tbuckley/cabot-search huggingface dataset:
Predictors of the Response to Gefitinib in Refractory Non–Small Cell Lung Cancer
Authors: Kyu-Sik Kim, Ju-Yeon Jeong, Young-Chul Kim, Kook-Joo Na, Yun-Hyeon Kim, Sung-Ja Ahn, Sun-Mi Baek, Chang-Soo Park, Chang-Min Park, Yu-Il Kim, Sung-Chul Lim, Kyung-Ok Park
Journal: Clinical Cancer Research (2005)

Abstract Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has a response rate of 10% to 20% in refractory non–small cell lung carcinoma. Although female gender, adenocarcinoma, and never having smoked are possible markers of a favorable response, mutations of the EGFR gene have also been reported to be highly significant predictors of response. Seventy patients with relapsed non–small cell lung carcinoma were enrolled in the Expanded Access Program. After the drug became available commercially, 28 more patients were treated with gefitinib. Response evaluations were feasible in 80 patients. Twenty-seven tumor specimens (8 responders and 19 nonresponders) were available for the sequence analysis of the EGFR gene. The response rate was 25% (20/80) and the disease control rate (remission + stable disease) was 47.5% (38/80). The response rate was significantly higher for adenocarcinoma (41.0%) versus non-adenocarcinoma (9.8%, P = 0.001), in those who never smoked (58.8%) versus smokers (15.9%, P &amp;lt; 0.001), and in females (42.1%) versus males (19.7%, P = 0.049). A deletion or mutation of the EGFR gene was found in six of eight responders. Remission was noted in all patients with a mutation, whereas the response rate was 9.5% (2/21) in patients without a mutation (P &amp;lt; 0.001). The predictors of response showed significant correlations with survival and time to progression. In a multivariate logistic analysis, the independent predictors of response were smoking history and adenocarcinoma. Given that 9.5% of smokers and 6.7% of those with non-adenocarcinoma showed a mutation of the EGFR gene, the genetic profile may replace those variables as an independent predictor of a response.
West Africa polio campaign boycotted by Nigerian states
Authors: Fiona Fleck
Journal: BMJ (2004)

A mass poliomyelitis vaccination campaign got under way on Monday to immunise 63 million children across west Africa but was boycotted by four predominantly Muslim states in Nigeria, where leaders claim the oral vaccine causes sterility and spreads AIDS.

The west African campaign was intended as a final push to stamp out the disease in the region and is part of the World Health Organization's 15 year drive to halt transmission of the poliomyelitis virus across the world by 2005.

Since its launch in 1988, the campaign has reduced the number of countries where polio is endemic from 125 …
Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer
Authors: Carsten Bokemeyer, Igor Bondarenko, Anatoly Makhson, Joerg T. Hartmann, Jorge Aparicio, Filippo de Braud, Serban Donea, Heinz Ludwig, Gunter Schuch, Christopher Stroh, Anja H. Loos, Angela Zubel, Piotr Koralewski
Journal: Journal of Clinical Oncology (2008)

Purpose This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated. Patients and Methods Patients received cetuximab (400 mg/m 2 initial dose followed by 250 mg/m 2 /wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m 2 on day 1, plus leucovorin 200 mg/m 2 and fluorouracil as a 400 mg/m 2 bolus followed by a 600 mg/m 2 infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233). Results The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated. Conclusion KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.
Myocardial Lysosomes in Experimental Atrial Septal Defects
Authors: CHARLES A. KOTTMEIER, MYRON W. WHEAT
Journal: Circulation Research (1967)

Preliminary observations in patients undergoing open-heart surgery have suggested that the lysosomes in the right atrium are increased in patients with atrial septal defects. This increase in lysosomes per myocardial cell appears to be directly related to the size of the left to right shunt. The following experiments were performed to see if similar findings could be produced in an experimental model. Atrial septal defects were produced in seven dogs. The biopsy specimens were prepared for ultrastructural examination and viewed with an electron microscope. Lysosomes were counted in representative sections and an estimate of the lysosomes per square micron of heart tissue obtained. The number of lysosomes per square micron of myocardium increased significantly following the creation of atrial septal defects in dogs, with the most marked increase occurring in the right ventricle. Several small atrial septal defects closed spontaneously, as proved by cardiac catheterization, and in these animals the elevated lysosome counts present initially returned toward normal after obliteration of the left to right shunt at the atrial level. Control dogs showed no significant increase in myocardial lysosomes over the 18-month period despite repeated thoracotomies and myocardial biopsy. These studies add further evidence to support the role of the lysosome as an important intracellular organelle which is related to cellular stress.
Four-Year Change in Cardiorespiratory Fitness and Influence on Glycemic Control in Adults With Type 2 Diabetes in a Randomized Trial
Authors: John M. Jakicic, Caitlin M. Egan, Anthony N. Fabricatore, Sarah A. Gaussoin, Stephen P. Glasser, Louise A. Hesson, William C. Knowler, Wei Lang, Judith G. Regensteiner, Paul M. Ribisl, Donna H. Ryan
Journal: Diabetes Care (2012)

To examine an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) on 4-year change in fitness and physical activity (PA), and to examine the effect of change in fitness and PA, adjusting for potential confounders, on glycemic control in the Look AHEAD Trial.Subjects were overweight/obese adults with type 2 diabetes mellitus (T2DM) with available fitness data at 4 years (n = 3,942).This clinical trial randomized subjects to DSE or ILI. DSE subjects received standard care plus information related to diet, PA, and social support three times per year. ILI subjects received weekly intervention contact for 6 months, which was reduced over the 4-year period, and were prescribed diet and PA. Measures included weight, fitness, PA, and HbA1c.The difference in percent fitness change between ILI and DSE at 4 years was significant after adjustment for baseline fitness and change in weight (3.70 vs. 0.94%; P < 0.01). At 4 years, PA increased by 348 (1,562) kcal/week in ILI vs. 105 (1,309) kcal/week in DSE (P < 0.01). Fitness change at 4 years was inversely related to change in HbA1c after adjustment for clinical site, treatment, baseline HbA1c, prescribed diabetes medication, baseline fitness, and weight change (P < 0.01). Change in PA was not related to change in HbA1c.A 4-year ILI increased fitness and PA in overweight/obese individuals with T2DM. Change in fitness was associated with improvements in glycemic control, which provides support for interventions to improve fitness in adults with T2DM.
Local ablative procedures designed to destroy squamous-cell carcinoma.
Authors: J M Lee, F P Stitik, D Carter, R R Baker
Journal: Thorax (1975)

In a series of experiments in dogs, the bronchial mucosa was either excised or destroyed prior to closure of a bronchial stump following a lobectomy or the reanastomosis of a divided bronchus. The experiments were designed to simulate the clinical situation in which focal areas of squamous-cell carcinoma in situ in the bronchial margin would be managed by local ablation of the mucosa rather than by excision of additional bronchus. The experiments demonstrated that the bronchial mucosa is not necessary for bronchial healing. They also demonstrated that functionally and morphologically normal bronchial epithelium regenerates across the denuded bronchus. The source of this regenerated epithelium appears to be the submucosal glands which remain in the bronchial wall after a variety of local ablative procedures. Since our clinical experience has demonstrated that these submucosal glands frequently contain small foci of squamous-cell carcinoma in situ, we have concluded that either excision or thermal destruction of the bronchial mucosa has very limited clinical application and should be considered only in patients who cannot tolerate excision of more than one lobe of the lung.
TCT-510 Treating Patients With Massive Pulmonary Embolism By Local Fibrinolysis, Rotational Thrombus Fragmentation And Thrombus Aspiration
Authors: Alexander Alexandrov, Dobrin Vassilev, Hristo F. Mateev, Iliana Petrova, Elina Trendafilova
Journal: Journal of the American College of Cardiology (2014)
Pharmacogenetics in the rheumatic diseases
Authors: B N Cronstein
Journal: Annals of the Rheumatic Diseases (2004)

One of the promises of the human genome project is individualised pharmacological therapy. An individual’s genetic type would be determined, and the resulting diseases which the person was susceptible to would be determined. In addition, the drugs to which an individual would respond well would be enumerated, and the drugs which were more likely to be toxic could be established. At present we are just beginning to determine those associations which would help us tailor an individual’s pharmacological therapy so as to maximise efficacy and minimise toxicity. In this report we review the considerations involved in determining the pharmacogenetic profile of any given drug and to review the current level of understanding of the association between genetic polymorphisms and drug toxicity/efficacy in rheumatology.

Establishing an association between genetic types and toxicity is perhaps an easier task to accomplish than understanding the association between a given genetic type and drug efficacy. Drug toxicities are generally discrete events and a specific toxicity can often be traced to the agent in question. Thus, it is fairly easy to study a given population and define those with a specific drug toxicity. Nonetheless, a sufficiently large population must be studied to establish an association. Although this restates the obvious, most drugs for chronic conditions such as rheumatoid arthritis (RA) are toxic to only a modest proportion of the patients taking them otherwise they would have long ago been pulled off the market. To establish a relative risk association for a toxicity that occurs in only 5–10% of patients taking a given drug might require hundreds or even thousands of patients if the observed increase in risk of toxicity is modest.

There are many reasons why any given drug may fail in any given individual. Clearly, genetically associated resistance may account for failure of a given …
Vascular Endothelial Growth Factor Mediates Intracrine Survival in Human Breast Carcinoma Cells through Internally Expressed VEGFR1/FLT1
Authors: Tae-Hee Lee, Seyha Seng, Masayuki Sekine, Cimona Hinton, Yigong Fu, Hava Karsenty Avraham, Shalom Avraham
Journal: PLoS Medicine (2007)

Background While vascular endothelial growth factor (VEGF) expression in breast tumors has been correlated with a poor outcome in the pathogenesis of breast cancer, the expression, localization, and function of VEGF receptors VEGFR1 (also known as FLT1) and VEGFR2 (also known as KDR or FLK1), as well as neuropilin 1 (NRP1), in breast cancer are controversial. Methods and Findings We investigated the expression and function of VEGF and VEGF receptors in breast cancer cells. We observed that VEGFR1 expression was abundant, VEGFR2 expression was low, and NRP1 expression was variable. MDA-MB-231 and MCF-7 breast cancer cells, transfected with antisense VEGF cDNA or with siVEGF (VEGF-targeted small interfering RNA), showed a significant reduction in VEGF expression and increased apoptosis as compared to the control cells. Additionally, specifically targeted knockdown of VEGFR1 expression by siRNA (siVEGFR1) significantly decreased the survival of breast cancer cells through down-regulation of protein kinase B (AKT) phosphorylation, while targeted knockdown of VEGFR2 or NRP1 expression had no effect on the survival of these cancer cells. Since a VEGFR1-specific ligand, placenta growth factor (PGF), did not, as expected, inhibit the breast cancer cell apoptosis induced by siVEGF, and since VEGFR1 antibody also had no effects on the survival of these cells, we examined VEGFR1 localization. VEGFR1 was predominantly expressed internally in MDA-MB-231 and MCF-7 breast cancer cells. Specifically, VEGFR1 was found to be colocalized with lamin A/C and was expressed mainly in the nuclear envelope in breast cancer cell lines and primary breast cancer tumors. Breast cancer cells treated with siVEGFR1 showed significantly decreased VEGFR1 expression levels and a lack of VEGFR1 expression in the nuclear envelope. Conclusions This study provides, to our knowledge for the first time, evidence of a unique survival system in breast cancer cells by which VEGF can act as an internal autocrine (intracrine) survival factor through its binding to VEGFR1. These results may lead to an improved strategy for tumor therapy based on the inhibition of angiogenesis.
Mechanism of Action of Donor-Specific Transfusion in Inducing Tolerance
Authors: Koji Kishimoto, Xueli Yuan, Hugh Auchincloss, Arlene H. Sharpe, Didier A. Mandelbrot, Mohamed H. Sayegh
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Donor-specific transfusion (DST) can synergize with T cell co-stimulatory blockade in inducing tolerance in several transplant models, but the mechanism of action of DST is poorly characterized. This study used genetically altered mice in an established model of cardiac transplantation to study the role of MHC and co-stimulatory molecule expression on DST cells in mediating the immunomodulatory effects of DST. In addition, to examine the role of indirect antigen presentation in the effect of DST, experiments used recipient mice that do not express MHC class II molecules on peripheral antigen-presenting cells, but do have functional CD4<sup>+</sup> T cells (II<sup>−</sup>4<sup>+</sup>). As previously reported, treatment with DST from wild-type donors in combination with CD154 blockade induced tolerance in wild-type recipients of cardiac allografts. Tolerance in this model is also induced despite the absence of MHC class I and II, CD40, or B7 molecules on transfused cells. In contrast, eliminating the indirect pathway using II<sup>−</sup>4<sup>+</sup> recipients blocked the induction of long-term cardiac allograft survival by DST. These results indicate that the indirect antigen recognition pathway mediates the immunomodulatory effect of DST in inducing transplantation tolerance <i>in vivo</i>.
Upregulation of microRNA-125b contributes to leukemogenesis and increases drug resistance in pediatric acute promyelocytic leukemia
Authors: Hua Zhang, Xue-Qun Luo, Dan-Dan Feng, Xing-Ju Zhang, Jun Wu, Yu-Sheng Zheng, Xiao Chen, Ling Xu, Yue-Qin Chen
Journal: Molecular Cancer (2011)

Abstract Background Although current chemotherapy regimens have remarkably improved the cure rate of pediatric acute promyelocytic leukemia (APL) over the past decade, more than 20% of patients still die of the disease, and the 5-year cumulative incidence of relapse is 17%. The precise gene pathways that exert critical control over the determination of cell lineage fate during the development of pediatric APL remain unclear. Methods In this study, we analyzed miR-125b expression in 169 pediatric acute myelogenous leukemia (AML) samples including 76 APL samples before therapy and 38 APL samples after therapy. The effects of enforced expression of miR-125b were evaluated in leukemic cell and drug-resistant cell lines. Results miR-125b is highly expressed in pediatric APL compared with other subtypes of AML and is correlated with treatment response, as well as relapse of pediatric APL. Our results further demonstrated that miR-125b could promote leukemic cell proliferation and inhibit cell apoptosis by regulating the expression of tumor suppressor BCL2-antagonist/killer 1 (Bak1). Remarkably, miR-125b was also found to be up-regulated in leukemic drug-resistant cells, and transfection of a miR-125b duplex into AML cells can increase their resistance to therapeutic drugs, Conclusions These findings strongly indicate that miR-125b plays an important role in the development of pediatric APL at least partially mediated by repressing BAK1 protein expression and could be a potential therapeutic target for treating pediatric APL failure.
A Phase I, multicenter, open-label trial to evaluate the safety of talimogene laherparepvec (T-VEC) injected into liver tumors
Authors: J Randolph Hecht, Steven Raman, Daniel Y Sze, A Craig Lockhart, Rebecca A Moss, Kate Liu, Jeffrey Chou, Tony Reid
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts T-VEC, an intralesionally-delivered oncolytic immunotherapy, is a herpes simplex virus-1 engineered to selectively replicate in tumors and stimulate an anti-tumor immune response through expression of GM-CSF. T-VEC has the ability to lyse various cancer cell types in vitro[[1][1
Preferential Cytotoxicity of Bortezomib toward Hypoxic Tumor Cells via Overactivation of Endoplasmic Reticulum Stress Pathways
Authors: Diane R. Fels, Jiangbin Ye, Andrew T. Segan, Steven J. Kridel, Michael Spiotto, Michael Olson, Albert C. Koong, Constantinos Koumenis
Journal: Cancer Research (2008)

Abstract Hypoxia is a dynamic feature of the tumor microenvironment that contributes to drug resistance and cancer progression. We previously showed that components of the unfolded protein response (UPR), elicited by endoplasmic reticulum (ER) stress, are also activated by hypoxia in vitro and in vivo animal and human patient tumors. Here, we report that ER stressors, such as thapsigargin or the clinically used proteasome inhibitor bortezomib, exhibit significantly higher cytotoxicity toward hypoxic compared with normoxic tumor cells, which is accompanied by enhanced activation of UPR effectors in vitro and UPR reporter activity in vivo. Treatment of cells with the translation inhibitor cycloheximide, which relieves ER load, ameliorated this enhanced cytotoxicity, indicating that the increased cytotoxicity is ER stress–dependent. The mode of cell death was cell type–dependent, because DLD1 colorectal carcinoma cells exhibited enhanced apoptosis, whereas HeLa cervical carcinoma cells activated autophagy, blocked apoptosis, and eventually led to necrosis. Pharmacologic or genetic ablation of autophagy increased the levels of apoptosis. These results show that hypoxic tumor cells, which are generally more resistant to genotoxic agents, are hypersensitive to proteasome inhibitors and suggest that combining bortezomib with therapies that target the normoxic fraction of human tumors can lead to more effective tumor control. [Cancer Res 2008;68(22):9323–30]
Leptin Does Not Directly Regulate the Pancreatic Hormones Amylin and Pancreatic Polypeptide
Authors: Janice J. Hwang, Jean L. Chan, Georgia Ntali, Dalia Malkova, Christos S. Mantzoros
Journal: Diabetes Care (2008)

OBJECTIVE—Leptin and the pancreatic hormones amylin and pancreatic polypeptide are being evaluated alone or in combination for the treatment of obesity, but their physiological regulation has not yet been fully elucidated. Thus, we examined whether amylin and pancreatic polypeptide are regulated by caloric intake and/or short- and long-term energy deprivation and whether any potential regulation is mediated by changes in leptin levels. RESEARCH DESIGN AND METHODS—We measured circulating levels of amylin and pancreatic polypeptide after 1) a 75-g glucose load in 28 healthy, normal-weight women, 2) 72-h complete energy deficiency (severe hypoleptinemia) with administration of either placebo or replacement-dose recombinant methionyl human leptin (r-metHuLeptin) in normal-weight men (n = 6) and women (n = 7), and 3) chronic mild energy deficiency (mild hypoleptinemia) in 7 women with hypothalamic amenorrhea before and after r-metHuLeptin administration for 3 months. RESULTS—Amylin and pancreatic polypeptide levels increased 15 min after a 75-g glucose load and remained elevated at 60 and 120 min (P &amp;lt; 0.0001). Fasting for 72 h decreased leptin (to 21%) and amylin (to 67%) of baseline but not pancreatic polypeptide levels. Normalizing leptin levels with r-metHuLeptin did not alter the fasting-induced decrease in amylin and had no effect on pancreatic polypeptide levels. Neither amylin nor pancreatic polypeptide levels were different in leptin-deficient women with hypothalamic amenorrhea compared with weight-matched control subjects, and normalization of leptin levels with r-metHuLeptin treatment did not alter amylin or pancreatic polypeptide levels. CONCLUSIONS—Circulating amylin levels increase after a glucose load and decrease in response to short-term complete fasting, but these changes are not mediated by leptin.
Pulmonary Veno-occlusive Disease Caused by an Inherited Mutation in Bone Morphogenetic Protein Receptor II
Authors: James R. Runo, Cindy L. Vnencak-Jones, Melissa Prince, James E. Loyd, Lisa Wheeler, Ivan M. Robbins, Kirk B. Lane, John H. Newman, Joyce Johnson, William C. Nichols, John A. Phillips
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Section:ChooseTop of pageAbstract <<CASE HISTORYMETHODSRESULTSDISCUSSIONReferencesCITING ARTICLES