tbuckley/cabot-search huggingface dataset:
Alternative BCR/ABL Splice Variants in Philadelphia Chromosome–Positive Leukemias Result in Novel Tumor-Specific Fusion Proteins that May Represent Potential Targets for Immunotherapy Approaches
Authors: Gisella Volpe, Alessandro Cignetti, Cristina Panuzzo, Mirela Kuka, Katiuscia Vitaggio, Mara Brancaccio, Giuseppe Perrone, Monica Rinaldi, Giuseppina Prato, Milena Fava, Massimo Geuna, Marisa Pautasso, Claudia Casnici, Emanuela Signori, Giancarlo Tonon, Guido Tarone, Ornella Marelli, Vito M. Fazio, Giuseppe Saglio
Journal: Cancer Research (2007)

Abstract Imatinib currently represents the standard treatment in the early chronic phase of chronic myelogenous leukemia (CML), thanks to the high percentage of cytogenetic complete remission achieved, but it is yet unclear to what extent it can eradicate leukemia. Therefore, different vaccination strategies have been suggested, mainly based on the exploitment of the junctional peptides spanning the fusion region of the Bcr/Abl proteins. To identify new potential immunologic targets, 63 Philadelphia chromosome–positive patients and 6 BCR/ABL–positive cell lines were tested in nested reverse transcriptase PCR to detect the presence of BCR/ABL transcripts arising from the alternative splicing of the main BCR/ABL transcripts. We could detect BCR/ABL transcripts with junctions between BCR exon 1, 13, or 14 and ABL exon 4 in ∼80% of patients and 84% of cell lines, beside the main fusion transcripts. Translation products of these transcripts were characterized at their COOH terminus by a large amino acid portion derived from the out of frame (OOF) reading of ABL gene. These proteins were detected in BCR/ABL–positive cell lines by immunoprecipitation and immunohistochemistry. Finally, we determined whether OOF-specific CD8+ T cells could be found in the peripheral blood of CML patients and whether they could acquire effector function following in vitro sensitization with OOF-derived peptides predicted to bind to human leucocyte antigen (HLA)-A2 and HLA-A3 molecules. We detected the presence of OOF-specific CD8+ T cells in four of four patients studied, and in one case, these T cells exhibited specific cytotoxic activity against both peptide-pulsed targets and autologous primary CML cells. [Cancer Res 2007;67(11):5300–7]
Dietary Intake of Total, Animal, and Vegetable Protein and Risk of Type 2 Diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL Study
Authors: Ivonne Sluijs, Joline W.J. Beulens, Daphne L. van der A, Annemieke M.W. Spijkerman, Diederick E. Grobbee, Yvonne T. van der Schouw
Journal: Diabetes Care (2009)

Dietary recommendations are focused mainly on relative dietary fat and carbohydrate content in relation to diabetes risk. Meanwhile, high-protein diets may contribute to disturbance of glucose metabolism, but evidence from prospective studies is scarce. We examined the association among dietary total, vegetable, and animal protein intake and diabetes incidence and whether consuming 5 energy % from protein at the expense of 5 energy % from either carbohydrates or fat was associated with diabetes risk.A prospective cohort study was conducted among 38,094 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL study. Dietary protein intake was measured with a validated food frequency questionnaire. Incident diabetes was verified against medical records.During 10 years of follow-up, 918 incident cases of diabetes were documented. Diabetes risk increased with higher total protein (hazard ratio 2.15 [95% CI 1.77-2.60] highest vs. lowest quartile) and animal protein (2.18 [1.80-2.63]) intake. Adjustment for confounders did not materially change these results. Further adjustment for adiposity measures attenuated the associations. Vegetable protein was not related to diabetes. Consuming 5 energy % from total or animal protein at the expense of 5 energy % from carbohydrates or fat increased diabetes risk.Diets high in animal protein are associated with an increased diabetes risk. Our findings also suggest a similar association for total protein itself instead of only animal sources. Consumption of energy from protein at the expense of energy from either carbohydrates or fat may similarly increase diabetes risk. This finding indicates that accounting for protein content in dietary recommendations for diabetes prevention may be useful.
The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes
Authors: Mary-Elizabeth Patti, Silvia Corvera
Journal: Endocrine Reviews (2010)

The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease. Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis. Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years. Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM. We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function. We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain. However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load. This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction. More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM.
Infectious complications from full extension endobronchial ultrasound transbronchial needle aspiration
Authors: A. R. Haas
Journal: European Respiratory Journal (2009)

The development of a convex probe endobronchial ultrasound (CP-EBUS) videobronchoscope to allow real-time transbronchial needle aspiration (TBNA) has been a significant advance in minimally invasive lung cancer staging and diagnosis. Several recent studies have demonstrated CP-EBUS-TBNA to have recovery rivalling that of the current gold standard, cervical mediastinoscopy. These same studies have indicated that the safety of this procedure has no reported complications. The present case study presents two infectious complications from full extension endobronchial ultrasound transbronchial needle aspiration and discusses possible aetiologies of these infections, as well as implications for future application of this technology.
Association between Wegener's granulomatosis and Staphylococcus aureus infection?
Authors: JW van Putten, EH van Haren, JW Lammers
Journal: European Respiratory Journal (1996)

Two patients are presented with Wegener's granulomatosis (WG) and lower respiratory tract infections with Staphyloccus aureus (SA). It is posulated that there is a relationship between the infection and the induction or relapse of the disease. We suggest that bronchoalveolar lavages should be performed in cases of suspected WG to identify SA-infections. The co-existence of WG and SA support the reported beneficial effects of sulfamethoxazole/trimethoprim, but needs further evaluation in patients with and without SA-infection of the airways.
A New Venture in Administrative Psychiatry
Authors: J. HOENIG, MARIAN W. HAMILTON
Journal: American Journal of Psychiatry (1966)

A four-year follow-up study at two general hospital psychiatric units included a stratified sample of all first referrals for psychiatric evaluation in their catchment area. The authors found that long-term hospitalization as well as transfer to a mental hospital was largely avoided; both patients and relatives seemed satisfied with the services of the unit and preferred such a unit to mental hospital referral. However, patients living in the community on follow-up showed a relatively high rate of morbidity, unemployment, and social isolation.
Modulation of growth factor action in the cardiovascular system
Authors: M POST, J WALTENBERGER
Journal: Cardiovascular Research (2004)

When the Nobel prize for physiology and medicine was awarded for the discovery of the first peptide growth factors to Rita Levi-Montalcini and Stanley Cohen in 1986, Russel Ross in Seattle was among the first to realize the potential power of growth factors in mediating vascular function and dysfunction with regard to the proliferative activity associated with the development of human atherosclerotic lesions [1].

The concept of growth factors in the vascular literature has been a success story. This is true for the cardiovascular field related to atherosclerosis, angiogenesis, arteriogenesis and collateral artery growth, but maybe even more so for the field of tumor angiogenesis as introduced by Judah Folkman in 1971 [2]. The clinical success of growth factor-directed and -related therapy is exemplified by two growth factor inhibitors that recently have been introduced in optimal anti-tumor therapy, namely the tyrosine kinase inhibitor STI-571 for the treatment of chronic myelogenous leukemia and other tumors [3] and the anti-VEGF antibody Avastin as an anti-angiogenic drug for use in colon cancer [4]. Likewise, the concept of therapeutic use of growth factors for stimulation of neovascularization/collateral artery growth has entered the arena of clinical testing several years ago [5]. The cardiovascular scientific community apparently has shown appreciable interest in the topic, which is attested by Fig. 1 highlighting the continuous and growing impact of growth factors in articles published in Cardiovascular Research .



Fig. 1 
Articles published in Cardiovascular Research using the keyword “growth factors”. *2004 contains all articles published before 16th November 2004.



This Spotlight Issue of Cardiovascular … 

*Corresponding authors. Johannes Waltenberger is to be contacted at Tel.: +31 43 38 75 106; fax: +31 43 38 75 104. Mark J. Post, Tel.: +31 43 38 81 085; fax: +31 43 38 84 166. Email address: m.post{at}fys.unimaas.nl j.waltenberger{at}cardio.azm.nl
High Expression of Ligands for Chemokine Receptor CXCR2 in Alveolar Epithelial Neoplasia Induced by Oncogenic Kras
Authors: Marie Wislez, Nobukazu Fujimoto, Julie G. Izzo, Amy E. Hanna, Dianna D. Cody, Robert R. Langley, Hongli Tang, Marie D. Burdick, Mitsuo Sato, John D. Minna, Li Mao, Ignacio Wistuba, Robert M. Strieter, Jonathan M. Kurie
Journal: Cancer Research (2006)

Abstract CXCL8, a ligand for the chemokine receptor CXCR2, was recently reported to be a transcriptional target of Ras signaling, but its role in Ras-induced tumorigenesis has not been fully defined. Here, we investigated the role of KC and MIP-2, the murine homologues of CXCL8, in KrasLA1 mice, which develop lung adenocarcinoma owing to somatic activation of the KRAS oncogene. We first investigated biological evidence of CXCR2 ligands in KrasLA1 mice. Malignant progression of normal alveolar epithelial cells to adenocarcinoma in KrasLA1 mice was associated with enhanced intralesional vascularity and neutrophilic inflammation, which are hallmarks of chemoattraction by CXCR2 ligands. In in vitro migration assays, supernatants of bronchoalveolar lavage samples from KrasLA1 mice chemoattracted murine endothelial cells, alveolar inflammatory cells, and the LKR-13 lung adenocarcinoma cell line derived from KrasLA1 mice, an effect that was abrogated by pretreatment of the cells with a CXCR2-neutralizing antibody. CXCR2 and its ligands were highly expressed in LKR-13 cells and premalignant alveolar lesions in KrasLA1 mice. Treatment of KrasLA1 mice with a CXCR2-neutralizing antibody inhibited the progression of premalignant alveolar lesions and induced apoptosis of vascular endothelial cells within alveolar lesions. Whereas the proliferation of LKR-13 cells in vitro was resistant to treatment with the antibody, LKR-13 cells established as syngeneic tumors were sensitive, supporting a role for the tumor microenvironment in the activity of CXCR2. Thus, high expression of CXCR2 ligands may contribute to the expansion of early alveolar neoplastic lesions induced by oncogenic KRAS. (Cancer Res 2006; 66(8): 4198-207)
Primary amyloidosis presenting as an isolated mediastinal mass: diagnosis by fine needle biopsy.
Authors: N Hiller, D Fisher, O Shmesh, S Gottschalk-Sabag, M Dollberg
Journal: Thorax (1995)

Intrathoracic amyloidosis affecting the lungs or mediastinum is rare, and mediastinal lymphadenopathy in the absence of pulmonary involvement is even more rare. The case history is presented of a previously healthy man who developed nodular mediastinal amyloidosis without pulmonary involvement. Diagnosis was made by percutaneous fine needle biopsy.
The p53Pro72Arg Polymorphism is Associated with Albuminuria among Aboriginal Australians
Authors: Stephen P. McDonald, Wendy E. Hoy, Graeme P. Maguire, Natalia L. Duarte, David E. L. Wilcken, Xing L. Wang
Journal: Journal of the American Society of Nephrology (2002)

Albuminuria is a widely recognized marker of renal disease and cardiovascular risk. This is especially true in Aboriginal Australians living in remote communities who suffer high rates of end-stage renal disease and cardiovascular mortality. During a survey of risk factors for renal and cardiovascular disease in one such community, an association between a common polymorphism at codon 72 (Arg/Pro) of the p53 gene and markers of renal disease was sought. A cross-sectional community survey including 217 people was performed. Genotypes of the polymorphism were distributed in Hardy-Weinberg equilibrium, with p53Arg allele frequency of 0.45 (range, 0.41 to 0.50). Overall prevalence of albuminuria was high (31% microalbuminuria; 14% overt albuminuria). Urine albumin/creatinine ratio (ACR) was significantly associated with the number of p53Pro alleles (P = 0.01), and there was an interaction with tobacco smoking (P = 0.04). The p53 genotype was also associated with increasing HbA1c, but the relationship between p53 and ACR was independent of this. This is a previously unreported association. This study does not address the mechanism, but this finding, if confirmed, expands the described effects of p53 in cellular proliferation and apoptosis to include a role in the course of renal and possibly cardiovascular disease in this population.
A Transcriptional and Metabolic Signature of Primary Aneuploidy Is Present in Chromosomally Unstable Cancer Cells and Informs Clinical Prognosis
Authors: Jason M. Sheltzer
Journal: Cancer Research (2013)

Abstract Aneuploidy is invariably associated with poor proliferation of primary cells, but the specific contributions of abnormal karyotypes to cancer, a disease characterized by aneuploidy and dysregulated proliferation, remain unclear. In this study, I demonstrate that the transcriptional alterations caused by aneuploidy in primary cells are also present in chromosomally unstable cancer cell lines, but the same alterations are not common to all aneuploid cancers. Chromosomally unstable cancer lines and aneuploid primary cells also share an increase in glycolytic and TCA cycle flux. The biological response to aneuploidy is associated with cellular stress and slow proliferation, and a 70-gene signature derived from primary aneuploid cells was defined as a strong predictor of increased survival in several cancers. Inversely, a transcriptional signature derived from clonal aneuploidy in tumors correlated with high mitotic activity and poor prognosis. Together, these findings suggested that there are two types of aneuploidy in cancer: one is clonal aneuploidy, which is selected during tumor evolution and associated with robust growth, and the other is subclonal aneuploidy caused by chromosomal instability (CIN). Subclonal aneuploidy more closely resembles the stressed state of primary aneuploid cells, yet CIN is not benign; a subset of genes upregulated in high-CIN cancers predict aggressive disease in human patients in a proliferation-independent manner. Cancer Res; 73(21); 6401–12. ©2013 AACR.
Maternal Concentrations of Persistent Organochlorine Pollutants and the Risk of Asthma in Offspring: Results from a Prospective Cohort with 20 Years of Follow-up
Authors: Susanne Hansen, Marin Strøm, Sjurdur F. Olsen, Ekaterina Maslova, Panu Rantakokko, Hannu Kiviranta, Dorte Rytter, Bodil H. Bech, Linda V. Hansen, Thorhallur I. Halldorsson
Journal: Environmental Health Perspectives (2013)

Background: Previous findings suggest that developmental exposures to persistent organochlorine pollutants (POPs) may be detrimental for the development of the immune system in the offspring. Whether these suspected immunoregulatory effects persist beyond early childhood remains unclear.Objectives: The objective of this study was to evaluate the association between maternal serum concentrations of POPs and the risk of asthma in offspring after 20 years of follow-up.Methods: A birth cohort with 965 women was formed in 1988–1989 in Aarhus, Denmark. Concentrations of six polychlorinated biphenyls (PCBs) (congeners 118, 138, 153, 156, 170, 180), hexachlorobenzene (HCB), and dichlorodiphenyldichloroethylene (p,p´-DDE) were quantified in maternal serum (n = 872) collected in gestation week 30. Information about offspring use of asthma medications was obtained from the Danish Registry of Medicinal Product Statistics.Results: Maternal serum concentrations of HCB and dioxin-like PCB-118 were positively associated with offspring asthma medication use after 20 years of follow-up (p for trend &lt; 0.05). Compared with subjects in the first tertile of maternal concentration, those in the third tertile of PCB-118 had an adjusted hazard ratio (HR) of 1.90 (95% CI: 1.12, 3.23). For HCB the HR for the third versus the first tertile of maternal concentration was 1.92 (95% CI: 1.15, 3.21). Weak positive associations were also estimated for PCB-156 and the non-dioxin-like PCBs (PCBs 138, 153, 170, 180). No associations were found for p,p´-DDE.Conclusions: Maternal concentrations of PCB-118 and HCB were associated with increased risk of asthma in offspring followed through 20 years of age.Citation: Hansen S, Strøm M, Olsen SF, Maslova E, Rantakokko P, Kiviranta H, Rytter D, Bech BH, Hansen LV, Halldorsson TI. 2014. Maternal concentrations of persistent organochlorine pollutants and the risk of asthma in offspring: results from a prospective cohort with 20 years of follow-up. Environ Health Perspect 122:93–99; http://dx.doi.org/10.1289/ehp.1206397
Reduced Vessel Elasticity Alters Cardiovascular Structure and Function in Newborn Mice
Authors: Jessica E. Wagenseil, Chris H. Ciliberto, Russell H. Knutsen, Marilyn A. Levy, Attila Kovacs, Robert P. Mecham
Journal: Circulation Research (2009)

Elastic blood vessels provide capacitance and pulse-wave dampening, which are critically important in a pulsatile circulatory system. By studying newborn mice with reduced (Eln(+/)(-)) or no (Eln(-)(/)(-)) elastin, we determined the effects of altered vessel elasticity on cardiovascular development and function. Eln(-)(/)(-) mice die within 72 hours of birth but are viable throughout fetal development when dramatic cardiovascular structural and hemodynamic changes occur. Thus, newborn Eln(-)(/)(-) mice provide unique insight into how a closed circulatory system develops when the arteries cannot provide the elastic recoil required for normal heart function. Compared with wild type, the Eln(-)(/)(-) aorta has a smaller unloaded diameter and thicker wall because of smooth muscle cell overproliferation and has greatly reduced compliance. Arteries in Eln(-)(/)(-) mice are also tortuous with stenoses and dilations. Left ventricular pressure is 2-fold higher than wild type, and heart function is impaired. Newborn Eln(+/)(-) mice, in contrast, have normal heart function despite left ventricular pressures 25% higher than wild type. The major vessels have smaller unloaded diameters and longer lengths. The Eln(+/)(-) aorta has additional smooth muscle cell layers that appear in the adventitia at or just before birth. These results show that the major adaptive changes in cardiovascular hemodynamics and in vessel wall structure seen in the adult Eln(+/)(-) mouse are defined in late fetal development. Together, these results show that reduced elastin in mice leads to adaptive remodeling, whereas the complete lack of elastin leads to pathological remodeling and death.
Second-line therapy in elderly patients with advanced nonsmall cell lung cancer
Authors: Elisabeth Quoix, Virginie Westeel, Lionel Moreau, Eric Pichon, Armelle Lavolé, Jérome Dauba, Didier Debieuvre, Pierre Jean Souquet, Laurence Bigay-Game, Eric Dansin, Michel Poudenx, Olivier Molinier, Fabien Vaylet, Denis Moro-Sibilot, Denis Herman, Helene Sennelart, Jean Tredaniel, Bertrand Mennecier, Franck Morin, Laurence Baudrin, Bernard Milleron, Gérard Zalcman
Journal: European Respiratory Journal (2013)

There is no dedicated study on second-line treatment for elderly patients with advanced nonsmall cell lung cancer (NSCLC). We report the results on second-line erlotinib therapy from our previously published phase III study comparing single-agent therapy with platinum-based doublet (carboplatin plus paclitaxel) therapy in 451elderly patients. Erlotinib was given to patients exhibiting disease progression or experiencing excessive toxicity during first-line therapy, until further progression or unacceptable toxicity. In total, 292 (64.7%) patients received erlotinib as second-line therapy. Initial performance status 0–1, stage IV NSCLC and an Activities of Daily Living score of 6 were independent factors for receiving erlotinib. Median (95% CI) overall survival was 4 (3.2–6.7) versus 6.8 (5.0–8.3) months in the single-agent and doublet arms, respectively (p=0.089). Performance status 0–1, never having smoked, adenocarcinoma and weight loss ≤5% were favourable independent prognostic factors of survival, whereas the randomisation arm had no significant impact. Among the 292 patients who received erlotinib, 60 (20.5%) experienced grade 3–4 toxic effects, the most frequent being rash. Erlotinib as second-line therapy is feasible, leading to efficacy results similar to those obtained in a previous randomised study that was not dedicated to elderly patients, with acceptable toxicity.