tbuckley/cabot-search huggingface dataset:
Do We Have to Change the Way Targeted Drugs Are Developed?
Authors: Alberto Ocana, Eitan Amir, Bostjan Seruga, Atanasio Pandiella
Journal: Journal of Clinical Oncology (2010)

The one-size-fits-all approach for drug development of targeted agents in solid tumors has shown disappointing results in recent years.Although some new drugs have been approved, for most of them, the clinical benefit demonstrated in pivotal phase III trials has been small.Interestingly, even for drugs tested in enriched populations for a specific target, the improvement in clinical benefits was tiny.These results, in association with the high cost of these medicines, have been the topic of a recent controversial debate in the oncology community and also the focus of some commentaries in Journal of Clinical Oncology.These articles called for a reduction in the cost of these drugs and a change in the design of clinical studies with the intention of detecting more clinically meaningful benefits.Although we agree with the aspects mentioned in these articles, we will like to add some suggestions that in our view could enrich the ideas mentioned in them.
Inflammation and insulin resistance
Authors: Steven E Shoelson, Jongsoon Lee, Allison B Goldfine
Journal: Journal of Clinical Investigation (2006)

Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.
Serum cholesterol and triglyceride levels in 3,446 children from a biracial community: the Bogalusa Heart Study.
Authors: R R Frerichs, S R Srinivasan, L S Webber, G R Berenson
Journal: Circulation (1976)

Serum lipid profiles of 3,446 (91% of population) children, ages 5-14 years, were determined in a biracial community (Bogalusa, Louisiana) as part of a program investigating the early natural history of atherosclerosis. Black children had significantly higher mean levels of serum cholesterol than white children (170 mg/dl vs 162 mg/dl, P less than 0.0001). On the other hand, significantly lower levels of triglycerides were found in blacks than in whites (61 mg/dl vs 73 mg/dl, P less than 0.0001). Girls had higher levels of triglycerides than boys in both races (blacks, 64 mg/dl vs 59 mg/dl, P less than 0.001; whites, 77 mg/dl vs 69 mg/dl, P less than 0.001). The racial differences in serum cholesterol and triglyceride levels were even more apparent at the 95th percentile. The serum cholesterol level remained relatively constant in all children until ages 11 and 12 years, after which a slight reduction occurred. This reduction was more pronounced in boys than in girls. In contrast, a significant increase in the level of triglycerides with age was observed in all children except black girls, the increasing slope being most pronounced in white girls.
The Impact of Abnormalities in IGF and Inflammatory Systems on the Metabolic Syndrome
Authors: Kalpana Kaushal, Adrian H. Heald, Kirk W. Siddals, Manjinder S. Sandhu, David B. Dunger, John M. Gibson, Nick J. Wareham
Journal: Diabetes Care (2004)

Low plasma levels of IGF-I, particularly when coupled with low levels of the potentially inhibitory IGF binding protein (IGFBP)-1 and higher levels of C-reactive protein (CRP), have been implicated in the pathogenesis of metabolic syndrome X and cardiovascular disease. We report the relative contributions of IGFBP-1 and CRP to the occurrence of the metabolic syndrome in a healthy population cohort to establish the extent to which these factors may contribute to subsequent risk of cardiovascular disease.The volunteers in the study were all participants in the Ely study, a continuing population-based cohort in Ely, Cambridgeshire, U.K. Of 839 individuals studied, 154 (18.4%) fulfilled criteria for the metabolic syndrome.Subjects with the metabolic syndrome had lower IGFBP-1 (14.4 microg/l [95% CI 12.9-16.0] vs. 25.4 [24.1-26.7], P < 0.001) and higher CRP (1.9 mg/l [1.6-2.2] vs. 1.0 [0.9-1.1], P < 0.001). Logistic regression, adjusted for age, sex, fasting insulin, and IGF-I, demonstrated a striking 14-fold increased risk for the metabolic syndrome (odds ratio 14.1 [4.1-48.4], P < 0.001) in individuals with a CRP value in the highest tertile and IGFBP-1 levels below the median.The combination of a high CRP concentration coupled with a low IGFBP-1 results in a dramatic increase in an individual's risk of having the metabolic syndrome. Further elucidation of the biological processes linking the IGF and inflammatory systems may allow the identification of novel therapeutic targets for cardiovascular risk reduction.
Effect of hyperinflation on the diaphragm
Authors: A De Troyer
Journal: European Respiratory Journal (1997)

Acute hyperinflation causes the inspiratory muscles to operate at shorter than normal lengths. The ability of these muscles, in particular the diaphragm, to lower intrathoracic pressure is therefore reduced. Skeletal muscles, however, adapt to chronic shortening, and animals models of emphysema have shown that with chronic hyperinflation, the diaphragmatic muscle fibres lose sacromeres. As a result, the force-generating ability of these fibres is relatively preserved. In patients with hyperinflation due to chronic obstructive pulmonary disease, the ability of the diaphragm to generate pressure is also better than anticipated on the basis of hyperinflation alone. However, the diaphragm in these patients is also lower in the chest wall than in healthy subjects. Consequently, even though the neural drive to the muscle is greater than normal, its ability to descend during inspiration is impaired. Its rib cage expanding action is also reduced; in patients with severe hyperinflation, contraction of the diaphragm even produces deflation, rather than expansion, of the rib cage. In such patients, therefore, the ability of the diaphragm to increase lung volume is reduced, and hence the act of breathing is more dependent on the rib cage inspiratory muscles.
Radiation-Induced Caspase-8 Mediates p53-Independent Apoptosis in Glioma Cells
Authors: Golnar Afshar, Nannette Jelluma, Xiaodong Yang, Daniel Basila, Nils D. Arvold, Amelia Karlsson, Garret L. Yount, Tobias B. Dansen, Erich Koller, Daphne A. Haas-Kogan
Journal: Cancer Research (2006)

Abstract Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation. (Cancer Res 2006; 66(8): 4223-32)
Divergent effects of muscarinic receptor subtype gene ablation on murine colon tumorigenesis reveals association of M3R and zinc finger protein 277 expression in colon neoplasia
Authors: Kunrong Cheng, Guofeng Xie, Sandeep Khurana, Jonathon Heath, Cinthia B Drachenberg, Jennifer Timmons, Nirish Shah, Jean-Pierre Raufman
Journal: Molecular Cancer (2014)

M3 and M1 subtype muscarinic receptors are co-expressed in normal and neoplastic intestinal epithelial cells. In mice, ablating Chrm3, the gene encoding M3R, robustly attenuates intestinal tumor formation. Here we investigated the effects of Chrm1 gene ablation, alone and in combination with Chrm3 ablation. We used wild-type, Chrm1 -/- , Chrm3 -/- and combined Chrm1 -/- /Chrm3 -/- knockout (dual knockout) mice. Animals were treated with azoxymethane, an intestine-selective carcinogen. After 20 weeks, colon tumors were counted and analyzed histologically and by immunohistochemical staining. Tumor gene expression was analyzed using microarray and results validated by RT-PCR. Key findings were extended by analyzing gene and protein expression in human colon cancers and adjacent normal colon tissue. Azoxymethane-treated Chrm3 -/- mice had fewer and smaller colon tumors than wild-type mice. Reductions in colon tumor number and size were not observed in Chrm1 -/- or dual knockout mice. To gain genetic insight into these divergent phenotypes we used an unbiased microarray approach to compare gene expression in tumors from Chrm3 -/- to those in wild-type mice. We detected altered expression of 430 genes, validated by quantitative RT-PCR for the top 14 up- and 14 down-regulated genes. Comparing expression of this 28-gene subset in tumors from wild-type, Chrm3 -/- , Chrm1 -/- and dual knockout mice revealed significantly reduced expression of Zfp277, encoding zinc finger protein 277, in tissue from M3R-deficient and dual knockout mice, and parallel changes in Zfp277 protein expression. Notably, mRNA and protein for ZNF277, the human analogue of Zfp277, were increased in human colon cancer compared to adjacent normal colon, along with parallel changes in expression of M3R. Our results identify a novel candidate mouse gene, Zfp277, whose expression pattern is compatible with a role in mediating divergent effects of Chrm3 and Chrm1 gene ablation on murine intestinal neoplasia. The biological importance of this observation is strengthened by finding increased expression of ZNF277 in human colon cancer with a parallel increase in M3R expression. The role of zinc finger protein 277 in colon cancer and its relationship to M3R expression and activation are worthy of further investigation.
Neutrophil infiltration, glial reaction, and neurological disease in transgenic mice expressing the chemokine N51/KC in oligodendrocytes.
Authors: M Tani, M E Fuentes, J W Peterson, B D Trapp, S K Durham, J K Loy, R Bravo, R M Ransohoff, S A Lira
Journal: Journal of Clinical Investigation (1996)

Chemokines (pro-inflammatory chemoattractant cytokines) are expressed in pathological conditions of the central nervous system (CNS). Previous studies suggested that the CNS is relatively resistant to leukocyte diapedesis after chemokine injection, leaving their functional role unresolved. The CNS function of N51/KC, a neutrophil-selective chemokine, was addressed by expressing N51/KC under control of the myelin basic protein (MBP) promoter in transgenic (tg) mice (MBP-N51/KC mice). CNS-specific N51/KC expression produced remarkable neutrophil infiltration into perivascular, meningeal, and parenchymal sites, demonstrating that this chemokine exerts the multiple functions in vivo required to recruit leukocytes into the CNS. MBP-N5 1/KC mice represent an incisive model for the molecular dissection of neutrophil entry into the CNS. Unexpectedly, MBP-N51/KC mice developed a neurological syndrome of pronounced postural instability and rigidity at high frequency beginning at 40 days of age, well after peak chemokine expression. 68/182 mice in one tg fine were found dead before one year of age, with prominent neurological symptoms premortem in 26 (38%). Florid microglial activation and blood-brain barrier disruption without dysmyelination were the major neuropathological alterations. Late-onset neurological symptoms in MBP-N51/KC mice may indicate unanticipated consequences of CNS chemokine expression.
A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC
Authors: Paul I W de Bakker, Gil McVean, Pardis C Sabeti, Marcos M Miretti, Todd Green, Jonathan Marchini, Xiayi Ke, Alienke J Monsuur, Pamela Whittaker, Marcos Delgado, Jonathan Morrison, Angela Richardson, Emily C Walsh, Xiaojiang Gao, Luana Galver, John Hart, David A Hafler, Margaret Pericak-Vance, John A Todd, Mark J Daly, John Trowsdale, Cisca Wijmenga, Tim J Vyse, Stephan Beck, Sarah Shaw Murray, Mary Carrington, Simon Gregory, Panos Deloukas, John D Rioux
Journal: Nature Genetics (2006)
Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial
Authors: Geert D'Haens, Filip Baert, Gert van Assche, Philip Caenepeel, Philippe Vergauwe, Hans Tuynman, Martine De Vos, Sander van Deventer, Larry Stitt, Allan Donner, Severine Vermeire, Frank J Van De Mierop, Jean-Charles R Coche, Janneke van der Woude, Thomas Ochsenkühn, Ad A van Bodegraven, Philippe P Van Hootegem, Guy L Lambrecht, Fazia Mana, Paul Rutgeerts, Brian G Feagan, Daniel Hommes
Journal: The Lancet (2008)
SHIP deficiency causes Crohn's disease-like ileitis
Authors: W. G. Kerr, M.-Y. Park, M. Maubert, R. W. Engelman
Journal: Gut (2010)

<h3>Background</h3> Inflammatory bowel disease (IBD) can arise from genetic mutations that compromise intestinal epithelial cell integrity or immune regulation. SHIP has previously been shown to play a pivotal role in limiting the number of immunoregulatory cells and their function. <h3>Aim</h3> To determine whether SHIP plays a pivotal role in control of immune tolerance in the gut mucosa. <h3>Methods</h3> Gastrointestinal pathology was assessed in three separate strains of SHIP-deficient mice and their respective wild-type (WT) littermates. Gastrointestinal pathology was analysed in SHIP-deficient hosts reconstituted with WT haematopoietic cell grafts, and WT hosts reconstituted with SHIP-deficient haematopoietic cell grafts including whole splenocytes, purified T cells or natural killer (NK) cells. Major immune cell populations were also analysed in the small intestine of SHIP-deficient mice and WT controls. <h3>Results</h3> SHIP-deficient mice developed segmental, transmural pyo-granulomatous ilietis that recapitulated classical features of Crohn9s disease enteric pathology. Analysis of haematopoietic chimeras showed that WT bone marrow reconstitution of SHIP<sup>−/−</sup> hosts corrects ileitis. Reconstitution with SHIP<sup>−/−</sup> splenocytes transferred ileitis to WT hosts. Adoptive transfer of purified SHIP<sup>−/−</sup> T cells or NK cells to WT hosts did not transfer ileitis. There was a paucity of both CD4 and CD8 T cells in the small intestines of SHIP-deficient mice; however, neutrophil numbers were significantly increased. <h3>Conclusions</h3> SHIP plays a pivotal role in immune function in the intestine; further scrutiny of this pathway in IBD patients is warranted. It is proposed that SHIP-deficient ileitis results from a local deficit in mucosal T cell immunity that promotes a damaging granulocyte–monocyte inflammation of the distal ileum.
Involvement of a cyclic adenosine monophosphate–dependent signal in the diet‐induced canalicular trafficking of adenosine triphosphate–binding cassette transporter g5/g8
Authors: Yasuhiro Yamazaki, Kenta Yasui, Takahiro Hashizume, Arisa Suto, Ayaka Mori, Yuzuki Murata, Masahiko Yamaguchi, Akira Ikari, Junko Sugatani
Journal: Hepatology (2015)

The adenosine triphosphate–binding cassette (ABC) half‐transporters Abcg5 and Abcg8 promote the secretion of neutral sterol into bile. Studies have demonstrated the diet‐induced gene expression of these transporters, but the regulation of their trafficking when the nutritional status changes in the liver remains to be elucidated. Here, we generated a novel in vivo kinetic analysis that can monitor the intracellular trafficking of Abcg5/Abcg8 in living mouse liver by in vivo transfection of the genes of fluorescent protein‐tagged transporters and investigated how hypernutrition affects the canalicular trafficking of these transporters. The kinetic analysis showed that lithogenic diet consumption accelerated the translocation of newly synthesized fluorescent‐tagged transporters to intracellular pools in an endosomal compartment and enhanced the recruitment of these pooled gene products into the bile canalicular membrane in mouse liver. Because some ABC transporters are reported to be recruited from intracellular pools to the bile canaliculi by cyclic adenosine monophosphate (cAMP) signaling, we next evaluated the involvement of this machinery in a diet‐induced event. Administration of a protein kinase A inhibitor, N ‐(2‐{[3‐(4‐bromophenyl)−2‐propenyl]amino}ethyl)−5‐isoquinolinesulfonamide, decreased the canalicular expression of native Abcg5/Abcg8 in lithogenic diet–fed mice, and injection of a cAMP analog, dibutyryl cAMP, transiently increased their levels in standard diet–fed mice, indicating the involvement of cAMP signaling. Indeed, canalicular trafficking of the fluorescent‐tagged Abcg5/Abcg8 was enhanced by dibutyryl cAMP administration. Conclusion : These observations suggest that diet‐induced lipid loading into liver accelerates the trafficking of Abcg5/Abcg8 to the bile canalicular membrane through cAMP signaling machinery. (H epatology 2015;62:1215‐1226)
Exonic Splicing Regulatory Elements Skew Synonymous Codon Usage near Intron-exon Boundaries in Mammals
Authors: Joanna L. Parmley, Laurence D. Hurst
Journal: Molecular Biology and Evolution (2007)

In mammals there is a bias in amino acid usage near splice sites that is explained, in large part, by the high density of exonic splicing enhancers (ESEs) in these regions. Is there a similar bias for the relative use of synonymous codons, and can any such bias be predicted by their abundance in ESEs? Prior reports suggested that such trends may exist. From analysis of human exons, we find that 47 of the 59 codons with at least one synonym show differential usage in the proximity of exon ends, of which 42 remain significant after correction for multiple testing. Within sets of synonymous codons those more preferred near splice sites are generally those that are relatively more abundant within the ESEs. However, the examples given previously appear exceptionally good fits and there exist many exceptions, the usage of lysine's codons being a case in point. Similar results are observed in mouse exons. We conclude that splice regulation impacts on the choice of synonymous codons in mammals, but the magnitude of this effect is less than might at first have been supposed.
The effect of zinc in the form of erythromycin-zinc complex (ZinerytR lotion) and zinc acetate on metallothionein expression and distribution in hamster skin
Authors: A. J. MORGAN, G. LEWIS, W.E. HOVEN, P.J. AKKERBOOM
Journal: British Journal of Dermatology (1993)

The occurrence of zinc-induced synthesis of metallothionein in skin after topical application of the anti-acne drug Zineryt lotion was investigated in hamster ears. The dinitrophenyl hapten-sandwich immunohistochemical method involving a monoclonal anti-metallothionein (MT) antibody (E9) was used to detect and localize zinc-binding MT in the 'treated' and untreated hamster skin. Atomic absorption spectrophotometry and dithizone histochemistry indicated that zinc penetrated the skin more readily, and accumulated more efficiently within the sebaceous glands, when applied to the skin surface as the organo-zinc complex, rather than as the inorganic zinc salt. MT and zinc had similar distributions in hamster skin exposed to the metal. Thus, MT immunoreactivity was especially intense in the sebaceous glands of Zineryt lotion-treated skin, with evidence of nuclear distribution in some cells. Zinc delivered to the sebaceous glands, and released from the organo-complex under the prevailing aqueous conditions, certainly induced MT synthesis; the cysteine-rich protein may protect the pilosebaceous units during the inflammatory phase of acne by scavenging generated oxyradical species.
Congenital sucrase-isomaltase deficiency. Identification of a glutamine to proline substitution that leads to a transport block of sucrase-isomaltase in a pre-Golgi compartment.
Authors: J Ouwendijk, C E Moolenaar, W J Peters, C P Hollenberg, L A Ginsel, J A Fransen, H Y Naim
Journal: Journal of Clinical Investigation (1996)

Congenital sucrase-isomaltase deficiency is an example of a disease in which mutant phenotypes generate transport-incompetent molecules. Here, we analyze at the molecular level a phenotype of congenital sucrase-isomaltase deficiency in which sucrase-isomaltase (SI) is not transported to the brush border membrane but accumulates as a mannose-rich precursor in the endoplasmic reticulum (ER), ER-Golgi intermediate compartment, and the cis-Golgi, where it is finally degraded. A 6-kb clone containing the full-length cDNA encoding SI was isolated from the patient's intestinal tissue and from normal controls. Sequencing of the cDNA revealed a single mutation, A/C at nucleotide 3298 in the coding region of the sucrase subunit of the enzyme complex. The mutation leads to a substitution of the glutamine residue by a proline at amino acid 1098 (Q1098P). The Q1098P mutation lies in a region that is highly conserved between sucrase and isomaltase from different species and several other structurally and functionally related proteins. This is the first report that characterizes a point mutation in the SI gene that is responsible for the transport incompetence of SI and for its retention between the ER and the Golgi.
Resistance Exercise in Individuals With and Without Cardiovascular Disease
Authors: Michael L. Pollock, Barry A. Franklin, Gary J. Balady, Bernard L. Chaitman, Jerome L. Fleg, Barbara Fletcher, Marian Limacher, Ileana L. Piña, Richard A. Stein, Mark Williams, Terry Bazzarre
Journal: Circulation (2000)

A lthough exercise programs have traditionally empha- sized dynamic lower-extremity exercise, research increasingly suggests that complementary resistance training, when appropriately prescribed and supervised, has favorable effects on muscular strength and endurance, cardiovascular function, metabolism, coronary risk factors, and psychosocial well-being.This advisory reviews the role of resistance training in persons with and without cardiovascular disease, with specific reference to health and fitness benefits, rationale, the complementary role of stretching, relevant physiological considerations, and safety.Participation criteria and prescriptive guidelines are also provided.
Destructive arthritis associated with acne fulminans: a case report.
Authors: L.Y Hunter, R.N Hensinger
Journal: Annals of the Rheumatic Diseases (1980)

Arthralgias have previously been reported in association with acne fulminans, but the following case in the first report of osseous lesions associated with this disease. The destructive bony lesion was rapid in onset but self-limited.