tbuckley/cabot-search huggingface dataset:
Mechanical Stretch Regimen Enhances the Formation of Bioengineered Autologous Cardiac Muscle Grafts
Authors: Payam Akhyari, Paul W. M. Fedak, Richard D. Weisel, Tsu-Yee Joseph Lee, Subodh Verma, Donald A. G. Mickle, Ren-Ke Li
Journal: Circulation (2002)

Surgical repair of congenital and acquired cardiac defects may be enhanced by the use of autologous bioengineered muscle grafts. These tissue-engineered constructs are not optimal in their formation and function. We hypothesized that a mechanical stretch regimen applied to human heart cells that were seeded on a three-dimensional gelatin scaffold (Gelfoam) would improve tissue formation and enhance graft strength.Heart cells from children undergoing repair of Tetralogy of Fallot were isolated and cultured. Heart cells were seeded on gelatin-matrix scaffolds (Gelfoam) and subjected to cyclical mechanical stress (n=7) using the Bio-Stretch Apparatus (80 cycles/minute for 14 days). Control scaffolds (n=7) were maintained under identical conditions but without cyclical stretch. Cell counting, histology, and computerized image analysis determined cell proliferation and their spatial distribution within the tissue-engineered grafts. Collagen matrix formation and organization was determined with polarized light and laser confocal microscopy. Uniaxial tensile testing assessed tissue-engineered graft function. Human heart cells proliferated within the gelatin scaffold. Remarkably, grafts that were subjected to cyclical stretch demonstrated increased cell proliferation and a marked improvement of cell distribution. Collagen matrix formation and organization was enhanced by mechanical stretch. Both maximal tensile strength and resistance to stretch were improved by cyclical mechanical stretch.The cyclical mechanical stretch regimen enhanced the formation of a three-dimensional tissue-engineered cardiac graft by improving the proliferation and distribution of seeded human heart cells and by stimulating organized matrix formation resulting in an order of magnitude increase in the mechanical strength of the graft.
Abstract 3059: Role of End Diastolic Volume on cardiac function induced changes by Surgical Ventricular Restoration
Authors: Marisa Di Donato, Fabio Fantini, Serenella Castelvecchio, Claudio Bussadori, Francesca Giacomazzi, Matteo Quarenghi, Lorenzo Menicanti
Journal: Circulation (2007)

Background. LV-End diastolic volume (EDV) following surgical ventricular restoration (SVR) is highly dependent on surgical induced changes in ventricular chamber. Aim. To investigate the role of pre and post-operative EDV on SVR induced changes in cardiac function. Methods. We analyzed 298 patients submitted to SVR following an anterior MI. All had an echo study pre and post-operatively. SVR was conducted on arrested heart using an endoventricular sizing. Results. Post-op EDV was directly related to pre-op EDV, r=0.63; P&lt;.001.The larger pre-op EDV the greater surgical volume reduction (average −32%) and the greater EF improvement. At a certain range of EDV (150 –200 ml) either pre or post surgery EF does not differ significantly (34±7% and 34±7%, ns), confirming the central role of EDV. Conclusions. EF improvement was relatively greater in patients with greater pre-op EDV and greater surgical reduction, although the absolute values of post-op EF are mainly linked to post-op EDV. Our results underline the need for a correct pre-op estimate of EDV reduction in each single patient. Tab. 1
Phase II Study of Vinorelbine With Protracted Fluorouracil Infusion as a Second- or Third-Line Approach for Advanced Breast Cancer Patients Previously Treated With Anthracyclines
Authors: Alfredo Berruti, Paola Sperone, Alberto Bottini, Gabriella Gorzegno, Vito Lorusso, Antonio Brunelli, Mario Botta, Marco Tampellini, Michela Donadio, Sergio Mancarella, Mario De Lena, Palmiro Alquati, Luigi Dogliotti
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens. PATIENTS AND METHODS: Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m 2 administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m 2 /d given continuously over a 24-hour period. RESULTS: Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months. CONCLUSION: Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.
Role of aberrant Wnt signaling in the lung epithelial response to cigarette smoke in COPD
Authors: Irene Heijink, Harold De Bruin, Maarten Van den Berge, Reinoud Gosens, Antoon Van Oosterhout, Dirkje Postma
Journal: European Respiratory Journal (2011)

It is still unclear how exposure to cigarette smoke, the major risk factor for COPD, leads to different phenotypes of COPD, i.e. inflammation and remodelling with increased extracellular matrix (ECM) deposition in the airways and loss of ECM in the parenchyma. The Wnt signaling pathway is known to regulate inflammation, tissue repair and remodelling. We aimed to determine whether dysregulation of Wnt genes may contribute to COPD development. We studied the effects of cigarette smoke extract (CSE, 5%) on expression of a variety of Wnt ligands, Wnt receptors (frizzled, Fzd) and Wnt target genes, including IL-8, MMP-2/9 and fibronectin (qPCR, ELISA, immunodetection) in alveolar A549 and human bronchial epithelial 16HBE cells. Furthermore, we compared expression of Wnt genes in primary bronchial epithelium from COPD patients, healthy smokers and non-smokers. CSE induced Wnt4, Wnt7b and Fzd8 mRNA expression in A549 cells, without significant changes in the other detected genes, i.e. Wnt5a,b, Fzd1 and 2 and MMP-2. In contrast, CSE significantly decreased Wnt4 and Fzd2, and increased Wnt5b mRNA in 16HBE cells. Interestingly, expression of Wnt4, but none of the other detected genes, was significantly higher in COPD than in healthy smoker epithelium. Therefore, we were interested in potential autocrine effects of Wnt4. We observed that recombinant Wnt4 significantly increased IL-8 production in 16HBE cells. Thus, inefficient downregulation of Wnt4 mRNA expression in response to cigarette smoke may have important consequences for the development of airway inflammation in COPD. Furthermore, our results suggest that CSE differentially affects Wnt gene expression in alveolar and bronchial epithelium.
Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial
Authors: Elizabeth P Rakoczy, Chooi-May Lai, Aaron L Magno, Matthew E Wikstrom, Martyn A French, Cora M Pierce, Steven D Schwartz, Mark S Blumenkranz, Thomas W Chalberg, Mariapia A Degli-Esposti, Ian J Constable
Journal: The Lancet (2015)
Low cholesterol and cancer.
Authors: H Kritz, C Zielinski, H Sinzinger
Journal: Journal of Clinical Oncology (1996)

The relation between plasma cholesterol (CH) concentration and mortality is complex. The plasma CH concentration correlates positively with mortality from coronary heart disease, but some studies have shown a negative relation with death from cancer. If these two relations reflect causal mechanisms that are reversible by changing the plasma CH concentration, the benefits of lipid reduction for heart disease might be offset by an increased mortality from cancer. Different aspects between lipid metabolism and cancer, as well as new insights into this interesting field, are discussed.The literature was searched using MedLine through 1966 and January 1996.There is no evidence from the data available at present that the association between low CH and a higher risk of cancer is causal.This issue should not affect the advice on health matters offered by doctors, especially to patients with other risk factors for cardiovascular disease. The possibility that hypercholesterolemia (HC) drugs can induce a reduction of tumor-cell growth makes them potentially useful as an adjuvant to chemotherapy and ultimately increases the probabilities in the prevention and treatment of cancer.
Relationship between Complete Pathologic Response to Neoadjuvant Chemotherapy and Survival in Triple-Negative Breast Cancer
Authors: Christos Hatzis, W. Fraser Symmans, Ya Zhang, Rebekah E. Gould, Stacy L. Moulder, Kelly K. Hunt, Maysa Abu-Khalaf, Erin W. Hofstatter, Donald Lannin, Anees B. Chagpar, Lajos Pusztai
Journal: Clinical Cancer Research (2015)

Pathologic complete response (pCR) to neoadjuvant chemotherapy reflects the cytotoxic efficacy of a drug, but patient survival is influenced by many other factors. The purpose of this study was to assess the relationship between increased pCR rate and trial-level survival benefit in triple-negative breast cancer (TNBC).We used bootstrap resampling from a neoadjuvant trial to simulate trials with different pCR rates. We used estimates from Adjuvant!Online to simulate trial populations with different baseline prognosis and estimated survival improvements associated with changes in pCR rate.Assuming that survival is similar for patients with pCR regardless of treatment arm, a linear relationship exists between increasing pCR rate and increasing recurrence-free survival (RFS). The slope is equal to the difference in survival between those with pCR and residual disease, which in turn is influenced by (i) the baseline prognosis of the trial population, (ii) interactions between prognostic variables and pCR, and (iii) the efficacy of the postneoadjuvant therapies. For example, if the pCR rates are 30% and 60% (OR = 3.5) and the 10-year RFS of the control arm is 0.74, the trial would require 3,550 patients per arm, whereas if the RFS is 0.54, the trial would require only 425 patients per arm to detect significant survival benefit.We provide a framework for understanding the relationship between pCR and overall survival benefit that can help inform the design of neoadjuvant trials aiming to demonstrate improved survival from a regimen that results in higher pCR rate.
Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors.
Authors: S Guruangan, I J Dunkel, S Goldman, J H Garvin, M Rosenblum, J M Boyett, S Gardner, T E Merchant, S Gollamudi, J L Finlay
Journal: Journal of Clinical Oncology (1998)

PURPOSE This study evaluates the outcome of myeloablative chemotherapy and autologous bone marrow rescue (ABMR) with or without radiotherapy in children younger than 6 years of age with recurrent malignant brain tumors who had not previously been exposed to conventional fractionated external-beam irradiation. PATIENTS AND METHODS Patients underwent surgery and/or conventional chemotherapy at the time of recurrence to achieve minimal residual disease (two of these patients also underwent local single-fraction gamma-knife radiosurgery). Myeloablative chemotherapy was then administered with carboplatin, thiotepa, and etoposide (16 patients), thiotepa and etoposide (three patients), or thiotepa, etoposide, and carmustine (BCNU; one patient). Autologous bone marrow was re-infused 72 hours after chemotherapy. Twelve patients received external-beam irradiation after recovery from ABMR. RESULTS Twenty patients with recurrent brain tumors aged 0.7 to 5.9 years (median, 2.9 years) at ABMR were evaluated. Two patients died of toxicity related to myeloablative therapy. Eight patients died of progressive disease. Ten of 20 (50%) patients (primitive neuroectodermal tumor (PNET)/medulloblastoma, three patients; cerebral PNET, three patients; glioblastoma multiforme, two patients; anaplastic astrocytoma, one patient; pineal PNET, one patient) are alive and disease free at a median of 37.9 months (range, 9.7 to 98.2 months) from ABMR (3-year overall survival [OS] rate of 43% +/- 13% and event-free survival [EFS] rate of 47% +/- 14%]. Seven of these 10 patients also received irradiation post-ABMR. CONCLUSION Myeloablative chemotherapy with ABMR followed by additional external-beam irradiation appears to be an effective retrieval therapy for some young children with recurrent malignant brain tumors.
Is therapy adherence with inhaled tiotropium in COPD related to hospitalization, pneumonia or mortality?
Authors: Kirsten Koehorst-ter Huurne, Kris Movig, Paul VanderValk, Job Van der Palen, Marjolein Brusse-Keizer
Journal: European Respiratory Journal (2014)

Objective: To study the relationship between therapy adherence to tiotropium and morbidity and mortality in COPD.  Methods: Therapy adherence of tiotropium Handihaler of 438 patients was recorded from pharmacy records over 3 years. It was expressed as percentage and deemed good at 75–125%, suboptimal 50-75%, and poor  125%. The relationship between adherence and morbidity and mortality was analyzed by Cox Regression. We corrected for lung function at baseline.  Results: Overuse of tiotropium is related to increased risk of hospital admission and mortality compared to optimal use, with respectively hazard ratio9s of 2.2 and 2.9. Patients with underuse have a 2.4-fold higher risk of dying compared to optimal use. Adherence was not related to time to first pneumonia.  Conclusion: Patients with overuse and underuse of tiotropium Handihaler have a higher risk of dying. Furthermore, overuse is related to increased risk of hospital admission.The question remains whether improving adherence reduces mortality and morbidity.
Royal Naval Dockyards Asbestosis Research Project: Nine-Year follow-up Study of Men Exposed to Asbestos in Devonport Dockyard
Authors: C E Rossiter, J R Heath, P G Harries
Journal: Journal of the Royal Society of Medicine (1980)

Progression of asbestos-related disease was assessed in a group of 253 dockyard workers examined in 1966 and 1975. Despite the almost complete protection from exposure to asbestos since 1966, radiographic parenchymal abnormalities increased and occurred more frequently during the next 9 years in those men who had been more heavily exposed to asbestos. Lung function values were lower in those most heavily exposed and were declining at a faster rate than in those with less dust exposure. The most sensitive lung function index was the transfer factor.Those men with persistent crackles in 1966 exhibited a restrictive pattern of lung function, whereas an obstructive pattern was seen in men with wheezes in 1966. The men with irregular small opacities of category 1/1 or more or with diffuse pleural change in 1966 and who survived to 1975 had worse lung functions than any other groups.Progression of disease was greater for smokers than non-smokers, with those who gave up smoking between 1966 and 1975 suffering the greatest changes. This latter group showed most increase in small opacities and included almost all new cases of diffuse pleural changes. They also showed the greatest declines in forced expiratory volume and forced vital capacity.
Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group.
Authors: B A Gusterson, R D Gelber, A Goldhirsch, K N Price, J Säve-Söderborgh, R Anbazhagan, J Styles, C M Rudenstam, R Golouh, R Reed
Journal: Journal of Clinical Oncology (1992)

PURPOSE To evaluate the prognostic importance of immunocytochemically determined c-erbB-2 overexpression in the primary tumors of patients with breast cancer. PATIENTS AND METHODS Primary tumors from 1,506 breast cancer patients (760 node-negative and 746 node-positive) who were treated in the International (Ludwig) Breast Cancer Study Group Trial V were studied. Node-negative patients were allocated randomly to either a single cycle of perioperative chemotherapy (PeCT) or no adjuvant treatment, and node-positive patients received either a prolonged chemotherapy (with tamoxifen for postmenopausal patients) or a single perioperative cycle. RESULTS Tumors from 16% of the node-negative patients and 19% of the node-positive patients were found to be c-erbB-2-positive. In both groups c-erbB-2 positivity correlated with negative progesterone receptors (PR), negative estrogen receptors (ER), and high tumor grade. Lobular carcinomas were all negative, and, thus support the view that such tumors represent a defined subtype of breast carcinoma. The expression of c-erbB-2 was prognostically significant for node-positive but not for node-negative patients. However, in both subgroups, the prognostic significance was greater for patients who had received more adjuvant therapy. For node-positive patients, the effect of prolonged-duration therapy on disease-free survival (DFS) was greater for patients without c-erbB-2 overexpression (hazards ratio [HR], = 0.57; 95% confidence interval [CI], 0.46 to 0.72) than for those with c-erbB-2 overexpression (HR, 0.77; 95% CI, 0.51 to 1.16). Similarly, for node-negative patients, the effect of PeCT on DFS was greater for those without c-erbB-2 overexpression (HR, 0.82; 95% CI, 0.61 to 1.09) than for those with c-erbB-2 overexpression (HR, 1.22; 95% CI, 0.66 to 2.25). CONCLUSION We conclude that tumors with overexpression of the c-erbB-2 oncogene are less responsive to cyclophosphamide, methotrexate, and fluorouracil (CMF)-containing adjuvant therapy regimens than those with a normal amount of gene product.
Predicting Response to Histone Deacetylase Inhibitors Using High-Throughput Genomics
Authors: Paul Geeleher, Andrey Loboda, Divya Lenkala, Fan Wang, Bonnie LaCroix, Sanja Karovic, Jacqueline Wang, Michael Nebozhyn, Michael Chisamore, James Hardwick, Michael L. Maitland, R. Stephanie Huang
Journal: JNCI Journal of the National Cancer Institute (2015)

Many disparate biomarkers have been proposed as predictors of response to histone deacetylase inhibitors (HDI); however, all have failed when applied clinically. Rather than this being entirely an issue of reproducibility, response to the HDI vorinostat may be determined by the additive effect of multiple molecular factors, many of which have previously been demonstrated. We conducted a large-scale gene expression analysis using the Cancer Genome Project for discovery and generated another large independent cancer cell line dataset across different cancers for validation. We compared different approaches in terms of how accurately vorinostat response can be predicted on an independent out-of-batch set of samples and applied the polygenic marker prediction principles in a clinical trial. Using machine learning, the small effects that aggregate, resulting in sensitivity or resistance, can be recovered from gene expression data in a large panel of cancer cell lines. This approach can predict vorinostat response accurately, whereas single gene or pathway markers cannot. Our analyses recapitulated and contextualized many previous findings and suggest an important role for processes such as chromatin remodeling, autophagy, and apoptosis. As a proof of concept, we also discovered a novel causative role for CHD4, a helicase involved in the histone deacetylase complex that is associated with poor clinical outcome. As a clinical validation, we demonstrated that a common dose-limiting toxicity of vorinostat, thrombocytopenia, can be predicted (r = 0.55, P = .004) several days before it is detected clinically. Our work suggests a paradigm shift from single-gene/pathway evaluation to simultaneously evaluating multiple independent high-throughput gene expression datasets, which can be easily extended to other investigational compounds where similar issues are hampering clinical adoption.
Long-term survivors in metastatic non-small-cell lung cancer: an Eastern Cooperative Oncology Group Study.
Authors: D M Finkelstein, D S Ettinger, J C Ruckdeschel
Journal: Journal of Clinical Oncology (1986)

Between December 1979 and June 1983 the Eastern Cooperative Oncology Group (ECOG) treated 893 good-performance status patients with metastatic non-small-cell lung cancer (NSCLC) on one of seven phase III combination chemotherapies. The overall median survival was 23.5 weeks with no significant differences between treatments. One hundred sixty-eight patients (19%) survived greater than 1 year and 36 (4%) for greater than 2 years. The etoposide-platinum combination had the highest proportion of 1-year survivors (25%). Mitomycin-vinblastine-platinum (MVP), which had demonstrated the highest response rate, had significantly fewer 1-year survivors (12%) than any other regimen (P = .003). Analysis of pretreatment characteristics that distinguished patients who survived greater than 1 year from those who did not demonstrated that an initial performance status of 0, no bone metastases, female sex, no subcutaneous metastases, non-large-cell histology, less than 5% prior weight loss, no symptoms of shoulder or arm pain, and no liver metastases were predictors of longer survival. Of particular interest was the finding that response duration was significantly longer (P = .002) for those patients who experienced a longer time to best response. In addition, patients who survived greater than 1 year experienced greater degrees of nonlethal toxicity, in particular, gastrointestinal and hematologic, than patients who did not survive 1 year, (P = .006). A detailed chart review of 32 2-year survivors and 32 matched controls demonstrated that maintenance or improvement of performance status and maintenance of serum albumin levels at 3 months from the initiation of treatment were both important predictors of longer survival.