tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Single-Agent Pertuzumab (rhuMAb 2C4), a Human Epidermal Growth Factor Receptor Dimerization Inhibitor, in Castration-Resistant Prostate Cancer After Progression From Taxane-Based Therapy
Authors: David B. Agus, Christopher J. Sweeney, Michael J. Morris, David S. Mendelson, Douglas G. McNeel, Frederick R. Ahmann, Jin Wang, Mika K. Derynck, Kimmie Ng, Benjamin Lyons, David E. Allison, Michael W. Kattan, Howard I. Scher
Journal: Journal of Clinical Oncology (2007)

Purpose Pertuzumab represents a new class of targeted anticancer agents, human epidermal growth factor receptor (HER) dimerization inhibitors. The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent pertuzumab in castration-resistant prostate cancer (CRPC) patients who had experienced progression after prior chemotherapy. Patients and Methods Patients received pertuzumab every 3 weeks. All castration-resistant patients had experienced progression after at least one taxane-based regimen. Patients received a loading dose of 840 mg pertuzumab (cycle 1) followed by 420 mg for subsequent cycles. The primary end point was overall response and safety. A separate retrospective analysis of actual survival time versus predicted survival time for a patient population with comparable prognostic features was performed. Results Patients were enrolled (N = 42) and treated (n = 41). No patients had complete or partial response (as defined by Response Evaluation Criteria in Solid Tumors Group or ≥ 50% decline in prostate-specific antigen). Of 30 efficacy-assessable patients, five had stable disease (SD) for at least 23 weeks; one of five had SD for 36 weeks. Pertuzumab was well tolerated; diarrhea was the most common adverse effect (61.0%, grades 1 to 3). Retrospective analysis of survival using a validated nomogram suggested that survival was prolonged with pertuzumab treatment, compared with historic controls with similar baseline prognostic features. Conclusion Pertuzumab was well tolerated and resulted in no objective responses, but several patients had SD more than 23 weeks from a heavily pretreated population. Retrospective analysis suggested prolonged median survival time with pertuzumab compared with historical controls. Thus, inhibition of HER dimerization may have clinical utility in CRPC patients.
Scaling Laws for Plasma Concentrations and Tolerable Doses of Anticancer Drugs
Authors: Thomas H. Dawson
Journal: Cancer Research (2010)

Abstract General scaling laws are developed for projecting measurements of the plasma concentrations of anticancer drugs from laboratory animals to humans and among humans of different sizes. Associated scaling laws for critical drug doses are established from these laws. Broad categories of single and periodic i.v. bolus dosings are considered. Validity of the relations is shown using measurement from the literature for several well-known cytotoxic agents. The scaling theory is also shown to apply to novel anticancer drugs now available or presently under development, as represented by the p.o. administered prodrug capecitabine, the gene silencing inhibitor zebularine, and the blood vessel inhibitor bevacizumab. Scaling considerations for the modern practice of combination chemotherapy are also discussed. Cancer Res; 70(12); 4801–8. ©2010 AACR.
Potential Confounding of Particulate Matter on the Short-Term Association between Ozone and Mortality in Multisite Time-Series Studies
Authors: Michelle L. Bell, Jee Young Kim, Francesca Dominici
Journal: Environmental Health Perspectives (2007)

BackgroundA critical question regarding the association between short-term exposure to ozone and mortality is the extent to which this relationship is confounded by ambient exposure to particles.ObjectivesWe investigated whether particulate matter < 10 and < 2.5 μm in aerodynamic diameter (PM10 and PM2.5) is a confounder of the ozone and mortality association using data for 98 U.S. urban communities from 1987 to 2000.MethodsWe a) estimated correlations between daily ozone and daily PM concentrations stratified by ozone or PM levels; b) included PM as a covariate in time-series models; and c) included PM as a covariate as in d), but within a subset approach considering only days with ozone below a specified value.ResultsAnalysis was hindered by data availability. In the 93 communities with PM10 data, only 25.0% of study days had data on both ozone and PM10. In the 91 communities with PM2.5 data, only 9.2% of days in the study period had data on ozone and PM2.5. Neither PM measure was highly correlated with ozone at any level of ozone or PM. National and community-specific effect estimates of the short-term effects of ozone on mortality were robust to inclusion of PM10 or PM2.5 in time-series models. The robustness remains even at low ozone levels (< 10 ppb) using a subset approach.ConclusionsResults provide evidence that neither PM10 nor PM2.5 is a likely confounder of observed ozone and mortality relationships. Further investigation is needed to investigate potential confounding of the short-term effects of ozone on mortality by PM chemical composition.
The Learning Curve for Transradial Percutaneous Coronary Intervention Among Operators in the United States
Authors: Connie N. Hess, Eric D. Peterson, Megan L. Neely, David Dai, William B. Hillegass, Mitchell W. Krucoff, Michael A. Kutcher, John C. Messenger, Samir Pancholy, Robert N. Piana, Sunil V. Rao
Journal: Circulation (2014)

Background— Adoption of transradial percutaneous coronary intervention (TRI) in the United States is low and may be related to challenges learning the technique. We examined the relationships between operator TRI volume and procedural metrics and outcomes. Methods and Results— We used CathPCI Registry data from July 2009 to December 2012 to identify new radial operators, defined by an exclusively femoral percutaneous coronary intervention approach for 6 months after their first percutaneous coronary intervention in the database and ≥15 total TRIs thereafter. Primary outcomes of fluoroscopy time, contrast volume, and procedure success were chosen as markers of technical proficiency. Secondary outcomes included in-hospital mortality, bleeding, and vascular complications. Adjusted outcomes were analyzed by using operator TRI experience as a continuous variable with generalized linear mixed models. Among 54 561 TRI procedures performed at 704 sites, 942 operators performed 1 to 10 procedures, 942 operators performed 11 to 50 procedures, 375 operators performed 51 to 100 procedures, and 148 operators performed 101 to 200 procedures. As radial caseload increased, more TRIs were performed in women, in patients presenting with ST-segment elevation myocardial infarction, and for emergency indications. Decreased fluoroscopy time and contrast use were nonlinearly associated with greater operator TRI experience, with faster reductions observed for newer (&lt;30–50 cases) compared with more experienced (&gt;30–50 cases) operators. Procedure success was high, whereas mortality, bleeding, and vascular complications remained low across TRI volumes. Conclusions— As operator TRI volume increases, higher-risk patients are chosen for TRI. Despite this, operator proficiency improves with greater TRI experience, and safety is maintained. The threshold to overcome the learning curve appears to be approximately 30 to 50 cases.
Notes of a Case of Suprapublic Lithotomy
Authors: J. R. Morison
Journal: BMJ (1886)

Biogenesis of nuclear pore complexes (NPCs) includes the formation of the permeability barrier composed of phenylalanine-glycine-rich nucleoporins (FG-Nups) that regulate the selective passage/crossing of biomolecules. The FG-Nups are intrinsically disordered and prone to liquid-liquid phase separate<sup>1,2</sup> and aggregate when isolated<sup>3</sup>. It has remained largely unclear how FG-Nups are protected from making inappropriate interactions during NPC biogenesis. We found that DNAJB6, a molecular chaperone of the heat shock protein network, formed foci next to NPCs. The number of these foci decreases upon removal of proteins involved in the early steps of interphase NPC biogenesis. Reversely, when this process is stalled in the last steps, the number of DNAJB6-containing foci increases and they could be identified as herniations at the nuclear envelope (NE). Immunoelectron tomography showed that DNAJB6 localizes inside the lumen of the herniations arising at NPC biogenesis intermediates. Interestingly, loss of DNAJB6 results in annulate lamellae, which are structures containing partly assembled NPCs associated with disturbances in NPC biogenesis. We find that DNAJB6 binds to FG-Nups and can prevent the aggregation of the FG-region of several FG-Nups in cells and <i>in vitro</i>. Together, our data show that DNAJB6 provides quality control during NPC biogenesis and is the first molecular chaperone that is involved in the surveillance of native intrinsically disordered proteins, including FG-Nups.
Effects of somatostatin and octreotide on portal-systemic collaterals in portal hypertensive rats
Authors: Hui-Chun Huang, Fa-Yauh Lee, Che-Chang Chan, Full-Young Chang, Sun-Sang Wang, Han-Chieh Lin, Ming-Chih Hou, Chien-Ting Chen, Chun-Ching Tai, I-Nien Lai, Shou-Dong Lee
Journal: Journal of Hepatology (2002)
The Biology of IgE and the Basis of Allergic Disease
Authors: Hannah J. Gould, Brian J. Sutton, Andrew J. Beavil, Rebecca L. Beavil, Natalie McCloskey, Heather A. Coker, David Fear, Lyn Smurthwaite
Journal: Annual Review of Immunology (2003)

Allergic individuals exposed to minute quantities of allergen experience an immediate response. Immediate hypersensitivity reflects the permanent sensitization of mucosal mast cells by allergen-specific IgE antibodies bound to their high-affinity receptors (FcεRI). A combination of factors contributes to such long-lasting sensitization of the mast cells. They include the homing of mast cells to mucosal tissues, the local synthesis of IgE, the induction of FcεRI expression on mast cells by IgE, the consequent downregulation of FcγR (through an insufficiency of the common γ-chains), and the exceptionally slow dissociation of IgE from FcεRI. To understand the mechanism of the immediate hypersensitivity phenomenon, we need explanations of why IgE antibodies are synthesized in preference to IgG in mucosal tissues and why the IgE is so tenaciously retained on mast cell–surface receptors. There is now compelling evidence that the microenvironment of mucosal tissues of allergic disease favors class switching to IgE; and the exceptionally high affinity of IgE for FcεRI can now be interpreted in terms of the recently determined crystal structures of IgE-FcεRI and IgG-FcγR complexes. The rate of local IgE synthesis can easily compensate for the rate of the antibody dissociation from its receptors on mucosal mast cells. Effective mechanisms ensure that allergic reactions are confined to mucosal tissues, thereby minimizing the risk of systemic anaphylaxis.
Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis
Authors: Harish Nair, D James Nokes, Bradford D Gessner, Mukesh Dherani, Shabir A Madhi, Rosalyn J Singleton, Katherine L O'Brien, Anna Roca, Peter F Wright, Nigel Bruce, Aruna Chandran, Evropi Theodoratou, Agustinus Sutanto, Endang R Sedyaningsih, Mwanajuma Ngama, Patrick K Munywoki, Cissy Kartasasmita, Eric AF Simões, Igor Rudan, Martin W Weber, Harry Campbell
Journal: The Lancet (2010)
Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia.
Authors: M Merkel, P H Weinstock, T Chajek-Shaul, H Radner, B Yin, J L Breslow, I J Goldberg
Journal: Journal of Clinical Investigation (1998)

Lipoprotein lipase (LPL), the rate-limiting enzyme in triglyceride hydrolysis, is normally not expressed in the liver of adult humans and animals. However, liver LPL is found in the perinatal period, and in adults it can be induced by cytokines. To study the metabolic consequences of liver LPL expression, transgenic mice producing human LPL specifically in the liver were generated and crossed onto the LPL knockout (LPL0) background. LPL expression exclusively in liver rescued LPL0 mice from neonatal death. The mice developed a severe cachexia during high fat suckling, but caught up in weight after switching to a chow diet. At 18 h of age, compared with LPL0 mice, liver-only LPL-expressing mice had equally elevated triglycerides (10,700 vs. 14,800 mg/dl, P = NS), increased plasma ketones (4.3 vs. 1.7 mg/dl, P < 0.05) and glucose (28 vs. 15 mg/dl, P < 0.05), and excessive amounts of intracellular liver lipid droplets. Adult mice expressing LPL exclusively in liver had slower VLDL turnover than wild-type mice, but greater VLDL mass clearance, increased VLDL triglyceride production, and three- to fourfold more plasma ketones. In summary, it appears that liver LPL shunts circulating triglycerides to the liver, which results in a futile cycle of enhanced VLDL production and increased ketone production, and subsequently spares glucose. This may be important to sustain brain and muscle function at times of metabolic stress with limited glucose availability.
Fabrication of Pulsatile Cardiac Tissue Grafts Using a Novel 3-Dimensional Cell Sheet Manipulation Technique and Temperature-Responsive Cell Culture Surfaces
Authors: Tatsuya Shimizu, Masayuki Yamato, Yuki Isoi, Takumitsu Akutsu, Takeshi Setomaru, Kazuhiko Abe, Akihiko Kikuchi, Mitsuo Umezu, Teruo Okano
Journal: Circulation Research (2002)

Recent progress in cell transplantation therapy to repair impaired hearts has encouraged further attempts to bioengineer 3-dimensional (3-D) heart tissue from cultured cardiomyocytes. Cardiac tissue engineering is currently pursued utilizing conventional technology to fabricate 3-D biodegradable scaffolds as a temporary extracellular matrix. By contrast, new methods are now described to fabricate pulsatile cardiac grafts using new technology that layers cell sheets 3-dimensionally. We apply novel cell culture surfaces grafted with temperature-responsive polymer, poly( N -isopropylacrylamide) (PIPAAm), from which confluent cells detach as a cell sheet simply by reducing temperature without any enzymatic treatments. Neonatal rat cardiomyocyte sheets detached from PIPAAm-grafted surfaces were overlaid to construct cardiac grafts. Layered cell sheets began to pulse simultaneously and morphological communication via connexin43 was established between the sheets. When 4 sheets were layered, engineered constructs were macroscopically observed to pulse spontaneously. In vivo, layered cardiomyocyte sheets were transplanted into subcutaneous tissues of nude rats. Three weeks after transplantation, surface electrograms originating from transplanted grafts were detected and spontaneous beating was macroscopically observed. Histological studies showed characteristic structures of heart tissue and multiple neovascularization within contractile tissues. Constructs transplanted into 3-week-old rats exhibited more cardiomyocyte hypertrophy and less connective tissue than those placed into 8-week-old rats. Long-term survival of pulsatile cardiac grafts was confirmed up to 12 weeks. These results demonstrate that electrically communicative pulsatile 3-D cardiac constructs were achieved both in vitro and in vivo by layering cardiomyocyte sheets. Cardiac tissue engineering based on this technology may prove useful for heart model fabrication and cardiovascular tissue repair. The full text of this article is available at http://www.circresaha.org.
Aspirin Suppresses the Growth and Metastasis of Osteosarcoma through the NF-κB Pathway
Authors: Dan Liao, Li Zhong, Tingmei Duan, Ru-Hua Zhang, Xin Wang, Gang Wang, Kaishun Hu, Xiaobin Lv, Tiebang Kang
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Aspirin has recently been reported to reduce both the incidence and the risk of metastasis in colon cancer. However, there is no evidence at the cellular levels or in the animal models for such an effect of aspirin on cancer metastasis. Experimental Design: MTT assay, colony formation assay, and apoptosis assay were employed to analyze the effects of aspirin on the osteosarcoma cell viability in vitro. The NF-κB activity was measured by the NF-κB p65 luciferase reporter. Western blotting was used to analyze the proteins in cells. The migration and invasion abilities of osteosarcoma cells in vitro were measured by the Transwell assay. Xenograft-bearing mice were used to assess the roles of aspirin in both tumor growth and metastasis of osteosarcoma in vivo (n = 5–8 mice/group). An unpaired Student t test or ANOVA with the Bonferroni post hoc test were used for the statistical comparisons. Results: Aspirin reduced cell viability in a dose- and time-dependent manner in osteosarcoma cell lines, and aspirin synergistically sensitized osteosarcoma cells to cisplatin (DDP) in vitro and in vivo (P &amp;lt; 0.001). Moreover, aspirin markedly repressed the migration and invasion of osteosarcoma cells in vitro (P &amp;lt; 0.001), and dramatically diminished the occurrence of osteosarcoma xenograft metastases to the lungs in vivo (P &amp;lt; 0.001). Mechanistically, aspirin diminishes osteosarcoma migration, invasion, and metastasis through the NF-κB pathway. Conclusions: Aspirin suppresses both the growth and metastasis of osteosarcoma through the NF-κB pathway at the cellular level and in the animal models. Clin Cancer Res; 21(23); 5349–59. ©2015 AACR.
Early noninvasive ventilation failure in COPD with acute on chronic respiratory failure
Authors: A. Cuvelier, L. C. Molano, J-F. Muir
Journal: European Respiratory Journal (2005)

Early noninvasive ventilation failure in COPD with acute on chronic respiratory failureTo the Editors:Noninvasive ventilation (NIV) has proven to be of great interest in the management of acute respiratory failure (ARF) due to exacerbations of chronic obstructive pulmonary disease (COPD), with an improvement in arterial blood gas tensions and respiratory frequency usually observed 1-6 h after initiation [1,2].We describe an unusual and reversible condition of early NIV failure as follows.
Post-Traumatic Stress Symptoms in Long-Term Non-Hodgkin's Lymphoma Survivors: Does Time Heal?
Authors: Sophia K. Smith, Sheryl Zimmerman, Christianna S. Williams, Habtamu Benecha, Amy P. Abernethy, Deborah K. Mayer, Lloyd J. Edwards, Patricia A. Ganz
Journal: Journal of Clinical Oncology (2011)

Little is known about the trajectory of post-traumatic stress disorder (PTSD) symptoms in cancer survivors, despite the fact that such knowledge can guide treatment. Therefore, this study examined changes in PTSD symptoms among long-term survivors of non-Hodgkin's lymphoma (NHL) and identified demographic, clinical, and psychosocial predictors and correlates of PTSD symptomatology.Surveys were mailed to 682 NHL survivors who participated in an earlier survey and now were at least 7 years postdiagnosis. Information was obtained regarding PTSD symptoms, positive and negative perceptions of the cancer experience (ie, impact of cancer), and other potential correlates of PTSD.A total of 566 individuals participated (83% response rate) with a median of 12.9 years since diagnosis; respondents were 52% female and 87% white. Although half (51%) of the respondents reported no PTSD symptoms and 12% reported a resolution of symptoms, more than one-third (37%) reported persistence or worsening of symptoms over 5 years. Survivors who reported a low income, stage ≥ 2 at diagnosis, aggressive lymphoma, having received chemotherapy, and greater impact of cancer (both positive and negative) at the initial survey had more PTSD symptoms at follow-up. In multivariable analysis, income and negative impacts of cancer were independent predictors of PTSD symptoms.More than one-third of long-term NHL survivors experience persisting or worsening PTSD symptoms. Providers should be aware of enduring risk; early identification of those at prolonged risk with standardized measures and treatments that target perceptions of the cancer experience might improve long-term outcomes.
Effects of ligustrazine on the pressure/flow relationship in isolated perfused rat lungs
Authors: A Oddoy, D Bee, C Emery, G Barer
Journal: European Respiratory Journal (1991)

Ligustrazine, the synthesized principle of a Chinese herbal remedy shown previously to be a pulmonary vasodilator, was tested in chronically hypoxic and normal rats. Pressure/flow, (P/Q), relations were measured in isolated perfused lungs during normoxia, hypoxia and after reversal of hypoxic vasoconstriction by increasing doses of ligustrazine. P/Q lines were linear over a wide range and extrapolation to the pressure axis gave an intercept which was the effective downstream pressure for flow. In chronically hypoxic rats the slope of the line was steeper and the intercept greater than in control rats, which we attributed to newly muscularized arterioles with tone. Hypoxia caused an increase in slope and intercept in both groups but the intercept increase was greater in chronically hypoxic rats. In both groups of rats increasing doses of ligustrazine given during continued hypoxia caused a fan of lines which moved progressively towards the control normoxic line. In chronically hypoxic rats it required only 2 mg of ligustrazine to bring the line back to the normoxic position, whereas in controls it required 4 mg. In chronically hypoxic rats the change in intercept with every dose was greater than in control rats; this suggests that ligustrazine mainly relaxes the muscle of small collapsible vessels. The action of ligustrazine remained in both control and chronically hypoxic rats after administration of an arginine analogue which blocks synthesis of the endothelial relaxant factor nitric oxide. This and previous evidence suggest that ligustrazine is a non-endothelial-dependent pulmonary vasodilator.
Transforming Growth Factor-β Activation Promotes Genetic Context–Dependent Invasion of Immortalized Melanocytes
Authors: Roger S. Lo, Owen N. Witte
Journal: Cancer Research (2008)

Abstract Accumulation of distinct sets of genetic/epigenetic alterations is thought to contribute to stepwise progression of human cutaneous melanomas. We found evidence of frequent tumor cell autonomous transforming growth factor-β (TGF-β) signal activation in both premalignant and malignant stages of human cutaneous melanoma histogenesis and investigated its potential causative roles using human organotypic skin cultures. PTEN deficiency and Braf activation, two common coincident genetic alterations found in primary cutaneous melanomas, were first introduced into human melanocytes previously immortalized by the SV40 large T antigen and telomerase. These changes individually supported anchorage-independent growth and conferred benign, hyperplastic growth in a skin-like environment. In addition, PTEN deficiency combined with Braf activation together induced a melanoma in situ–like phenotype without dermal invasion. Further addition of cell autonomous TGF-β activation in the context of PTEN deficiency and Braf activation promoted dermal invasion in skin cultures without significantly promoting proliferation in vitro and in vivo. This proinvasive phenotype of cell autonomous TGF-β activation is genetic context–dependent, as hyperactivating the TGF-β type I receptor without PTEN deficiency and Braf activation failed to induce an invasive behavior. Evidence of genetic interactions among PTEN deficiency, Braf activation, and cell autonomous TGF-β activation shows that distinct stages of human melanoma are genetically tractable in the proper tissue architecture. [Cancer Res 2008;68(11):4248–57]