tbuckley/cabot-search huggingface dataset:
Arylsulfonamide KCN1 Inhibits<i>In Vivo</i>Glioma Growth and Interferes with HIF Signaling by Disrupting HIF-1α Interaction with Cofactors p300/CBP
Authors: Shaoman Yin, Stefan Kaluz, Narra S. Devi, Adnan A. Jabbar, Rita G. de Noronha, Jiyoung Mun, Zhaobin Zhang, Purushotham R. Boreddy, Wei Wang, Zhibo Wang, Thomas Abbruscato, Zhengjia Chen, Jeffrey J. Olson, Ruiwen Zhang, Mark M. Goodman, K.C. Nicolaou, Erwin G. Van Meir
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The hypoxia-inducible factor-1 (HIF-1) plays a critical role in tumor adaptation to hypoxia, and its elevated expression correlates with poor prognosis and treatment failure in patients with cancer. In this study, we determined whether 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the HIF-1 pathway, had antitumorigenic properties in vivo and further defined its mechanism of action. Experimental Design: We studied the inhibitory effect of systemic KCN1 delivery on the growth of human brain tumors in mice. To define mechanisms of KCN1 anti-HIF activities, we examined its influence on the assembly of a functional HIF-1α/HIF-1β/p300 transcription complex. Results: KCN1 specifically inhibited HIF reporter gene activity in several glioma cell lines at the nanomolar level. KCN1 also downregulated transcription of endogenous HIF-1 target genes, such as VEGF, Glut-1, and carbonic anhydrase 9, in a hypoxia-responsive element (HRE)-dependent manner. KCN1 potently inhibited the growth of subcutaneous malignant glioma tumor xenografts with minimal adverse effects on the host. It also induced a temporary survival benefit in an intracranial model of glioma but had no effect in a model of melanoma metastasis to the brain. Mechanistically, KCN1 did not downregulate the levels of HIF-1α or other components of the HIF transcriptional complex; rather, it antagonized hypoxia-inducible transcription by disrupting the interaction of HIF-1α with transcriptional coactivators p300/CBP. Conclusions: Our results suggest that the new HIF pathway inhibitor KCN1 has antitumor activity in mouse models, supporting its further translation for the treatment of human tumors displaying hypoxia or HIF overexpression. Clin Cancer Res; 18(24); 6623–33. ©2012 AACR.
Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease.
Authors: K Hillier, R Jewell, L Dorrell, C L Smith
Journal: Gut (1991)

The incorporation of the fatty acids in fish and olive oil into the colonic mucosa of patients with inflammatory bowel disease was examined during 12 weeks' dietary supplementation with the oils, and the influence on colonic mucosal prostaglandin and thromboxane generation was measured. With a dietary supplement of 18 g fish oil daily, concentrations of the major polyunsaturated fatty acids in fish oil, eicosapentaenoic acid and docosahexaenoic acid, were significantly raised in mucosal lipids. The first time these were measured, after three weeks' supplementation, the mean increases in eicosapentaenoic and docosahexaenoic acid were seven fold and 1.5 fold respectively, and these increases were maintained during the 12 week study. Arachidonic acid values fell throughout the study and this reduction was significant at 12 weeks. Mucosal prostaglandin E2 (PGE2), thromboxane B2, and 6-keto prostaglandin F1 alpha synthesis were suppressed, and this reached significance (p less than 0.05) at three and 12 weeks for PGE2 and at 12 weeks for thromboxane B2. The predominant fatty acid in olive oil is oleic acid. Supplementation with 18 g/day resulted in a significant increase in oleic acid in colonic mucosa at 12 weeks (p less than 0.05) and a fall in stearic acid and docosahexaenoic acid; there was no significant change in eicosanoid synthesis. It is concluded that colonic lipids and prostaglandin and thromboxane synthesis can be readily altered by dietary supplementation with fish oil. The extent of incorporation of the fatty acids present in oils is dependent upon the individual fatty acid.
Human Leukocyte Antigen Class I, MHC Class I Chain-Related Molecule A, and CD8+/Regulatory T-Cell Ratio: Which Variable Determines Survival of Cervical Cancer Patients?
Authors: Ekaterina S. Jordanova, Arko Gorter, Ouissam Ayachi, Frans Prins, Lindy G. Durrant, Gemma G. Kenter, Sjoerd H. van der Burg, Gert Jan Fleuren
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To investigate the effect of intraepithelial tumor-infiltrating lymphocytes (ieTIL) and their ligands expressed by cervical tumor cells on the outcome of cervical cancer patients. Experimental Design: The prognostic value of ieTILs was investigated in 115 cases of cervical cancer. T-cell subsets, CD57+ cells, and regulatory T cells (Treg) were enumerated. The associations of these different ieTIL subtypes with human leukocyte antigen (HLA) class I and MHC class I chain-related molecule A (MICA) expression were determined in relation to clinical variables and patient survival. Results: Survival analysis showed that a high number of intraepithelial Treg (FoxP3+), a low CD8+/regulatory T-cell ratio, and a weak HLA-A expression were all associated with worse survival (P = 0.034, 0.025, and 0.033, respectively, log-rank test). Further stratification of patient groups based on HLA-A-MICA expression and HLA-A-MICA-CD8+/Treg ratio revealed an even poorer survival (P = 0.005). In a multivariate Cox analysis, low CD8+/Treg ratio (P = 0.047), weak HLA-A-MICA expression (P = 0.003), and weak HLA-A-MICA expression combined with low CD8+/Treg ratio (P = 0.002) were all found to be independent unfavorable prognostic predictors in cervical carcinoma (hazard ratios, 2.7, 4.0, and 4.9, respectively). Conclusion: Weak HLA-A-MICA expression combined with low CD8+/Treg ratio reveals a patient group with the poorest survival in cervical cancer. As a single variable, low CD8+/Treg ratio was a significant independent unfavorable prognostic factor.
Effect of community-based newborn-care intervention package implemented through two service-delivery strategies in Sylhet district, Bangladesh: a cluster-randomised controlled trial
Authors: Abdullah H Baqui, Shams El-Arifeen, Gary L Darmstadt, Saifuddin Ahmed, Emma K Williams, Habibur R Seraji, Ishtiaq Mannan, Syed M Rahman, Rasheduzzaman Shah, Samir K Saha, Uzma Syed, Peter J Winch, Amnesty Lefevre, Mathuram Santosham, Robert E Black
Journal: The Lancet (2008)
Alcohol Consumption and Stroke Incidence in Male Smokers
Authors: Jaana M. Leppälä, Mikko Paunio, Jarmo Virtamo, Rainer Fogelholm, Demetrius Albanes, Philip R. Taylor, Olli P. Heinonen
Journal: Circulation (1999)

Background —Studies on alcohol consumption and incidences of stroke subtypes have suggested distinct dose-response relationships. Blood pressure and HDL cholesterol mediate the effect of alcohol on coronary heart disease, but similar evidence on cerebrovascular diseases is not available. Methods and Results —We studied the risk of stroke in 26 556 male cigarette smokers 50 to 69 years of age without history of stroke. The men were categorized as nondrinkers, light (≤24 g/d), moderate (25 to 60 g/d), or heavy (&gt;60 g/d) drinkers. A total of 960 men suffered from incident stroke: 83 with subarachnoid and 95 with intracerebral hemorrhage, 733 with cerebral infarction, and 49 with unspecified stroke. The adjusted relative risk of subarachnoid hemorrhage was 1.0 in light drinkers, 1.3 in moderate drinkers, and 1.6 in heavy drinkers compared with nondrinkers. The respective relative risks of intracerebral hemorrhage were 0.8, 0.6, and 1.8; of cerebral infarction, 0.9, 1.2, and 1.5. Systolic blood pressure attenuated the effect of alcohol consumption in all subtypes of stroke, whereas HDL cholesterol strengthened the effect of alcohol in subarachnoid hemorrhage and cerebral infarction but attenuated the effect in intracerebral hemorrhage. Conclusions —Alcohol consumption may have a distinct dose-response relationship within each stroke subtype—linear in subarachnoid hemorrhage, U-shaped in intracerebral hemorrhage, and J-shaped in cerebral infarction—but further studies are warranted. Systolic blood pressure and HDL cholesterol seem to mediate the effect of alcohol on stroke incidence, but evidently additional mechanisms are involved.
How molecular diagnosis can change allergen‐specific immunotherapy prescription in a complex pollen area
Authors: J. Sastre, M. E. Landivar, M. Ruiz‐García, M. V. Andregnette‐Rosigno, I. Mahillo
Journal: Allergy (2012)

Abstract Background The identification of disease‐eliciting allergens is a prerequisite for accurate prescription of allergen‐specific immunotherapy ( SIT ). The aim of this study was to determine whether molecular diagnosis ( MD ) may change indication and allergen prescription of SIT . Methods A total of 141 patients with allergic rhinoconjunctivitis and/or asthma sensitized to pollen with or without concomitant food allergy were included. Skin prick testing with a panel of aeroallergens and a microarray‐based panel of allergens ( ISAC ® ; Phadia, Sweden) was performed in all patients. Prior to learning the results of molecular diagnosis, three of the authors reached a consensus on the indication of SIT and use of allergens following EAACI recommendations, basing their judgment on clinical history and skin prick test results before and after obtaining the ISAC results. The agreement coefficient (kappa index) was used to analyze the results. Results Fifty‐nine percent of the patients were women with a mean age of 31 ± 13.63. Agreement in SIT indication before and after ISAC ® results was found in only 62 (46%) patients (kappa = 0.1057 ± 0.0413). Concerning allergens used in the most common prescriptions before and after MD results, we obtained the following results: κ = 0.117 ± 0.0825 for grass; κ = 0.1624 ± 0.0639 for olive; κ = 0.0505 ± 0.0548 for olive and grass; κ = 0.1711 ± 0.0471 for grass and cypress; κ = 0.1897 ± 0.0493 for grass and London plane; κ = 1 ± 0.0842 for olive and cypress, and κ = 0.3586 ± 0.0798 for other combinations. Conclusions There was very low agreement concerning indication and use of allergens for SIT before and after performing MD . This discrepancy emphasizes the usefulness of MD , at least in areas of complex sensitization to pollen, in determining correct indication of SIT .
American Society of Clinical Oncology Recommendations for the Initial Hormonal Management of Androgen-Sensitive Metastatic, Recurrent, or Progressive Prostate Cancer
Authors: D. Andrew Loblaw, David S. Mendelson, James A. Talcott, Katherine S. Virgo, Mark R. Somerfield, Edgar Ben-Josef, Richard Middleton, Henry Porterfield, Stewart A. Sharp, Thomas J. Smith, Mary Ellen Taplin, Nicholas J. Vogelzang, James L. Wade, Charles L. Bennett, Howard I. Scher
Journal: Journal of Clinical Oncology (2004)

Purpose To develop a clinical practice guideline for the management of men with metastatic, recurrent, or progressive carcinoma of the prostate. The focus of this document is on the use, combinations, and timing of various forms of androgen deprivation therapy (ADT) for the palliation of men with androgen-sensitive disease. Methods An expert panel and writing committee were formed. The questions to be addressed by the guideline were determined, and a systematic review of the literature was performed, which included a search of online databases, bibliographic review, and consultation with content experts. A priori criteria were used to select studies for analysis and study authors were contacted when necessary. Results There were 10 randomized controlled trials, six systematic reviews, and one Markov model available to inform the guidelines. Conclusion A full discussion between practitioner and patient should occur to determine which therapy is best for the patient. Bilateral orchiectomy or luteinizing hormone releasing hormone agonists are the recommended initial treatments. Nonsteroidal antiandrogen therapy may be discussed as an alternative, but steroidal antiandrogens should not be offered as monotherapy. Patients willing to accept the increased toxicity of combined androgen blockage for a small benefit in survival should be offered nonsteroidal antiandrogen in addition to castrate therapy. Until data from studies using modern medical diagnostic/biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.
Mucosal Adjuvanticity and Immunogenicity of LTR72, a Novel Mutant of <i>Escherichia coli</i> Heat-labile Enterotoxin with Partial Knockout of ADP-ribosyltransferase Activity
Authors: Marzia Monica Giuliani, Giuseppe Del Giudice, Valentina Giannelli, Gordon Dougan, Gill Douce, Rino Rappuoli, Mariagrazia Pizza
Journal: The Journal of Experimental Medicine (1998)

Heat-labile Escherichia coli enterotoxin (LT) has the innate property of being a strong mucosal immunogen and adjuvant. In the attempt to reduce toxicity and maintain the useful immunological properties, several LT mutants have been produced. Some of these are promising mucosal adjuvants. However, so far, only those that were still toxic maintained full adjuvanticity. In this paper we describe a novel LT mutant with greatly reduced toxicity that maintains most of the adjuvanticity. The new mutant (LTR72), that contains a substitution Ala → Arg in position 72 of the A subunit, showed only 0.6% of the LT enzymatic activity, was 100,000-fold less toxic than wild-type LT in Y1 cells in vitro, and was at least 20 times less effective than wild-type LT in the rabbit ileal loop assay in vivo. At a dose of 1 μg, LTR72 exhibited a mucosal adjuvanticity, similar to that observed with wild-type LT, better than that induced by the nontoxic, enzymatically inactive LTK63 mutant, and much greater than that of the recombinant B subunit. This trend was consistent for both the amounts and kinetics of the antibody induced, and priming of antigen-specific T lymphocytes. The data suggest that the innate high adjuvanticity of LT derives from the independent contribution of the nontoxic AB complex and the enzymatic activity. LTR72 optimizes the use of both properties: the enzymatic activity for which traces are enough, and the nontoxic AB complex, the effect of which is dose dependent. In fact, in dose–response experiments in mice, 20 μg of LTR72 were a stronger mucosal adjuvant than wild-type LT. This suggests that LTR72 may be an excellent candidate to be tested in clinical trials.
Inotuzumab ozogamicin, an anti-CD22–calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study
Authors: Hagop Kantarjian, Deborah Thomas, Jeffrey Jorgensen, Elias Jabbour, Partow Kebriaei, Michael Rytting, Sergernne York, Farhad Ravandi, Monica Kwari, Stefan Faderl, Mary Beth Rios, Jorge Cortes, Luis Fayad, Robert Tarnai, Sa A Wang, Richard Champlin, Anjali Advani, Susan O'Brien
Journal: The Lancet Oncology (2012)
Quantitation of the histological changes found in small intestinal biopsy specimens from children with suspected coeliac disease
Authors: R. A. Risdon, J. W. Keeling
Journal: Gut (1974)

The histological appearances in 85 peroral small intestinal biopsies from children have been analysed quantitatively by the method of Dunnill and Whitehead (1972). As applied to such biopsy specimens, this technique provides indices of both the mucosal volume and of the mucosal surface-to-volume ratio. When compared with controls, ;flat' biopsies from children with untreated coeliac disease invariably showed much smaller surface-to-volume (c:lh) ratios. The mucosal volumes (h) of these biopsies were, however, significantly increased. Specimens showing less marked abnormalities (socalled ;partial villous atrophy') had c:lh ratios in an intermediate range, but, like the biopsies from untreated coeliacs, h values were significantly increased. In morphologically normal biopsies correlation of surface-to-volume ratios with age showed that c:lh ratios were significantly smaller in younger children. Some of these lower c:lh ratios overlapped the range observed in abnormal biopsies showing partial villous atrophy. However, in the atrophic biopsies additional histological changes, such as abnormalities of the surface epithelial cells and an increased inflammatory cell infiltration of the lamina propria, were invariably present. Slight changes in biopsies from children under 2 years of age should, therefore, be interpreted cautiously, and should not necessarily be regarded as pathological on the evidence of the villous pattern alone. The quantitative technique employed proved reproducible under normal working conditions, and its greatest practical value would appear to be in following accurately serial changes in biopsies from the same patient.
Effect of Androgenic Hormone in Myelofibrosis
Authors: B. J. Kennedy
Journal: JAMA (1962)

Androgenic hormones have stimulated erythropoiesis in patients with breast cancer and those with refractory anemia, as well as in castrated and in normal experimental animals. Observation of this erythropoietic effect by several investigators has led to use of androgens in treatment of myelofibrosis. Six of 8 such patients treated by the author for prolonged periods with massive doses of androgenic hormone showed improvement. Two women, aged 55 and 75, and 1 man of 64 responded with increased hemoglobin, reticulocytosis, cessation of transfusion requirements, and hypercellular marrow. Three women, aged 56 to 62, required fewer or no transfusions and showed reticulocytosis. Corticosteroids were found to potentiate the effect in some instances. A prolonged remission persisted after cessation of androgen therapy in one case but could not be sustained. Therapeutic levels have in some cases led to polycythemia.
Tight Glycemic Control in Critically Ill Patients
Authors: Mario R. Castellanos
Journal: JAMA (2010)

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Increased cancer risk in heavy drinkers with the alcohol dehydrogenase 1C*1 allele, possibly due to salivary acetaldehyde
Authors: J P Visapaa
Journal: Gut (2004)

<b>Background:</b> Chronic ethanol consumption is associated with an increased risk of upper aerodigestive tract cancer. As acetaldehyde seems to be a carcinogenic factor associated with chronic alcohol consumption, alcoholics with the alcohol dehydrogenase (ADH) 1C*1 allele seem to be particularly at risk as this allele encodes for a rapidly ethanol metabolising enzyme leading to increased acetaldehyde levels. Recent epidemiological studies resulted in contradictory results and therefore we have investigated ADH1C genotypes in heavy alcohol consumers only. <b>Methods:</b> We analysed the ADH1C genotype in 107 heavy drinkers with upper aerodigestive tract cancer and in 103 age matched alcoholic controls without cancer who consumed similar amounts of alcohol. Genotyping of the ADH1C locus was performed using polymerase chain reaction based on restriction fragment length polymorphism methods on leucocyte DNA. In addition, ethanol was administered orally (0.3 g/kg body weight) to 21 healthy volunteers with the ADH1C*1,1, ADH1C*1,2, and ADH1C*2,2 genotypes, and 12 volunteers with various ADH genotypes consumed ethanol ad libitum (mean 211 (29) g). Subsequently, salivary acetaldehyde concentrations were measured by gas chromatography or high performance liquid chromatography. <b>Results:</b> The allele frequency of the ADH1C*1 allele was found to be significantly increased in heavy drinkers with upper aerodigestive tract cancer compared with age matched alcoholic controls without cancer (61.7% <i>v</i> 49.0%; p = 0.011). The unadjusted and adjusted odds ratios for all cancer cases versus all alcoholic controls were 1.67 and 1.69, respectively. Healthy volunteers homozygous for the ADH1C*1 allele had higher salivary acetaldehyde concentrations following alcohol ingestion than volunteers heterozygous for ADH1C (p = 0.056) or homozygous for ADH1C*2 (p = 0.011). <b>Conclusions:</b> These data demonstrate that heavy drinkers homozygous for the ADH1C*1 allele have a predisposition to develop upper aerodigestive tract cancer, possibly due to elevated salivary acetaldehyde levels following alcohol consumption.
Diagnosis of pulmonary lymphangioleiomyomatosis by HMB45 in surgically treated spontaneous pneumothorax
Authors: H Tanaka, A Imada, T Morikawa, T Shibusa, M Satoh, K Sekine, S Abe
Journal: European Respiratory Journal (1995)

Pulmonary lymphangioleiomyomatosis (PLAM) is a rare disease with poor prognosis, characterized by an abnormal proliferation of smooth muscle. The patients are females and recurrent pneumothorax is a frequent complication. HMB45 is a monoclonal antibody with specific immunoreactivity for malignant melanoma. Recently, it was reported that some of the smooth muscle cells in PLAM had reactivity for HMB45. The aim of this study was to assess the sensitivity and specificity of HMB45 for the diagnosis of PLAM in cystic pulmonary diseases that cause recurrent pneumothorax. We compared immunoreactivity of the specimens obtained by open lung biopsy at surgical resection of bullae in 72 patients. The specimens of five females with PLAM, one female with suspected PLAM, 49 patients with primary spontaneous pneumothorax (19 females and 30 males), four with pulmonary eosinophilic granuloma (2 females and 2 males), seven with pulmonary emphysema (7 males), and six with idiopathic pulmonary fibrosis with apical bullous change (2 females and 4 males) were stained with HMB45 and anti-smooth muscle actin. All PLAM cases had HMB45 positive cells, which also stained with anti-smooth muscle actin. The biopsy specimens of a PLAM suspected case also stained with HMB45. None of the specimens from other diseases reacted with HMB45. HMB45 appears to provide a highly specific and highly sensitive diagnosis for PLAM in females. It may also be useful in patients with subtle smooth muscle proliferation. where the diagnosis of PLAM is difficult to confirm by conventional histological examination.