tbuckley/cabot-search huggingface dataset:
Feasibility of multiple courses of high-dose cyclophosphamide, thiotepa, and carboplatin for breast cancer or germ cell cancer.
Authors: S Rodenhuis, A Westermann, M J Holtkamp, W J Nooijen, J W Baars, E van der Wall, I C Slaper-Cortenbach, J H Schornagel
Journal: Journal of Clinical Oncology (1996)

PURPOSE To determine the feasibility and safety of multiple, closely timed courses of high-dose cyclophosphamide, thiotepa, and carboplatin (CTC) with peripheral-blood progenitor-cell transplantation (PBPCT). PATIENTS AND METHODS Forty-eight patients with advanced cancer were scheduled to undergo either two or three courses of CTC with PBPCT. All PBPCs were harvested before high-dose therapy began. Full-dose CTC courses incorporated cyclophosphamide (6,000 mg/m2), thiotepa (480 mg/m2), and carboplatin (1,600 mg/m2) divided over days -6, -5, -4, and -3. Tiny CTC courses (tCTC) contained 67% of the doses of each of these agents. Second or third courses of CTC or tCTC began on day 28. RESULTS A sufficient number of PBPC could be harvested from all but two patients. Thirty-five first full-dose courses of CTC were given, 28 second courses, and 10 third courses. Second courses could be given on time and at full dose in 80% of the patients, but there was one toxic death from venoocclusive disease (VOD). Only four of 12 patients scheduled to receive three courses of full-dose CTC could be treated at the time and dose planned. There were three toxic deaths: one of VOD, one of sepsis, and one of hemolytic uremic syndrome (HUS). Eight patients were scheduled to receive three courses of tCTC. Eight first, seven second, and six third courses were given. One of the third courses had to be delayed and one had to be reduced in dose. CONCLUSION A sufficient number of PBPCs for two or three transplantations can be harvested from most patients without much difficulty before high-dose therapy. Two full-dose CTC courses or three tCTC courses can be given safely and with acceptable toxicity at 5-week intervals. Organ toxicity rather than bone marrow toxicity has become dose-limiting for alkylating agents.
Course of FEV<sub>1</sub>after Onset of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients
Authors: Vibha N. Lama, Susan Murray, Robert J. Lonigro, Galen B. Toews, Andrew Chang, Christine Lau, Andrew Flint, Kevin M. Chan, Fernando J. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Bronchiolitis obliterans syndrome (BOS), defined by loss of lung function, develops in the majority of lung transplant recipients. However, there is a paucity of information on the subsequent course of lung function in these patients.To characterize the course of FEV(1) over time after development of BOS and to determine the predictors that influence the rate of functional decline of FEV(1).FEV(1)% predicted (FEV(1)%pred) trajectories were studied in 111 lung transplant recipients with BOS by multivariate, linear, mixed-effects statistical models.FEV(1)%pred varied over time after BOS onset, with the steepest decline typically seen in the first 6 months (12% decline; p < 0.0001). Bilateral lung transplant recipients had significantly higher FEV(1)%pred at BOS diagnosis (71 vs. 47%; p < 0.0001) and at 24 months after BOS onset (58 vs. 41%; p = 0.0001). Female gender and pretransplant diagnosis of idiopathic pulmonary fibrosis were associated with a steeper decline in FEV(1)%pred in the first 6 months after BOS diagnosis (p = 0.02 and 0.04, respectively). A fall in FEV(1) greater than 20% in the 6 months preceding BOS (termed "rapid onset") was associated with shorter time to BOS onset (p = 0.01), lower FEV(1)%pred at BOS onset (p < 0.0001), steeper decline in the first 6 months (p = 0.03), and lower FEV(1)%pred at 2 years after onset (p = 0.0002).Rapid onset of BOS, female gender, pretransplant diagnosis of idiopathic pulmonary fibrosis, and single-lung transplantation are associated with worse pulmonary function after BOS onset.
HIRA, a DiGeorge Syndrome Candidate Gene, Is Required for Cardiac Outflow Tract Septation
Authors: Michael J. Farrell, Harriett Stadt, Kathleen T. Wallis, Peter Scambler, R. Lester Hixon, Raymond Wolfe, Linda Leatherbury, Margaret L. Kirby
Journal: Circulation Research (1999)

Abstract —DiGeorge syndrome (DGS) is a congenital disease characterized by defects in organs and tissues that depend on contributions by cell populations derived from neural crest for proper development. A number of candidate genes that lie within the q11 region of chromosome 22 commonly deleted in DGS patients have been identified. Orthologues of the DGS candidate gene HIRA are expressed in the neural crest and in neural crest–derived tissues in both chick and mouse embryos. By exposing a portion of the premigratory chick neural crest to phosphorothioate end–protected antisense oligonucleotides, ex ovo, followed by orthotopic backtransplantation to the untreated embryos, we have shown that the functional attenuation of cHIRA in the chick cardiac neural crest results in a significantly increased incidence of persistent truncus arteriosus, a phenotypic change characteristic of DGS, but does not affect the repatterning aortic arch arteries, the ventricular function, or the alignment of the outflow tract.
Cellular Senescence Limits Regenerative Capacity and Allograft Survival
Authors: Heidi Braun, Bernhard M.W. Schmidt, Mirja Raiss, Arpita Baisantry, Dan Mircea-Constantin, Shijun Wang, Marie-Luise Gross, Manuel Serrano, Roland Schmitt, Anette Melk
Journal: Journal of the American Society of Nephrology (2012)

Long-term graft survival after kidney transplantation remains unsatisfactory and unpredictable. Interstitial fibrosis and tubular atrophy are major contributors to late graft loss; features of tubular cell senescence, such as increased p16INK4a expression, associate with these tubulointerstitial changes, but it is unknown whether the relationship is causal. Here, loss of the INK4a locus in mice, which allows escape from p16INK4a-dependent senescence, significantly reduced interstitial fibrosis and tubular atrophy and associated with improved renal function, conservation of nephron mass, and transplant survival. Compared with wild-type controls, kidneys from INK4a−/− mice developed significantly less interstitial fibrosis and tubular atrophy after ischemia-reperfusion injury. Consistently, mice that received kidney transplants from INK4a/ARF−/− donors had significantly better survival 21 days after life-supporting kidney transplantation and developed less tubulointerstitial changes. This correlated with higher proliferative rates of tubular cells and significantly fewer senescent cells. Taken together, these data suggest a pathogenic role of renal cellular senescence in the development of interstitial fibrosis and tubular atrophy and kidney graft deterioration by preventing the recovery from injury. Inhibiting premature senescence could have therapeutic benefit in kidney transplantation but has to be balanced against the risks of suspending antitumor defenses.
Misclassification of disease activity when assessing individual patients with early rheumatoid arthritis using disease activity indices that do not include joints of feet
Authors: Marije F Bakker, Johannes WG Jacobs, Aike A Kruize, Maaike J van der Veen, Catharina van Booma-Frankfort, Simone A Vreugdenhil, Johannes WJ Bijlsma, Floris PJG Lafeber, Paco MJ Welsing
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To study whether assessment of rheumatoid arthritis (RA) disease activity in individual patients using the disease activity score in 28 joints (DAS28) or other instruments excluding joints of feet may lead to misclassification of disease activity. <h3>Methods</h3> A cohort of RA patients was classified into three 'regional radiographic damage progression' groups: predominantly progression in feet, similar progression in hands and feet and predominantly progression in hands; both in early (0–2 years) and later (2–5 years) disease. Baseline and mean DAS28, individual DAS28 variables and tender joint counts (TJC) and swollen joint counts (SJC) of the feet were compared between groups. The longitudinal relation of DAS28 with radiographic damage was investigated using a mixed model analysis with rheumatoid factor status, baseline joint damage and TJC and SJC of the feet as covariates. <h3>Results</h3> Early (n=265) and later (n=200) in the disease course, by definition, the classification procedure resulted in 25% as predominantly foot, 25% as predominantly hand and 50% as similar progressors. In early RA predominantly foot progressors had higher TJC and SJC of the feet compared with predominantly hand progressors (p&lt;0.001), but DAS28 was similar. This was not seen in later disease. The longitudinal relation between DAS28 and radiographic progression was influenced by the region of progression (predominantly foot progressors vs others, p&lt;0.001), suggesting that DAS28 underestimates disease activity in predominantly foot progressors. In this group, joint counts for the feet were independently related to radiographic progression. <h3>Conclusions</h3> DAS28 underestimates actual disease activity and expected joint damage of individual early RA patients predominantly with disease in the feet.
Effect of Ventilator Flow Rate on Respiratory Timing in Normal Humans
Authors: RAFAEL FERNANDEZ, MANUEL MENDEZ, MAGDY YOUNES
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Respiratory rate (RR) increases as a function of ventilator flow rate (V˙). We wished to determine whether this is due to a decrease in neural inspiratory time (T in), neural expiratory time (Ten), or both. To accomplish this, we ventilated 15 normal subjects in the assist, volume cycled mode. Ventilator flow rate was varied at random, at four breaths with each step, over the flow range from 0.8 (V˙min) to 2.5 (V˙max) L/s. V t was kept constant. The pressure developed by respiratory muscles (Pmus) was calculated with the equation of motion (Pmus = V˙ · R + V · E − Paw, where R = resistance, V = volume, E = elastance, and Paw = airway pressure). Electromyography of the diaphragm (Edi) was also done in five subjects. Tin and Ten were determined from the Pmus or Edi waveform. Tin decreased progressively as a function of V˙, from 1.44 ± 0.34 s at V˙min to 0.62 ± 0.26 s at V˙max (p < 0.00001). Changes in Ten were inconsistent and not significant. Tin/Ttot decreased significantly (0.30 ± 0.06 at V˙min to 0.18 ± 0.09 at V˙max; p < 0.00001). We conclude that Ti is highly sensitive to ventilator flow, and that the RR response to V˙ is primarily related to this T in response. Because an increase in V˙ progressively reduces T in/Ttot, and this variable is an important determinant of inspiratory muscle energetics, we further conclude that inspiratory muscle energy expenditure is quite sensitive to V˙ over the range from 0.8 to 2.5 L/s.
Electron microscopic immunohistochemical identification of endothelial cells in the rabbit.
Authors: M B Stemerman, F A Pitlick, H M Dembitzer
Journal: Circulation Research (1976)

Antibody to tissue factor apoprotein was adsorbed against gamma-globulin and coupled to horseradish peroxidase; this complex was applied to various rabbit tissues. The distribution of the peroxidase marker then was observed by electron microscopy. We examined fixed or frozen sections, as well as breis of aorta, vena cava, brain, heart, lung, liver, spleen, kidney, bone marrow, mesothelial gut lining, erythrocytes, and platelets. All endothelial cells that had been exposed to the antibody complex were positive and in all cases only the endothelial cells showed localization of the electron-dense reaction product. Tissues that had been incubated with complexes prepared with gamma-globulin from animals not immunized with tissue factor apoprotein showed no staining. Prior treatment of the tissue with uncoupled anti-tissue factor gamma-globulin blocked binding by the coupled antibody. In blood vessel preparations that had been specifically designed to expose the media to the anti-tissue factor complex, medial smooth muscle cells and connective tissue showed no reaction product. Parenchymal cells of the other other organs mentioned likewise were devoid of reaction product. Similarly, the leukocytes and platelets occasionally observed in vessel lumens showed no evidence of binding. Platelets adhering to arterial subendothelial structure after injury also were unreactive. These findings suggest that in normal rabbits anti-tissue factor-horseradish peroxidase complex combines selectively with endothelial cells.
A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: Results of a department of veterans affairs cooperative study
Authors: Charles L. Mendenhall, Thomas E. Moritz, Gary A. Roselle, Timothy R. Morgan, Bernard A. Nemchausky, Carlo H. Tamburro, Eugene R. Schiff, Craig J. McClain, Luis S. Marsano, John I. Allen, Arun Samanta, Robert E. Weesner, William Henderson, Peter Gartside, Thomas S. Chen, Samuel W. French, Antonio Chedid
Journal: Hepatology (1993)

A Veterans Affairs cooperative study involving 273 male patients was performed to evaluate efficacy of oxandrolone in combination with an enteral food supplement in severe alcoholic hepatitis. All patients had some degree of protein calorie malnutrition. On an intention-to-treat basis, only minimal changes in mortality were observed. However, in patients with moderate malnutrition mortality on active treatment at 1 mo was 9.4% compared with 20.9% in patients receiving placebo. This beneficial effect was maintained so that after 6 mo on active treatment 79.7% of patients were still alive, compared with 62.7% of placebo-treated patients (p = 0.037). Improvements in both the severity of the liver injury (p = 0.03) and malnutrition (p = 0.05) also occurred. No significant improvement was observed with severe malnutrition. To better determine the effect on therapeutic efficacy, we compared results with those from a nearly identical population (cooperative study 119) treated with oxandrolone but not given the food supplement. Patients were stratified according to their caloric intake (greater than 2,500 kcal/day was considered adequate to supply energy needs and promote anabolism). For patients with moderate malnutrition and adequate caloric intake, oxandrolone treatment reduced 6-mo mortality (4% active treatment vs. 28% placebo [p = 0.002]). For patients with moderate malnutrition and inadequate calorie intake, oxandrolone had no effect on mortality (30% active treatment vs. 33% placebo). In cases of severe malnutrition, oxandrolone had no effect on survival. However, adequate caloric intake was associated with 19% mortality, whereas patients with inadequate intake exhibited 51% mortality (p = 0.0001). These results indicate that nutritional status should be evaluated in patients with alcoholic hepatitis. When malnutrition is present, vigorous nutrition therapy should be provided, and in patients with moderate malnutrition oxandrolone should be added to the regimen. (Hepatology 1993;17:564-576.)
Exon Array Analyses across the NCI-60 Reveal Potential Regulation of TOP1 by Transcription Pausing at Guanosine Quartets in the First Intron
Authors: William C. Reinhold, Jean-Louis Mergny, Hongfang Liu, Michael Ryan, Thomas D. Pfister, Robert Kinders, Ralph Parchment, James Doroshow, John N. Weinstein, Yves Pommier
Journal: Cancer Research (2010)

Because topoisomerase 1 (TOP1) is critical for the relaxation of DNA supercoils and because it is the target for the anticancer activity of camptothecins, we assessed TOP1 transcript levels in the 60 cell line panel (the NCI-60) of the National Cancer Institute's anticancer drug screen. TOP1 expression levels varied over a 5.7-fold range across the NCI-60. HCT116 colon and MCF-7 breast cancer cells were the highest expressers; SK-MEL-28 melanoma and HS578T breast carcinoma cells were the lowest. TOP1 mRNA expression was highly correlated with Top1 protein levels, indicating that TOP1 transcripts could be conveniently used to monitor Top1 protein levels and activity in tissues. Assessment of the TOP1 locus by array comparative genomic hybridization across the NCI-60 showed copy numbers ranging from 1.71 to 4.13 and a statistically significant correlation with TOP1 transcript levels (P < 0.01). Further analyses of TOP1 expression on an exon-specific basis revealed that exon 1 expression was generally higher and less variable than expression of the other exons, suggesting some form of transcriptional pausing regulation between exons 1 and 2. Accordingly, we found the presence of multiple evolutionarily conserved potential G-quadruplex-forming sequences in the first TOP1 intron. Physicochemical tests for actual quadruplex formation by several of those sequences yielded quadruplex formation for two of them and duplex formation for one. The observations reported here suggest the hypothesis that there is a conserved negative transcription regulator within intron 1 of the TOP1 gene associated with a quadruplex-prone region.
Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro
Authors: I.R. Garrett, D. Chen, G. Gutierrez, M. Zhao, A. Escobedo, G. Rossini, S.E. Harris, W. Gallwitz, K.B. Kim, S. Hu, C.M. Crews, G.R. Mundy
Journal: Journal of Clinical Investigation (2003)

We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differentiation and bone formation in vitro and in vivo in rodents. Structurally different inhibitors that bind to specific catalytic beta subunits of the 20S proteasome stimulated bone formation in bone organ cultures in concentrations as low as 10 nM. When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor-1 increased bone volume and bone formation rates over 70% after only 5 days of treatment. Since the ubiquitin-proteasome pathway has been shown to modulate expression of the Drosophila homologue of the bone morphogenetic protein-2 and -4 (BMP-2 and BMP-4) genes, we examined the effects of noggin, an endogenous inhibitor of BMP-2 and BMP-4 on bone formation stimulated by these compounds and found that it was abrogated. These compounds increased BMP-2 but not BMP-4 or BMP-6 mRNA expression in osteoblastic cells, suggesting that BMP-2 was responsible for the observed bone formation that was inhibited by noggin. We show proteasome inhibitors regulate BMP-2 gene expression at least in part through inhibiting the proteolytic processing of Gli3 protein. Our results suggest that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation and that inhibition of specific components of this system may be useful therapeutically in common diseases of bone loss.
Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963
Authors: Steve H. Thorne, Tae-Ho H. Hwang, William E. O’Gorman, David L. Bartlett, Shizuko Sei, Femina Kanji, Christopher Brown, Joel Werier, Jin-Han Cho, Dong-Ewon Lee, Yaohe Wang, John Bell, David H. Kirn
Journal: Journal of Clinical Investigation (2007)

Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing.
Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjogren's syndrome
Authors: J-E Gottenberg
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To investigate the prevalence of anti-cyclic citrullinated peptide (anti-CCP) and anti-keratin antibodies (AKA) in patients with primary Sjögren's syndrome. <b>Methods:</b> 149 patients with a diagnosis of primary Sjögren's syndrome according to the European/American consensus criteria were recruited from three French medical centres. The presence of anti-CCP was determined by enzyme linked immunosorbent assay and of AKA antibodies by indirect immunofluorescence. Radiographs of hands and feet were evaluated at the time of anti-CCP analysis. <b>Results:</b> Six patients with radiological erosions and nine patients with non-erosive arthritis fulfilling ACR criteria for rheumatoid arthritis were thought to have rheumatoid arthritis and secondary Sjögren's syndrome, while 134 were considered to have primary Sjögren's syndrome (mean (SD) disease duration, 11.1 (6.6) years). Of these, 80 tested positive for IgM rheumatoid factor (RF) (59%), 10 (7.5%) for anti-CCP, 7 (5.2%) for AKA, and 5 (3.7%) for both anti-CCP and AKA. There was no difference in clinical and biological features, including prevalence of RF, between anti-CCP positive and negative patients. The nine Sjögren patients with non-erosive arthritis, fulfilling ACR criteria for rheumatoid arthritis, were all CCP positive. Their response to disease modifying antirheumatic drugs could be different from classical rheumatoid patients. <b>Conclusions:</b> Most patients with primary Sjögren's syndrome are negative for AKA and anti-CCP, but positive test results should not rule out this diagnosis. Anti-CCP positive patients, who may be prone to developing rheumatoid arthritis, require cautious clinical and radiographic follow up.
Sensory Perceptual Limitation in Schizophrenia
Authors: A.M. Ghadirian
Journal: Psychotherapy and Psychosomatics (1976)

Sensory perception and selective attention capacity of schizophrenic patients have drawn particular interest. Schizophrenic patients show a peculiar deficit in screening and processing of incoming sensory data. Review of the literature suggests a breakdown in the selective-inhibitory function of attention in schizophrenic patients facing multiple sensory modalities. Although disorganization of attention is a focal point in schizophrenic perception, the influence of memory on the perceptual process deserves further investigation. Distracting sensory stimuli particularly of an auditory nature seem to interfere with visual perception and motor performance in these patients. Avoidance of sensory overload and improving selective attention through psychotherapy though of some therapeutic value, requires further exploration. A case of a young schizophrenic patient exposed to distractible environmental stimuli was presented and discussed.