tbuckley/cabot-search huggingface dataset:
Dose-Dense Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel With Trastuzumab and Lapatinib in HER2/<i>neu</i>–Overexpressed/Amplified Breast Cancer Is Not Feasible Because of Excessive Diarrhea
Authors: Chau Dang, Nancy Lin, Beverly Moy, Steven Come, Steven Sugarman, Patrick Morris, Alyson Abbruzzi, Carol Chen, Richard Steingart, Sujata Patil, Larry Norton, Eric Winer, Clifford Hudis
Journal: Journal of Clinical Oncology (2010)

Dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel and trastuzumab (PT) is feasible. Lapatinib is effective in the treatment of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer. We conducted a pilot study of dose-dense AC followed by PT plus lapatinib (PTL) followed by trastuzumab plus lapatinib (TL).
1. Effects of Season and Indoor Heating on Indoor and Outdoor Residential Levels of Airborne Polycyclic Aromatic Hydrocarbons, Absorbance and Particulate Matter 2.5 in an Inner City Cohort of Young Children
Authors: K. Jung, M.M. Patel, P.L. Kinney, S.N. Chillrud, R. Whyatt, L. Hoepner, B. Yan, R. Garfinkel, J. Ross, D. Camann, F.P. Perera, R.L. Miller
Journal: Journal of Allergy and Clinical Immunology (2010)
Small molecule kinase inhibitor LRRK2-IN-1 demonstrates potent activity against colorectal and pancreatic cancer through inhibition of doublecortin-like kinase 1
Authors: Nathaniel Weygant, Dongfeng Qu, William L Berry, Randal May, Parthasarathy Chandrakesan, Daniel B Owen, Sripathi M Sureban, Naushad Ali, Ralf Janknecht, Courtney W Houchen
Journal: Molecular Cancer (2014)

Doublecortin-like kinase 1 (DCLK1) is emerging as a tumor specific stem cell marker in colorectal and pancreatic cancer. Previous in vitro and in vivo studies have demonstrated the therapeutic effects of inhibiting DCLK1 with small interfering RNA (siRNA) as well as genetically targeting the DCLK1+ cell for deletion. However, the effects of inhibiting DCLK1 kinase activity have not been studied directly. Therefore, we assessed the effects of inhibiting DCLK1 kinase activity using the novel small molecule kinase inhibitor, LRRK2-IN-1, which demonstrates significant affinity for DCLK1. Here we report that LRRK2-IN-1 demonstrates potent anti-cancer activity including inhibition of cancer cell proliferation, migration, and invasion as well as induction of apoptosis and cell cycle arrest. Additionally we found that it regulates stemness, epithelial-mesenchymal transition, and oncogenic targets on the molecular level. Moreover, we show that LRRK2-IN-1 suppresses DCLK1 kinase activity and downstream DCLK1 effector c-MYC, and demonstrate that DCLK1 kinase activity is a significant factor in resistance to LRRK2-IN-1. Given DCLK1’s tumor stem cell marker status, a strong understanding of its biological role and interactions in gastrointestinal tumors may lead to discoveries that improve patient outcomes. The results of this study suggest that small molecule inhibitors of DCLK1 kinase should be further investigated as they may hold promise as anti-tumor stem cell drugs.
A Case–Control Analysis of Exposure to Traffic and Acute Myocardial Infarction
Authors: Cathryn Tonne, Steve Melly, Murray Mittleman, Brent Coull, Robert Goldberg, Joel Schwartz
Journal: Environmental Health Perspectives (2006)

BackgroundLong-term exposure to particulate air pollution has been associated with an increased risk of dying from cardiopulmonary and ischemic heart disease, yet few studies have evaluated cardiovascular end points other than mortality. We investigated the relationship between long-term exposure to traffic and occurrence of acute myocardial infarction (AMI) in a case–control study.MethodsA total of 5,049 confirmed cases of AMI were identified between 1995 and 2003 as part of the Worcester Heart Attack Study, a community-wide study examining changes over time in the incidence of AMI among greater Worcester, Massachusetts, residents. Population controls were selected from Massachusetts resident lists. We used cumulative traffic within 100 m of subjects' residence and distance from major roadway as proxies for exposure to traffic-related air pollution. We estimated the relationship between exposure to traffic and occurrence of AMI using logistic regression, and we adjusted for the following potential confounders: age, sex, section of the study area, point sources emissions of particulate matter with aerodynamic diameter < 2.5 μm, area socioeconomic characteristics, and percentage of open space.ResultsAn increase in cumulative traffic near the home was associated with a 4% increase in the odds of AMI per interquartile range [95% confidence interval (CI), 2–7%], whereas living near a major roadway was associated with a 5% increase in the odds of AMI per kilometer (95% CI, 3–6%).Conclusionshese results provide support for an association between long-term exposure to traffic and the risk of AMI.
Pharmacokinetics of PCBs
Authors: H B Matthews, R L Dedrick
Journal: The Annual Review of Pharmacology and Toxicology (1984)

The pharmacokinetics of PCBs are complicated by numerous factors, not the least of which is the existence of up to 209 different chlorinated biphenyls. Whereas all PCB congeners are highly lipophilic and most are readily absorbed and rapidly distributed to all tissues, PCBs are cleared from tissues at very different rates, and the same congeners may be cleared at different rates by different species. With the exception of special situations in which PCBs may be passively eliminated in lipid sinks, e.g. milk or eggs, clearance is minimal prior to metabolism to more polar compounds. Rates of PBC metabolism vary greatly with species and with the degree and positions of chlorination. Mammals metabolize these compounds most rapidly, but even among mammalian species rates of metabolism vary greatly. In all species studied, the more readily metabolized chlorinated biphenyls have adjacent unsubstituted carbon atoms in the 3-4 positions. Congeners that do not have adjacent unsubstituted carbon atoms may be metabolized very slowly and are therefore cleared very slowly. These PCBs not readily cleared concentrate in adipose tissue. A physiologic pharmacokinetic model best illustrates how the concentrations of PCBs in all tissues approach equilibrium with the blood and with one another. Thus, the model illustrates how a depot of PCBs in any tissue, e.g. adipose tissue, will result in exposure of all tissues in proportion to the respective tissue/blood ratios and the body burden. The disposition of a number of PCBs in the rate has been accurately described by a physiologic model, and the model has been extrapolated to predict the disposition of these same PCBs in the mouse (58). Therefore, the physiologic pharmacokinetic model is believed to offer the best opportunity to extrapolate data obtained with laboratory animals to predict the disposition of PCBs in other species, including man. Most of the parameters of a model of PCB disposition in man are available or could be estimated. The major limitation to the construction of such a model is the absence of accurate estimates of metabolic clearance of individual PCBs by man. Accurate estimates of metabolic clearance depend on development of suitable in vitro methods to accurately predict clearance in vivo.
Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region
Authors: Stanislav Rybtsov, Malgorzata Sobiesiak, Samir Taoudi, Céline Souilhol, Jordi Senserrich, Anna Liakhovitskaia, Andrejs Ivanovs, Jon Frampton, Suling Zhao, Alexander Medvinsky
Journal: The Journal of Experimental Medicine (2011)

The aorta-gonad-mesonephros region plays an important role in hematopoietic stem cell (HSC) development during mouse embryogenesis. The vascular endothelial cadherin⁺ CD45⁺ (VE-cad⁺CD45⁺) population contains the major type of immature pre-HSCs capable of developing into long-term repopulating definitive HSCs. In this study, we developed a new coaggregation culture system, which supports maturation of a novel population of CD45-negative (VE-cad⁺CD45⁻CD41⁺) pre-HSCs into definitive HSCs. The appearance of these pre-HSCs precedes development of the VE-cad⁺CD45⁺ pre-HSCs (termed here type I and type II pre-HSCs, respectively), thus establishing a hierarchical directionality in the developing HSC lineage. By labeling the luminal surface of the dorsal aorta, we show that both type I and type II pre-HSCs are distributed broadly within the endothelial and subendothelial aortic layers, in contrast to mature definitive HSCs which localize to the aortic endothelial layer. In agreement with expression of CD41 in pre-HSCs, in vivo CD41-Cre-mediated genetic tagging occurs in embryonic pre-HSCs and persists in all lymphomyeloid lineages of the adult animal.
Multiaxial Mechanical Behavior of Biological Materials
Authors: Michael S. Sacks, Wei Sun
Journal: Annual Review of Biomedical Engineering (2003)

▪ Abstract For native and engineered biological tissues, there exist many physiological, surgical, and medical device applications where multiaxial material characterization and modeling is required. Because biological tissues and many biocompatible elastomers are incompressible, planar biaxial testing allows for a two-dimensional (2-D) stress-state that can be used to fully characterize their three-dimensional (3-D) mechanical properties. Biological tissues exhibit complex mechanical behaviors not easily accounted for in classic elastomeric constitutive models. Accounting for these behaviors by careful experimental evaluation and formulation of constitutive models continues to be a challenging area in biomechanical modeling and simulation. The focus of this review is to describe the application of multiaxial testing techniques to soft tissues and their relation to modern biomechanical constitutive theories.
A Multicenter Phase II Study of Ganetespib Monotherapy in Patients with Genotypically Defined Advanced Non–Small Cell Lung Cancer
Authors: Mark A. Socinski, Jonathan Goldman, Iman El-Hariry, Marianna Koczywas, Vojo Vukovic, Leora Horn, Eugene Paschold, Ravi Salgia, Howard West, Lecia V. Sequist, Philip Bonomi, Julie Brahmer, Lin-Chi Chen, Alan Sandler, Chandra P. Belani, Timothy Webb, Harry Harper, Mark Huberman, Suresh Ramalingam, Kwok-Kin Wong, Florentina Teofilovici, Wei Guo, Geoffrey I. Shapiro
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non–small cell lung cancer (NSCLC). Experimental Design: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies. Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia. Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement. Clin Cancer Res; 19(11); 3068–77. ©2013 AACR.
Expression of Hypoxia-Inducible Factor-1α Protein Predicts Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract
Authors: Kuniaki Nakanishi, Sadayuki Hiroi, Susumu Tominaga, Shinsuke Aida, Hiroyasu Kasamatsu, Shigeo Matsuyama, Tomokazu Matsuyama, Toshiaki Kawai
Journal: Clinical Cancer Research (2005)

Hypoxia-inducible factor-1 (HIF-1), identified as one of the transcription factors, has been found to play an essential role in oxygen homeostasis. HIF-1 is a heterodimer composed of HIF-1alpha and HIF-1beta. Increased levels of HIF-1alpha have been reported during the carcinogenesis and progress of several tumors. We investigated the prognostic importance of HIF-1alpha expression in transitional cell carcinoma of the upper urinary tract. In 127 cases of transitional cell carcinoma of the upper urinary tract, we examined its expression (using immunohistochemistry and in situ hybridization), and also its relation to the expression of p53 oncoprotein, as well as to proliferating cell nuclear antigen (PCNA) immunoreactivity, microvessel density, clinicopathologic parameters, and clinical outcome. A positive expression of HIF-1alpha protein was recognized in 55.1% of samples, the expression being apparent within the nucleus in tumor cells. HIF-1alpha protein expression correlated with grade, growth pattern, p53 oncoprotein expression, and PCNA index, but not with stage. Furthermore, a significant correlation was found between HIF-1alpha protein expression and both overall and disease-free survival rates in the univariate and multivariate analyses (in all tumors and in invasive tumors). A positive expression of HIF-1alpha mRNA was recognized in 69.6% of 125 samples which were available, the expression being apparent within the cytoplasm in tumor cells. The positive expression of HIF-1alpha mRNA by in situ hybridization correlated significantly with HIF-1alpha protein expression by immunohistochemistry. HIF-1alpha mRNA expression only correlated with pattern of growth (P = 0.0078). In conclusion, the detection of HIF-1alpha protein would seem to be of value in informing the prognosis of transitional cell carcinoma of the upper urinary tract.
Dynamic mitral regurgitation. An important determinant of the hemodynamic response to load alterations and inotropic therapy in severe heart failure.
Authors: G Keren, S Katz, J Strom, E H Sonnenblick, T H LeJemtel
Journal: Circulation (1989)

Cardiac performance and mitral regurgitation were measured by Doppler echocardiography and right heart catheterization in 12 patients with severe congestive heart failure who performed isometric exercise during control and intravenous administration of dobutamine and nitroglycerin. During control isometric exercise, mitral regurgitant volume increased from 18 +/- 13 to 31 +/- 17 ml (p less than 0.01), while forward stroke volume, by both thermodilution and Doppler echocardiography, substantially decreased. At rest, dobutamine decreased mitral regurgitant volume from 18 +/- 13 to 11 +/- 10 ml (p less than 0.05), while forward stroke volume increased from 46 +/- 13 to 55 +/- 15 ml (p less than 0.05). During isometric exercise, dobutamine tended to decrease mitral regurgitant volume (24 +/- 12 vs. 31 +/- 17 ml; NS) when compared with control exercise. At rest, nitroglycerin decreased mitral regurgitant volume from 18 +/- 13 to 11 +/- 11 ml (p less than 0.05), while forward stroke volume, by both thermodilution and Doppler echocardiography, substantially increased. Similarly, during isometric exercise, nitroglycerin decreased mitral regurgitant volume from 31 +/- 17 to 20 +/- 14 ml (p less than 0.05), while significantly increasing forward stroke volume. At control rest, the median mitral regurgitant fraction was 24% for the 12 patients. Neither dobutamine nor nitroglycerin changed significantly forward stroke and mitral regurgitant volumes at rest and during isometric exercise in the six patients with resting mitral regurgitant fraction below the median. In contrast, dobutamine and nitroglycerin significantly decreased mitral regurgitant volume and increased forward stroke volume both at rest and during isometric exercise in the six patients with mitral regurgitant fraction greater than the median.(ABSTRACT TRUNCATED AT 250 WORDS)
Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma
Authors: Tsunao Kishida, Hidetsugu Asada, Yoshiki Itokawa, Feng-De Cui, Masaharu Shin-Ya, Satoshi Gojo, Kakei Yasutomi, Yuji Ueda, Hisakazu Yamagishi, Jiro Imanishi, Osam Mazda
Journal: Molecular Therapy (2003)

IL-21 supports proliferation of mature T and B cells and facilitates expansion and maturation of natural killer (NK) cells in synergy with IL-15. However, the biological implications of IL-21 in vivo have not been fully elucidated. IL-21 and IL-15 expression plasmids were intravenously injected under high pressure into the tail veins of mice, which were subsequently challenged by an intravenous injection of RLmale1 lymphoma cells. The IL15 gene transfection significantly reduced the numbers of metastatic tumor foci in the liver. In contrast, when IL21 and IL15 genes were cotransfected, complete regression was achieved in 80% of the mice. The cytokine gene therapy was also performed in mice that had been intravenously inoculated with the tumor cells. Forty percent of mice that received a single injection of a mixture of cytokine genes successfully rejected the preestablished metastatic lymphoma and showed tumor-free survival for more than 300 days. IL-21 significantly elevated the cytotoxic T lymphocyte activity in the spleens of tumor-inoculated mice, while the two cytokines augmented NK killing activity in a synergistic manner. These results strongly suggest that the codelivery of IL-21 and IL-15 elicits powerful antitumor immune responses, resulting in marked therapeutic efficacy against metastatic tumors.
Atypical Lyme borreliosis in an HIV-infected man
Authors: F. CORDOLIANI, M.D. VIGNON-PENNAMEN, M.V. ASSOUS, P. VABRES, P. DRONNE, M. RYBOJAD, P. MOREL
Journal: British Journal of Dermatology (1997)

We report the fourth case of Lyme borreliosis in a man infected with human immunodeficiency virus (HIV). The erythema chronicum migrans was persistent, overlapping with meningoradiculitis. Repeated immunofluorescence tests for Borrelia burgdorferi sensu lato remained negative in both sera and cerebrospinal fluid (CSF), the enzyme-linked immunosorbent assay was weakly positive in serum and CSF and a Western blot was positive. The skin infiltrate was composed mostly of T lymphocytes with a CD4/CD8 ratio of 0.5. The course of the disease was favourable after treatment with intravenous ceftriaxone. Further studies are necessary to evaluate whether HIV infection influences, as does syphilis, the course and response to treatment of Lyme borreliosis. Serological tests are insufficiently sensitive and the Western blot assay is necessary to confirm Lyme disease in HIV-positive patients.
Course of bereavement over 8-10 years in first degree relatives and spouses of people who committed suicide: longitudinal community based cohort study
Authors: M. de Groot, B. J. Kollen
Journal: BMJ (2013)

<b>Objective</b> To identify factors predicting the long term course of complicated grief, depression, and suicide ideation in a community based sample of relatives bereaved through suicide. <b>Design</b> Longitudinal cohort study. Included in the multilevel regression models were sociodemographic and personality features, mental health history, records of received help, long term complicated grief, depression, and suicide ideation. <b>Setting</b> Community based sample located in the northern part of the Netherlands. <b>Participants</b> 153 first degree relatives and spouses of 74 people who had committed suicide. <b>Main outcome measures</b> Complicated grief, depression, and suicide ideation assessed at 2.5 months, 13 months and 96-120 months (8-10 years) by means of self report questionnaires. <b>Results</b> Complicated grief, depression, and suicide ideation were mutually associated in relatives and spouses of people who had committed suicide. A history of attempted suicide was associated with long term suicide ideation (odds ratio 5.5, 95% confidence interval 1.8 to 16.7; P=0.003). Depression was more likely to be predicted by female sex and low mastery, whereas complicated grief was more likely to be predicted by the trauma of losing a child. The risk of both complicated grief and depression decreased over time; for complicated grief the change corresponded with a Cohen's d effect size of 0.36 at 13 months and 0.89 at 96-120 months; for depression these figures were 0.28 at 13 months and 0.94 at 96-120 months. The long term course of bereavement was not affected by family based cognitive behavioural therapy, support from a general practitioner, and/or mental healthcare. Mutual support was associated with an increased risk of complicated grief: B regression coefficient=6.4 (95% confidence interval 1.8 to 11.0; P=0.006). Throughout this long term study, selection bias might have affected some outcomes. <b>Conclusion</b> In relatives bereaved by suicide, suicide ideation is associated with an increased risk of long term complicated grief and depression. The risk of complicated grief and depression decreases over time. Although mutual support is associated with an increased risk of complicated grief, we could not draw conclusions about a causal relation.
Human embryonic hemopoiesis. Kinetics of progenitors and precursors underlying the yolk sac----liver transition.
Authors: G Migliaccio, A R Migliaccio, S Petti, F Mavilio, G Russo, D Lazzaro, U Testa, M Marinucci, C Peschle
Journal: Journal of Clinical Investigation (1986)

Human embryonic development involves transition from yolk sac (YS) to liver (L) hemopoiesis. We report the identification of pluripotent, erythroid, and granulo-macrophage progenitors in YS, L, and blood from human embryos. Furthermore, comprehensive studies are presented on the number of hemopoietic progenitors and precursors, as well as of other cell types, in YS, L, and blood at precisely sequential stages in embryos and early fetuses (i.e., at 4.5-8 wk and 9-10 wk postconception, respectively). Our results provide circumstantial support to a monoclonal hypothesis for human embryonic hemopoiesis, based on migration of stem and early progenitor cells from a generation site (YS) to a colonization site (L) via circulating blood. The YS----L transition is associated with development of the differentiation program in proliferating stem cells: their erythroid progeny shows, therefore, parallel switches of multiple parameters, e.g., morphology (megaloblasts----macrocytes) and globin expression (zeta----alpha, epsilon----gamma).