tbuckley/cabot-search huggingface dataset:
Cyclophosphamide Facilitates Antitumor Efficacy against Subcutaneous Tumors following Intravenous Delivery of Reovirus
Authors: Jian Qiao, Hongxun Wang, Timothy Kottke, Christine White, Katie Twigger, Rosa Maria Diaz, Jill Thompson, Peter Selby, Johann de Bono, Alan Melcher, Hardev Pandha, Matt Coffey, Richard Vile, Kevin Harrington
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The purpose of the present study was to investigate whether it is possible to achieve truly systemic delivery of oncolytic reovirus, in immunocompetent hosts, using cyclophosphamide to overcome some of the barriers to effective intratumoral delivery and replication of i.v. injected virus. Experimental Design: I.v. delivery of reovirus was combined with different regimens of i.p. administered cyclophosphamide in C57Bl/6 mice bearing established s.c. B16 tumors. Intratumoral viral replication, tumor size, and survival were measured along with levels of neutralizing antibody (NAb) in the blood. Finally, differential toxicities of the virus/cyclophosphamide regimens were monitored through viral replication in systemic organs, survival, and cardiac damage. Results: Repeated i.v. injection of reovirus was poorly effective at seeding intratumoral viral replication/oncolysis. However, by combining i.v. virus with cyclophosphamide, viral titers of between 107 and 108 plaque-forming units per milligram were recovered from regressing tumors. Doses of cyclophosphamide that ablated NAb were associated with severe toxicities, characterized by viral replication in systemic organs—toxicities that are mirrored by repeated reovirus injections into B-cell knockout mice. Next, we restructured the dosing of cyclophosphamide and i.v. virus such that a dose of 3 mg cyclophosphamide was administered 24 h before reovirus injection, and this schedule was repeated every 6 days. Using this protocol, high levels of intratumoral viral access and replication (∼107 plaque-forming units per milligram tumor) were maintained along with systemically protective levels of NAb and only very mild, non–life-threatening toxicity. Conclusion: NAb to oncolytic viruses play a dual role in the context of systemic viral delivery; on one hand, they hinder repeated administration of virus but on the other, they provide an important safety mechanism by which virus released from vigorous intratumoral replication is neutralized before it can disseminate and cause toxicity. These data support the use of cyclophosphamide to modulate, but not ablate, patient NAb, in development of carefully controlled clinical trials of the systemic administration of oncolytic viruses.
Is a functional variant of ANXA11 R230C associated with impaired apoptosis? Pilot data
Authors: Regina Fillerova, Frantisek Mrazek, Monika Zurkova, Vitezslav Kolek, Martin Petrek, Eva Kriegova
Journal: European Respiratory Journal (2012)

Sarcoidosis is a granulomatous disorder of an unknown etiology, where the granuloma formation has been associated with impaired apoptosis of activated inflammatory cells. There is no information concerning the influence of  ANXA11  R230C, a functional annexin A11 variant associated with protection/disease modification of sarcoidosis, on the sensitivity of peripheral blood mononuclear cells (PBMC) to apoptosis yet.  We therefore compared the sensitivity to apoptosis of PBMC obtained from 30 sarcoid patients and 9 healthy controls. Tributyltin was used as apoptosis stimulus; annexin V positive cells were detected by flow cytometry. Pilot analysis was performed in subgroups according to ANXA11 R230C (rs1049550) genotype (TT, n=7; CC, n=7).  When compared to healthy controls, lower number of annexin V positive cells was detected in tributyltin-stimulated PBMC from sarcoid patients (mean 55.9%; range 23.3–77.2%) than in cells from controls (64.8%; 54.7–74.1%; p=0.01). After subdivision according to genotypes, the number of annexin V positive cells did not differ between patients carrying TT genotype (50.8%; 23.3–58.8%) and those with CC genotype (54.5%; 41.7–71.7%; p>0.05). Genotyping and investigations on association between apoptosis and genotypes in larger patient/control groups are under progress.  In conclusion, PBMC obtained from sarcoidosis patients showed more apoptosis resistant phenotype than cells from control subjects. In our pilot cohort, wild type  ANXA11  genotype and its R230C variant did not differ in terms of sensitivity to apoptosis. Further studies in a larger patient cohort are ongoing.Grant support: IGA MZ CR NS/11117, IGA_PU_LF_2012_07, CZ.1.05/2.1.00/01.0030.
Postoperative Irradiation with or without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer
Authors: Jacques Bernier, Christian Domenge, Mahmut Ozsahin, Katarzyna Matuszewska, Jean-Louis Lefèbvre, Richard H. Greiner, Jordi Giralt, Philippe Maingon, Frédéric Rolland, Michel Bolla, Francesco Cognetti, Jean Bourhis, Anne Kirkpatrick, Martine van Glabbeke
Journal: New England Journal of Medicine (2004)

We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer.
Sinusal localization of nodal micrometastases is a prognostic factor in breast cancer
Authors: G. Masci, L. Di Tommaso, I. Del Prato, S. Orefice, A. Rubino, G. Gullo, M. Zuradelli, R. Sacco, M. Alloisio, M. Eboli, M. Incarbone, L. Giordano, M. Roncalli, A. Santoro
Journal: Annals of Oncology (2009)
Polyunsaturated Fat Intake Estimated by Circulating Biomarkers and Risk of Cardiovascular Disease and All-Cause Mortality in a Population-Based Cohort of 60-Year-Old Men and Women
Authors: Matti Marklund, Karin Leander, Max Vikström, Federica Laguzzi, Bruna Gigante, Per Sjögren, Tommy Cederholm, Ulf de Faire, Mai-Lis Hellénius, Ulf Risérus
Journal: Circulation (2015)

High intake of polyunsaturated fatty acids (PUFAs) may reduce the risk of cardiovascular disease (CVD) and mortality. Large, prospective studies including both sexes and circulating PUFAs as dietary biomarkers are needed. We investigated sex-specific associations of the major dietary PUFAs, eicosapentaenoic acid, docohexaenoic acid, linoleic acid, and α-linolenic acid, with incident CVD and all-cause mortality in a population-based cohort.PUFAs in serum cholesterol esters were measured at baseline in 60-year-old Swedish women (n=2193) and men (n=2039). With the use of national registers, 484 incident CVD events (294 men and 190 women) and 456 all-cause deaths (265 men and 191 women) were identified during follow-up (median, 14.5 years) in individuals without prior CVD at baseline. Associations of PUFAs with CVD and mortality were evaluated with Cox proportional hazard models. In multivariable-adjusted models, 1-SD increases in eicosapentaenoic acid and docohexaenoic acid were associated with lower risk of incident CVD among women (hazard ratio [HR], 0.79 [95% confidence interval (CI), 0.64-0.97] and 0.74 [95% CI, 0.61-0.89], respectively). α-Linolenic acid was associated with moderately increased CVD risk in women (HR, 1.16; 95% CI, 1.02-1.32). Inverse associations with all-cause mortality were observed for eicosapentaenoic acid and docohexaenoic acid among all participants (HR, 0.81 [95% CI, 0.72-0.91] and 0.80 [95% CI, 0.72-0.89], respectively) and for linoleic acid in men (HR, 0.73; 95% CI, 0.64-0.83).Serum linoleic acid and very-long-chain n-3 PUFAs, partly reflecting vegetable oil and fish intake, respectively, were inversely associated with all-cause mortality. Inverse associations of eicosapentaenoic acid and docohexaenoic acid with incident CVD were observed only in women.
Benefits and problems of a physical training programme for asthmatic patients.
Authors: L M Cochrane, C J Clark
Journal: Thorax (1990)

The clinical and physiological effects of a medically supervised, indoor physical training programme were investigated in 36 asthmatic subjects aged 16-40 years. After clinical evaluation, lung function assessment, and progressive incremental exercise testing subjects were randomly allocated to control and training groups. The measurements were repeated after a six week run in period and after a further three months in which those in the training group underwent an indoor training programme. The measurements made at three months were compared with those at the end of the run in period. There was no significant change in anthropometric characteristics, blood lipid profiles, or the provocative concentration of histamine causing a 20% fall in FEV1 (histamine PC20) in the group who underwent training. After training there were significant increases in mean maximal oxygen uptake (ml kg-1 min-1) from 23 (5) to 28 (6), oxygen pulse (ml/beat) from 8.8 (2.3) to 10.8 (2.4), and anaerobic threshold (1/min) from 1.11 (0.27) to 1.38 (0.33). These changes were significantly greater in the group undergoing training than in the control group. There was also a significant fall in breathlessness scores (Borg ratings), blood lactate, carbon dioxide output, and minute ventilation during submaximal exercise in the training group, with no change in the control group. The subject9s motivation, the initial level of fitness, and the symptom score at the time of training were the most important factors influencing improvements in cardiorespiratory fitness. Thus submaximal physical exercise of controlled intensity, sustained for three months, produced significant improvements in fitness and cardiorespiratory performance that should be advantageous to the exercising asthmatic patient. The availability of medical supervision throughout the exercise programme appears to have contributed to the successful outcome.
Analysis of Thymocyte Development Reveals That the Gtpase Rhoa Is a Positive Regulator of T Cell Receptor Responses in Vivo
Authors: Isabelle Corre, Manuel Gomez, Susina Vielkind, Doreen A. Cantrell
Journal: The Journal of Experimental Medicine (2001)

Loss of function of the guanine nucleotide binding protein RhoA blocks pre-T cell differentiation and survival indicating that this GTPase is a critical signaling molecule during early thymocyte development. Previous work has shown that the Rho family GTPase Rac-1 can initiate changes in actin dynamics necessary and sufficient for pre-T cell development. The present data now show that Rac-1 actions in pre-T cells require Rho function but that RhoA cannot substitute for Rac-1 and induce the actin cytoskeletal changes necessary for pre-T cell development. Activation of Rho is thus not sufficient to induce pre-T cell differentiation or survival in the absence of the pre-T cell receptor (TCR). The failure of RhoA activation to impact on pre-TCR–mediated signaling was in marked contrast to its actions on T cell responses mediated by the mature TCR α/β complex. Cells expressing active RhoA were thus hyperresponsive in the context of TCR-induced proliferation in vitro and in vivo showed augmented positive selection of thymocytes expressing defined TCR complexes. This reveals that RhoA function is not only important for pre-T cells but also plays a role in determining the fate of mature T cells.
Impact of Treatment with Calcimimetics on Hyperparathyroidism and Vascular Mineralization
Authors: Angel L.M. de Francisco, Celestino Piñera, Rosa Palomar, Manuel Arias
Journal: Journal of the American Society of Nephrology (2006)

Soft tissue calcification that involves primarily the medial portion of the arterial vasculature is a widely recognized and common complication of chronic kidney disease Vascular calcification (VC) causes increased arterial stiffness and contributes to the high cardiovascular mortality and morbidity in dialysis patients. The pathogenesis of VC is complex and includes factors that promote calcification and others that inhibit calcification. Studies in dialysis patients have shown a correlation between VC and a number of uremia-related factors. Overall, abnormalities in calcium and phosphate metabolism, such as hyperphosphatemia and a raised serum calcium-phosphorus product traditionally have been thought of as important determinants in patients with chronic renal failure. Common therapeutic interventions in secondary hyperparathyroidism have come under scrutiny for associations with the development of VC. Calcimimetics provide a means of controlling serum levels of parathyroid hormone in secondary hyperparathyroidism without increasing the calcium-phosphorus product and, more important, may lower the risk for VC in these patients.
Myoblast transfer of human erythropoietin gene in a mouse model of renal failure.
Authors: Y Hamamori, B Samal, J Tian, L Kedes
Journal: Journal of Clinical Investigation (1995)

Anemia is an invariable consequence of end-stage renal failure (ESRF) and recombinant erythropoietin has dramatically improved the quality of life of patients with ESRF. As an alternative approach, we developed a myoblast gene transfer system for the systemic delivery of human erythropoietin (EPO). We recently reported that transplantation of 4 x 10(7) cells of a C2 myoblast cell clone that stably secretes high level of functional human EPO, increased hematocrit from 44.6 +/- 3.0 to 71.2 +/- 7.9(%) in 2 wk, and the increase was sustained for at least 12 wk in nude mice. A renal failure model was created by a two-step nephrectomy in nude mice, and myoblasts were transplanted 3 wk after the second nephrectomy, when mean blood urea nitrogen level had increased from 26.3 +/- 6.1 to 85.4 +/- 24.0 (mg/dl) and the hematocrit had decreased from 45.2 +/- 2.7 to 33.9 +/- 3.7(%). After transplantation, the hematocrit markedly increased to 68.6 +/- 4.2(%) 2 wk, and to 68.5 +/- 4.0(%) 7 wk after the transplantation. Serum human EPO concentration determined by ELISA indicated a persistent steady EPO production from the transplanted muscle cells 8 wk after the transplantation. The fate of transplanted myoblasts in uremic mice was monitored by transplanting the EPO-secreting clone which had also been transduced with BAG retrovirus bearing the beta-galactosidase gene. 8 wk later, X-gal positive myofibers were detected in the entire transplanted area. The results demonstrate that myoblasts can be transplanted in uremic mice, and that myoblast gene transfer can achieve sufficient and sustained delivery of functionally active EPO to correct anemia associated with renal failure in mice.
Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme
Authors: Ren-Yuan Bai, Verena Staedtke, Colette M. Aprhys, Gary L. Gallia, Gregory J. Riggins
Journal: Neuro-Oncology (2011)

Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer, and despite treatment advances, patient prognosis remains poor. During routine animal studies, we serendipitously observed that fenbendazole, a benzimidazole antihelminthic used to treat pinworm infection, inhibited brain tumor engraftment. Subsequent in vitro and in vivo experiments with benzimidazoles identified mebendazole as the more promising drug for GBM therapy. In GBM cell lines, mebendazole displayed cytotoxicity, with half-maximal inhibitory concentrations ranging from 0.1 to 0.3 µM. Mebendazole disrupted microtubule formation in GBM cells, and in vitro activity was correlated with reduced tubulin polymerization. Subsequently, we showed that mebendazole significantly extended mean survival up to 63% in syngeneic and xenograft orthotopic mouse glioma models. Mebendazole has been approved by the US Food and Drug Administration for parasitic infections, has a long track-record of safe human use, and was effective in our animal models with doses documented as safe in humans. Our findings indicate that mebendazole is a possible novel anti-brain tumor therapeutic that could be further tested in clinical trials.
Respiratory dysfunction in congestive heart failure: correction after heart transplantation
Authors: G Niset, V Ninane, M Antoine, JC Yernault
Journal: European Respiratory Journal (1993)

Severe chronic congestive heart failure (CCHF) is known to induce a restrictive ventilatory defect, with a small decrease in lung transfer factor for carbon monoxide (TLCO). The aim of the present work was to assess the reversibility of this dysfunction. We studied a group of 47 patients with CCHF, before and one year after heart transplantation. The measurements included static and dynamic lung volumes, TLCO and cardiac function. On initial evaluation, vital capacity (VC), total lung capacity (TLC) and TLCO were reduced to 76, 79 and 64% of the predicted value (% pred), respectively. Forced expiratory volume in one second (FEV1) was decreased to 69% pred, with a FEV1/VC ratio below 0.70 in 13 out of 47 patients. One year after transplantation, cardiac function had markedly improved, as shown by a normalized left ventricular ejection fraction (from 18% preoperatively to 59% postoperatively), and mean pulmonary wedge pressure (from 26 to 12 mmHg). At this time, VC (94% pred) and TLC (98% pred) were within the normal range, whereas TLCO remained low (67% pred). The FEV1/VC ratio did not change, even in the subgroup with an initial low value. Smoking habits did contribute to the low TLCO and FEV1/VC ratio. In conclusion, respiratory dysfunction induced by CCHF is reversible, with the exception of the reduction in TLCO, which probably reflects permanent changes in the lung vasculature. CCHF does not induce an obstructive ventilatory pattern.
Peri-ictal pseudoprogression in patients with brain tumor
Authors: S. Rheims, D. Ricard, M. van den Bent, L. Taillandier, V. Bourg, V. Desestret, S. Cartalat-Carel, M. Hermier, A. Monjour, J.-Y. Delattre, M. Sanson, J. Honnorat, F. Ducray
Journal: Neuro-Oncology (2011)

Recent advances in the treatment of malignant gliomas have highlighted the fact that the appearance of new contrast-enhancing lesions on magnetic resonance imaging (MRI) is not always indicative of tumor recurrence. It has been suggested that transient seizure-related MRI changes could mimic disease progression (peri-ictal pseudoprogression [PIPG]). However, the clinical and MRI features associated with this situation have not been well described. Here, we consulted the databases of 6 institutions to identify patients with brain tumor who presented during the follow-up period transient MRI lesions wrongly suggesting tumor progression in a context of epileptic seizures. Ten patients were identified. All patients but 1 were long-term survivors who had initially been treated with radiotherapy. The PIPG episode occurred after a median interval of 11 years after radiotherapy. MRI features were highly similar across patients and consisted of transient focal cortical and/or leptomeningeal enhancing lesions that erroneously suggested tumor progression. All patients improved after adjustment of their antiepileptic drugs and transient oral corticosteroids, and MRI findings were normalized 3 months after the PIPG episode. Two patients demonstrated several seizure relapses with the same clinicoradiological pattern. After a median follow-up period of 3.5 years after the initial PIPG episode, only 1 patient presented with a tumor recurrence. In conclusion, in patients with brain tumor, especially in long-term survivors of radiotherapy, the appearance of new cortical and/or leptomeningeal contrast-enhancing lesions in a context of frequent seizures should raise the suspicion of PIPG. This phenomenon is important to recognize in order to avoid futile therapeutic escalation.
Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts
Authors: M. Reck, F. Barlesi, L. Crinò, C.I. Henschke, D. Isla, S. Stiebeler, D.R. Spigel
Journal: Annals of Oncology (2011)

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor. Severe pulmonary haemorrhage (PH) is a rare but serious potential adverse event associated with bevacizumab therapy for advanced non-squamous non-small-cell lung cancer (NSCLC).
A Turkish family with a novel mutation in the promoter region of the C1 inhibitor gene
Authors: Suna Büyüköztürk, Belgin Kesim Eroğlu, Aslı Gelincik, Abdullah Üzümcü, Ferhan Özşeker, Bahattin Çolakoğlu, Murat Dal, Z. Oya Uyguner
Journal: Journal of Allergy and Clinical Immunology (2009)
Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer
Authors: Kevin C. Conlon, Enrico Lugli, Hugh C. Welles, Steven A. Rosenberg, Antonio Tito Fojo, John C. Morris, Thomas A. Fleisher, Sigrid P. Dubois, Liyanage P. Perera, Donn M. Stewart, Carolyn K. Goldman, Bonita R. Bryant, Jean M. Decker, Jing Chen, Tat'Yana A. Worthy, William D. Figg, Cody J. Peer, Michael C. Sneller, H. Clifford Lane, Jason L. Yovandich, Stephen P. Creekmore, Mario Roederer, Thomas A. Waldmann
Journal: Journal of Clinical Oncology (2014)

Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy.We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer.Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients.IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.
Regulation of Secondary Antigen-Specific CD8+ T-Cell Responses by Natural Killer T Cells
Authors: Changwan Hong, Hyunji Lee, Yoon-Kyung Park, Junghoon Shin, Sundo Jung, Hoyeon Kim, Seokmann Hong, Se-Ho Park
Journal: Cancer Research (2009)

The physiologic function of natural killer T (NKT) cells in adaptive immunity remains largely unknown because most studies have used NKT cell agonists. In the present study, the role of NKT cells during the secondary effector phase was investigated separately from the primary immunization phase via adoptive transfer of differentiated effector T cells into naive recipients. We found that secondary antitumor CD8(+) T-cell responses were optimal when NKT cells were present. Tumor-specific CD8(+) effector T cells responded less strongly to tumor cell challenge in NKT cell-deficient recipients than in recipients with intact NKT cells. NKT cell-mediated enhancement of the secondary antitumor CD8(+) T-cell response was concurrent with increased number and activity of tumor-specific CD8(+) T cells. These findings provide the first demonstration of a direct role for NKT cells in the regulation of antigen-specific secondary T-cell responses without the use of exogenous NKT cell agonists such as alpha-galactosylceramide (alpha-GalCer). Furthermore, forced activation of NKT cells with alpha-GalCer during the secondary immune response in suboptimally immunized animals enhanced otherwise poor tumor rejection responses. Taken together, our findings strongly emphasize the importance of NKT cells in secondary CD8(+) T-cell immune responses.