tbuckley/cabot-search huggingface dataset:
Impact of disseminated tumor cells in bone marrow on outcome of patients with primary ovarian cancer.
Authors: M. L. Heubner, S. Kasimir-Bauer, R. Kimmig, P. Wimberger
Journal: Journal of Clinical Oncology (2010)

e15545 Background: Data concerning the impact of disseminated tumor cells (DTC) in ovarian cancer (EOC) on outcome are still rare. In 109 patients with primary epithelial ovarian cancer, we evaluated whether first-line therapy including radical tumor debulking surgery and chemotherapy with carboplatinum and paclitaxel can impact upon DTC in bone marrow (BM) and analyzed associations of DTC in the BM with clinical data. Methods: DTC were detected in bilateral BM aspirates (10 mL) using density gradient centrifugation and immunocytochemistry, applying the anti-CK antibody A45-B/B3. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method and statistically evaluated using a two-sided log-rank test. Associations with other clinical data were tested by the chi-squared-test according to Pearson. A significant increase of DTC was assessed if the difference was > = 2 CK+ cells. Results: Before chemotherapy, we identified CK+ cells in 45% (49/109) BM samples with a mean number of 1.9 cells/9x10E6 BM cells (range: 0-37). Puncture after chemotherapy was performed in 67 patients, detecting CK+ cells in 37% (25/67) with a mean number of 3.7 cells/9x10E6 BM (range: 0-100). A significant increase of DTC in the BM was noted in 24% (15/62). In 31% (19/62), chemotherapy eliminated preexisting CK+ cells. In advanced tumor stages FIGOIII/IV, the presence of more than 5 CK+cells before chemotherapy was associated of DTC with less macroscopic complete resection rates in primary surgery (p = 0.042). No other significant associations with clinical data including platinum-sensitivity, grading, tumor stage or the patients' age were observed. FIGO III/IV patients showed a trend for a diminished DFS in patients with a significant increase of DTC in the BM during therapy (estimated means: 24.6 months and 36.2 months, respectively). However, this difference was not statistically significant (p = 0.061). Conclusions: A longer follow-up and greater study population is planned to further evaluate the impact of DTC in ovarian cancer patients. An increase of DTC during therapy might be a prognostic factor in ovarian cancer patients. No significant financial relationships to disclose.
The Structural Basis of Repertoire Shift in an Immune Response to Phosphocholine
Authors: McKay Brown, Maria A. Schumacher, Gregory D. Wiens, Richard G. Brennan, Marvin B. Rittenberg
Journal: The Journal of Experimental Medicine (2000)

The immune response to phosphocholine (PC)–protein is characterized by a shift in antibody repertoire as the response progresses. This change in expressed gene combinations is accompanied by a shift in fine specificity toward the carrier, resulting in high affinity to PC–protein. The somatically mutated memory hybridoma, M3C65, possesses high affinity for PC–protein and the phenyl-hapten analogue, p-nitrophenyl phosphocholine (NPPC). Affinity measurements using related PC–phenyl analogues, including peptides of varying lengths, demonstrate that carrier determinants contribute to binding affinity and that somatic mutations alter this recognition. The crystal structure of an M3C65–NPPC complex at 2.35-Å resolution allows evaluation of the three light chain mutations that confer high-affinity binding to NPPC. Only one of the mutations involves a contact residue, whereas the other two have indirect effects on the shape of the combining site. Comparison of the M3C65 structure to that of T15, an antibody dominating the primary response, provides clear structural evidence for the role of carrier determinants in promoting repertoire shift. These two antibodies express unrelated variable region heavy and light chain genes and represent a classic example of the effect of repertoire shift on maturation of the immune response.
Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group
Authors: Malcolm J. Moore, David Goldstein, John Hamm, Arie Figer, Joel R. Hecht, Steven Gallinger, Heather J. Au, Pawel Murawa, David Walde, Robert A. Wolff, Daniel Campos, Robert Lim, Keyue Ding, Gary Clark, Theodora Voskoglou-Nomikos, Mieke Ptasynski, Wendy Parulekar
Journal: Journal of Clinical Oncology (2007)

Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.
Interaction of sulfonylureas and exercise on glucose homeostasis in type 2 diabetic patients.
Authors: J J Larsen, F Dela, S Madsbad, J Vibe-Petersen, H Galbo
Journal: Diabetes Care (1999)

OBJECTIVE: To determine whether the plasma glucose-lowering effects of sulfonylureas and acute submaximal exercise are additive and, accordingly, to determine whether they may increase the risk of hypoglycemia when combined in fasting patients. RESEARCH DESIGN AND METHODS: Eight postabsorptive type 2 diabetic patients were examined at three occasions: after oral sulfonylurea (7 mg glibenclamide), during 60 min of ergometer cycle exercise at 57 +/- 3% of VO2max, and during exercise after glibenclamide. RESULTS: Heart rate, VO2, and lactate responses to exercise were comparable (P &amp;gt; 0.05) on days with and without glibenclamide. Plasma insulin concentrations were always increased by glibenclamide, and they were lowered identically by exercise with and without glibenclamide. However, throughout exercise, absolute concentrations of insulin were lower on days without glibenclamide compared with days with glibenclamide (34.5 +/- 4.7 vs. 47.4 +/- 5.5 pmol/l; P &amp;lt; 0.05). At the start of exercise, glucose concentrations were similar between experiments (P &amp;gt; 0.05). The rate of decrease in glucose during exercise was higher (P &amp;lt; 0.05) on days with both glibenclamide and exercise, compared with days with glibenclamide alone and days with exercise alone (-0.035 +/- 0.009 vs. -0.016 +/- 0.002 and -0.022 +/- 0.005 mmol.l-1.min-1, respectively). Consequently, the glucose nadir was lower on days with glibenclamide and exercise than on days with glibenclamide or exercise alone (6.7 +/- 1.1 vs. 8.1 +/- 0.9 and 7.6 +/- 1.0 mmol/l, respectively; P &amp;lt; 0.05). During exercise, the rate of appearance of plasma glucose determined by 3-[3H]glucose infusion was lower on days with glibenclamide than on days without glibenclamide (2.3 +/- 0.1 vs. 2.9 +/- 0.1 mg.min-1.kg-1; P &amp;lt; 0.05). In contrast, glucose clearance was identical (P &amp;gt; 0.05). CONCLUSIONS: In postabsorptive type 2 diabetic patients, the hypoglycemic action of glibenclamide and exercise is enhanced when the treatments are combined. The interaction reflects an increased inhibition by glibenclamide-enhanced insulin levels of hepatic glucose production when hepatic glucose production is accelerated by exercise.
Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation
Authors: Yanqiu Liu, Agnes D. Berendsen, Shidong Jia, Sutada Lotinun, Roland Baron, Napoleone Ferrara, Bjorn R. Olsen
Journal: Journal of Clinical Investigation (2012)

Osteoporotic bones have reduced spongy bone mass, altered bone architecture, and increased marrow fat. Bone marrow stem cells from osteoporotic patients are more likely to differentiate into adipocytes than control cells, suggesting that adipocyte differentiation may play a role in osteoporosis. VEGF is highly expressed in osteoblastic precursor cells and is known to stimulate bone formation. Here we tested the hypothesis that VEGF is also an important regulator of cell fate, determining whether differentiation gives rise to osteoblasts or adipocytes. Mice with conditional VEGF deficiency in osteoblastic precursor cells exhibited an osteoporosis-like phenotype characterized by reduced bone mass and increased bone marrow fat. In addition, reduced VEGF expression in mesenchymal stem cells resulted in reduced osteoblast and increased adipocyte differentiation. Osteoblast differentiation was reduced when VEGF receptor 1 or 2 was knocked down but was unaffected by treatment with recombinant VEGF or neutralizing antibodies against VEGF. Our results suggested that VEGF controls differentiation in mesenchymal stem cells by regulating the transcription factors RUNX2 and PPARγ2 as well as through a reciprocal interaction with nuclear envelope proteins lamin A/C. Importantly, our data support a model whereby VEGF regulates differentiation through an intracrine mechanism that is distinct from the role of secreted VEGF and its receptors.
PTTG/securin activates expression of p53 and modulates its function.
Authors: Tariq Hamid, Sham S Kakar
Journal: Molecular Cancer (2004)

Pituitary tumor transforming gene (PTTG) is a novel oncogene that is expressed abundantly in most tumors. Overexpression of PTTG induces cellular transformation and promotes tumor formation in nude mice. PTTG has been implicated in various cellular processes including sister chromatid separation during cell division as well as induction of apoptosis through p53-dependent and p53-independent mechanisms. The relationship between PTTG and p53 remains unclear, however.Here we report the effects of overexpression of PTTG on the expression and function of p53. Our results indicate that overexpression of PTTG regulates the expression of the p53 gene at both the transcriptional and translational levels and that this ability of PTTG to activate the expression of p53 gene is dependent upon the p53 status of the cell. Deletion analysis of the p53 gene promoter revealed that only a small region of the p53 gene promoter is required for its activation by PTTG and further indicated that the activation of p53 gene by PTTG is an indirect effect that is mediated through the regulation of the expression of c-myc, which then interacts with the p53 gene promoter. Our results also indicate that overexpression of PTTG stimulates expression of the Bax gene, one of the known downstream targets of p53, and induces apoptosis in a human embryonic kidney cell line (HEK293). This stimulation of bax expression by PTTG is indirect and is mediated through modulation of p53 gene expression.Overexpression of PTTG activates the expression of p53 and modulates its function, with this action of PTTG being mediated through the regulation of c-myc expression. PTTG also up-regulates the activity of the bax promoter and increases the expression of bax through modulation of p53 expression.
Activation of Nuclear Factor-κB Significantly Contributes to Lumen Loss in a Rabbit Iliac Artery Balloon Angioplasty Model
Authors: J.M. Breuss, M. Cejna, H. Bergmeister, A. Kadl, G. Baumgartl, S. Steurer, Z. Xu, Y. Koshelnick, J. Lipp, R. De Martin, U. Losert, J. Lammer, B.R. Binder
Journal: Circulation (2002)

To investigate the contribution of inflammation to postangioplasty lumen loss, we used an adenoviral gene therapy approach to inhibit the central inflammatory mediator nuclear factor-kappaB (NF-kappaB) by overexpression of its natural inhibitor, IkappaBalpha.The adenovirus carrying human IkappaBalpha was applied immediately after balloon dilatation by a double-balloon catheter in a rabbit iliac artery restenosis model. Immunohistochemistry of IkappaBalpha revealed that mainly smooth muscle cells of the media but also cells of the adventitia were transduced and expressed the transgene IkappaB alpha for >/= 8 days. At this time point, intercellular adhesion molecule-1 (30%) and monocyte chemotactic protein-1 (50%) expression, as well as recruitment of macrophages into the wounded area (90%), were significantly reduced in IkappaB alpha-treated vessels. In addition, expression of inhibitor of apoptosis proteins was reduced and the percentage of apoptotic cells was increased compared with control-treated contralateral vessels. Animals killed 5 weeks after treatment exhibited a significantly reduced degree of lumen narrowing (P<0.02) on the side treated with adenovirus IkappaBalpha. The lumen gain of approximately 40% was due to positive remodeling.From these data, we conclude that balloon angioplasty-induced activation of NF-kappaB contributes to lumen loss likely via induction of an inflammatory response and a decrease in the rate of apoptosis. These data show for the first time that inflammation mediated by NF-kappaB is involved in postangioplasty lumen narrowing. Specific and more potent inhibitors of NF-kappaB might therefore be a useful therapeutic measure to improve clinical outcome after balloon dilatation.
Clearance of inhaled technetium-99m-DTPA as a clinical index of pulmonary vascular disease in systemic sclerosis
Authors: O.M. Kon, Z. Daniil, C.M. Black, R.M. du Bois
Journal: European Respiratory Journal (1999)

This study evaluated the utility of the clearance time of inhaled diethylenetriamine pentaacetate (DTPA) to distinguish pulmonary vascular disease from early fibrosing alveolitis (FA) in patients with systemic sclerosis (SSc). It was hypothesized that this would be preserved in patients with vascular disease compared with FA, despite similar gas-transfer deficits and matching lung volumes, because of the preservation of alveolar epithelial integrity. All patients had SSc and were categorized into a control group (C; n=9), pulmonary vascular group (VAS; n=14) or FA group (n=14) dependent on the appearance on a computed tomography (CT) scan and the transfer factor of the lung for carbon monoxide (T(L,CO)) (VAS and FA < or =70%, C > or =80%). All patients had a forced vital capacity (FVC) of >80%. The T(L,CO) (median) was similar in the VAS (57.5%) and FA (60%) groups. There was a significant difference in median DTPA clearance half-times between FA (21.25 min) and VAS (46.5 min) (p=0.014) and between FA and C (84.5 min) (p=0.0004). No difference was found between VAS and C (p=0.0778). Follow-up data from the VAS group showed no subsequent development of FA on the CT scan and no decrease in FVC (n=13, mean 42 months). These results suggest that clearance of diethylenetriamine pentaacetate is preserved in patients likely to have pulmonary vascular disease and may be useful in distinguishing fibrosing alveolitis from vascular disease in systemic sclerosis.
Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis
Authors: Jiangwen Zhang, Audrey F Jackson, Taku Naito, Marei Dose, John Seavitt, Feifei Liu, Elizabeth J Heller, Mariko Kashiwagi, Toshimi Yoshida, Fotini Gounari, Howard T Petrie, Katia Georgopoulos
Journal: Nature Immunology (2011)
Contributors to Mortality in High-Risk Diabetic Patients in the Diabetes Heart Study
Authors: Amanda J. Cox, Fang-Chi Hsu, Barry I. Freedman, David M. Herrington, Michael H. Criqui, J. Jeffrey Carr, Donald W. Bowden
Journal: Diabetes Care (2014)

Not all individuals with type 2 diabetes and high coronary artery calcified plaque (CAC) experience the same risk for adverse outcomes. This study examined a subset of high-risk individuals based on CAC >1,000 mg (using a total mass score) and evaluated whether differences in a range of modifiable cardiovascular disease (CVD) risk factors provided further insights into risk for mortality.We assessed contributors to all-cause mortality among 371 European American individuals with type 2 diabetes and CAC >1,000 from the Diabetes Heart Study (DHS) after 8.2 ± 3.0 years (mean ± SD) of follow-up. Differences in known CVD risk factors, including modifiable CVD risk factors, were compared between living (n = 218) and deceased (n = 153) participants. Cox proportional hazards regression models were used to quantify risk for all-cause mortality.Deceased participants had a longer duration of type 2 diabetes (P = 0.02) and reduced use of cholesterol-lowering medications (P = 0.004). Adjusted analyses revealed that vascular calcified plaque scores were associated with increased risk for mortality (hazard ratio 1.31-1.63; 3.89 × 10(-5) < P < 0.03). Higher HbA1c, lipids, and C-reactive protein and reduced kidney function also were associated with a 1.1- to 1.5-fold increased risk for mortality (3.45 × 10(-6) < P < 0.03) after adjusting for confounding factors.Even in this high-risk group, vascular calcification and known CVD risk factors provide useful information for ongoing assessment. The use of cholesterol-lowering medication seemed to be protective for mortality.
Comparison of the Numerical and Clinical Accuracy of Four Continuous Glucose Monitors
Authors: Boris Kovatchev, Stacey Anderson, Lutz Heinemann, William Clarke
Journal: Diabetes Care (2008)

The purpose of this study was to compare the numerical and clinical accuracy of four continuous glucose monitors (CGMs): Guardian, DexCom, Navigator, and Glucoday.Accuracy data for the four CGMs were collected in two studies: Study 1 enrolled 14 adults with type 1 diabetes at the University of Virginia (UVA), Charlottesville, Virginia; study 2 enrolled 20 adults with type 1 diabetes at the Profil Institute for Metabolic Research, Neuss, Germany. All participants underwent hyperinsulinemic clamps including 1.5-2 h of maintained euglycemia at 5.6 mmol/l followed by descent into hypoglycemia, sustained hypoglycemia at 2.5 mmol/l for 30 min, and recovery. Reference blood glucose sampling was performed every 5 min. The UVA study tested Guardian, DexCom, and Navigator simultaneously; the Profil study tested Glucoday.Regarding numerical accuracy, during euglycemia, the mean absolute relative differences (MARDs) of Guardian, DexCom, Navigator, and Glucoday were 15.2, 21.2, 15.3, and 15.6%, respectively. During hypoglycemia, the MARDs were 16.1, 21.5, 10.3, and 17.5%, respectively. Regarding clinical accuracy, continuous glucose-error grid analysis (CG-EGA) revealed 98.9, 98.3, 98.6, and 95.5% zones A + B hits in euglycemia. During hypoglycemia, zones A + B hits were 84.4, 97.0, and 96.2% for Guardian, Navigator, and Glucoday, respectively. Because of frequent loss of sensitivity, there were insufficient hypoglycemic DexCom data to perform CG-EGA.The numerical accuracy of Guardian, Navigator, and Glucoday was comparable, with an advantage to the Navigator in hypoglycemia; the numerical errors of the DexCom were approximately 30% larger. The clinical accuracy of the four sensors was similar in euglycemia and was higher for the Navigator and Glucoday in hypoglycemia.
A Randomized Clinical Trial of Acupuncture Compared with Sham Acupuncture in Fibromyalgia
Authors: Nassim P. Assefi, Karen J. Sherman, Clemma Jacobsen, Jack Goldberg, Wayne R. Smith, Dedra Buchwald
Journal: Annals of Internal Medicine (2005)

Background: Fibromyalgia is a common chronic pain condition for which patients frequently use acupuncture. Objective: To determine whether acupuncture relieves pain in fibromyalgia. Design: Randomized, sham-controlled trial in which participants, data collection staff, and data analysts were blinded to treatment group. Setting: Private acupuncture offices in the greater Seattle, Washington, metropolitan area. Patients: 100 adults with fibromyalgia. Intervention: Twice-weekly treatment for 12 weeks with an acupuncture program that was specifically designed to treat fibromyalgia, or 1 of 3 sham acupuncture treatments: acupuncture for an unrelated condition, needle insertion at nonacupoint locations, or noninsertive simulated acupuncture. Measurements: The primary outcome was subjective pain as measured by a 10-cm visual analogue scale ranging from 0 (no pain) to 10 (worst pain ever). Measurements were obtained at baseline; 1, 4, 8, and 12 weeks of treatment; and 3 and 6 months after completion of treatment. Participant blinding and adverse effects were ascertained by self-report. The primary outcomes were evaluated by pooling the 3 sham-control groups and comparing them with the group that received acupuncture to treat fibromyalgia. Results: The mean subjective pain rating among patients who received acupuncture for fibromyalgia did not differ from that in the pooled sham acupuncture group (mean between-group difference, 0.5 cm [95% CI, −0.3 cm to 1.2 cm]). Participant blinding was adequate throughout the trial, and no serious adverse effects were noted. Limitations: A prescription of acupuncture at fixed points may differ from acupuncture administered in clinical settings, in which therapy is individualized and often combined with herbal supplementation and other adjunctive measures. A usual-care comparison group was not studied. Conclusion: Acupuncture was no better than sham acupuncture at relieving pain in fibromyalgia.
Recent advances in the phencyclidine model of schizophrenia
Authors: D C Javitt, S R Zukin
Journal: American Journal of Psychiatry (1991)

Phencyclidine (PCP, "angel dust") induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding of schizophrenic pathophysiology.Twenty-five papers were identified that described the clinical dose and serum and CSF levels at which PCP induces its psychotomimetic effects. The dose range of PCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission.It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation of its receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition.These findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models of schizophrenia are discussed in relationship to the diagnosis and etiology of schizophrenia.