tbuckley/cabot-search huggingface dataset:
Nelfinavir Down-regulates Hypoxia-Inducible Factor 1α and VEGF Expression and Increases Tumor Oxygenation: Implications for Radiotherapy
Authors: Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Zibin Jiang, Eric J. Bernhard, Sydney M. Evans, Cameron J. Koch, Stephen M. Hahn, Amit Maity
Journal: Cancer Research (2006)

Abstract The phosphatidylinositol 3-kinase (PI3K)/Akt pathway can increase vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α) expression. We examined the effect of nelfinavir, an HIV protease inhibitor that inhibits Akt signaling, on VEGF and HIF-1α expression and on angiogenesis, tumor oxygenation, and radiosensitization. Nelfinavir decreases VEGF expression under normoxia via the transcription factor Sp1, which regulates the proximal core VEGF promoter. Nelfinavir decreased Sp1 phosphorylation and decreased Sp1 binding to a probe corresponding to the proximal VEGF promoter in a gel shift assay. Nelfinavir also decreased the hypoxic induction of HIF-1α, which also regulates the VEGF promoter, most likely by decreasing its translation. The effect of nelfinavir on VEGF expression had the functional consequence of decreasing angiogenesis in an in vivo Matrigel plug assay. To determine the effect this might have on tumor radiosensitization, we did tumor regrowth assays with xenografts in nude mice. The combination of nelfinavir and radiation increased time to regrowth compared with radiation alone whereas nelfinavir alone had little effect on tumor regrowth. This radiosensitizing effect was greater than suggested by in vitro clonogenic survival assays. One possible explanation for the discordance is that nelfinavir has an effect on tumor oxygenation. Therefore, we examined this with the hypoxia marker EF5 and found that nelfinavir leads to increased oxygenation within tumor xenografts. Our results suggest that nelfinavir decreases HIF-1α/VEGF expression and tumor hypoxia, which could play a role in its in vivo radiosensitizing effect. These data support the use of nelfinavir in combination with radiation in future clinical trials. (Cancer Res 2006; 66(18): 9252-9)
Protein Expression Profiling in High-Risk Breast Cancer Patients Treated with High-Dose or Conventional Dose–Dense Chemotherapy
Authors: Raihanatou Diallo-Danebrock, Evelyn Ting, Oleg Gluz, Alexander Herr, Svjetlana Mohrmann, Helene Geddert, Achim Rody, Karl-Ludwig Schaefer, Stephan E. Baldus, Arndt Hartmann, Peter J. Wild, Michael Burson, Helmut E. Gabbert, Ulrike Nitz, Christopher Poremba
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To characterize the prognostic and predictive impact of protein expression profiles in high-risk breast cancer patients who had previously been shown to benefit from high-dose chemotherapy (HDCT) in comparison to dose-dense chemotherapy (DDCT). Experimental Design: The expression of 34 protein markers was evaluated using tissue microarrays containing paraffin-embedded breast cancer samples from 236 patients who were randomized to the West German Study Group AM01 trial. Results: (a) 24 protein markers of the initial panel of 34 markers were sufficient to identify five profile clusters (subtypes) by K-means clustering: luminal-A (27%), luminal-B (12%), HER-2 (21%), basal-like (13%) cluster, and a so-called “multiple marker negative” (MMN) cluster (27%) characterized by the absence of specifying markers. (b) After DDCT, HER-2 and basal-like groups had significantly worse event-free survival [EFS; hazard ratio (HR), 3.6 [95% confidence interval (95% CI), 1.65-8.18; P = 0.001] and HR, 3.7 (95% CI, 1.68-8.48; P &amp;lt; 0.0001), respectively] when compared with both luminal groups. (c) After HDCT, the HR was 1.5 (95% CI, 0.76-3.05) for EFS in the HER-2 subgroup and 1.1 (95% CI, 0.37-3.32) in the basal-like subgroup, which indicates a better outcome for patients in the HER-2 and basal-like subgroups who received HDCT. The MMN cluster showed a trend to a better EFS after HDCT compared with DDCT. Conclusions: Protein expression profiling in high-risk breast cancers identified five subtypes, which differed with respect to survival and response to chemotherapy: In contrast to luminal-A and luminal-B subtypes, HER-2 and basal-like subgroups had a significant predictive benefit, and the MMN cluster had a trend to a predictive benefit, both from HDCT when compared with DDCT.
A phase II trial of a combination of pemetrexed and gemcitabine in patients with metastatic breast cancer: an NCCTG study
Authors: C.X. Ma, P. Steen, K.M. Rowland, R.D. Niedringhaus, T.R. Fitch, J.W. Kugler, D.W. Hillman, E.A. Perez, J.N. Ingle, A.A. Adjei
Journal: Annals of Oncology (2005)
Rapid and sustained health utility gain in anti-tumour necrosis factor-treated inflammatory arthritis: observational data during 7 years in southern Sweden
Authors: A Gülfe, L E Kristensen, T Saxne, L T H Jacobsson, I F Petersson, P Geborek
Journal: Annals of the Rheumatic Diseases (2009)

Rheumatoid arthritis (RA), psoriatic arthritis (PsA) and other spondylarthritides impose a great impact on the individual in addition to the costs on society, which may be reduced by effective pharmacological treatment. Industry-independent health economic studies should complement studies sponsored by industry.To study secular trends in baseline health utilities in patients commencing tumour necrosis factor (TNF) blockade for arthritis in clinical practice over 7 years; to address utility changes during treatment; to investigate the influence of previous treatment courses; to study the feasibility of health utility measures and to compare them across diagnostic entities.EuroQoL 5 dimensions (EQ-5D) utility data were collected from a structured clinical follow-up programme of anti-TNF-treated patients with RA (N = 2554), PsA (N = 574) or spondylarthritides (N = 586). Time trends were calculated. Completer analysis was used.There were weak or non-significant secular trends for increasing baseline utilities over time for RA, PsA and spondylarthritides. The maximum gain in utilities had already occurred after 2 weeks for all diagnoses and remained stable for patients remaining on therapy. The first and second anti-TNF courses performed similarly.Utilities at inclusion remained largely unchanged for RA, PsA and spondylarthritides over 7 years. Improvement occurred early during treatment and not beyond 6 weeks at the group level. Improvement during the first course was not consistently greater than the second. There were no major differences between RA, PsA and spondylarthritides. EQ-5D proved feasible and applicable across these diagnoses. These "real world" data may be useful for health economic modelling.
A familial case of renal cell carcinoma and a t(2;3) chromosome translocation
Authors: Marianne I. Koolen, Ad P.M. van der Meyden, Danielle Bodmer, Marc Eleveld, Erica van der Looij, Han Brunner, Arie Smits, Eva van den Berg, Dominique Smeets, Ad Geurts van Kessel
Journal: Kidney International (1998)
Recent trends in physician diagnosed COPD in women and men in the UK
Authors: Joan B Soriano, William C Maier, Peter Egger, George Visick, Bharat Thakrar, Jennie Sykes, Neil B Pride
Journal: Thorax (2000)

Recent trends in physician diagnosed chronic obstructive pulmonary disease (COPD) in the UK were estimated, with a particular focus on women.A retrospective cohort of British patients with COPD was constructed from the General Practice Research Database (GPRD), a large automated database of UK general practice data. Prevalence and all-cause mortality rates by sex, calendar year, and severity of COPD, based on treatment only, were estimated from January 1990 to December 1997.A total of 50 714 incident COPD patients were studied, 23 277 (45.9%) of whom were women. From 1990 to 1997 the annual prevalence rates of physician diagnosed COPD in women rose continuously from 0.80% (95% CI 0.75 to 0.83) to 1.36% (95% CI 1.34 to 1.39), (p for trend <0.01), rising to the rate observed in men in 1990. Increases in the prevalence of COPD were observed in women of all ages; in contrast, a plateau was observed in the prevalence of COPD in men from the mid 1990s. All-cause mortality rates were higher in men than in women (106.8 versus 82.2 per 1000 person-years), with a consistently increased relative risk in men of 1.3 even after controlling for the severity of COPD. Significantly increased mortality rates were also observed in adults aged less than 65 years. The mean age at death was 76.5 years; patients with severe COPD died an average of three years before those with mild disease (p<0.01) and four years before the age and sex matched reference population.While prevalence rates of COPD in the UK seem to have peaked in men, they are continuing to rise in women. This trend, together with the ageing of the population and the long term cumulative effect of pack-years of smoking in women, is likely to increase the present burden of COPD in the UK.
Accelerated Titration Designs for Phase I Clinical Trials in Oncology
Authors: R. Simon, L. Rubinstein, S. G. Arbuck, M. C. Christian, B. Freidlin, J. Collins
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Many cancer patients in phase I clinical trials are treated at doses of chemotherapeutic agents that are below the biologically active level, thus reducing their chances for therapeutic benefit. Current phase I trials often take a long time to complete and provide little information about interpatient variability or cumulative toxicity. Purpose: Our objective was to develop alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information (i.e., cumulative toxicity and maximum tolerated dose) needed to plan phase II trials is obtained. Methods: We fit a stochastic model to data from 20 phase I trials involving the study of nine different drugs. We then simulated new data from the model with the parameters estimated from the actual trials and evaluated the performance of alternative phase I designs on this simulated data. Four designs were evaluated. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted to standard cohorts of three to six patients, with 40% dose-step increments. Designs 2 through 4 used intrapatient dose escalation if the worst toxicity is grade 0–1 in the previous course for that patient. Results: Only three of the actual trials demonstrated cumulative toxic effects of the chemotherapeutic agents in patients. The average number of patients required for a phase I trial was reduced from 39.9 for design 1 to 24.4, 20.7, and 21.2 for designs 2, 3, and 4, respectively. The average number of patients who would be expected to have grade 0–1 toxicity as their worst toxicity over three cycles of treatment is 23.3 for design 1, but only 7.9, 3.9, and 4.8 for designs 2, 3, and 4, respectively. The average number of patients with grade 3 toxicity as their worst toxicity increases from 5.5 for design 1 to 6.2, 6.8, and 6.2 for designs 2, 3, and 4, respectively. The average number of patients with grade 4 toxicity as their worst toxicity increases from 1.9 for design 1 to 3.0, 4.3, and 3.2 for designs 2, 3, and 4, respectively. Conclusion: Accelerated titration (i.e., rapid intrapatient drug dose escalation) designs appear to effectively reduce the number of patients who are undertreated, speed the completion of phase I trials, and provide a substantial increase in the information obtained.
Choosing Medical Care in Old Age
Authors: M J. Bendall
Journal: BMJ (1995)

Muriel R Gillick Harvard University Press, $23.95, pp 213 ISBN 0674128125

Caring for elderly people raises, in Westernised societies, social and economic issues seemingly unrelated to how much is spent on health care. The United States has as many problems as Britain despite spending twice as much on health in relation to gross national product. There are, of course, major differences in culture and in health care systems, but much of what Muriel Gillick is saying in Choosing Medical Care in Old Age is very familiar to British geriatricians.

The book …
<i>NOTCH1</i> Mutations in T-Cell Acute Lymphoblastic Leukemia: Prognostic Significance and Implication in Multifactorial Leukemogenesis
Authors: Yong-Mei Zhu, Wei-Li Zhao, Jian-Fei Fu, Jing-Yi Shi, Qin Pan, Jiong Hu, Xiao-Dong Gao, Bing Chen, Jun-Min Li, Shu-Min Xiong, Long-Jun Gu, Jing-Yi Tang, Hui Liang, Hui Jiang, Yong-Quan Xue, Zhi-Xiang Shen, Zhu Chen, Sai-Juan Chen
Journal: Clinical Cancer Research (2006)

Abstract Purpose: NOTCH signaling pathway is essential in T-cell development and NOTCH1 mutations are frequently present in T-cell acute lymphoblastic leukemia (T-ALL). To gain insight into its clinical significance, NOTCH1 mutation was investigated in 77 patients with T-ALL. Experimental Design: Detection of NOTCH1 mutation was done using reverse transcription-PCR amplification and direct sequencing, and thereby compared according to the clinical/biological data of the patients. Results: Thirty-two mutations were identified in 29 patients (with dual mutations in 3 cases), involving not only the heterodimerization and proline/glutamic acid/serine/threonine domains as previously reported but also the transcription activation and ankyrin repeat domains revealed for the first time. These mutations were significantly associated with elevated WBC count at diagnosis and independently linked to short survival time. Interestingly, the statistically significant difference of survival according to NOTCH1 mutations was only observed in adult patients (&amp;gt;18 years) but not in pediatric patients (≤18 years), possibly due to the relatively good overall response of childhood T-ALL to the current chemotherapy. NOTCH1 mutations could coexist with HOX11, HOX11L2, or SIL-TAL1 expression. The negative effect of NOTCH1 mutation on prognosis was potentiated by HOX11L2 but was attenuated by HOX11. Conclusion: NOTCH1 mutation is an important prognostic marker in T-ALL and its predictive value could be even further increased if coevaluated with other T-cell-related regulatory genes. NOTCH pathway thus acts combinatorially with oncogenic transcriptional factors on T-ALL pathogenesis.
Selective Tyrosine Hyperphosphorylation of Cytoskeletal and Stress Proteins in Primary Human Breast Cancers
Authors: Yoon-Pin Lim, Chow Yin Wong, London Lucien Ooi, Brian J. Druker, Richard J. Epstein
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Small-molecule growth factor receptor inhibitors block cell growth in vitro and downstream signaling in vivo, but controlled trials in patients with advanced solid tumors have yielded disappointing response rates. To clarify this discrepancy, we compared the patterns of tyrosine phosphoprotein expression in human cancer cells and primary tumors. Experimental Design: Immunoaffinity chromatography, two-dimensional electrophoresis, and antiphosphotyrosine immunoblotting were combined with mass spectrometry to determine the phosphoproteomic signatures of 40 matched normal and malignant tissues from patients with breast or liver cancer. The identities and abundance of the detected tyrosine phosphoproteins were compared with those of ligand-responsive A431 cells. Results: Patterns of tyrosine-phosphorylated proteins are similar among normal tissues of the same origin but vary markedly between different tissues. Primary breast tumors exhibit a strikingly homogeneous tyrosine phosphorylation profile, whereas liver cancers display greater phosphoproteomic diversity. The main breast-tumor-specific tyrosine phosphoproteins are cytoskeletal molecules (actin, tubulin, and vimentin) and molecular chaperones (Hsp70, Hsc71, and Grp75). In contrast, control studies in ligand-stimulated A431 human cancer cells revealed an additional phosphorylated subset of promitogenic phosphoproteins (Grb2, Shc, Jnk2, phospholipase C-γ, and phosphatidylinositol 3′-kinase). Conclusions: Identification of cytoskeletal and stress proteins as the most abundant tyrosine phosphoproteins in breast tumors implicates these molecules, rather than promitogenic effectors, as the prime stoichiometric substrates for kinase-inhibitory anticancer drugs in vivo. Because phosphorylated cytoskeletal proteins and chaperones mediate cell motility and apoptotic resistance, respectively, these data raise the intriguing possibility that small-molecule tyrosine kinase inhibitors may be of greatest value either as adjuvant antimetastatic/-invasive drugs or as chemo-/radiosensitizers.
The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction
Authors: David Varga-Szabo, Attila Braun, Christoph Kleinschnitz, Markus Bender, Irina Pleines, Mirko Pham, Thomas Renné, Guido Stoll, Bernhard Nieswandt
Journal: The Journal of Experimental Medicine (2008)

Platelet activation and aggregation are essential to limit posttraumatic blood loss at sites of vascular injury but also contributes to arterial thrombosis, leading to myocardial infarction and stroke. Agonist-induced elevation of [Ca2+]i is a central step in platelet activation, but the underlying mechanisms are not fully understood. A major pathway for Ca2+ entry in nonexcitable cells involves receptor-mediated release of intracellular Ca2+ stores, followed by activation of store-operated calcium (SOC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) has been identified as the Ca2+ sensor in the endoplasmic reticulum (ER) that activates Ca2+ release–activated channels in T cells, but its role in mammalian physiology is unknown. Platelets express high levels of STIM1, but its exact function has been elusive, because these cells lack a normal ER and Ca2+ is stored in a tubular system referred to as the sarcoplasmatic reticulum. We report that mice lacking STIM1 display early postnatal lethality and growth retardation. STIM1-deficient platelets have a marked defect in agonist-induced Ca2+ responses, and impaired activation and thrombus formation under flow in vitro. Importantly, mice with STIM1-deficient platelets are significantly protected from arterial thrombosis and ischemic brain infarction but have only a mild bleeding time prolongation. These results establish STIM1 as an important mediator in the pathogenesis of ischemic cardio- and cerebrovascular events.
High-Density Lipoproteins Induce Transforming Growth Factor-β <sub>2</sub> Expression in Endothelial Cells
Authors: Giuseppe D. Norata, Elisa Callegari, Marta Marchesi, Giulia Chiesa, Per Eriksson, Alberico L. Catapano
Journal: Circulation (2005)

HDL is endowed with cardiovascular protective activities. In addition to its role in reverse cholesterol transport, HDL influences different functions of endothelial cells. In the present study, we investigated in endothelial cells the genes involved in inflammation modulated by HDL.Through cDNA array analysis, transforming growth factor (TGF)-beta2 appeared to be a gene responsive to HDL treatment in endothelial cells. Quantitative real-time polymerase chain reaction confirmed that HDL subfraction 3 selectively induces TGF-beta2 mRNA expression and protein release, whereas TGF-beta1 and TGF-beta3 were not affected. This effect was mainly PI3K/Akt dependent. Lysosphingolipids present in HDL such as sphingosine 1 phosphate and sphingosylphosphorylcholine mimicked the effects of the whole HDL. These results were confirmed in vivo in transgenic mice overexpressing human apolipoprotein (apo) A-I. Compared with apoA-I-knockout mice, phospho-Akt, phospho-ERK1/2, and TGF-beta2 expression was increased in the aorta of transgenic mice overexpressing human apoA-I. In addition, the expression of phospho-Smad2/3, the transcription factor activated by TGF-beta, is increased in transgenic mice compared with knockout mice.Because TGF-beta possesses antiinflammatory properties and stabilizes the plaque, the results of the present work suggest a novel target for the antiatherosclerotic effect of HDL.
Optimization of Patient Selection for Gefitinib in Non–Small Cell Lung Cancer by Combined Analysis of Epidermal Growth Factor Receptor Mutation, K-ras Mutation, and Akt Phosphorylation
Authors: Sae-Won Han, Tae-You Kim, Yoon Kyung Jeon, Pil Gyu Hwang, Seock-Ah Im, Kyung-Hun Lee, Jee Hyun Kim, Dong-Wan Kim, Dae Seog Heo, Noe Kyeong Kim, Doo Hyun Chung, Yung-Jue Bang
Journal: Clinical Cancer Research (2006)

Mutations in epidermal growth factor receptor (EGFR) are strongly predictive of gefitinib efficacy in non-small-cell lung cancer. However, the presence of EGFR mutant nonresponses and nonmutant responses points out the need for more comprehensive analysis.For 69 non-small-cell lung cancer patients treated with gefitinib, we have extended our analysis to EGFR gene copy number by fluorescence in situ hybridization, mutations in K-ras, HER2, and exon 20 of EGFR by direct sequencing, and phosphatase and tensin homologue expression by immunohistochemistry, in addition to EGFR exons 18, 19, and 21, and phosphorylations of Akt and extracellular signal-regulated kinase reported previously.EGFR mutation and high gene copy number were associated with better objective response in univariate analysis. However, only gefitinib-sensitive EGFR mutation was independently predictive of both response (P = 0.011) and survival (P = 0.002) in multivariate analysis. No patients with K-ras mutation, including two EGFR mutants, showed response. In EGFR nonmutants, patients with either K-ras mutation or p-Akt overexpression exhibited poor response and time-to-progression whereas patients with high gene copy number tended to have better outcomes in univariate analysis. In multivariate analysis of time-to-progression in EGFR nonmutants, K-ras mutation or p-Akt overexpression was associated with shorter time-to-progression (P = 0.017). No patient with HER2 mutation showed response to gefitinib. Reduced phosphatase and tensin homologue expression was not associated with gefitinib sensitivity.Gefitinib-sensitive EGFR mutation is the single most important predictor of gefitinib sensitivity. In addition to EGFR mutation, K-ras mutation and Akt phosphorylation aid in better prediction of gefitinib responsiveness in non-small-cell lung cancer.
The Ins and Outs of Leukocyte Integrin Signaling
Authors: Clare L. Abram, Clifford A. Lowell
Journal: Annual Review of Immunology (2009)

Integrins are the principal cell adhesion receptors that mediate leukocyte migration and activation in the immune system. These receptors signal bidirectionally through the plasma membrane in pathways referred to as inside-out and outside-in signaling. Each of these pathways is mediated by conformational changes in the integrin structure. Such changes allow high-affinity binding of the receptor with counter-adhesion molecules on the vascular endothelium or extracellular matrix and lead to association of the cytoplasmic tails of the integrins with intracellular signaling molecules. Leukocyte functional responses resulting from outside-in signaling include migration, proliferation, cytokine secretion, and degranulation. Here, we review the key signaling events that occur in the inside-out versus outside-in pathways, highlighting recent advances in our understanding of how integrins are activated by a variety of stimuli and how they mediate a diverse array of cellular responses.
Microfluidics-based diagnostics of infectious diseases in the developing world
Authors: Curtis D Chin, Tassaneewan Laksanasopin, Yuk Kee Cheung, David Steinmiller, Vincent Linder, Hesam Parsa, Jennifer Wang, Hannah Moore, Robert Rouse, Gisele Umviligihozo, Etienne Karita, Lambert Mwambarangwe, Sarah L Braunstein, Janneke van de Wijgert, Ruben Sahabo, Jessica E Justman, Wafaa El-Sadr, Samuel K Sia
Journal: Nature Medicine (2011)