tbuckley/cabot-search huggingface dataset:
Enrollment of Elderly Patients in Clinical Trials for Cancer Drug Registration: A 7-Year Experience by the US Food and Drug Administration
Authors: Lilia Talarico, Gang Chen, Richard Pazdur
Journal: Journal of Clinical Oncology (2004)

To analyze the age-related enrollment of cancer patients onto registration trials of new drugs or new indications approved by the US Food and Drug Administration from 1995 to 2002.This study involved retrospective analyses of demographic data of cancer patients enrolled onto registration trials. The data on 28,766 cancer patients from 55 registration trials were analyzed according to age distributions of > or = 65, > or = 70, and > or = 75 years. The rates of enrollment in each age group for each cancer were compared with the corresponding rates in the US cancer population. The age distributions of the US cancer population were derived from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for the period 1995 to 1999 based on the 2000 US Census.The proportions of the overall patient populations aged > or = 65, > or = 70, and > or = 75 years were 36%, 20%, and 9% compared with 60%, 46%, and 31%, respectively, in the US cancer population. Statistically significant under-representation of the elderly (P < .001) was noted in registration trials for all cancer treatment except for breast cancer hormonal therapies. Patients aged > or = 70 years accounted for most of the under-representation.Elderly were under-represented in the registration trials of new cancer therapies. Various strategies may be needed to evaluate cancer therapies for the elderly in prospective clinical trials and to improve cancer care in the elderly population.
Sequence Evolution Correlates with Structural Dynamics
Authors: Ying Liu, Ivet Bahar
Journal: Molecular Biology and Evolution (2012)

Biochemical activity and core stability are essential properties of proteins, maintained usually by conserved amino acids. Structural dynamics emerged in recent years as another essential aspect of protein functionality. Structural dynamics enable the adaptation of the protein to binding substrates and to undergo allosteric transitions, while maintaining the native fold. Key residues that mediate structural dynamics would thus be expected to be conserved or exhibit coevolutionary patterns at least. Yet, the correlation between sequence evolution and structural dynamics is yet to be established. With recent advances in efficient characterization of structural dynamics, we are now in a position to perform a systematic analysis. In the present study, a set of 34 enzymes representing various folds and functional classes is analyzed using information theory and elastic network models. Our analysis shows that the structural regions distinguished by their coevolution propensity as well as high mobility are predisposed to serve as substrate recognition sites, whereas residues acting as global hinges during collective dynamics are often supported by conserved residues. We propose a mobility scale for different types of amino acids, which tends to vary inversely with amino acid conservation. Our findings suggest the balance between physical adaptability (enabled by structure-encoded motions) and chemical specificity (conferred by correlated amino acid substitutions) underlies the selection of a relatively small set of versatile folds by proteins.
Paracrine Regulation of Pancreatic Cancer Cell Invasion by Peripheral Nerves
Authors: Ziv Gil, Oren Cavel, Kaitlyn Kelly, Peter Brader, Avigail Rein, Sizhi P. Gao, Diane L. Carlson, Jatin P. Shah, Yuman Fong, Richard J. Wong
Journal: JNCI Journal of the National Cancer Institute (2010)

The ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown.We used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function.Nerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean = 187.1 microm, 95% confidence interval [CI] = 148 to 226 microm vs 14.4 microm, 95% CI = 9.58 to 19.22 microm, difference = 143 microm; P < .001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras-mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/-, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P < .001; n = 60-66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFalpha1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice.These data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer.
Sequential therapy in pediatric cadaveric renal transplantation
Authors: R Ettenger, J Marik, J T Rosenthal
Journal: Journal of the American Society of Nephrology (1992)

Cadaveric renal transplant survival rates in children are still somewhat inferior to those reported in adults. Sequential therapy, an immunosuppressive program in which a course of antilymphocyte preparation is used immediately postoperatively and followed in sequence by oral maintenance immunosuppression, has a number of features that might be expected to improve pediatric transplant outcome by addressing some of the metabolic and immunologic difficulties encountered in children. This article examines the rationale for sequential therapy in pediatric renal transplantation. It also examines the use of sequential therapy in children. Sequential therapy appears to significantly improve cadaver renal allograft outcome in children without compromising patient survival. There was a slight improvement in 1- and 2-yr graft outcomes when OKT3 was used prophylactically when compared with antithymocyte globulin, but this difference did not reach statistical significance. Almost 60% of patients receiving OKT3 for sequential therapy remained free of rejection. Major drawbacks of sequential therapy include the adverse side effects of the antilymphocyte preparation, infection, and the possibility of lymphoproliferative syndrome. The implications of these problems as well as potential strategies for ameliorating them are discussed.
Quantification of human atrioventricular nodal concealed conduction utilizing S1S2S3 stimulation.
Authors: D Wu, P Denes, R C Dhingra, C R Wyndham, K M Rosen
Journal: Circulation Research (1976)

We studied antegrade concealed conduction of atrial extrastimuli (A2) that blocked in the atrioventricular (AV) node in eight subjects, using a third extrastimulus (A3), coupled at decreasing coupling intervals to A2. Three A1-A2 intervals were tested in each subject: late (just shorter than AV nodal effective refractory period), intermediate, and early (just longer than atrial functional refractory period). The curves relating the following variables were constructed for each A2: A1-A3, H1-H3 and A2-A3, A3-H3. The former was compared to the control A1-A2, H1-H2 curve. Concealment of A2 was demonstrated in all eight subjects at the three tested values of A1-A2. The A2-A3, A3-H3 curve allowed analysis of AV nodal conduction time (A3-H3) and AV nodal recovery time (defined as the shortest A2-A3 at which the impulse conducted to the His bundle) at identical values of A2-A3. In all subjects the timing of blocked A2 had minimal effect on both AV nodal conduction time and recovery time. In five of the eight subjects a late A2 sporadically conducted to the His bundle. Conduction of A2 to the His bundle resulted in marked lengthening of both AV nodal conduction and recovery times. Concealed conduction of A2 was always demonstrated, but the degree of concealment was relatively fixed, whether A2 was an early, intermediate, or late blocked premature beat. Slow conduction of A2 had a much greater effect than concealment of A2 on subsequent impulse conduction.
Enhanced retention of asbestos fibers in the airways of human smokers.
Authors: A Churg, B Stevens
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

To determine whether cigarette smoke increases the pulmonary retention of asbestos, we compared the asbestos-fiber burden in the airway mucosa of six cigarette smokers who had received heavy occupational asbestos exposure with that in a group of six subjects with similar exposure who were never smokers. The groups were matched in terms of age, sex, years of exposure, and mean parenchymal amosite burden. We found that the concentration of amosite in airway mucosa was significantly elevated (by approximately sixfold) in smokers (p < 0.02). Chrysotile parenchymal burdens were statistically similar in both groups, but the chrysotile airway burden was again higher (by approximately 50-fold) in smokers (p < 0.006). There were no differences in airway or parenchymal tremolite burdens between the two groups. Fibers of all three types of asbestos recovered from the airway mucosa or parenchyma of smokers were shorter than fibers recovered from nonsmokers, an observation in accord with experimental data suggesting that cigarette smoke leads to retention of shorter fibers. These findings indicate that cigarette smoking causes enhanced accumulation of both amosite and chrysotile in the airway mucosa. This process may play a role in potentiating the pathologic effects of asbestos.
Combined effects of parental and active smoking on early lung function deficits: a prospective study from birth to age 26 years
Authors: Stefano Guerra, Debra A Stern, Muhan Zhou, Duane L Sherrill, Anne L Wright, Wayne J Morgan, Fernando D Martinez
Journal: Thorax (2013)

<h3>Background</h3> Cross-sectional reports have suggested that, among active smokers, previous exposure to parental smoking may increase susceptibility to development of chronic obstructive pulmonary disease. We assessed prospectively whether parental smoking enhances the effects of active smoking on early deficits of lung function in young adults. <h3>Methods</h3> We used data from the prospective birth cohort, the Tucson Children9s Respiratory Study. Maternal and paternal smoking was assessed via questionnaires completed by the parents at the time of the participant9s birth. Active smoking by participants was assessed via personal questionnaires completed at ages 16 (YR16), 22 and 26 years. Four groups were generated based on the combination of parental and active smoking. Lung function parameters, including forced expiratory volume in 1 s (FEV<sub>1</sub>)/forced vital capacity (FVC) ratio, were assessed by spirometry before and after inhalation of 180 μg of albuterol at YR11, YR16, YR22 and YR26. <h3>Results</h3> Complete data were available for 519 participants. Pre-bronchodilator FEV<sub>1</sub>/FVC values did not differ at YR11, YR16 or YR22 by parental or active smoking. However, at YR26 participants with exposure to parental and active smoking had pre-bronchodilator FEV<sub>1</sub>/FVC levels that were, on average, 2.8% (0.9% to 4.8%; p=0.003) lower than participants who were not exposed to parental or active smoking. In contrast, subjects who were only exposed to active smoking or only exposed to parental smoking did not differ from those who were not exposed to either. Between YR11 and YR26, participants with exposure to parental and active smoking had the steepest decline in sex, age and height adjusted residuals of FEV<sub>1</sub>/FVC, FEV<sub>1</sub>, forced expiratory flow between 25% and 75% of the FVC (FEF<sub>25–75</sub>) and FEF<sub>25–75</sub>/FVC (all p values between 0.03 and &lt;0.001). <h3>Conclusions</h3> Parental and active smoking act synergistically to affect early lung function deficits in young adulthood.
Effects of Retinoids on Cancerous Phenotype and Apoptosis in Organotypic Cultures of Ovarian Carcinoma
Authors: S Guruswamy, S Lightfoot, M A Gold, R Hassan, K D Berlin, R T Ivey, D M Benbrook
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Retinoic acid analogues, called retinoids, have shown promise in clinical trials in preventing breast and ovarian cancers. Classic retinoids bind to retinoic acid receptors, which regulate cell growth. Some novel retinoids, such as fenretinide, i.e., N-(4-hydroxyphenyl)retinamide (4-HPR), induce apoptosis through retinoic acid receptor-independent mechanisms; however, they appear to do so only at concentrations above those achieved in clinical chemoprevention trials. At lower concentrations (≤1 μM), 4-HPR acts like classic retinoids, by inducing differentiation through a receptor-dependent mechanism. Our goal was to compare the effects of novel receptor-independent (apoptotic) retinoids with those of classic growth-inhibitory retinoids at clinically achievable doses on growth, differentiation, and apoptosis in ovarian tissue. Methods: Four receptor-independent (apoptotic) and seven growth-inhibitory retinoids, including synthetic, low-toxicity compounds called heteroarotinoids, were administered at concentrations of 1 μM to organotypic cultures of ovarian primary and cancer cell lines: OVCAR-3, Caov-3, and SK-OV-3. After fixation, embedding, and sectioning, the growth fraction was quantified by measuring expression of the proliferation marker Ki-67/myb, differentiation was assessed by expression of mucin, and apoptosis was evaluated by the TUNEL assay. Spearman correlation analysis was performed on the data, and all P values were two-sided. Results: All 11 retinoids reversed characteristics associated with the cancerous phenotype in all neoplastic cultures. Glandular structures were observed consistently in retinoid-treated, but not in untreated, OVCAR-3 and Caov-3 cultures. All retinoids decreased growth fractions, and some increased mucin expression. All receptor-independent retinoids and two receptor-dependent retinoids induced apoptosis, and the induction correlated significantly with increased expression of the mucin MUC1 (r = .83; P = .03). Retinoids with ester-linking groups did not induce apoptosis but decreased the growth fraction in correlation with MUC1 induction (r = −.93; P = .02). Conclusions: At clinically achievable concentrations, all retinoids tested decrease the growth fraction, induce differentiation and apoptosis. Induction of MUC1 expression is implicated in the mechanisms of action.
Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma
Authors: Folkert J. van Kemenade, Frank M. Raaphorst, Tjasso Blokzijl, Elly Fieret, Karien M. Hamer, David P. E. Satijn, Arie P. Otte, Chris J. L. M. Meijer
Journal: Blood (2001)
Do changes to the local street environment alter behaviour and quality of life of older adults? The ‘DIY Streets’ intervention
Authors: Catharine Ward Thompson, Angela Curl, Peter Aspinall, Susana Alves, Affonso Zuin
Journal: British Journal of Sports Medicine (2012)

Background The burden of ill-health due to inactivity has recently been highlighted. Better studies on environments that support physical activity are called for, including longitudinal studies of environmental interventions. A programme of residential street improvements in the UK (Sustrans ‘DIY Streets’) allowed a rare opportunity for a prospective, longitudinal study of the effect of such changes on older adults’ activities, health and quality of life. Methods Pre–post, cross-sectional surveys were carried out in locations across England, Wales and Scotland; participants were aged 65+ living in intervention or comparison streets. A questionnaire covered health and quality of life, frequency of outdoor trips, time outdoors in different activities and a 38-item scale on neighbourhood open space. A cohort study explored changes in self-report activity and well-being postintervention. Activity levels were also measured by accelerometer and accompanying diary records. Results The cross-sectional surveys showed outdoor activity predicted by having a clean, nuisance-free local park, attractive, barrier-free routes to it and other natural environments nearby. Being able to park one's car outside the house also predicted time outdoors. The environmental changes had an impact on perceptions of street walkability and safety at night, but not on overall activity levels, health or quality of life. Participants’ moderate-to-vigorous activity levels rarely met UK health recommendations. Conclusions Our study contributes to methodology in a longitudinal, pre–post design and points to factors in the built environment that support active ageing. We include an example of knowledge exchange guidance on age-friendly built environments for policy-makers and planners.
DNA damage in intact cells induced by bacterial metabolites of chloramphenicol
Authors: Mike Isildar, Joaquin J. Jimenez, Grace K. Arimura, Adel A. Yunis
Journal: American Journal of Hematology (1988)

Abstract Four chloramphenicol (CAP) metabolites known to be produced by intestinal bacteria were examined with respect to their capacity to induce DNA damage in intact cells. The induction of DNA single‐strand breaks in Raji cells, activated human lymphocytes, and human marrow cells was assayed by the alkaline elution technique. One of the four compounds tested, dehydro‐CAP, was capable of inducing DNA single‐strand breaks in all three cell systems at concentrations of 10 −4 M. This effect is comparable to that observed previously with nitroso‐CAP, the nitroreduction intermediate of CAP. The nitroreduction of dehydro‐CAP by human bone marrow cell homogenate was detected by the production of the corresponding amino derivative amounting to 5.6 × 10 −5 M from 2 × 10 −3 M substrate under aerobic conditions. In sharp contrast, nitroreduction of CAP by bone marrow could not be demonstrated. The genotoxicity of dehydro‐CAP, its relative stability compared to the nitroso‐CAP, and its nitroreducibility by bone marrow suggest that this bacterial metabolite of CAP may play a key role as a mediator of aplastic anemia in the predisposed host.
Urinary type II collagen C-telopeptide levels are increased in patients with rapidly destructive hip osteoarthritis
Authors: P Garnero
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To compare type II collagen degradation using a new urinary specific marker in patients with rapidly destructive and those with slowly progressive hip OA. <b>Methods:</b> Twelve patients with rapidly destructive and 28 patients with slowly progressive hip OA were included in a prospective, cross sectional case-control study. Urinary levels of C-terminal crosslinking telopeptide of collagen type II (CTX-II) as a marker of cartilage degradation were measured by an ELISA, and urinary free deoxypyridinoline (free DPD), a marker of bone resorption, was measured by high performance liquid chromatography. One <i>x</i> ray evaluation of the hips and urine samples was made in all patients when the diagnosis of OA was established. <b>Results:</b> Patients with hip OA had higher mean (SD) urinary CTX-II levels than 65 healthy age matched controls (492 (232) <i>v</i> 342 (141), p&lt;0.001), but no significant difference was seen for urinary free DPD (p=0.30). Increased urinary CTX-II, but not urinary free DPD, correlated significantly with decreased minimum joint space width assessed by radiograph of the hip. Mean urinary CTX-II levels were significantly higher in patients with rapidly progressive OA than in the slowly progressive group (612 (218) <i>v</i> 441 (221), p=0.015), whereas no significant difference of urinary free DPD was seen between the two groups (p=0.55). <b>Conclusion:</b> Patients with hip OA have increased CTX-II degradation as assessed by a new urinary marker. Increased urinary CTX-II levels are associated with rapidly destructive disease, suggesting that this marker might be useful in identifying patients with hip OA at high risk for rapid progression of joint damage.
Preclinical and Clinical Evaluation of Intraductally Administered Agents in Early Breast Cancer
Authors: Vered Stearns, Tsuyoshi Mori, Lisa K. Jacobs, Nagi F. Khouri, Edward Gabrielson, Takahiro Yoshida, Scott L. Kominsky, David L. Huso, Stacie Jeter, Penny Powers, Karineh Tarpinian, Regina J. Brown, Julie R. Lange, Michelle A. Rudek, Zhe Zhang, Theodore N. Tsangaris, Saraswati Sukumar
Journal: Science Translational Medicine (2011)

Intraductal administration of chemotherapeutic agents may reduce new breast cancer formation and offer a less toxic treatment regimen than intravenous therapy.
Ceruloplasmin, Copper Ions, and Angiogenesis&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: K S Raju, G Alessandri, M Ziche, P M Gullino
Journal: JNCI Journal of the National Cancer Institute (1982)

Ceruloplasmin, Copper Ions, and Angiogenesis Get access Katari S. Raju, Katari S. Raju Search for other works by this author on: Oxford Academic PubMed Google Scholar Giulio Alessandri, Giulio Alessandri Search for other works by this author on: Oxford Academic PubMed Google Scholar Marina Ziche, Marina Ziche Search for other works by this author on: Oxford Academic PubMed Google Scholar Pietro M. Gullino Pietro M. Gullino 4 4Address reprint requests to Dr. Gullino, Building 10, Room 5B36, National Institutes of Health, Bethesda, Md. 20205. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 69, Issue 5, November 1982, Pages 1183–1188, https://doi.org/10.1093/jnci/69.5.1183 Published: 01 November 1982 Article history Received: 24 March 1982 Accepted: 17 June 1982 Published: 01 November 1982
Statins inhibit matrix metalloproteinase release from human lung fibroblasts
Authors: K. Kamio, X. D. Liu, H. Sugiura, S. Togo, S. Kawasaki, X. Wang, Y. Ahn, C. Hogaboam, S. I. Rennard
Journal: European Respiratory Journal (2009)

Pleiotropic effects of statins have been reported to include inhibition of matrix metalloproteinase (MMP) release from macrophages and endothelial cells. We evaluated whether statins would inhibit MMP release from human lung fibroblasts, which play a major role in remodelling processes. Monolayer and three-dimensional (3D) collagen gel cultures of fibroblasts were used. Cytokines (tumour necrosis factor-α and interleukin-1α) were used to induce MMP release and mRNA expression. Collagen degradation induced by cytokines and neutrophil elastase (NE) was evaluated by quantifying hydroxyproline. Atorvastatin inhibited MMP-1 and -3 release and mRNA expression in both culture systems. Similar results were obtained with simvastatin and fluvastatin. In 3D cultures where cytokines also stimulated MMP-9 release, atorvastatin also inhibited MMP-9 release. In 3D cultures, cytokines together with NE induced collagen degradation, which was also inhibited by atorvastatin. The effect of atorvastatin was reversed by mevalonate and geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate. The current data suggest that statins may modulate remodelling processes mediated by fibroblasts by inhibiting MMP release.
Gene expression and angiotropism in primary CNS lymphoma
Authors: James L. Rubenstein, Jane Fridlyand, Arthur Shen, Ken Aldape, David Ginzinger, Tracy Batchelor, Patrick Treseler, Mitchel Berger, Michael McDermott, Michael Prados, Jon Karch, Craig Okada, William Hyun, Seema Parikh, Chris Haqq, Marc Shuman
Journal: Blood (2006)