specific NK receptors. These receptors were expressed at normal levels, apart from the CD94–NKG2A complex, which appeared to be overexpressed. This latter finding could reflect an adaptation to the low expression of HLA class I molecules. Finally, functional analyses indicated that the inhibitory receptors in TAP− individuals can transduce inhibitory signals. Our results suggest that in vivo, the NK cells of TAP− patients could participate in immune defense, at least through ADCC, but upon activation, may be involved in autoimmune processes.
Fasting Compared With Nonfasting Lipids and Apolipoproteins for Predicting Incident Cardiovascular Events
Authors: Samia Mora, Nader Rifai, Julie E. Buring, Paul M Ridker
Journal: Circulation (2008)

Background— Although guidelines recommend measuring fasting lipids for initial screening of adults without cardiovascular disease (CVD), recent studies suggest that nonfasting triglycerides may be superior to fasting. Whether fasting status alters associations of nontriglyceride lipids with CVD is unclear. Methods and Results— In a prospective study of 26 330 healthy women (19 983 fasting; 6347 nonfasting), associations of baseline lipids with incident CVD (754 fasting; 207 nonfasting) were examined over an 11-year follow-up. Except for triglycerides, lipid concentrations differed minimally (&lt;5%) for fasting versus nonfasting. However, stronger associations with CVD were noted for fasting total cholesterol (adjusted fasting hazard ratio [HR], 1.22 per 1-SD increment; 95% CI, 1.14 to 1.30; nonfasting HR, 1.07; 95% CI, 0.93 to 1.21), low-density lipoprotein (LDL) cholesterol (fasting HR, 1.21; 95% CI, 1.13 to 1.29; nonfasting HR, 1.00; 95% CI, 0.87 to 1.15), apolipoprotein B-100 (fasting HR, 1.36; 95% CI, 1.27 to 1.45; nonfasting HR, 1.20; 95% CI, 1.05 to 1.36), non–high-density lipoprotein (HDL) cholesterol (fasting HR, 1.29; 95% CI, 1.21 to 1.38; nonfasting HR, 1.15; 95% CI, 1.01 to 1.31), and apolipoprotein B-100/A-1 ratio (fasting HR, 1.39; 95% CI, 1.30 to 1.48; nonfasting HR, 1.18; 95% CI, 1.09 to 1.27). Compared with fasting levels, nonfasting HDL cholesterol, apolipoprotein A-1, and total/HDL cholesterol ratio had similar associations, and triglycerides had a stronger association, with CVD. Significant interactions were seen for LDL cholesterol and apolipoprotein B-100/A-1 ratio with fasting status ( P for interaction=0.03 and &lt;0.001, respectively). Conclusions— This study demonstrates that HDL cholesterol, triglycerides, total/HDL cholesterol ratio, and apolipoprotein A-1 predict CVD when measured nonfasting. By contrast, total, LDL, and non-HDL cholesterol, in addition to apolipoprotein B-100 and B-100/A-1 ratio, provide less useful CVD risk information when nonfasting, despite small changes in their concentrations. Guidelines for lipid screening may need to consider these differences.
Therapeutic efficacy of metronomic chemotherapy with cyclophosphamide and doxorubicin on murine mammary adenocarcinomas
Authors: L.E. Mainetti, M.J. Rico, M.V. Fernández-Zenobi, H.A. Perroud, E.A. Roggero, V.R. Rozados, O.G. Scharovsky
Journal: Annals of Oncology (2013)
Characteristics of Polymeric λ-IgA Binding to Leukocytes in IgA Nephropathy
Authors: Kar Neng Lai, Loretta Y. Y. Chan, Sydney C. W. Tang, Anita W. L. Tsang, Hong Guo, Kai Chung Tse, Terrance Yip, Joseph C. K. Leung
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. IgA nephropathy (IgAN) is characterized by predominant mesangial polymeric IgA1 (pIgA1) deposits, with increased plasma IgA1 levels. Plasma IgA levels are determined by the rate of IgA production, uptake by leukocytes, and removal by hepatocytes. Fcα receptor 1 (FcαR1) is a candidate molecule for the regulation of IgA levels, but reports of its expression in leukocytes in IgAN are conflicting. Increased binding of endogenous IgA to circulating granulocytes and monocytes in IgAN was demonstrated in this study. FcαR1 expression on leukocytes was increased, independently of plasma IgA levels. FcαR1 was not saturated in leukocytes, because of internalization of IgA after uptake. Further binding of exogenous IgA isolated from individual subjects was observed with leukocytes from the same subjects. Compared with cells from control subjects, granulocytes but not monocytes from patients with IgAN exhibited a greater binding capacity for exogenous IgA, predominantly pIgA. To circumvent the possibility that endogenous IgA might alter FcαR1 expression, granulocytes or monocytes derived from the HL-60 or U937 cell lines were used to explore the nature of IgA binding. A higher affinity for pIgA was demonstrated. Inhibition studies using unlabeled IgA, other serum proteins, or a specific FcαR1-blocking antibody suggested binding mechanisms other than FcαR1 for pIgA uptake by leukocytes. This study also suggested the migration and/or sequestration of "activated" leukocytes with predominant λ-IgA in the mononuclear phagocytic system or inflammatory tissues, after the initial binding of λ-pIgA. These immunologic abnormalities might contribute to the glomerulointerstitial injury in IgAN, in the presence of leukocytic infiltration.
THE OCCURRENCE DURING ACUTE INFECTIONS OF A PROTEIN NOT NORMALLY PRESENT IN THE BLOOD
Authors: Colin M. MacLeod, Oswald T. Avery
Journal: The Journal of Experimental Medicine (1941)

The C-reactive protein present in the albumin fraction of the serum of patients during certain acute bacterial infections is highly antigenic upon injection into rabbits. The antiserum thus prepared reacts specifically with this protein and does not react with the proteins of normal human serum. Immunological specificity has been demonstrated by both precipitin and complement-fixation tests. Antiserum prepared in rabbits to the C-reactive protein from human sources also reacts specifically with the similar protein in the serum of monkeys acutely ill with experimental pneumococcus infection. By means of immunological reactions it is possible to detect amounts of reactive protein which are too small to yield a visible precipitate in tests with the C polysaccharide. Certain of the properties are discussed which distinguish the C-reactive protein from the proteins of normal human serum.
Effects of nitroglycerin on regional myocardial ischemia induced by atrial pacing in dogs.
Authors: J L Gerry, H V Schaff, C H Kallman, J T Flaherty
Journal: Circulation Research (1981)

The exact mechanism or mechanisms by which nitroglycerin exerts its beneficial effect on pacing-induced regional myocardial ischemia has not been ellucidated previously. In an open-chest, anesthetized canine preparation a fixed, flow limiting stenosis was applied to the left anterior descending (LAD) coronary artery and heart rate was increased by atrial pacing. Mass spectrometry was used to measure myocardial oxygen (PmO2) and carbon dioxide (PmCO2) tensions. Myocardial blood flow was measured by the radioactive microsphere technique. Application of the stenosis resulted in regional decreases in PmO2 and increases in PmCO2 of greater magnitude in the subendocardial than in the subepicardial layer. Atrial pacing resulted in a further decrease in PmO2 and increase in PmCO2 as well as a reduction in subendocardial blood flow. Nitroglycerin (TNG) infusion reduced mean arterial pressure 20 mm Hg, resulting in a 14 mm Hg reduction in PmCO2 in the more ischemic subendocardial layer (P less than 0.05). Myocardial blood flow decreased in all regions; however, the magnitude of this decrease was less in the ischemic region. Addition of aortic constriction abolished both the afterload and preload lowering effects of nitroglycerin but improved ischemic zone blood flow. These data demonstrate that nitroglycerin reduces the severity of pacing-induced regional myocardial ischemia primarily by reducing the determinants of myocardial oxygen demand. We found that when these effects are counteracted, improvement in myocardial oxygen supply becomes the dominant mechanism.
Coexistent Multiple Myeloma or Increased Bone Marrow Plasma Cells Define Equally High-Risk Populations in Patients With Immunoglobulin Light Chain Amyloidosis
Authors: Taxiarchis V. Kourelis, Shaji K. Kumar, Morie A. Gertz, Martha Q. Lacy, Francis K. Buadi, Suzanne R. Hayman, Steven Zeldenrust, Nelson Leung, Robert A. Kyle, Stephen Russell, David Dingli, John A. Lust, Yi Lin, Prashant Kapoor, S. Vincent Rajkumar, Arleigh McCurdy, Angela Dispenzieri
Journal: Journal of Clinical Oncology (2013)

There is consensus that patients with light chain (AL) amyloidosis with hypercalcemia, renal failure, anemia, and lytic bone lesions attributable to clonal expansion of plasma cells (CRAB criteria) also have multiple myeloma (MM). The aim of this study was to examine the spectrum of immunoglobulin AL amyloidosis with and without MM, with a goal of defining the optimal bone marrow plasma cell (BMPC) number to qualify as AL amyloidosis with MM.We identified 1,255 patients with AL amyloidosis seen within 90 days of diagnosis between January 1, 2000, and December 31, 2010. We defined a population of patients with coexisting MM on the basis of the existence of CRAB criteria (AL-CRAB). Receiver operating characteristic analysis determined the optimal BMPC cut point to predict for 1-year mortality in patients with AL amyloidosis without CRAB to produce two additional groups: AL only (≤ 10% BMPCs) and AL plasma cell MM (AL-PCMM; > 10% BMPCs).Among the 1,255 patients, 100 (8%) had AL-CRAB, 476 (38%) had AL-PCMM, and 679 (54%) had AL only. Their respective median overall survival rates were 10.6, 16.2, and 46 months (P < .001). Because the outcomes of AL-CRAB and AL-PCMM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, pooled AL-CRAB and AL-PCMM retained negative prognostic value independent of age, Mayo Clinic AL amyloidosis stage, prior autologous stem-cell transplantation, and difference between the involved and uninvolved free light chain.Patients with AL amyloidosis who have more than 10% BMPCs have a poor prognosis, similar to that of patients with AL-CRAB, and should therefore be considered together as AL amyloidosis with MM.
Quercetin attenuates inflammation in cigarette smoke stimulated airway epithelial cells: Possible involvement of autophagy
Authors: Diandian Li, Ting Yang, Yongchun Shen, Shujin Guo, Fuqiang Wen
Journal: European Respiratory Journal (2013)

Objectives: Cigarette smoke is known to cause inflammatory response in human bronchial epithelial cells. In this study, we investigated the effects of quercetin, a flavonoid abundant in fruits and vegetables, on cigarette smoke extract (CSE)-induced inflammation in human bronchial epithelial cells (HBEC) and roles of autophagy in this process.

Methods: HBEC were exposed to CSE (4%) for 24h, with or without pretreatment of quercetin (10μM or 20μM). The autophagy activation marker, LC3 II protein, was detected with western blotting. Autophagy was inhibited by 3-methyladenine (3-MA) (2.5mM). TNF-α and IL-1β levels in the supernatant were determined by ELISA.

Results: Exposure of HBEC to CSE significantly increased TNF-α and IL-1β expression and this upregulaion was significantly attenuated by quercetin (p < 0.05). Meanwhile, the pre-treatment of quercetin decreased the ratio of LC3 II to LC3 I, which was increased by CSE (p < 0.05). Inhibiting autophagy by 3-MA also decreased TNF-α and IL-1β levels to a similar level as that of quercetin.

Conclusion: These results suggest that quercetin attenuated inflammation induced by cigarette smoke. The anti- inflammatory effect might act through modulating autophagy.
Intraperitoneal Oxidative Stress in Rabbits with Papillomavirus-Associated Head and Neck Cancer Induces Tumoricidal Immune Response That Is Adoptively Transferable
Authors: Annette Rossmann, Robert Mandic, Jochen Heinis, Helmut Höffken, Oliver Küssner, Ralf Kinscherf, Eberhard Weihe, Michael Bette
Journal: Clinical Cancer Research (2014)

How tumors evade or suppress immune surveillance is a key question in cancer research, and overcoming immune escape is a major goal for lengthening remission after cancer treatment. Here, we used the papillomavirus-associated rabbit auricular VX2 carcinoma, a model for studying human head and neck cancer, to reveal the mechanisms underlying the antitumorigenic effects of intraperitoneal oxidative stress following O3/O2-pneumoperitoneum (O3/O2-PP) treatment.Solid auricular VX2 tumors were induced in immune-competent adult New Zealand White Rabbits. Animals were O3/O2-PP- or sham-treated, after which they underwent tumor ablation upon reaching no-go criteria. CD3(+) tumor-infiltrating lymphocytes (TIL) were evaluated by immunohistochemistry, and expression levels of 84 immune response genes were measured by quantitative real-time PCR. Adoptive transfer of peripheral blood leukocytes (PBL)-derived from animals with tumor regression-into control animals with progressing tumors was implemented to assess acquired tumor resistance functionally.Auricular VX2 tumors regressing after O3/O2-PP treatment exhibited increased levels of CD3(+) TILs; they also exhibited enhanced expression of genes that encode receptors involved in pattern recognition, molecules that are required for antigen presentation and T cell activation, and inflammatory mediators. Adoptive cell transfer of PBLs from donor rabbits with regressing tumors to recipient rabbits with newly implanted VX2 carcinoma resulted in acquired tumor resistance of the host and tumor regression.Intraperitoneal oxidative stress effectively converts the immune response against the papillomavirus-associated rabbit VX2 carcinoma from tumor permissive to tumoricidal and leads to a sustainable, adoptively transferable oncolytic immune response.