tbuckley/cabot-search huggingface dataset:
Cardiac Stem Cells Possess Growth Factor-Receptor Systems That After Activation Regenerate the Infarcted Myocardium, Improving Ventricular Function and Long-Term Survival
Authors: Konrad Urbanek, Marcello Rota, Stefano Cascapera, Claudia Bearzi, Angelo Nascimbene, Antonella De Angelis, Toru Hosoda, Stefano Chimenti, Mathue Baker, Federica Limana, Daria Nurzynska, Daniele Torella, Francesco Rotatori, Raffaella Rastaldo, Ezio Musso, Federico Quaini, Annarosa Leri, Jan Kajstura, Piero Anversa
Journal: Circulation Research (2005)

Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 μm 3 at 16 days after treatment and reached 5100 μm 3 at 4 months. In this interval, nearly 20% of myocytes reached the adult phenotype, varying in size from 10 000 to 20 000 μm 3 . Moreover, there were 43±13 arterioles and 155±48 capillaries/mm 2 myocardium at 16 days, and 31±6 arterioles and 390±56 capillaries at 4 months. Myocardial regeneration induced increased survival and rescued animals with infarcts that were up to 86% of the ventricle, which are commonly fatal. In conclusion, the heart has an endogenous reserve of CSCs-ECCs that can be activated to reconstitute dead myocardium and recover cardiac function.
Expression of the K303R Estrogen Receptor-α Breast Cancer Mutation Induces Resistance to an Aromatase Inhibitor via Addiction to the PI3K/Akt Kinase Pathway
Authors: Ines Barone, Yukun Cui, Matthew H. Herynk, Arnoldo Corona-Rodriguez, Cinzia Giordano, Jennifer Selever, Amanda Beyer, Sebastiano Andò, Suzanne A.W. Fuqua
Journal: Cancer Research (2009)

Abstract Aromatase inhibitors (AI) are rapidly becoming the first choice for hormonal treatment of estrogen receptor-α (ERα)–positive breast cancer in postmenopausal women. However, de novo and acquired resistance frequently occurs. We have previously identified a lysine to arginine transition at residue 303 (K303R) in ERα in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to tamoxifen treatment. Thus, we questioned whether resistance to AIs could arise in breast cancer cells expressing the ERα mutation. As preclinical models to directly test this possibility, we generated K303R-overexpressing MCF-7 cells stably transfected with an aromatase expression vector. Cells were stimulated with the aromatase substrate, androstenedione, with or without the AI anastrozole (Ana). We found that Ana decreased androstenedione-stimulated growth of wild-type cells, whereas K303R-expressing cells were resistant to the inhibitory effect of Ana on growth. We propose that a mechanism of resistance involves an increased binding between the mutant receptor and the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K), leading to increased PI3K activity and activation of protein kinase B/Akt survival pathways. Inhibition of the selective “addiction” to the PI3K/Akt pathway reversed AI resistance associated with expression of the mutant receptor. Our findings suggest that the K303R ERα mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and that targeting the PI3K/Akt pathway may be a useful strategy for treating patients with tumors resistant to hormone therapy. [Cancer Res 2009;69(11):4724–32]
Bioreducible PAA-g-PEG graft micelles with high doxorubicin loading for targeted antitumor effect against mouse breast carcinoma
Authors: Yong Sun, Wen Zou, Shaoquan Bian, Yihang Huang, Yanfei Tan, Jie Liang, Yujiang Fan, Xingdong Zhang
Journal: Biomaterials (2013)
Immunity and Viral Carcinogenesis. Effect of Thymectomy on Polyoma Virus Carcinogenesis in Mice
Authors: Richard A. Malmgren, Alan S. Rabson, Paula G. Carney
Journal: JNCI Journal of the National Cancer Institute (1964)

In this study of the importance of immune factors in carcinogenesis, the immunologic capabilities of the host were impaired by thymectomy of newborn C57BL/6JN and C3H/Bi mice. After thymectomy, the C57BL/6JN strain, known to be resistant to the polyoma virus, received injections of the highly oncogenic strain S polyoma virus. Thymectomized C3H/Bi mice, highly susceptible to the oncogenic effect of the polyoma virus, received injections of the weakly oncogenic strain M polyoma virus. Sham-operated mice of both strains were given the corresponding virus injections. In both experiments the thymectomized animals developed a significantly greater number of tumors than did the sham-operated controls. The significance of this impairment of host immune factors in increasing host susceptibility to viral carcinogenesis and the oncogenic activity of the polyoma virus is discussed.
Golimumab 3-year safety update: an analysis of pooled data from the long-term extensions of randomised, double-blind, placebo-controlled trials conducted in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis
Authors: Jonathan Kay, Roy Fleischmann, Edward Keystone, Elizabeth C Hsia, Benjamin Hsu, Michael Mack, Neil Goldstein, Jürgen Braun, Arthur Kavanaugh
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To assess pooled golimumab safety up to year 3 of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) trials. <h3>Methods</h3> Golimumab 50 and 100 mg, administered subcutaneously (SC) every 4 weeks (q4wk), were assessed in patients with active RA (methotrexate-naïve, methotrexate-experienced and anti-TNF (tumour necrosis factor)-experienced), PsA or AS, despite conventional therapy. Placebo control continued up to week (wk) 24 (wk 52, methotrexate-naïve), with early escape at wk 16 (wk 28, methotrexate-naïve); subsequently, all patients received golimumab 50 or 100 mg q4wk. After the blinded controlled period, golimumab doses could be adjusted per investigator discretion. Pooled safety analyses reported herein include data from placebo-controlled and uncontrolled study periods up to wk 160. Determinations of incidences/100 patient-years (pt-yrs) for rare events also included RA patients from a phase IIb trial. <h3>Results</h3> Across five phase III trials of SC golimumab, 639 patients received placebo and 2226 received golimumab 50 mg (n=1249) and/or 100 mg (n=1501) up to wk 160 (patients may be included in more than one group because non-responders were allowed early escape); 1179 patients were treated for ≥156 weeks. For placebo, golimumab 50 mg and golimumab 100 mg, respective adverse event incidences/100 pt-yrs (95% CIs) up to wk 160 were: 0.28 (0.01 to 1.56), 0.30 (0.12 to 0.62), 0.41 (0.23 to 0.69) for death; 5.31 (3.20 to 8.30), 3.03 (2.36 to 3.82), 5.09 (4.36 to 5.90) for serious infection; 0.00 (0.00 to 0.84), 0.17 (0.05 to 0.44), 0.35 (0.18 to 0.62) for tuberculosis; 0.00 (0.00 to 0.84), 0.13 (0.03 to 0.38), 0.24 (0.10 to 0.46) for opportunistic infection; 0.00 (0.00 to 0.84), 0.00 (0.00 to 0.13), 0.12 (0.03 to 0.30) for demyelination; and 0.00 (0.00 to 0.84), 0.04 (0.00 to 0.24), 0.18 (0.06 to 0.38) for lymphoma. <h3>Conclusions</h3> SC golimumab safety up to 3 years remained consistent with that of other TNF antagonists. Golimumab 100 mg showed numerically higher incidences of serious infections, demyelinating events and lymphoma than 50 mg; safety follow-up up to year 5 continues.
Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug Resistance
Authors: William Matsui, Qiuju Wang, James P. Barber, Sarah Brennan, B. Douglas Smith, Ivan Borrello, Ian McNiece, Lan Lin, Richard F. Ambinder, Craig Peacock, D. Neil Watkins, Carol Ann Huff, Richard J. Jones
Journal: Cancer Research (2008)

Abstract Many agents are active in multiple myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138+ multiple myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138neg B cells. We compared the relative sensitivity of these distinct cell types to clinical antimyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138+ multiple myeloma plasma cells but had little effect on CD138neg precursors in vitro. We further characterized clonogenic multiple myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138neg cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that multiple myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic multiple myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of multiple myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent multiple myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury. [Cancer Res 2008;68(1):190–7]
Curcumin Potentiates Antitumor Activity of Gemcitabine in an Orthotopic Model of Pancreatic Cancer through Suppression of Proliferation, Angiogenesis, and Inhibition of Nuclear Factor-κB–Regulated Gene Products
Authors: Ajaikumar B. Kunnumakkara, Sushovan Guha, Sunil Krishnan, Parmeswaran Diagaradjane, Juri Gelovani, Bharat B. Aggarwal
Journal: Cancer Research (2007)

Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that has been shown to suppress the transcription factor nuclear factor-kappaB (NF-kappaB), which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-kappaB activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant reductions in volume (P = 0.008 versus control; P = 0.036 versus gemcitabine alone), Ki-67 proliferation index (P = 0.030 versus control), NF-kappaB activation, and expression of NF-kappaB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31(+) microvessel density (P = 0.018 versus control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing proliferation, angiogenesis, NF-kappaB, and NF-kappaB-regulated gene products.
Identification of a Mutated Fibronectin As a Tumor Antigen Recognized by CD4<b>+</b>T Cells
Authors: Helen Y. Wang, Juhua Zhou, Kuichun Zhu, Adam I. Riker, Francesco M. Marincola, Rong-Fu Wang
Journal: The Journal of Experimental Medicine (2002)

CD4+ T cells play an important role in orchestrating host immune responses against cancer, particularly by providing critical help for priming and extending the survival of CD8+ T cells. However, relatively little is known about major histocompatibility complex class II–restricted human tumor antigens capable of activating CD4+ T cells. Here, we describe the identification of a mutated fibronectin (FN) as a tumor antigen recognized by human histocompatibility leukocyte antigen-DR2–restricted CD4+ T cells. Deoxyribonucleic acid (DNA) sequencing analysis indicated that this gene contains a mutation that results in the substitution of lysine for glutamic acid and gives rise to a new T cell epitope recognized by CD4+ T cells. Tumor cells harboring the mutant FN resulted in the loss of FN matrix formation and the gain of metastatic potential based on the migration pattern compared with that of tumor cells that express wild-type FN. Additional experiments using cell lines stably expressing the mutated FN cDNA demonstrated that the point mutation in FN was responsible for the loss of FN staining in extracellular matrices and the enhancement of tumor cell migration. These findings represent the first demonstration that a mutated gene product recognized by CD4+ T cells is directly involved in tumor metastasis, which indicates the importance of CD4+ T cells in controlling the spread of tumor cells to distant anatomic sites.
Spatially Discordant Alternans in Cardiac Tissue
Authors: Daisuke Sato, Yohannes Shiferaw, Alan Garfinkel, James N. Weiss, Zhilin Qu, Alain Karma
Journal: Circulation Research (2006)

Spatially discordant alternans, where the action potential duration (APD) and intracellular calcium transient (Ca i ) alternate with opposite phase in different regions of tissue, is known to promote wave break and reentry. However, this phenomenon is not completely understood. It is known that alternans at the cellular level can be caused by dynamical instabilities arising from either membrane voltage ( V m ) attributable to steep APD restitution or to calcium (Ca) cycling. Here, we used a mathematical model of intracellular Ca cycling, coupled with membrane ion currents, to investigate the dynamics of V m and Ca i transient alternans in an isolated cell, in two electrotonically coupled cells, and in 1D spatially homogeneous tissue. Our main finding is a novel instability mechanism in which the bidirectional coupling of V m and Ca i can drive the Ca i transient of two neighboring cells to be out of phase. This instability is manifested in cardiac tissue by the dynamical formation of spatially discordant alternans. In this case, Ca i transient alternans can reverse phase over a length scale of one cell, whereas APD alternans reverses phase over a much longer length scale set by the electrotonic coupling. We analyze this mechanism in detail and show that it is a robust consequence of experimentally established properties of the bidirectional coupling between Ca cycling and V m dynamics. Finally, we address the experimental relevance of these findings and suggest physiological conditions under which these patterns can be observed.
Abstract 252: Critical Incident Debriefing After Cardiopulmonary Resuscitation in Pediatric Cardiac ICU: Effect on Patient Safety, Performance Improvement and Survey
Authors: Janie Kane, Christopher Swearingen, Umesh Dyamenahalli
Journal: Circulation (2012)

Background: Critical incident debriefing has been established in many industries, including healthcare. To our knowledge, there have not been any published data about debriefing in the pediatric cardiac ICU (PCICU) setting. Objective: The goal of this initiative was to test the feasibility of debriefing and to establish a multidisciplinary team process after CPR for the purpose of improvements. Methods: This qualitative process as part of rapid cycle improvement was initiated as a method to improve patient management, and included assimilation of pertinent information, provision of immediate team feedback, safety and system improvement. After every CPR, we involved frontline staff in an informative, non-punitive, continuous quality improvement process. Debriefings lasting 10 to 15 minutes were led by the attending physicians. Issues related to communication, response time, effectiveness of the resuscitation, and support of family members was included. Participants were encouraged to express concerns and questions related to pre-code and code events to improve patient management and enhance unit safety culture. A survey of team members assessed effectiveness of the debriefing process using REDCap web application. Results: From 2008 to 2011, 68/71 consecutive debriefings were performed. As a result, there have been several rapid cycle improvements in patient care, including preventative and anticipatory patient management, timely notification of team members, comprehensive team training via simulation training, restructuring of supply availability, family support during acute events and hospital-wide revision of the code record. One hundred twenty-three PCICU personnel were invited to complete the survey. Sixty [49%] responses were received: 100% from patient care nurse managers, 36%bedside nurses, 50% APNs, 63%physicians and 100%respiratory therapists. The beneficial aspects of the debriefing included the examination of opportunities to improve (88%), asking questions, reviewing performance (85%), and receiving education (80%). Conclusion: Clinical debriefing in a PCICU is feasible. It positively affected the quality of patient care, enhanced the safety culture, improved occurrence reporting, and staff felt empowered.
The Colugo (Cynocephalus variegatus, Dermoptera): The Primates' Gliding Sister?
Authors: Jürgen Schmitz, Martina Ohme, Bambang Suryobroto, Hans Zischler
Journal: Molecular Biology and Evolution (2002)

Although a general agreement on the major groups of eutherian orders and their phylogenetic affiliations is emerging, the evolutionary affiliations among the members constituting these groups are still subject to debate. A prominent example is the recently published molecular evidence that challenges the long assumed monophyly of primates, displaying the colugo or flying lemur (Cynocephalus, Dermoptera) as a sister to anthropoid primates (Arnason et al. 2002 ) and positioning them after the prosimian primates (tarsiers and strepsirhines) split off. The phylogenetic analysis of the complete mitochondrial (mt) genome sequence of Cynocephalus variegatus presented in this study first appears to corroborate interpretations of primates as a paraphyletic group. However, more detailed analyses disclosed that mt nucleotide composition and consequently amino acid (AA) composition varied considerably among the species analyzed. This led us to assume that the flying lemur may be incorrectly grouped with anthropoids on the basis of similar mt nucleotide and AA compositions, rather than reflecting the true evolutionary relationship. To reanalyze the flying lemur's evolutionary association with other eutherian orders from a completely different molecular perspective, a molecular cladistic approach was applied. To this end, we determined the presence/absence pattern of transposable elements that provide a nearly homoplasy-free and copious source of molecular evolutionary markers, with well-defined character polarity. We could identify transposable elements, both on a multilocus and single-locus level, being present in all extant primate infraorders but absent in the flying lemur, thus clearly supporting the monophyly of primates by retropositional evidence.
Natural history of early gastric cancer: a non-concurrent, long term, follow up study
Authors: H Tsukuma
Journal: Gut (2000)

<h3>BACKGROUND</h3> Controversy has arisen on the natural history of early gastric cancer (EGC). While some emphasise the effectiveness of early detection in reducing mortality from gastric cancer, others insist that EGC is a pseudo-cancer. <h3>AIMS/PATIENTS/METHODS</h3> To elucidate the natural history of EGC, a non-concurrent, long term, follow up study was conducted in 71 patients who were diagnosed endoscopically as having EGC, which was confirmed as cancer on biopsy, but in whom surgical resection was not conducted or delayed by more than six months. <h3>RESULTS</h3> The natural course of EGC was observed in 56 cases. Over a period of 6–137 months, 20 remained in the early stage while 36 progressed to the advanced stage. The proportion remaining in the early stage consistently decreased with time. Median duration of those who remained in the early stage was estimated as 44 months. The cumulative five year risk for progressing to the advanced stage was 63.0%. In 38 cases there was no evidence for undergoing surgical resection for gastric cancer. The cumulative five year corrected survival was estimated as 62.8% among those unresected. Hazard rate ratio for gastric cancer mortality was 0.65 (p=0.34) for screening detected versus non-screening detected. Hazard rate ratio for gastric cancer mortality was 0.51, significantly lower for patients whose operations were delayed compared with those unresected. <h3>CONCLUSIONS</h3> Although EGC showed a relatively long natural history in general, it progressed to the advanced stage with time and led to death from gastric cancer for the most part if left untreated.
Point: Chemosensitivity Assays Have a Role in the Management of Recurrent Ovarian Cancer
Authors: Julian C. Schink, Larry J. Copeland
Journal: Journal of the National Comprehensive Cancer Network (2011)

In this era of personalized medicine, patients with recurrent ovarian cancer deserve better than the 25% response rate that is associated with drugs selected based on clinical information alone. In the past decade, marked laboratory improvements have enabled chemosensitivity assay testing to yield a 0.70 correlation with response, and to accurately predict progression-free and overall survival. Compelling retrospective data supporting the use of this technology cannot be ignored while waiting for a cooperative group to test whether chemosensitivity assay should be used to direct salvage therapy.