tbuckley/cabot-search huggingface dataset:
Development of Human Anti-Murine T-Cell Receptor Antibodies in Both Responding and Nonresponding Patients Enrolled in TCR Gene Therapy Trials
Authors: Jeremy L. Davis, Marc R. Theoret, Zhili Zheng, Cor H.J. Lamers, Steven A. Rosenberg, Richard A. Morgan
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Immune responses to gene-modified cells are a concern in the field of human gene therapy, as they may impede effective treatment. We conducted 2 clinical trials in which cancer patients were treated with lymphocytes genetically engineered to express murine T-cell receptors (mTCR) specific for tumor-associated antigens p53 and gp100. Experimental Design: Twenty-six patients treated with autologous lymphocytes expressing mTCR had blood and serum samples available for analysis. Patient sera were assayed for the development of a humoral immune response. Adoptive cell transfer characteristics were analyzed to identify correlates to immune response. Results: Six of 26 (23%) patients' posttreatment sera exhibited specific binding of human anti-mTCR antibodies to lymphocytes transduced with the mTCR. Antibody development was found in both responding and nonresponding patients. The posttreatment sera of 3 of these 6 patients mediated a 60% to 99% inhibition of mTCR activity as measured by a reduction in antigen-specific interferon-γ release. Detailed analysis of posttreatment serum revealed that antibody binding was β-chain specific in 1 patient whereas it was α-chain specific in another. Conclusions: A subset of patients treated with mTCR-engineered T cells developed antibodies directed to the mTCR variable regions and not to the constant region domains common to all mTCR. Overall, the development of a host immune response was not associated with the level of transduced cell persistence or response to therapy. In summary, patients treated with mTCR can develop an immune response to gene-modified cells in a minority of cases, but this may not affect clinical outcome. Clin Cancer Res; 16(23); 5852–61. ©2010 AACR.
Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sézary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor.
Authors: T A Waldmann, W C Greene, P S Sarin, C Saxinger, D W Blayney, W A Blattner, C K Goldman, K Bongiovanni, S Sharrow, J M Depper
Journal: Journal of Clinical Investigation (1984)

Adult T cell leukemia (ATL) and Sézary leukemia are malignant proliferations of T lymphocytes that share similar cell morphology and clinical features. ATL is associated with HTLV (human T cell leukemia/lymphoma virus), a unique human type C retrovirus, whereas most patients with the Sézary syndrome do not have antibodies to this virus. Leukemic cells of both groups were of the T3, T4-positive, T8-negative phenotype. Despite the similar phenotype, HTLV-negative Sézary leukemic cells frequently functioned as helper cells, whereas some HTLV-positive ATL and HTLV-positive Sézary cells appeared to function as suppressors of immunoglobulin synthesis. One can distinguish the HTLV-positive from the HTLV-negative leukemias using a monoclonal antibody (anti-Tac) that appears to identify the human receptor for T cell growth factor (TCGF). Resting normal T cells and most HTLV-negative Sézary cells were Tac-negative, whereas all ATL cell populations were Tac-positive. The observation that ATL cells manifest TCGF receptors suggests the possibility that an abnormality of the TCGF-TCGF receptor system may partially explain the uncontrolled growth of these cells.
Moderators of Outcome in Late-Life Depression: A Patient-Level Meta-Analysis
Authors: J. Craig Nelson, Kevin L. Delucchi, Lon S. Schneider
Journal: American Journal of Psychiatry (2013)

Age at onset, severity of symptoms, and illness duration are all important moderators in tailoring depression treatment. This meta-analysis found that antidepressants were not effective in elderly patients with late-onset depression of short duration, but they were effective in patients with a longer duration of illness that was at least moderately severe.
Mechanisms of remote myocardial dysfunction during coronary artery occlusion in the presence of multivessel disease.
Authors: D C Homans, E Sublett, K J Elsperger, J S Schwartz, R J Bache
Journal: Circulation (1986)

Myocardial dysfunction may occur in areas remote from an acutely occluded coronary artery if those areas are served by a critically stenosed vessel. Although subendocardial hypoperfusion of such remote myocardium has been demonstrated in experimental preparations of this situation, this study was undertaken to determine whether actual reductions in subendocardial perfusion below control levels were necessary for such dysfunction to occur. A 20 mg dose of pentobarbital was injected into the left anterior descending artery (LAD) in 14 anesthetized dogs to create a large anterior regional wall motion abnormality without drawing significant collateral flow from the circumflex vascular bed. Circumflex subendocardial flow was found to rise during injections of pentobarbital and occlusion of the LAD (1.12 +/- 0.38 and 1.17 +/- 0.34 ml/min/g, respectively, vs control 0.91 +/- 0.23 ml/min/g; p less than .05) in the absence of circumflex stenosis. In the presence of circumflex stenosis, circumflex subendocardial flow fell during left anterior descending occlusion (0.59 +/- 0.21 vs 0.89 +/- 0.19 ml/min/g control; p less than .01) but did not change during pentobarbital injections in the LAD (0.77 +/- 0.36 ml/min/g). In the absence of circumflex stenosis, circumflex segment shortening increased during injection of pentobarbital or occlusion of the LAD (14.3 +/- 4.9% and 14.4 +/- 3.5%, respectively, vs 12.3 +/- 3.3% control). In the presence of circumflex stenosis, it did not change (12.5 +/- 4.0% pentobarbital, 11.8 +/- 3.6 LAD occlusion vs 13.1 +/- 4.0% control). We concluded that the presence of large regional wall motion abnormalities may increase the oxygen consumption of remaining myocardium and that dysfunction of that myocardium may result from relative hypoperfusion if blood flow cannot increase appropriately.
RETRACTED: Biomechanical and biocompatibility characteristics of electrospun polymeric tracheal scaffolds
Authors: Fatemeh Ajalloueian, Mei Ling Lim, Greg Lemon, Johannes C. Haag, Ylva Gustafsson, Sebastian Sjöqvist, Antonio Beltrán-Rodríguez, Costantino Del Gaudio, Silvia Baiguera, Alessandra Bianco, Philipp Jungebluth, Paolo Macchiarini
Journal: Biomaterials (2014)
Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population
Authors: G-Q Wang
Journal: Gut (2005)

Oesophageal squamous cell carcinoma (OSCC) has a very poor prognosis, which is largely due to late diagnosis. Successful early detection strategies will require identification of clinically relevant precursor lesions that can be targets for screening and treatment.To identify the clinically relevant histological precursors of OSCC.A cohort of 682 endoscoped patients from a high risk rural population in Linxian, China.Subjects were endoscoped and biopsied at baseline and followed for 13.5 years. We estimated the relative risk of developing OSCC for each of the initial histological diagnoses using Cox proportional hazards regression models.A total of 114 (16.7%) patients developed OSCC during the follow up period. After adjusting for potential confounding factors, relative risks (95% confidence intervals) for incidence of this tumour, by initial histological diagnosis, were: normal 1.0 (reference), oesophagitis 0.8 (0.2-3.2), basal cell hyperplasia 1.9 (0.8-4.5), mild dysplasia 2.9 (1.6-5.2), moderate dysplasia 9.8 (5.3-18.3), severe dysplasia 28.3 (15.3-52.3), and carcinoma in situ 34.4 (16.6-71.4).In this study, squamous dysplasia and carcinoma in situ were the only histological lesions associated with a significantly increased risk of developing OSCC within 13.5 years after endoscopy. There was no evidence that oesophagitis predisposed to this tumour. Increasing grades of dysplasia were strongly associated with increasing risk, indicating that the histological grading was clinically meaningful. The follow up experience of severe dysplasia and carcinoma in situ was equivalent, suggesting that this distinction is not clinically relevant. Documenting these precursor lesions of OSCC should assist in the development of effective prevention, early detection, and treatment strategies for this disease.
Effect of recombinant human erythropoietin treatment on circulating reticulated platelets in uremic patients: Association with early improvement in platelet function
Authors: Dolors Tàssies, Joan Carles Reverter, Aleix Cases, Jordi Calls, Ginés Escolar, Antonio Ordinas
Journal: American Journal of Hematology (1998)

Recombinant human erythropoietin improves platelet function in uremia through the correction of anemia, but this effect can be seen also before the hematocrit rise. We studied 12 hemodialyzed patients (seven men, five women) who received recombinant human erythropoietin (40 IU kg(-1)i.v., three times weekly) and were evaluated before treatment and after three doses; 24 control subjects were used. Platelet aggregation induced by adenosine 5'-diphosphate (ADP), epinephrine, collagen, arachidonic acid, and ristocetin, and reticulated platelets determined by flow cytometry after staining with thiazole orange were measured. Platelet aggregation induced by all the agonists were impaired in uremic patients (P < 0.01), but ADP and ristocetin-induced aggregations improved after treatment (P < 0.01). Hemodialyzed patients had less reticulated platelets than controls (P < 0.01). Reticulated platelets increased after three doses of treatment (P < 0.01). In conclusion, improvement of platelet function at early stages of recombinant human erythropoietin treatment may be attributed to the increase in young platelets detected as reticulated platelets.
Generation of Functional Cardiomyocytes From Adult Mouse Spermatogonial Stem Cells
Authors: Kaomei Guan, Stefan Wagner, Bernhard Unsöld, Lars S. Maier, Diana Kaiser, Bernhard Hemmerlein, Karim Nayernia, Wolfgang Engel, Gerd Hasenfuss
Journal: Circulation Research (2007)

Stem cell–based therapy is a promising approach for the treatment of heart failure. Adult stem cells with the pluripotency of embryonic stem cells (ESCs) would be an ideal cell source. Recently, we reported the successful establishment of multipotent adult germline stem cells (maGSCs) from mouse testis. These cultured maGSCs show phenotypic characteristics similar to ESCs and can spontaneously differentiate into cells from all 3 germ layers. In the present study, we used the hanging drop method to differentiate maGSCs into cardiomyocytes and analyzed their functional properties. Differentiation efficiency of beating cardiomyocytes from maGSCs was similar to that from ESCs. The maGSC-derived cardiomyocytes expressed cardiac-specific L-type Ca 2+ channels and responded to Ca 2+ channel–modulating drugs. Cx43 was expressed at cell-to-cell contacts in cardiac clusters, and fluorescence recovery after photobleaching assay showed the presence of functional gap junctions among cardiomyocytes. Action potential analyses demonstrated the presence of pacemaker-, ventricle-, atrial-, and Purkinje-like cardiomyocytes. Stimulation with isoproterenol resulted in a significant increase in beating frequency, whereas the addition of cadmium chloride abolished spontaneous electrical activity. Confocal microscopy analysis of intracellular Ca 2+ in maGSC-derived cardiomyocytes showed that calcium increased periodically throughout the cell in a homogenous fashion, pointing to a fine regulated Ca 2+ release from intracellular Ca 2+ stores. By using line-scan mode, we found rhythmic Ca 2+ transients. Furthermore, we transplanted maGSCs into normal hearts of mice and found that maGSCs were able to proliferate and differentiate. No tumor formation was found up to 1 month after cell transplantation. Taken together, we believe that maGSCs provide a new source of distinct types of cardiomyocytes for basic research and potential therapeutic application.
MicroRNA Expression Abnormalities in Pancreatic Endocrine and Acinar Tumors Are Associated With Distinctive Pathologic Features and Clinical Behavior
Authors: Claudia Roldo, Edoardo Missiaglia, John P. Hagan, Massimo Falconi, Paola Capelli, Samantha Bersani, George Adrian Calin, Stefano Volinia, Chang-Gong Liu, Aldo Scarpa, Carlo M. Croce
Journal: Journal of Clinical Oncology (2006)

We investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumors and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumor types. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs can contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies.Using a custom microarray, we studied the global microRNA expression in 12 nontumor pancreas and 44 pancreatic primary tumors, including 12 insulinomas, 28 nonfunctioning endocrine tumors, and four acinar carcinomas.Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis.These results suggest that alteration in microRNA expression is related to endocrine and acinar neoplastic transformation and progression of malignancy, and might prove useful in distinguishing tumors with different clinical behavior.
Back and leg pain and directional preference exercises
Authors: Stephen May
Journal: British Journal of Sports Medicine (2011)

Lecture 13 Directional preference exercises are determined during the physical examination of patients with back pain and referred pain from the spine with the use of repeated movements by the patient. There maybe clues to this found during the history taking, such as the patient indicates they are better when walking and worse when sitting – this could be a clue to a favourable response to extension activity and negative response to flexion activity. This would be explored in the physical examination by testing out the response to repeated extension exercises. If the patient reported centralisation of pain, which is the abolition of distal symptoms, or a decrease in symptom intensity or abolition of symptoms in response to the repeated movement they would be deemed to have a directional preference for extension exercises. These would prescribed for the patient self-management exercises. There is considerable evidence supporting the favourable long-term prognosis associated with centralisation. Furthermore there is evidence to support the use of directional preference exercises in favour of non-specific exercises. This presentation will examine the evidence for directional preference in general, but also specifically as it relates to patients who present with back pain and referred symptoms. The evidence provided will demonstrate the value of directional preference exercises for this group of patients in the athletic and non-athletic populations.
Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition
Authors: Richard D. Carvajal, Donald P. Lawrence, Jeffrey S. Weber, Thomas F. Gajewski, Rene Gonzalez, Jose Lutzky, Steven J. O'Day, Omid Hamid, Jedd D. Wolchok, Paul B. Chapman, Ryan J. Sullivan, Jerrold B. Teitcher, Nikhil Ramaiya, Anita Giobbie-Hurder, Cristina R. Antonescu, Michael C. Heinrich, Boris C. Bastian, Christopher L. Corless, Jonathan A. Fletcher, F. Stephen Hodi
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. Experimental Design: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. Results: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%–56%] and 1 on cohort B (12.5%; 90% CI, 0.6%–47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%–47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1–3.9 months) and 9.1 months (90% CI, 4.3–14.2 months), respectively, in all treated patients. Conclusions: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited. Clin Cancer Res; 21(10); 2289–96. ©2015 AACR.
Role of Noninvasive Testing in the Clinical Evaluation of Women With Suspected Coronary Artery Disease
Authors: Jennifer H. Mieres, Leslee J. Shaw, Andrew Arai, Matthew J. Budoff, Scott D. Flamm, W. Gregory Hundley, Thomas H. Marwick, Lori Mosca, Ayan R. Patel, Miguel A. Quinones, Rita F. Redberg, Kathryn A. Taubert, Allen J. Taylor, Gregory S. Thomas, Nanette K. Wenger
Journal: Circulation (2005)

Cardiovascular disease is the leading cause of mortality for women in the United States. Coronary heart disease, which includes coronary atherosclerotic disease, myocardial infarction, acute coronary syndromes, and angina, is the largest subset of this mortality, with &gt;240 000 women dying annually from the disease. Atherosclerotic coronary artery disease (CAD) is the focus of this consensus statement. Research continues to report underrecognition and underdiagnosis of CAD as contributory to high mortality rates in women. Timely and accurate diagnosis can significantly reduce CAD mortality for women; indeed, once the diagnosis is made, it does appear that current treatments are equally effective at reducing risk in both women and men. As such, noninvasive diagnostic and prognostic testing offers the potential to identify women at increased CAD risk as the basis for instituting preventive and therapeutic interventions. Nevertheless, the recent evidence-based practice program report from the Agency for Healthcare Research and Quality noted the paucity of women enrolled in diagnostic research studies. Consequently, much of the evidence supporting contemporary recommendations for noninvasive diagnostic studies in women is extrapolated from studies conducted predominantly in cohorts of middle-aged men. The majority of diagnostic and prognostic evidence in cardiac imaging in women and men has been derived from observational registries and referral populations that are affected by selection and other biases. Thus, a better understanding of the potential impact of sex differences on noninvasive cardiac testing in women may greatly improve clinical decision making. This consensus statement provides a synopsis of available evidence on the role of the exercise ECG and cardiac imaging modalities, both those in common use as well as developing technologies that may add clinical value to the diagnosis and risk assessment of the symptomatic and asymptomatic woman with suspected CAD.
Genomic analysis of emerging pathogens: methods, application and future trends
Authors: Lucy M Li, Nicholas C Grassly, Christophe Fraser
Journal: Genome biology (2014)

The number of emerging infectious diseases is increasing. Characterizing novel or re-emerging infections is aided by the availability of pathogen genomes. In this review, we evaluate methods that exploit pathogen sequences and the contribution of genomic analysis to understand the epidemiology of recently emerged infectious diseases.
miR-150 regulates the development of NK and iNKT cells
Authors: Natalie A. Bezman, Tirtha Chakraborty, Timothy Bender, Lewis L. Lanier
Journal: The Journal of Experimental Medicine (2011)

Natural killer (NK) and invariant NK T (iNKT) cells are critical in host defense against pathogens and for the initiation of adaptive immune responses. miRNAs play important roles in NK and iNKT cell development, maturation, and function, but the roles of specific miRNAs are unclear. We show that modulation of miR-150 expression levels has a differential effect on NK and iNKT cell development. Mice with a targeted deletion of miR-150 have an impaired, cell lineage–intrinsic defect in their ability to generate mature NK cells. Conversely, a gain-of-function miR-150 transgene promotes the development of NK cells, which display a more mature phenotype and are more responsive to activation. In contrast, overexpression of miR-150 results in a substantial reduction of iNKT cells in the thymus and in the peripheral lymphoid organs. The transcription factor c-Myb has been shown to be a direct target of miR-150. Our finding of increased NK cell and decreased iNKT cell frequencies in Myb heterozygous bone marrow chimeras suggests that miR-150 differentially controls the development of NK and iNKT cell lineages by targeting c-Myb.
Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer
Authors: G Feldmann, N Habbe, S Dhara, S Bisht, H Alvarez, V Fendrich, R Beaty, M Mullendore, C Karikari, N Bardeesy, M M Ouellette, W Yu, A Maitra
Journal: Gut (2008)

<h3>Background and aims:</h3> Pancreatic cancer is among the most dismal of human malignancies. Current therapeutic strategies are virtually ineffective in controlling advanced, metastatic disease. Recent evidence suggests that the Hedgehog signalling pathway is aberrantly reactivated in the majority of pancreatic cancers, and that Hedgehog blockade has the potential to prevent disease progression and metastatic spread. <h3>Methods:</h3> Here it is shown that the Hedgehog pathway is activated in the Pdx1-Cre;LsL-Kras<sup>G12D</sup>;Ink4a/Arf<sup>lox/lox</sup> transgenic mouse model of pancreatic cancer. The effect of Hedgehog pathway inhibition on survival was determined by continuous application of the small molecule cyclopamine, a smoothened antagonist. Microarray analysis was performed on non-malignant human pancreatic ductal cells overexpressing Gli1 in order to screen for downstream Hedgehog target genes likely to be involved in pancreatic cancer progression. <h3>Results:</h3> Hedgehog inhibition with cyclopamine significantly prolonged median survival in the transgenic mouse model used here (67 vs 61 days; p = 0.026). In vitro data indicated that Hedgehog activation might at least in part be ascribed to oncogenic Kras signalling. Microarray analysis identified 26 potential Hedgehog target genes that had previously been found to be overexpressed in pancreatic cancer. Five of them, BIRC3, COL11A1, NNMT, PLAU and TGM2, had been described as upregulated in more than one global gene expression analysis before. <h3>Conclusion:</h3> This study provides another line of evidence that Hedgehog signalling is a valid target for the development of novel therapeutics for pancreatic cancer that might be worth evaluating soon in a clinical setting.