tbuckley/cabot-search huggingface dataset:
Genetically Induced Pancreatic Adenocarcinoma Is Highly Immunogenic and Causes Spontaneous Tumor-Specific Immune Responses
Authors: Annette I. Garbe, Benjamin Vermeer, Jaba Gamrekelashvili, Reinhard von Wasielewski, Florian R. Greten, Astrid M. Westendorf, Jan Buer, Roland M. Schmid, Michael P. Manns, Firouzeh Korangy, Tim F. Greten
Journal: Cancer Research (2006)

Treatment options for pancreatic cancer are limited and often ineffective. Immunotherapeutic approaches are one possible option that needs to be evaluated in appropriate animal models. The aim of the present study was to analyze tumor-specific immune responses in a mouse model of pancreatic cancer, which mimics the human disease closely. C57BL/6 EL-TGF-alpha x Trp53-/- mice, which develop spontaneous ductal pancreatic carcinoma, were generated. EL-TGF-alpha x Trp53-/- mice developed spontaneous pancreatic tumors with pathomorphologic features close to the human disease. Tumor-specific CD8+ T-cell responses and IgG responses were analyzed in EL-TGF-alpha x Trp53-/- mice during tumor development and compared with mice with s.c. growing pancreatic tumors. In contrast to spontaneous pancreatic tumors, cell lines generated from these tumors were rejected after s.c. injection into wild-type mice but not in nude or RAG knockout mice. Direct comparison of spontaneous and s.c. injected tumors revealed an impaired infiltration of CD8+ T cells in spontaneous pancreatic tumors, which was also evident after adoptive transfer of tumor-specific T cells. Intratumoral cytokine secretion of tumor necrosis factor-alpha, IFN-gamma, IL-6, and MCP-1 was lower in spontaneous tumors as well as the number of adoptively transferred tumor-specific T cells. Our data provide clear evidence for tumor-specific immune responses in a genetic mouse model for pancreatic carcinoma. Comparative analysis of s.c. injected tumors and spontaneous tumors showed significant differences in tumor-specific immune responses, which will help in improving current immune-based cancer therapies against adenocarcinoma of the pancreas.
Review: Monoclonal Antibodies to the Vascular Endothelial Growth Factor Receptor-2 in Cancer Therapy
Authors: Hagop Youssoufian, Daniel J. Hicklin, Eric K. Rowinsky
Journal: Clinical Cancer Research (2007)

Angiogenesis is a fundamental mechanism of cancer growth and invasion. Current translational approaches are using both small-molecule inhibitors and antibodies that modulate various steps of these processes, and several such compounds have already received regulatory approval for the therapy of specific indications in cancer. Among the many molecular targets involved in the control of angiogenesis, the vascular endothelial growth factor receptor-2 (VEGFR-2; or kinase insert domain-containing receptor) is attractive as shown in part by the efficacy of small-molecule inhibitors directed to this receptor. Two small-molecule inhibitors that target VEGFR-2 have recently been granted approval for the treatment of renal cell cancer and gastrointestinal stromal tumors. The development of antibodies that can selectively block VEGFR-2 could potentially result in improved potency or tolerability. Here, we discuss the role of VEGFR-2 in cancer and ongoing efforts to develop highly specific monoclonal antibodies for cancer therapy.
The American Diabetes Association's 57th Annual Advanced Postgraduate Course
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2010)

The American Diabetes Aassociation's 57th Annual Advanced Postgraduate Course was held 5–7 February 2010 in San Francisco, California. Free webcasts of the talks from the 57th Annual Advanced Postgraduate Course are available at http://professional.diabetes.org/pg10.

### Risk prediction in diabetes

Michael Stern (San Antonio, TX) discussed risk prediction in diabetes, addressing the use of biomarkers and approaches with risk calculation engines. In general, he noted, the state of wellness is inherently asymptomatic without functional impairments, and many individual with diagnosed diabetes, hypertension, and even with cardiovascular disease (CVD) are “well.” For these individuals, treatment provides no current benefit but only the promise of a future benefit, which may never come to pass. If a well person in this sense cannot be made better, Stern pointed out that we must be particularly cognizant of the dictum ascribed to Niels Bohr: “Prediction is very difficult, especially about the future.”

A tool used in analysis of tests is the calculation of the area under the curve (AUC) of the receiver-operating characteristic graph of sensitivity versus (1-specificity). The AUC can be interpreted to equal the likelihood that a person destined to develop the disease or characteristic being tested for has a higher score, comparing one person who is with another who is not going to develop the given outcome (1). The AUC should be contrasted with an odds ratio (OR) or relative risk, which may be calculated as equaling (sensitivity) × (1 − false positive rate)/[(1 − sensitivity) × (false positive rate)]. This may better be thought of as pertaining to populations, with an OR of 1.5–3.0 giving rise to AUCs of 0.57–0.68, which Stern termed not terribly impressive levels, as can be observed in the overlap of distribution curves of those developing versus not developing the disease or characteristic. An OR of 10 is needed to give a …
On Congenital Diaphragmatic Hernia
Authors: A. M. Paterson
Journal: BMJ (1888)

tain point advantageous to the individual in performing his par- ticular form of labour.When the normal mechanical condition of the body is altered, the transmission of the body weight alone may be.sufficient to produce ossification of the ligaments, which sustain an abnormal amount of weight habitually.For instance, in more than one well-marked example of dorsal excurvation acquired early in life, I have found a good-sized piece of bone in the hypertrophied liga- mentum nuchae, as well as considerable prominence of the bony attachment of that ligament to the occiput.
Evidence for Heterogeneous Pathogenesis of Insulin-Treated Diabetes in Black and White Children
Authors: Ingrid M. Libman, Massimo Pietropaolo, Silva A. Arslanian, Ronald E. LaPorte, Dorothy J. Becker
Journal: Diabetes Care (2003)

OBJECTIVE—We have previously reported differences in the prevalence of β-cell autoantibodies (AAs) in black and white children with insulin-treated diabetes, suggesting that the disease pathogenesis may be more heterogeneous among racial groups than previously thought. To further explore this issue, we compared clinical, biochemical, and autoimmune characteristics at disease diagnosis and follow-up treatment in an expanded number of black and white children with and without the presence of AAs. RESEARCH DESIGN AND METHODS—The study cohort of 130 black children and adolescents, aged &amp;lt;19 years, diagnosed with diabetes and treated with insulin at time of diagnosis (January 1979 to December 1998) were matched with an equal number of white children by age at onset, sex, and year of diagnosis. RESULTS—The black children had a higher prevalence of obesity (43 vs. 11%) and acanthosis nigricans (21 vs. 1%) than white children and a lower prevalence of AAs. Compared with black children who had AAs, those with no AAs were older and had a higher prevalence of obesity, acanthosis nigricans, and parental diabetes. However, one of four of the black children with AAs was obese and/or had acanthosis nigricans. Among white children, the absence of AAs was not associated with any differences in terms of obesity or acanthosis nigricans compared with those with AAs. Similar to their black counterparts, white children without antibodies were older and had a higher prevalence of parental diabetes. Although treatment with an insulin sensitizer was used, insulin therapy was rarely discontinued on follow-up. CONCLUSIONS—These pediatric subjects, irrespective of autoimmunity, often showed characteristics associated with type 2 diabetes. These characteristics were more frequently displayed in black than in white children. Our data suggest that childhood diabetes may constitute a spectrum of pathogenic mechanisms that may overlap, including those typically associated with both type 1 and type 2 diabetes. This finding could have therapeutic implications.
Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma
Authors: J G Koopmans
Journal: Thorax (2006)

<b>Background:</b> Addition of the long acting β<sub>2</sub> agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids. However, little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process, control of which is considered important for the long term outcome of asthma. <b>Methods:</b> After a 4 week fluticasone run-in period, 54 patients with allergic asthma were randomised to receive twice daily treatment with fluticasone 250 μg with or without salmeterol 50 μg for 1 year in a double blind, parallel group design (total daily dose of fluticasone 500 μg in both treatment groups). Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations. Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker. The effects on allergen induced changes were determined before and at the end of the treatment period. <b>Results:</b> Adding salmeterol to fluticasone resulted in improved peak expiratory flow, symptom scores, rescue medication usage, and bronchial hyperresponsiveness (p&lt;0.05 for all). There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment (p&gt;0.05). However, adding salmeterol significantly reduced sputum ratios of α<sub>2</sub>-macroglobulin and albumin during the treatment period (p = 0.001). <b>Conclusions:</b> The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane. This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting β<sub>2</sub> agonist is combined with inhaled corticosteroids.
THE INFLUENCE OF TETHELIN, AND OF OTHER ALCOHOL-SOLUBLE EXTRACTIVES FROM THE ANTERIOR LOBE OF THE PITUITARY BODY, UPON THE GROWTH OF CARCINOMATA IN RATS
Authors: T. Brailsford Robertson, Theodore C. Burnett
Journal: The Journal of Experimental Medicine (1916)

1. The hypodermic administration of tethelin increases markedly the rate of growth of the primary tumor and the tendency to form metastases in rats inoculated with carcinoma, in this, as in other respects, reproducing the action of the whole anterior lobe of the pituitary body. 2. Other alcohol-soluble extractives of the anterior lobe of the pituitary body, with the exception of the lecithin fraction, exert no appreciable effect upon the growth of carcinomata in rats. 3. The lecithin fraction, as in previously reported experiments in which we employed lecithin obtained from eggs, causes evident retardation of the growth of carcinomata in rats.
Inactivation of oxidized and<i>S</i>-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats
Authors: Kwan-Hoon Moon, Brian L. Hood, Bong-Jo Kim, James P. Hardwick, Thomas P. Conrads, Timothy D. Veenstra, Byoung J. Song
Journal: Hepatology (2006)

Increased oxidative/nitrosative stress is a major contributing factor to alcohol-mediated mitochondrial dysfunction. However, which mitochondrial proteins are oxidatively modified under alcohol-induced oxidative/nitrosative stress is poorly understood. The aim of this study was to systematically investigate oxidized and/or S -nitrosylated mitochondrial proteins and to use a biotin - N -maleimide probe to evaluate their inactivation in alcoholic fatty livers of rats. Binge or chronic alcohol exposure significantly elevated nitric oxide, inducible nitric oxide synthase, and ethanol-inducible CYP2E1. The biotin - N -maleimide-labeled oxidized and/or S -nitrosylated mitochondrial proteins from pair-fed controls or alcohol-fed rat livers were subsequently purified with streptavidin-agarose. The overall patterns of oxidized and/or S -nitrosylated proteins resolved by 2-dimensional polyacrylamide gel electrophoresis were very similar in the chronic and binge alcohol treatment groups. Seventy-nine proteins that displayed differential spot intensities from those of control rats were identified by mass spectrometry. These include mitochondrial aldehyde dehydrogenase 2 (ALDH2), ATP synthase, acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase, and many proteins involved in chaperone activity, mitochondrial electron transfer, and ion transport. The activity of 3-ketoacyl-CoA thiolase involved in mitochondrial β-oxidation of fatty acids was significantly inhibited in alcohol-exposed rat livers, consistent with hepatic fat accumulation, as determined by biochemical and histological analyses. Measurement of activity and immunoblot results showed that ALDH2 and ATP synthase were also inhibited through oxidative modification of their cysteine or tyrosine residues in alcoholic fatty livers of rats. In conclusion , our results help to explain the underlying mechanism for mitochondrial dysfunction and increased susceptibility to alcohol-mediated liver damage. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
Divide and Conquer
Authors: Giulio Agnetti, Cathrine Husberg, Jennifer E. Van Eyk
Journal: Circulation Research (2011)

Chronic heart failure is a worldwide cause of mortality and morbidity and is the final outcome of a number of different etiologies. This reflects both the complexity of the disease and our incomplete understanding of its underlying molecular mechanisms. One experimental approach to address this is to study subcellular organelles and how their functions are activated and synchronized under physiological and pathological conditions. In this review, we discuss the application of proteomic technologies to organelles and how this has deepened our perception of the cellular proteome and its alterations with heart failure. The use of proteomics to monitor protein quantity and posttranslational modifications has revealed a highly intricate and sophisticated level of protein regulation. Posttranslational modifications have the potential to regulate organelle function and interplay most likely by targeting both structural and signaling proteins throughout the cell, ultimately coordinating their responses. The potentials and limitations of existing proteomic technologies are also discussed emphasizing that the development of novel methods will enhance our ability to further investigate organelles and decode intracellular communication.
Incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms of the pancreas
Authors: K. Kawakubo, M. Tada, H. Isayama, N. Sasahira, Y. Nakai, K. Yamamoto, H. Kogure, T. Sasaki, K. Hirano, H. Ijichi, K. Tateishi, H. Yoshida, K. Koike
Journal: Gut (2011)

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have been reported to be associated with extrapancreatic malignancies, but there have been no prospective studies evaluating the incidence of extrapancreatic cancers in patients with IPMNs. In this study, the frequency of patients with IPMNs developing extrapancreatic cancers during follow-up was examined.642 patients with IPMNs were prospectively followed up for 4.8 years on average. They underwent clinical examination at least twice a year. The incidence of the observed extrapancreatic malignancies was compared with the expected incidence of the age- and gender-matched general Japanese population based on the Vital Statistics of Japan.40 extrapancreatic cancers developed in 39 patients during follow-up (1.3% per year). The most common malignancies were hepatocellular (n=7), colorectal (n=6), gastric (n=6), lung (n=5) and prostate cancers (n=4). The calculated standardised incidence rate of each of the malignancies was not significant, as follows: hepatocellular 2.17 (95% CI 0.87 to 4.47), colorectal 1.02 (0.37 to 2.21), gastric 0.76 (0.28 to 1.66), lung 0.75 (0.24 to 1.76) and prostate 1.00 (0.71 to 1.29). Pancreatic cancer was observed in 17 patients during the same period, with a standardised incidence rate of 10.7 (6.2 to 17.1).The incidence of extrapancreatic malignancies in patients with IPMNs was similar to that in the general population, whereas the incidence of pancreatic cancers was significantly high. Intraductal papillary mucinous neoplasms are not associated with systemic carcinogenesis except for pancreatic cancer.
THE MOVEMENT OF WATER IN TISSUES REMOVED FROM THE BODY AND ITS RELATION TO MOVEMENT OF WATER DURING LIFE
Authors: Eugene L. Opie
Journal: The Journal of Experimental Medicine (1949)

During the initial period following immersion of parenchymatous cells of liver, kidney, or pancreas in various fluids immediately after their removal from the body water exchange is like that which occurs when water passes by osmosis through a semipermeable membrane; intake of water is proportional to the square root of the elapsed time and when liver tissue is immersed in solutions of sodium chloride movement of water is approximately proportional to the concentration of the solution. Solutions of sodium chloride isotonic for parenchymatous cells of liver have twice the molar concentration of sodium chloride in the blood serum; for those of the kidney slightly less than twice and for those of the pancreas three times this concentration. When interstitial tissue of thymus, omentum, or pancreas is immersed in water, it undergoes edema-like swelling caused by hydration of the colloids of the fibrous tissue; quantitative water exchange in an initial period accords with water movement by osmosis and is proportional to the square root of the elapsed time. Solutions of sodium chloride isotonic for fibrous tissue of the omentum have slightly greater molar concentration than the sodium chloride in the blood serum and for that of the thymus approximately the same as that of blood serum. Sodium chloride produces changes in fibrous tissue which increase with increasing concentration its power to hold water; the dense fibrous tissue of the corium of the skin and of the wall of the aorta takes up water in both weak an strong solutions of sodium chloride. The initial movement of water induced in tissues in the period immediately following removal from the body is dependent upon forces which are active during life but soon impaired by injury to the tissues. The molar concentration of the contents of secreting cells is greater than that of the blood serum and of the fluid surrounding them. These conditions are favorable to the passage of water from the tissue spaces to the cells.
Elevated intracellular Ca2+ acts through protein kinase C to regulate rabbit ileal NaCl absorption. Evidence for sequential control by Ca2+/calmodulin and protein kinase C.
Authors: M Donowitz, M E Cohen, M Gould, G W Sharp
Journal: Journal of Clinical Investigation (1989)

Calcium/calmodulin is involved in the regulation of basal rabbit ileal active Na and Cl absorption, but the mechanism by which elevated intracellular Ca2+ affects Na and Cl transport is unknown. To investigate the roles of the Ca2+/calmodulin and protein kinase C systems in ileal NaCl transport, two drugs, the isoquinolenesulfonamide, H-7, and the naphthalenesulfonamide, W13, were used in concentrations that conferred specificity in the antagonism of protein kinase C (60 microM H-7) and Ca2+/calmodulin (45 microM W13), respectively, as determined using phosphorylation assays in ileal villus cells. W13 but not H-7 stimulated basal active NaCl absorption. H-7 inhibited changes in Na and Cl absorption caused by maximal concentrations of Ca2+ ionophore A23187 and carbachol and serotonin, secretagogues that act by increasing cytosol Ca2+, while W13 had no effect. In contrast, neither H-7 nor W13 altered the change in NaCl transport caused by the cyclic nucleotides 8-Br-cAMP and 8-Br-cGMP. These data suggest that: (a) basal rabbit ileal NaCl absorption is regulated by the Ca2+/calmodulin complex and not by protein kinase C; (b) the effect of elevating intracellular Ca2+ to decrease NaCl absorption is mediated via protein kinase C but not by Ca2+/calmodulin; (c) the effects of protein kinase C are not overlapping or synergistic with those of Ca2+/calmodulin on either basal absorption or on the effects of increased Ca2+; and (d) neither Ca2+/calmodulin nor protein kinase C are involved in the effects of cAMP and cGMP on ileal active NaCl transport.
Managing Patient Expectations About Deidentification
Authors: Shawneequa L. Callier, Harald Schmidt
Journal: The American Journal of Bioethics (2010)

Click to increase image sizeClick to decrease image size Partial support for this essay came from the Postdoctoral fellowship program (Callier) of the Center for Genetic Research Ethics and Law, through the National Institutes of Health grant P50-HG003390 from the National Human Genome Research Institute. Harald Schmidt carried out this work while being supported by a Harkness Fellowship from the Commonwealth Fund. The views presented here are those of the author alone and should not be attributed to The Commonwealth Fund or its directors, officers, or staff or to CGREAL.
Nidogen 1 and 2 gene promoters are aberrantly methylated in human gastrointestinal cancer
Authors: Linda Ulazzi, Silvia Sabbioni, Elena Miotto, Angelo Veronese, Angela Angusti, Roberta Gafà, Stefano Manfredini, Fabio Farinati, Takako Sasaki, Giovanni Lanza, Massimo Negrini
Journal: Molecular Cancer (2007)

Nidogens are highly conserved proteins of basement membranes. Two nidogen proteins, nidogen 1 and nidogen 2, are known in mammals.We show that CpG islands of both NID1 and NID2 genes are aberrantly methylated in human cancer samples and cancer cell lines. For both genes, methylation was correlated with loss of gene transcription in human cell lines. Furthermore, demethylation of the NID1 and NID2 promoters restored gene transcription, demonstrating that methylation was responsible for silencing nidogen genes. In primary tumors, we detected NID1 promoter methylation in 67% of colon cancer samples and in 90% of gastric cancers. NID2 promoter was methylated in 29% of colon and 95% of gastric cancers. Immuno-staining for nidogen-2 confirmed the correlation between aberrant methylation and loss of nidogen expression also in primary tumors, implying that aberrant methylation was a mechanism for inhibiting nidogens expression in human gastrointestinal tumors.These results suggest that loss of nidogens expression has a potential pathogenetic role in colon and stomach tumorigenesis. Nidogens are believed to connect laminin and collagen IV networks, hence stabilizing the basement membrane structure. Nidogens are also important for cell adhesion, as they establish contacts with various cellular integrins. Loss of nidogen expression may favor invasion and metastasis of cancer cells by loosening cell interaction with basal membrane and by weakening the strength of the basement membrane itself, first barrier from the connective vascularized matrix.