tbuckley/cabot-search huggingface dataset:
Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids.
Authors: G Tiao, J Fagan, V Roegner, M Lieberman, J J Wang, J E Fischer, P O Hasselgren
Journal: Journal of Clinical Investigation (1996)

Recent studies suggest that sepsis-induced increase in muscle proteolysis mainly reflects energy-ubiquitin-dependent protein breakdown. We tested the hypothesis that glucocorticoids activate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis. Rats underwent induction of sepsis by cecal ligation and puncture or were sham-operated and muscle protein breakdown rates were measured 16 h later. The glucocorticoid receptor antagonist RU 38486 or vehicle was administered to groups of septic and sham-operated rats. In other experiments, dexamethasone (2.5 or 10 mg/kg) was injected subcutaneously in normal rats. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Energy-dependent proteolysis was determined in incubated muscles depleted of energy with 2-deoxyglucose and 2,4-dinitrophenol. Levels of muscle ubiquitin mRNA and free and conjugated ubiquitin were determined by Northern and Western blot, respectively. RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates and blunted the increase in ubiquitin mRNA levels and free ubiquitin. Some, but not all, sepsis-induced changes in ubiquitin protein conjugates were inhibited by RU 38486. Injection of dexamethasone in normal rats increased energy-dependent proteolysis and ubiquitin mRNA levels. The results suggest that glucocorticoids regulate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis.
Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia
Authors: Thomas O'Hare, Michael W.N. Deininger, Christopher A. Eide, Tim Clackson, Brian J. Druker
Journal: Clinical Cancer Research (2010)

Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABL(T315I). A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABL(T315I). The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABL(T315I) mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABL(T315I) in the development pipeline.
Folate and Vitamin B&lt;SUB&gt;6&lt;/SUB&gt; From Diet and Supplements in Relation to Risk of Coronary Heart Disease Among Women
Authors: Eric B. Rimm
Journal: JAMA (1998)

Context.-Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B 6 .However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available.Objective.-Toexamine intakes of folate and vitamin B 6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD.Design.-Prospective cohort study.Setting and Patients.-In1980, a total of 80 082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B 6 .Main Outcome Measure.-NonfatalMI and fatal CHD confirmed by World Health Organization criteria.Results.-During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD.After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87)for folate (median intake, 696 µg/d vs 158 µg/d) and 0.67 (95% CI, 0.53-0.85)for vitamin B 6 (median intake, 4.6 mg/d vs 1.1 mg/d).Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74)among women in the highest quintile of both folate and vitamin B 6 intake compared with the opposite extreme.Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76;95% CI, 0.65-0.90), the major source of folate and vitamin B 6 , and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B 6 .In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97)or more than 1 drink per day (RR=0.27;95% CI, 0.13-0.58).Conclusion.-These results suggest that intake of folate and vitamin B 6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.
Cellular requirements for lipopolysaccharide adjuvanticity. A role for both T lymphocytes and macrophages for in vitro responses to particulate antigens.
Authors: J R McGhee, J J Farrar, S M Michalek, S E Mergenhagen, D L Rosenstreich
Journal: The Journal of Experimental Medicine (1979)

By employing primary cultures of purified spleen cells from lipopolysaccharide (LPS) responder (C3H/HeN or C57BL/10Sn) or nonresponder (C3H/HeJ or C57BL/10ScN) mice incubated with particulate antigen and LPS prepared by phenol-water extraction (Ph), we have presented evidence that both T cells and macrophages (MO) are required for LPS-induced adjuvanticity. First, MO derived from C3H/HeN spleen cells, when mixed with responder, C3H/HeN lymphocytes and Ph-LPS, elicited enhanced antibody responses to sheep erythrocytes (SRC) antigen, whereas lymphocytes from the nonresponder, C3H/HeJ mouse strain did not evoke this response. Similarly, purified T cells from C3H/HeN spleens, when cultured with responder, nu/nu spleen cells, and Ph-LPS yielded enhanced anti-TNP PFC responses; whereas, C3H/HeJ T cells did not potentiate immune responses when mixed with optimal concentrations of Ph-LPS. LPS prepared by butanol-water extraction elicited significant adjuvant effects with all cell combinations. Finally, purified responder T cells and MO enabled either responder or nonresponder B cells to elicit LPS potentiation. These data indicate that T cells and MO are controlling LPS-induced augmentation of B-cell responses.
Endocan Expression and Relationship with Survival in Human Non–Small Cell Lung Cancer
Authors: Bogdan Dragos Grigoriu, Florence Depontieu, Arnaud Scherpereel, Delphine Gourcerol, Patrick Devos, Taoufik Ouatas, Jean-Jacques Lafitte, Marie-Christine Copin, Andre-Bernard Tonnel, Philippe Lassalle
Journal: Clinical Cancer Research (2006)

Abstract Purpose: We evaluated the expression of endocan, a soluble lung- and kidney-selective endothelial cell-specific dermatan sulfate proteoglycan, in non–small cell lung tumors compared with normal lung and studied the significance of high levels of circulating endocan in patients with non–small cell lung cancer. Material and Methods: Endocan and vascular endothelial growth factor mRNA expression were evaluated by semiquantitative PCR in tumoral and nontumoral lung tissue samples from a first series of 24 patients submitted to curative surgery. Relationships between survival, time to tumor progression, and serum levels of endocan were evaluated in a second series of 30 previously untreated patients addressed for staging. Results: In non–small cell lung cancers, endocan mRNA was overexpressed compared with control lung. Immunohistochemistry shows that endocan was expressed only by tumor endothelium in all cases, especially in the periphery of the tumors, with no differences between adenocarcinoma and squamous cell carcinoma. Endocan and vascular endothelial growth factor mRNA expression was positively correlated in lung tumors. Serum endocan levels, as well as tumor, node, and metastasis status, were correlated with both survival and time to tumor progression. However, endocan serum level was not an independent prognostic factor due to its correlation with the presence of metastasis. Conclusion: Endocan is overexpressed in non–small cell lung tumors compared with healthy lung and probably represents a response of tumoral endothelium to proangiogenic growth factor stimulation. Circulating levels of endocan might reflect tumor angiogenic stimulation and present prognostic significance.
Dietary Fat and Breast Cancer: Where Are We?
Authors: A. S. Whittemore, B. E. Henderson
Journal: JNCI Journal of the National Cancer Institute (1993)

A role for dietary fat in breast cancer development has been hypothesized for more than 30 years and has prompted vigorous debate in the past decade (1-3).Epidemiological evidence in support of the hypothesis is twofold: 1) International correlation studies indicate a positive correlation between national fat consumption and national breast cancer incidence and mortality rates, and 2) breast cancer rates increase among ethnic groups who migrate from low-risk countries to high-risk countries (4).Yet several cohort and case-control studies have not found an association between high fat intake and breast cancer incidence (5-7).There have been many attempts to reconcile the positive correlations from international studies with the lack of positive findings from case-control and cohort studies.Some researchers maintain that it is too difficult to detect an association in homogeneous populations in the face of large measurement error in reported dietary intake.This possibility provided the initial impetus for the Women's Health Trial, a randomized clinical trial proposed in 1983 by the National Cancer Institute (NCI) that was tested for feasibility in 1985, initiated in 1986, discontinued in 1988, and then resurrected in 1991 as part of the Women's Health Initiative.Its objective is to evaluate the fundamental question of whether change to a low-fat diet can reduce the incidence of breast cancer among adult women.
Plasma Cholesteryl Esters Provided by Lecithin:Cholesterol Acyltransferase and Acyl-Coenzyme A:Cholesterol Acyltransferase 2 Have Opposite Atherosclerotic Potential
Authors: Richard G. Lee, Kathryn L. Kelley, Janet K. Sawyer, Robert V. Farese, John S. Parks, Lawrence L. Rudel
Journal: Circulation Research (2004)

Evidence suggests that ACAT2 is a proatherogenic enzyme that contributes cholesteryl esters (CEs) to apoB-containing lipoproteins, whereas LCAT is an antiatherogenic enzyme that facilitates reverse cholesterol transport by esterifying free cholesterol on HDL particles. We hypothesized that deletion of LCAT and ACAT2 would lead to absence of plasma CEs and reduced atherosclerosis. To test this hypothesis, ACAT2-/- LCAT-/- LDLr-/-, ACAT2-/- LDLr-/-, and LCAT-/- LDLr-/- mice were fed a 0.15% cholesterol diet for 20 weeks. In comparison to LDLr-/- mice, the total plasma cholesterol (TPC) of ACAT2-/- LCAT-/- LDLr-/- mice was 67% lower because of the complete absence of plasma CEs, leading to 94% less CE accumulation in the aorta. In the LCAT-/- LDLr-/- mice, TPC and atherosclerosis were significantly higher because of increased accumulations of ACAT2-derived CE. In ACAT2-/- LDLr-/- mice, again compared with LDLr-/- mice, TPC was 19% lower, whereas atherosclerosis was 88% lower. Therefore, the absence of ACAT2 led to a significant reduction in TPC although benefits in reduction of atherosclerosis were much more pronounced. Overall, the data suggest that ACAT2-derived CE is the predominant atherogenic lipid in blood, and that an important goal for prevention of atherosclerosis is to limit ACAT2-derived CE accumulation in lipoproteins.
Inflammatory response to infectious pulmonary injury
Authors: C. Delclaux, E. Azoulay
Journal: European Respiratory Journal (2003)

This review describing the inflammatory response to infectious pulmonary injury is focused on the innate immunity of the distal lung to bacterial pneumonia. The fact that the inflammatory response varies to some extent with the bacterial strain responsible for the infection is emphasised. The key cellular components present in the distal lung are described. The major role of alveolar macrophage is described, inasmuch as it responds to the usual daily challenges of bacteria entering the terminal airways and is capable of initiating an inflammatory reaction if the microbial challenge is either too large or too virulent. Under these conditions, the alveolar macrophages initiate an inflammatory response that recruits large numbers of neutrophils into the alveolar spaces. The strategy of the innate immune response may not be to recognise every possible antigen, but rather to focus on a few, highly conserved structures present in large groups of microorganisms. These structures are referred to as pathogen-associated molecular patterns and the receptors of the innate immune system that evolved to recognise them are called pattern-recognition receptors. The soluble factors in innate defence, such as cytokines, are described, and a last paragraph discusses whether a specific inflammatory response could characterise nosocomial pneumonia.
Presentation of the Goodpasture Autoantigen Requires Proteolytic Unlocking Steps That Destroy Prominent T Cell Epitopes
Authors: Juan Zou, Lorna Henderson, Vicky Thomas, Patricia Swan, A. Neil Turner, Richard. G. Phelps
Journal: Journal of the American Society of Nephrology (2007)

The most abundant autoreactive T cells in patients with Goodpasture's disease are specific for peptides in the autoantigen that have high affinity for the disease-associated HLA class II molecule, DR15. How can such T cells escape self-tolerance mechanisms? This study showed that these peptides are highly susceptible to destruction in the earliest stages of antigen processing, and some must be cleaved for antigen digestion to be possible ("unlocking"). Goodpasture autoantigen [collagen alpha3(IV)NC1; approximately 31 kD] that was incubated with B cell lysosomes was cleaved within a few minutes to form approximately 9- and approximately 22-kD fragments, then increasing quantities of smaller peptides. The processing was completely abrogated by pepstatin A, a specific inhibitor of cathepsin D/E, even though lysosomal extracts contain a rich array of proteases. Purified cathepsin D generated the same major alpha3(IV)NC1 fragments as entire lysosomes, suggesting that cathepsin D cleavages are required to initiate alpha3(IV)NC1 processing. The initial unlocking cleavages destroyed two major self-epitopes, and subsequent preferred cleavages destroyed all of the other T cell epitopes that are recognized by most patients' autoreactive T cells. The responses of T cell clones that are specific for a major disease-associated peptide to antigen-pulsed intact antigen-presenting cells were substantially enhanced by pepstatin A treatment. Therefore, cathepsin D activity significantly diminishes presentation of alpha3(IV)NC1 peptides that are recognized by patients' T cells by destroying the peptides in early processing. These observations can explain why the mature T cell repertoire includes reactivity toward these self-peptides and suggests that a key factor in disease initiation is likely to be a shift in antigen processing.
Evaluation of Tumor-Size Response Metrics to Predict Overall Survival in Western and Chinese Patients With First-Line Metastatic Colorectal Cancer
Authors: Laurent Claret, Manish Gupta, Kelong Han, Amita Joshi, Nenad Sarapa, Jing He, Bob Powell, René Bruno
Journal: Journal of Clinical Oncology (2013)

To assess new metrics of tumor-size response to predict overall survival (OS) in colorectal cancer (CRC) in Western and Chinese patients.Various metrics of tumor-size response were estimated using longitudinal tumor size models and data from two phase III studies that compared bevacizumab plus chemotherapy versus chemotherapy as first-line therapy in Western (n = 923) and Chinese (n = 203) patients with CRC. Baseline prognostic factors and tumor-size metrics estimates were assessed in multivariate models to predict OS. Predictive performances of the models were assessed by simulating multiple replicas of the phase III studies.Time to tumor growth (TTG) was the best metric to predict OS. TTG fully captured bevacizumab effect. Chinese ethnicity had no impact on OS or on the TTG-OS relationships. The model correctly predicted OS distributions in each arm as well as bevacizumab hazard ratio (model prediction, 0.75 v 0.68 observed in Western patients; 95% prediction interval, 0.62 to 0.91).TTG captured therapeutic benefit with bevacizumab in first-line CRC patients. Chinese ethnicity had no impact. Longitudinal tumor size data coupled with model-based approaches may offer a powerful alternative in the design and analysis of early clinical studies.
THREE-DIMENSIONAL OPTICAL COHERENCE TOMOGRAPHY ASSESSMENT OF NEOINTIMAL COVERAGE AFTER STENT IMPLANTATION: A PROPOSAL FOR CLASSIFICATION
Authors: Takao Maeda, Takayuki Okamura, Jutaro Yamada, Tomoko Nao, Shintaro Akashi, Takeshi Suetomi, Susumu Matsuda, Yosuke Miyazaki, Akihiro Hino, Takamasa Oda, Tadaaki Nakashima, Kouzou Shiraishi, Tadamitsu Nakashima, Takeshi Nakamura, Toshiro Miura, Masunori Matsuzaki
Journal: Journal of the American College of Cardiology (2011)
Autism
Authors: Paul T. Shattuck, Anne M. Roux
Journal: JAMA Pediatrics (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
GKN1–miR-185–DNMT1 Axis Suppresses Gastric Carcinogenesis through Regulation of Epigenetic Alteration and Cell Cycle
Authors: Jung Hwan Yoon, Yoo Jin Choi, Won Suk Choi, Hassan Ashktorab, Duane T. Smoot, Suk Woo Nam, Jung Young Lee, Won Sang Park
Journal: Clinical Cancer Research (2013)

Gastrokine 1 (GKN1) functions to protect the gastric antral mucosa and promotes healing by facilitating restoration and proliferation after injury. GKN1 is downregulated in Helicobacter pylori-infected gastric epithelial cells and loss of GKN1 expression is closely associated with gastric carcinogenesis, but underlying mechanisms of the tumor-suppressing effects of GKN1 remain largely unknown.AGS, MKN1, MKN28 gastric cancer cells and HFE-145 immortalized non-neoplastic gastric mucosal cells were transfected with GKN1 or shGKN1. We conducted molecular and functional studies of GKN1 and miR-185 and investigated the mechanisms of alteration. We also analyzed epigenetic alterations in 80 gastric cancer tissues.Restoration of GKN1 protein suppressed gastric cancer cell growth by inducing endogenous miR-185 that directly targets epigenetic effectors DNMT1 and EZH2 in gastric cancer cells. In addition, ectopic expression of GKN1 upregulated Tip60 and downregulated HDAC1 in an miR-185-independent manner, thereby inducing cell-cycle arrest by regulating cell-cycle proteins in gastric cancer cells. Notably, GKN1 expression was inversely correlated with DNMT1 and EZH2 expression in a subset of 80 gastric cancer tissues and various gastric cancer cell lines. Interestingly, it was found that GKN1 exerted a synergistic anti-cancerous effect with 5-fluorouracil on tumor cell growth, which suggests a possible therapeutic intervention method for gastric cancer.Our results show that GKN1 has an miR-185-dependent and -independent mechanism for chromatic and DNA epigenetic modification, thereby regulating the cell cycle. Thus, the loss of GKN1 function contributes to malignant transformation and proliferation of gastric epithelial cells in gastric carcinogenesis.
Molecular Analysis of Endometrial Tumorigenesis: Importance of Complex Hyperplasia Regardless of Atypia
Authors: Taina T. Nieminen, Annette Gylling, Wael M. Abdel-Rahman, Kyösti Nuorva, Markku Aarnio, Laura Renkonen-Sinisalo, Heikki J. Järvinen, Jukka-Pekka Mecklin, Ralf Bützow, Päivi Peltomäki
Journal: Clinical Cancer Research (2009)

Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression.Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples).Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma.Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma.