tbuckley/cabot-search huggingface dataset:
Superior<i>In vivo</i>Efficacy of Afucosylated Trastuzumab in the Treatment of HER2-Amplified Breast Cancer
Authors: Teemu T. Junttila, Kathryn Parsons, Christine Olsson, Yanmei Lu, Yan Xin, Julie Theriault, Lisa Crocker, Oliver Pabonan, Tomasz Baginski, Gloria Meng, Klara Totpal, Robert F. Kelley, Mark X. Sliwkowski
Journal: Cancer Research (2010)

The enhancement of immune effector functions has been proposed as a potential strategy for increasing the efficacy of therapeutic antibodies. Here, we show that removing fucose from trastuzumab (Herceptin) increased its binding to FcgammaRIIIa, enhanced antibody-dependent cell-mediated cytotoxicity, and more than doubled the median progression-free survival when compared with conventional trastuzumab in treating preclinical models of HER2-amplified breast cancer. Our results show that afucosylated trastuzumab has superior efficacy in treating in vivo models of HER2-amplified breast cancer and support the development of effector function-enhanced antibodies for solid tumor therapy.
A Surprising Cross-Species Conservation in the Genomic Landscape of Mouse and Human Oral Cancer Identifies a Transcriptional Signature Predicting Metastatic Disease
Authors: Michael D. Onken, Ashley E. Winkler, Krishna-Latha Kanchi, Varun Chalivendra, Jonathan H. Law, Charles G. Rickert, Dorina Kallogjeri, Nancy P. Judd, Gavin P. Dunn, Jay F. Piccirillo, James S. Lewis, Elaine R. Mardis, Ravindra Uppaluri
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance. Experimental Design: Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes, and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature, and we assessed its representation in four independent human datasets comprising 324 patients using weighted voting and gene set enrichment analysis. Kaplan–Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A quantitative real-time PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an independent set of 31 patients with respect to metastatic lymphadenopathy. Results: NGS revealed conservation of human driver pathway mutations in mouse OSCC, including in Trp53, mitogen-activated protein kinase, phosphoinositide 3-kinase, NOTCH, JAK/STAT, and Fat1-4. Moreover, comparative analysis between The Cancer Genome Atlas and mouse samples defined AKAP9, MED12L, and MYH6 as novel putative cancer genes. Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in four independent human OSCC datasets. Finally, we harnessed the translational potential of this signature by creating a clinically feasible assay that stratified patients with OSCC with a 93.5% accuracy. Conclusions: These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer. Clin Cancer Res; 20(11); 2873–84. ©2014 AACR.
Cost-Effectiveness of Pertuzumab in Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer
Authors: Ben Y. Durkee, Yushen Qian, Erqi L. Pollom, Martin T. King, Sara A. Dudley, Jenny L. Shaffer, Daniel T. Chang, Iris C. Gibbs, Jeremy D. Goldhaber-Fiebert, Kathleen C. Horst
Journal: Journal of Clinical Oncology (2015)

Purpose The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study showed a 15.7-month survival benefit with the addition of pertuzumab to docetaxel and trastuzumab (THP) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2) –overexpressing metastatic breast cancer. We performed a cost-effectiveness analysis to assess the value of adding pertuzumab. Patient and Methods We developed a decision-analytic Markov model to evaluate the cost effectiveness of docetaxel plus trastuzumab (TH) with or without pertuzumab in US patients with metastatic breast cancer. The model followed patients weekly over their remaining lifetimes. Health states included stable disease, progressing disease, hospice, and death. Transition probabilities were based on the CLEOPATRA study. Costs reflected the 2014 Medicare rates. Health state utilities were the same as those used in other recent cost-effectiveness studies of trastuzumab and pertuzumab. Outcomes included health benefits expressed as discounted quality-adjusted life-years (QALYs), costs in US dollars, and cost effectiveness expressed as an incremental cost-effectiveness ratio. One- and multiway deterministic and probabilistic sensitivity analyses explored the effects of specific assumptions. Results Modeled median survival was 39.4 months for TH and 56.9 months for THP. The addition of pertuzumab resulted in an additional 1.81 life-years gained, or 0.62 QALYs, at a cost of $472,668 per QALY gained. Deterministic sensitivity analysis showed that THP is unlikely to be cost effective even under the most favorable assumptions, and probabilistic sensitivity analysis predicted 0% chance of cost effectiveness at a willingness to pay of $100,000 per QALY gained. Conclusion THP in patients with metastatic HER2-positive breast cancer is unlikely to be cost effective in the United States.
Role of a Decreased Expression of the Local Renin-Angiotensin System in the Etiology of Cerebral Aneurysms
Authors: Hiroki Ohkuma, Shigeharu Suzuki, Seiichiroh Fujita, Wataru Nakamura
Journal: Circulation (2003)

Local renin-angiotensin systems (RAS) have been implicated as playing an important role in vascular remodeling. The relationship of this system to the etiology of cerebral aneurysm was investigated.The aneurysmal wall from patients with a ruptured or unruptured cerebral aneurysm and the cortical cerebral artery in control patients with head trauma or a glioma were taken during surgery for study. Local RAS were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and/or immunohistochemistry. RT-PCR analysis revealed a significantly decreased expression of angiotensin-converting enzyme (ACE), angiotensin type 1 (AT1) receptor, basic fibroblast growth factor, platelet-derived growth factor-AA, and tissue inhibitor of matrix metalloproteinases-1 mRNA in the aneurysmal wall as compared with the control cortical arterial wall. Immunohistochemistry also revealed a decreased expression of ACE, AT1 receptor, and angiotensin II in the aneurysmal wall.Expression of local RAS was decreased in the aneurysmal wall, which may induce aneurysm formation caused by a lack of vascular remodeling that prevents the arterial wall from thickening under increased hemodynamic stress. This is the first report that suggests that a decreased expression of local RAS plays a part in the pathogenesis of any disease.
Spontaneously beating cardiomyocytes derived from white mature adipocytes
Authors: Medet Jumabay, Rui Zhang, Yucheng Yao, Joshua I. Goldhaber, Kristina I. Boström
Journal: Cardiovascular Research (2009)

Adipose stromal cells and dissociated brown adipose tissue have been shown to generate cardiomyocyte-like cells. However, it is not clear whether white mature adipocytes have the same potential, even though a close relationship has been found between adipocytes and vascular endothelial cells, another cardiovascular cell type. The objective of this study was to examine if white adipocytes would be able to supply cardiomyocytes. We prepared a highly purified population of lipid-filled adipocytes from mice, 6–7 weeks of age. When allowed to lose lipids, the adipocytes assumed a fibroblast-like morphology, so-called dedifferentiated fat (DFAT) cells. Subsequently, 10–15% of the DFAT cells spontaneously differentiated into cardiomyocyte-like cells, in which the cardiomyocyte phenotype was identified by morphological observations, expression of cardiomyocyte-specific markers, and immunocytochemical staining. In addition, electrophysiological studies revealed pacemaker activity in these cells, and functional studies showed that a β-adrenergic agonist stimulated the beating rate, whereas a β-antagonist reduced it. In vitro treatment of newly isolated adipocytes or DFAT cells with inhibitors of bone morphogenetic proteins (BMP) and Wnt signalling promoted the development of the cardiomyocyte phenotype as determined by the number or beating colonies of cardiomyocyte-like cells and expression of troponin I, a cardiomyocyte-specific marker. Inhibition of BMP was most effective in promoting the cardiomyocyte phenotype in adipocytes, whereas Wnt-inhibition was most effective in DFAT cells. White mature adipocytes can differentiate into cardiomyocyte-like cells, suggesting a link between adipocyte and cardiomyocyte differentiation.
Lactated Ringer's Solution Reduces Systemic Inflammation Compared With Saline in Patients With Acute Pancreatitis
Authors: Bechien U. Wu, James Q. Hwang, Timothy H. Gardner, Kathryn Repas, Ryan Delee, Song Yu, Benjamin Smith, Peter A. Banks, Darwin L. Conwell
Journal: Clinical Gastroenterology and Hepatology (2011)
Emerging Therapeutics for Chronic Hepatitis B
Authors: Mark E. Mailliard, John L. Gollan
Journal: Annual Review of Medicine (2005)

Hepatitis B is a global health problem. Patients with chronic hepatitis B (CHB) carry a significant risk to eventually develop cirrhotic liver disease. Recent therapeutic advances against CHB offer excellent potential for long-term suppression of hepatitis B virus (HBV) replication during antiviral therapy, and occasionally a durable remission off medication. Selection of appropriate patients for antiviral therapy depends on identification of HBV replication and an elevated alanine aminotransferase level or histologic liver injury. Pegylated interferon alpha offers potent immunomodulatory and antiviral activity with the potential for durability, but also with adverse effects and significant cost. The nucleoside or nucleotide analogs, lamivudine, adefovir, and entecavir, suppress HBV replication and are extremely well-tolerated, but long-term or even lifelong therapy is required. Most experience has been gained with lamivudine, but viral resistance occurs frequently. Newer analogs appear to be relatively free of this problem. Approaches using a combination of agents have promise, but have yet to be proven superior to individual drugs alone.
αβ T-Cell Receptor Engineered γδ T Cells Mediate Effective Antileukemic Reactivity
Authors: Lars T. van der Veken, Renate S. Hagedoorn, Marleen M. van Loenen, Roel Willemze, J.H. Frederik Falkenburg, Mirjam H.M. Heemskerk
Journal: Cancer Research (2006)

Abstract Retroviral transfer of T-cell receptors (TCR) to peripheral blood–derived T cells generates large numbers of T cells with the same antigen specificity, potentially useful for adoptive immunotherapy. One drawback of this procedure is the formation of mixed TCR dimers with unknown specificities due to pairing of endogenous and introduced TCR chains. We investigated whether γδ T cells can be an alternative effector population for TCR gene transfer because the γδTCR is not able to form dimers with the αβTCR. Peripheral blood–derived γδ T cells were transduced with human leukocyte antigen (HLA) class I– or HLA class II–restricted minor histocompatibility antigen (mHag) or virus-specific TCRs. Because most γδ T cells do not express CD4 and CD8, we subsequently transferred these coreceptors. The TCR-transduced γδ T cells exerted high levels of antigen-specific cytotoxicity and produced IFN-γ and IL-4, particularly in the presence of the relevant coreceptor. γδ T cells transferred with a TCR specific for the hematopoiesis-specific mHag HA-2 in combination with CD8 displayed high antileukemic reactivity against HA-2–expressing leukemic cells. These data show that transfer of αβTCRs to γδ T cells generated potent effector cells for immunotherapy of leukemia, without the expression of potentially hazardous mixed TCR dimers. (Cancer Res 2006; 66(6): 3331-7)
The role of risedronate in osteopenia in Crohn's disease
Authors: Alice Buchan, Ari Manuel
Journal: Gut (2013)

We read with great interest van Bodegraven et al 's1 paper about the treatment of osteopenia in patients with Crohn's disease. They have identified an evidence gap, as many studies of interventions to treat osteoporosis and prevent bone loss have been conducted on older and primarily female patients. In contrast, both male and female patients with Crohn's disease may develop osteopenia and osteoporosis at a younger age. …
Risk Factors for HIV Infection Among Young Adult Men in Northern Thailand
Authors: Kenrad E. Nelson
Journal: JAMA (1993)

To determine the sociodemographic and behavioral risk factors associated with human immunodeficiency virus (HIV) infection in two cohorts of young men selected for military service in northern Thailand.Military conscripts were studied cross-sectionally after conscription in May 1991 and November 1991. Risk factors were assessed by interview with trained nonmilitary interviewers.Two military training bases in Chiang Mai, Thailand.A total of 2417 young men aged 19 to 23 years (mean age, 21 years) conscripted by lottery into military service in the Royal Thai Army or Royal Thai Air Force from six provinces in northern Thailand.Human immunodeficiency virus seroprevalence by enzyme-linked immunosorbent assay confirmed by Western blot and univariate and multivariate analyses of sociodemographic and behavioral risk factors associated with HIV seroprevalence.Overall, 289 (12.0%) of 2417 men were HIV-seropositive at baseline. The strongest associations with being HIV positive were heterosexual activities. History of sex with a female commercial sex worker (CSW) was frequent (96.5% of men who were HIV-positive and 79.0% of men who were HIV-negative) and strongly associated with HIV infection on univariate and multivariate analyses (adjusted odds ratio, 1.60 to 2.07, depending on the frequency of CSW contact). Also, sexually transmitted diseases were common and associated with HIV infection in both univariate and multivariate analyses (adjusted odds ratio, 3.36). Sex with other males and injection drug use were uncommon and not associated with HIV infection. Condom use was reported in 61.5% of men at last sex with a CSW but was not shown to be protective of prevalent HIV infection.The epidemic of HIV infection has spread widely among young men in northern Thailand, despite reported frequent and recent use of condoms during sex with female CSWs. Control of HIV infection in this population will probably require more regular and effective use of condoms, prevention and treatment of sexually transmitted diseases, and reduction in the frequency of CSW contact.
Modelling sarcomeric cardiomyopathies in the dish: from human heart samples to iPSC cardiomyocytes
Authors: Thomas Eschenhagen, Christine Mummery, Bjorn C. Knollmann
Journal: Cardiovascular Research (2015)

One of the obstacles to a better understanding of the pathogenesis of human cardiomyopathies has been poor availability of heart-tissue samples at early stages of disease development. This has possibly changed by the advent of patient-derived induced pluripotent stem cell (hiPSC) from which cardiomyocytes can be derived in vitro. The main promise of hiPSC technology is that by capturing the effects of thousands of individual gene variants, the phenotype of differentiated derivatives of these cells will provide more information on a particular disease than simple genotyping. This article summarizes what is known about the 'human cardiomyopathy or heart failure phenotype in vitro', which constitutes the reference for modelling sarcomeric cardiomyopathies in hiPSC-derived cardiomyocytes. The current techniques for hiPSC generation and cardiac myocyte differentiation are briefly reviewed and the few published reports of hiPSC models of sarcomeric cardiomyopathies described. A discussion of promises and challenges of hiPSC-modelling of sarcomeric cardiomyopathies and individualized approaches is followed by a number of questions that, in the view of the authors, need to be answered before the true potential of this technology can be evaluated.
Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes.
Authors: F Malisan, F Brière, J M Bridon, N Harindranath, F C Mills, E E Max, J Banchereau, H Martinez-Valdez
Journal: The Journal of Experimental Medicine (1996)

Upon activation, B lymphocytes can change the isotype of the antibody they express by immunoglobulin (Ig) isotype switch recombination. In previous studies on the regulation of human IgG expression, we demonstrated that interleukin 10 (IL-10) could stimulate IgG1 and IgG3 secretion by human CD40-activated naive (sIgD+) tonsillar B cells. To assess whether IL-10 actually promotes the DNA recombination underlying switching to these isotypes, we examined the effect of IL-10 on the generation of reciprocal products that form DNA circles as by-products of switch recombination. The content of reciprocal products characteristic of mu-gamma recombination was elevated after culture of CD40-activated tonsillar sIgD+ B cells with either IL-4 or IL-10, although high levels of IgG secretion were observed only with IL-10. Unlike IL-4, IL-10 did not induce reciprocal products of mu-epsilon and gamma-epsilon switch recombination. These results demonstrate that IL-10 promotes both switching to gamma and IgG secretion.
The Affinity of the Organic Cation Transporter rOCT1 Is Increased by Protein Kinase C-Dependent Phosphorylation
Authors: THOMAS MEHRENS, SILKE LELLECK, IBRAHIM C[COMBINING CEDILLA]ETINKAYA, MARION KNOLLMANN, HELGE HOHAGE, VALENTIN GORBOULEV, PETER BOKNÍK, HERMANN KOEPSELL, EBERHARD SCHLATTER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Members of the organic cation transporter (OCT) family are mainly expressed in kidney, liver, intestine, and brain. The regulation of the OCT type 1 from rat (rOCT1) stably transfected in HEK293 cells was examined using a fluorimetric technique, 1-[ 3 H]methyl-4-phenylpyridinium uptake studies, and fast-whole-cell patch-clamp recordings. For the fluorescence measurements, the cation 4-(4-(dimethylamino)styryl)- N -methylpyridinium iodide (ASP + ) was used as substrate. Uptake of ASP + via rOCT1 was electrogenic, and its inhibition by other organic cations was consistent with previously reported radioactive tracer flux measurements. The inhibitor quinine was not translocated by the organic cation transporter in contrast to tetraethylammonium. Stimulation of diacyl glycerol-dependent protein kinase C (PKC) by sn -1,2-dioctanoyl glycerol (1 μM) resulted in an increase in initial ASP + uptake rate by 216 ± 28% ( n = 29). The effect was completely antagonized by the PKC inhibitor tamoxifen (20 μM, n = 22). Forskolin (1 μM), which activates adenylate cyclase and thereby protein kinase A (PKA), stimulated the initial rate of ASP + accumulation by 51 ± 6% ( n = 19). This effect was inhibited by the specific PKA inhibitor KT5720 (1 μM, n = 12). Inhibition of tyrosine kinases by aminogenestein (10 μM) reduced ASP + uptake by 63 ± 7% ( n = 7), while genestein or tyrphostin AG1295 (each 10 μM) were without significant effects. Incubation of the cells with sn -1,2-dioctanoyl glycerol (1 μM) increased the affinities of the transporter to tetraethylammonium, tetrapenthylammonium, and quinine by a factor of 58, 14.5, and 2.4, respectively. Western blot analysis revealed that rOCT1 protein was phosphorylated at a serine residue upon stimulation of PKC. In conclusion, it has been demonstrated that the organic cation transport by rOCT1 is stimulated by PKC, PKA, and endogenous tyrosine kinase activation. The PKC phosphorylates rOCT1 and leads to a conformational change at the substrate binding site.
Cost-effectiveness of Intensive Insulin Therapy in the Diabetes Control and Complications Trial
Authors: K. M. V. Narayan
Journal: JAMA (1997)

<h3>To the Editor.</h3> —The Diabetes Control and Complications Trial (DCCT) Research Group<sup>1</sup>has recently published data that suggest that intensive insulin therapy for management of insulin-dependent diabetes mellitus (IDDM) may be well within the range of cost-effectiveness considered to represent good value. The DCCT group needs to be commended for such a thorough analysis and for providing yet another dimension to our understanding of the public health aspects of diabetes. Economic analysis alongside randomized clinical trials offer another important perspective to trial findings and can provide a rational means of assessing the implications of translating research information into practice. Given the importance of this study, it would be useful to have the insights of the authors regarding 3 aspects of the analysis. First, while clinical trials may offer data that are internally valid, they are often not readily generalizable—an issue that may be particularly important when it comes to
Role of Comparative Effectiveness Research in Cancer Funding Decisions in Ontario, Canada
Authors: Jeffrey S. Hoch, David C. Hodgson, Craig C. Earle
Journal: Journal of Clinical Oncology (2012)

Recently, the evidence-based drug funding process in Ontario, Canada, was challenged by a young mother with a breast tumor too small, based on the evidence that existed at the time, to qualify for an expensive drug. In reality, this is only the latest in a number of challenges the publicly funded health care system has had to deal with in the face of an evolving drug policy landscape. This article defines comparative effectiveness research (CER), considering how it is viewed differently in the United States and Canada. It also reviews the role CER now plays in the Ontario drug funding process and concludes with a review of the challenges and opportunities of using observational data to conduct CER and incorporate it into policy making within a universal health care system. Many of the issues faced by Ontario are relevant beyond Canada, including in the United States during this period of health care reform.