tbuckley/cabot-search huggingface dataset:
Targeting TRAIL Agonistic Receptors for Cancer Therapy
Authors: Carmelo Carlo-Stella, Cristiana Lavazza, Alberta Locatelli, Lucia Viganò, Alessandro M. Gianni, Luca Gianni
Journal: Clinical Cancer Research (2007)

Based on preclinical studies demonstrating that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts a potent and cancer cell-specific proapoptotic activity, recombinant TRAIL as well as agonistic anti-TRAIL-R1 and anti-TRAIL-R2 antibodies recently entered clinical trials. Additionally, gene therapy approaches using TRAIL-encoding adenovirus (Ad-TRAIL) are currently being developed to overcome the limitations inherent to TRAIL receptor targeting, i.e., pharmacokinetic of soluble TRAIL, pattern of receptor expression, and tumor cell resistance. To optimize gene therapy approaches, CD34+ cells transduced with Ad-TRAIL (CD34-TRAIL+) have been investigated as cellular vehicles for TRAIL delivery. Transduced cells exhibit a potent tumor killing activity on a variety of tumor cell types both in vitro and in vivo and are also cytotoxic against tumor cells resistant to soluble TRAIL. Studies in tumor-bearing nonobese diabetic/severe combined immunodeficient mice suggest that the antitumor effect of CD34-TRAIL+ cells is mediated by both direct tumor cell killing due to apoptosis and indirect tumor cell killing due to vascular-disrupting mechanisms. The clinical translation of cell and gene therapy approaches represent a challenging strategy that might achieve systemic tumor targeting and increased intratumor delivery of the therapeutic agent.
Pathologic Complete Response to Trastuzumab-Based Neoadjuvant Therapy Is Related to the Level of HER-2 Amplification
Authors: Laurent Arnould, Patrick Arveux, Jerome Couturier, Marion Gelly-Marty, Catherine Loustalot, Francette Ettore, Christine Sagan, Martine Antoine, Frederique Penault-Llorca, Berangere Vasseur, Pierre Fumoleau, Bruno P. Coudert
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are used to determine human epidermal growth factor receptor-2 (HER-2) status and patient eligibility for trastuzumab therapy. Using FISH and IHC, we analyzed the relationship between pathologic complete response to trastuzumab-based neoadjuvant therapy and level of HER-2 amplification in locally advanced breast cancer. Experimental Design: Breast biopsies from 93 HER-2–positive patients treated with trastuzumab-based neoadjuvant therapy were centrally collected and analyzed retrospectively for HER-2 amplification using FISH and HER-2 overexpression using IHC. Tumors were classified by FISH as no, low, or high amplification. Biopsies were reassessed centrally by IHC and graded 0, 1+, 2+, or 3+. Results: HER-2 status of tumor samples as assessed by FISH and IHC correlated: 16 no amplification (11 IHC 1+ and 5 IHC 2+), 27 low amplification (26 IHC 3+ and 1 IHC 2+), and 50 high amplification (all IHC 3+). Trastuzumab-based neoadjuvant therapy achieved pathologic complete response in 35 of 93 (37.6%) tumors. Pathologic complete response rate in low- and high-amplification tumors was significantly higher than in no-amplification tumors (44% versus 6%; P &amp;lt; 0.004). Pathologic complete response rate in high-amplification tumors was significantly higher compared with low-amplification tumors (56% versus 22%; P &amp;lt; 0.005). In the subgroup of low- plus high-amplification tumors, no correlation was found between pathologic complete response rate and IHC score, treatment regimen, T or N stage, tumor grade, or hormonal receptors. Conclusions: This is the first study to show positive correlation between level of HER-2 amplification assessed by FISH and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment.
Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma
Authors: Jayasri G. Iyer, Barry E. Storer, Kelly G. Paulson, Bianca Lemos, Jerri Linn Phillips, Christopher K. Bichakjian, Nathalie Zeitouni, Jeffrey E. Gershenwald, Vernon Sondak, Clark C. Otley, Siegrid S. Yu, Timothy M. Johnson, Nanette J. Liegeois, David Byrd, Arthur Sober, Paul Nghiem
Journal: Journal of the American Academy of Dermatology (2014)
Obstructive Sleep Apnea as a Risk Factor for Stroke and Death
Authors: H. Klar Yaggi, John Concato, Walter N. Kernan, Judith H. Lichtman, Lawrence M. Brass, Vahid Mohsenin
Journal: New England Journal of Medicine (2005)

Previous studies have suggested that the obstructive sleep apnea syndrome may be an important risk factor for stroke. It has not been determined, however, whether the syndrome is independently related to the risk of stroke or death from any cause after adjustment for other risk factors, including hypertension.In this observational cohort study, consecutive patients underwent polysomnography, and subsequent events (strokes and deaths) were verified. The diagnosis of the obstructive sleep apnea syndrome was based on an apnea-hypopnea index of 5 or higher (five or more events per hour); patients with an apnea-hypopnea index of less than 5 served as the comparison group. Proportional-hazards analysis was used to determine the independent effect of the obstructive sleep apnea syndrome on the composite outcome of stroke or death from any cause.Among 1022 enrolled patients, 697 (68 percent) had the obstructive sleep apnea syndrome. At baseline, the mean apnea-hypopnea index in the patients with the syndrome was 35, as compared with a mean apnea-hypopnea index of 2 in the comparison group. In an unadjusted analysis, the obstructive sleep apnea syndrome was associated with stroke or death from any cause (hazard ratio, 2.24; 95 percent confidence interval, 1.30 to 3.86; P=0.004). After adjustment for age, sex, race, smoking status, alcohol-consumption status, body-mass index, and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension, the obstructive sleep apnea syndrome retained a statistically significant association with stroke or death (hazard ratio, 1.97; 95 percent confidence interval, 1.12 to 3.48; P=0.01). In a trend analysis, increased severity of sleep apnea at baseline was associated with an increased risk of the development of the composite end point (P=0.005).The obstructive sleep apnea syndrome significantly increases the risk of stroke or death from any cause, and the increase is independent of other risk factors, including hypertension.
Nitric Oxide Modulates Cardiac Na<sup>+</sup>Channel via Protein Kinase A and Protein Kinase G
Authors: Gias U. Ahmmed, Yanfang Xu, Pei Hong Dong, Zhao Zhang, Jason Eiserich, Nipavan Chiamvimonvat
Journal: Circulation Research (2001)

We directly tested the effects of nitric oxide (NO) on Na(+) channels in guinea pig and mouse ventricular myocytes using patch-clamp recordings. We have previously shown that NO donors have no observed effects on expressed Na(+) channels. In contrast, NO (half-blocking concentration of 523 nmol/L) significantly reduces peak whole-cell Na(+) current (I(Na)) in isolated ventricular myocytes. The inhibitory effect of NO on I(Na) was not associated with changes in activation, inactivation, or reactivation kinetics. At the single-channel level, the reduction in macroscopic current was mediated by a decrease in open probability and/or a decrease in the number of functional channels with no change in single-channel conductance. Application of cell permeable analogs of cGMP or cAMP mimics the inhibitory effects of NO. Furthermore, the effects of NO on I(Na) can only be blocked by inhibition of both cGMP and cAMP pathways. Sulfhydryl-reducing agent does not reverse the effect of NO. In summary, although NO exerts its action via the known guanylyl cyclase (GC)/cGMP pathway, our findings provide evidence that NO can mediate its function via a GC/cGMP-independent mechanism involving the activation of adynylyl cyclase (AC) and cAMP-dependent protein kinase.
CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans
Authors: Anne G. Kasmar, Ildiko van Rhijn, Tan-Yun Cheng, Marie Turner, Chetan Seshadri, Andre Schiefner, Ravi C. Kalathur, John W. Annand, Annemieke de Jong, John Shires, Luis Leon, Michael Brenner, Ian A. Wilson, John D. Altman, D. Branch Moody
Journal: The Journal of Experimental Medicine (2011)

Microbial lipids activate T cells by binding directly to CD1 and T cell receptors (TCRs) or by indirect effects on antigen-presenting cells involving induction of lipid autoantigens, CD1 transcription, or cytokine release. To distinguish among direct and indirect mechanisms, we developed fluorescent human CD1b tetramers and measured T cell staining. CD1b tetramer staining of T cells requires glucose monomycolate (GMM) antigens, is specific for TCR structure, and is blocked by a recombinant clonotypic TCR comprised of TRAV17 and TRBV4-1, proving that CD1b–glycolipid complexes bind the TCR. GMM-loaded tetramers brightly stain a small subpopulation of blood-derived cells from humans infected with Mycobacterium tuberculosis, providing direct detection of a CD1b-reactive T cell repertoire. Polyclonal T cells from patients sorted with tetramers are activated by GMM antigens presented by CD1b. Whereas prior studies emphasized CD8+ and CD4−CD8− CD1b-restricted clones, CD1b tetramer-based studies show that nearly all cells express the CD4 co-receptor. These findings prove a cognate mechanism whereby CD1b–glycolipid complexes bind to TCRs. CD1b tetramers detect a natural CD1b-restricted T cell repertoire ex vivo with unexpected features, opening a new investigative path to study the human CD1 system.
A small CD11b+ human B1 cell subpopulation stimulates T cells and is expanded in lupus
Authors: Daniel O. Griffin, Thomas L. Rothstein
Journal: The Journal of Experimental Medicine (2011)

A primary function of B lymphocytes is immunoglobulin production; however, the therapeutic benefit of B cell depletion in autoimmune diseases previously thought to be T cell mediated suggests that some B cells fulfill other roles in autoimmunity. We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, a CD11b(+) subset constitutes ~1 out of every 8-10 B1 cells, whereas a CD11b(-) subset constitutes the remaining B1 cells. These B1 cell populations differ functionally. CD11b(-) B1 cells spontaneously secrete much more IgM than CD11b(+) B1 cells. In contrast, CD11b(+) B1 cells express more CD86, and more efficiently stimulate allogeneic CD4(+) T cell expansion, than CD11b(-) B1 cells. The frequency of these CD11b(+) B1 cells is markedly elevated in lupus patients. CD11b(+) B1 cells in lupus patients express more CD86 and have increased T cell-stimulating activity in disease. This work distinguishes a novel, T cell-interacting B1 cell population whose abundance and activity may be a reflection of, and a therapeutic target in, autoimmune disease.
Association of Angiogenesis in Lymph Node Metastases With Outcome of Breast Cancer
Authors: Anthony J. Guidi, Donald A. Berry, Gloria Broadwater, Marjorie Perloff, Larry Norton, Maurice P. Barcos, Daniel F. Hayes
Journal: JNCI Journal of the National Cancer Institute (2000)

Microvessel density (MVD) is a measure of the extent of new blood vessel growth or angiogenesis, which is required for tumor progression. Increased MVD in primary breast cancers appears to adversely affect disease-free survival and overall survival in patients with breast cancer. However, the clinical implications of angiogenesis in breast cancer metastases have not been well studied. The purpose of this study was to compare intratumoral MVD in primary breast cancer tissues with MVD in axillary lymph node metastases and to evaluate the relationships among primary- and metastatic-tumor MVD, disease-free survival, and overall survival in patients with lymph node-positive, stage II breast cancer who were treated with adjuvant chemotherapy in Cancer and Leukemia Group B Protocol 8082.Immunostaining for factor VIII-related antigen was performed on tissue sections from 47 primary tumors and 91 axillary lymph nodes containing metastases from 110 patients with lymph node-positive breast cancer. Sections were examined for the presence or absence of focal areas of relatively intense neovascularization (vascular hot spots), and a quantitative assessment of intratumoral MVD was performed.The presence of vascular hot spots in axillary lymph node metastases, but not primary breast cancers, was associated with statistically significantly decreased disease-free survival (P =.006) and overall survival (P =.004) by univariate analysis. Similarly, increased MVD in metastases, but not in primary tumors, was statistically significantly associated with diminished overall survival in these patients (P =.02). In multivariate analysis, the number of positive axillary lymph nodes and the presence of vascular hot spots in axillary lymph node metastases predicted decreased disease-free survival (P =.0001 and.02, respectively) and overall survival (P =.0001 and.007, respectively). All P values were two-sided.This pilot study suggests that assessing neovascularization in axillary lymph node metastases may provide clinically useful information regarding survival in patients with primary breast cancer.
Screening <i>SMAD1</i>,<i>SMAD2</i>, <i>SMAD3</i>, and<i>SMAD5</i> for germline mutations in juvenile polyposis syndrome
Authors: S Bevan, K Woodford-Richens, P Rozen, C Eng, J Young, M Dunlop, K Neale, R Phillips, D Markie, M Rodriguez-Bigas, B Leggett, E Sheridan, S Hodgson, T Iwama, D Eccles, W Bodmer, R Houlston, I Tomlinson
Journal: Gut (1999)

BACKGROUND AND AIMS Juvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (juvenile polyposis syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in the SMAD4 ( DPC4 ) gene, providing further evidence for the importance of the TGFβ signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especially SMAD2 (which, like SMAD4 , is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when “knocked out” in mice), SMAD5 , and SMAD1 . METHODS SMAD1 , SMAD2 , SMAD3 , and SMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4 mutations. RESULTS No mutations were found in any of these genes. A G–A C89Y polymorphism with possible effects on protein function was found in SMAD3 , but the frequencies of the G and A alleles did not differ between patients with JPS and controls. CONCLUSIONS It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas. SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.
Toward preventing coronary death from ventricular fibrillation.
Authors: D G Julian
Journal: Circulation (1976)

Sudden coronary death from ventricular fibrillation is the biggest and possibly the most remediable of the major public health problems at the moment. Most of those liable to sudden death can be identified and it is possible that by the use of beta-adrenergic blocking or other antiarrhythmic drugs, by reducing the consumption of cigarettes and perhaps, by different therapies for hypertension, a substantial proportion of coronary deaths might be prevented or, at least, postponed.
Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial
Authors: Ulrik Pedersen-Bjergaard, Peter Lommer Kristensen, Henning Beck-Nielsen, Kirsten Nørgaard, Hans Perrild, Jens Sandahl Christiansen, Tonny Jensen, Philip Hougaard, Hans-Henrik Parving, Birger Thorsteinsson, Lise Tarnow
Journal: The Lancet Diabetes & Endocrinology (2014)
GLI1 genotypes do not predict basal cell carcinoma risk: a case control study
Authors: Andrea Watson, Paul Kent, Murad Alam, Amy S Paller, David M Umbach, Joon Won Yoon, Philip M Iannaccone, David O Walterhouse
Journal: Molecular Cancer (2009)

Abstract Background Susceptibility to basal cell carcinoma results from complex interactions between ultraviolet radiation exposure and genetic factors. The GLI1 oncogene is believed to play a role in the genesis of these tumors. We determined whether GLI1 polymorphisms were risk factors for developing basal cell carcinoma, either alone or in combination with patterns of past sun exposure, and whether there were functional differences among different GLI1 haplotypes. Results GLI1 genotypes at c.2798 and c.3298 from 201 basal cell carcinoma patients were compared to 201 age and sex-matched controls. Neither genotype nor haplotype frequencies differed between cases and controls. However, the odds of developing basal cell carcinoma on the trunk compared to the head/neck appeared somewhat lower with carriers of the c.3298GC than the CC genotype. There was no evidence for interactions between skin type, childhood sunburning, average adult sun exposure, adult sunbathing, or intermittency of sun exposure and GLI1 haplotype. Additionally, we found no significant differences in transcription activation or cell transforming ability among the four GLI1 haplotypes. Conclusion These results suggest that different GLI1 genotypes alone or in combination with past sun exposure patterns as assessed in this study do not affect basal cell carcinoma risk.
Chronic diarrhoea after allogenic bone marrow transplantation
Authors: B Radu
Journal: Gut (2004)

Background: Many determinants for a sustained response to lamivudine therapy have been reported but the role of T cell responsiveness remains unclear.The finding that tyrosine-methionine-aspartate-aspartate (YMDD) motif of the reverse transcriptase domain of hepatitis B virus (HBV) DNA polymerase carries a HLA-A2 restricted cytotoxic T lymphocyte (CTL) epitope makes quantitative measurement of the numbers of peptide specific CTLs feasible using MHC tetramer-peptide complex staining.Aim: To investigate the correlation between anti-YMDD motif CTL activity and the efficacy of lamivudine therapy in HLA-A2 positive patients with chronic hepatitis B (CH-B).Methods: The function and phenotype of peptide and interleukin 2 expanded peripheral blood mononuclear cells were quantified by cell lytic assay and immunocytochemical analysis by staining with HLA-A2-peptide tetramer complexes.Results: After in vitro expansion, sustained responders had more potent CTL responses against YMDD, YVDD, and YIDD, as well as other epitopes on HBV antigens than non-responders.The frequency of YMDD/YVDD/YIDD motif specific CTLs increased significantly with an effective cell lytic function during and after therapy in sustained responders but not in non-responders.YMDD specific CTLs cross reacted with YIDD and YVDD mutant epitopes, and shared T cell receptor gene usages with YIDD and YVDD specific CTLs.Conclusions: Sustained responders, at least HLA-A2 patients, elicited a more potent CTL immunity against YMDD and its mutants.YMDD specific CTLs are cross reactive with YVDD and YIDD mutant epitopes, which may further contribute to immune clearance of the mutant viruses and a successful response to lamivudine therapy in CH-B patients.www.gutjnl.com
Anatomic Bladder Neck Preservation During Robotic-Assisted Laparoscopic Radical Prostatectomy: Description of Technique and Outcomes
Authors: Marcos P. Freire, Aaron C. Weinberg, Yin Lei, Jane R. Soukup, Stuart R. Lipsitz, Sandip M. Prasad, Fernando Korkes, Tiffany Lin, Jim C. Hu
Journal: European Urology (2009)
Anti‐ENA Antibody in Serum Determined by ELISA‐Technique
Authors: J. Struckmann, R. Manthorpe, G. Bendixen
Journal: Allergy (1981)

An enzyme linked immune sorbent assay, ELISA, for determination of serum antibodies against two different extractable nuclear antigens, the RNAse sensitive ribonucleoprotein (RNP), and the RNAse resistant Sm‐antigen is described. The technical variables are systematically evaluated and a recommended procedure selected and described.
Bak deficiency inhibits liver carcinogenesis: A causal link between apoptosis and carcinogenesis
Authors: Hayato Hikita, Takahiro Kodama, Satoshi Shimizu, Wei Li, Minoru Shigekawa, Satoshi Tanaka, Atsushi Hosui, Takuya Miyagi, Tomohide Tatsumi, Tatsuya Kanto, Naoki Hiramatsu, Eiichi Morii, Norio Hayashi, Tetsuo Takehara
Journal: Journal of Hepatology (2012)
Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury
Authors: Keiichi Hishikari, Jun-ichi Suzuki, Masahito Ogawa, Kazuya Isobe, Teisuke Takahashi, Michihito Onishi, Kiyoshi Takayama, Mitsuaki Isobe
Journal: Cardiovascular Research (2008)

AimsIncreased expression of several subtypes of prostaglandin E2 receptors (EP1–4) has recently been described in clinical and experimental myocardial ischaemia/reperfusion (I/R) injury. However, their pathophysiological significance in I/R remains obscure. Thus, we determined whether the activation of the prostanoid receptor, EP4, suppresses myocardial I/R injury.
Histochemical properties of upper airway muscles: comparison of dilator and nondilator muscles
Authors: A Bracher, R Coleman, R Schnall, A Oliven
Journal: European Respiratory Journal (1997)

The upper airway dilator muscles (UADMs) represent a subgroup of muscles in the pharyngeal area which, in addition to their roles in mastication, vocalization, etc., also have an important respiratory function. Failure of these muscles to maintain upper airway patency during sleep is important in the development of the obstructive sleep apnoea syndrome. In the present study, we evaluated the histochemical properties of the UADMs and compared them to those of neighbouring muscles without respiratory functions, and to the diaphragm, to determine whether the UADMs are specifically adapted to their respiratory role. Our results, both in dogs and rats, indicate that the dilator and nondilator upper airway muscles are similar and differ from the diaphragm. In rats, there were significantly less type I fibres (&lt;12% as compared to 42% for the diaphragm) and more type IIb fibres (39-67% as compared to 27% for the diaphragm). A similar pattern was seen in dogs: type I fibres &lt;38% as compared to 46% for the diaphragm, and type IIb fibres, 29-35% as compared to 10% for the diaphragm. These findings suggest that the upper airway dilator muscles are not specifically designed for their respiratory role. They may fail in the presence of increased loads, often encountered in patients with obstructive sleep apnoea, unless appropriate adaptive structural changes take place.