tbuckley/cabot-search huggingface dataset:
Biological Therapy and Other Novel Therapies in Early-Stage Disease: Are They Appropriate?
Authors: Axel Grothey
Journal: Clinical Cancer Research (2007)

For nearly two decades, adjuvant chemotherapy has been the standard of care in patients with early-stage colon cancer at high risk of recurrence. Until now, treatment has been based on the use of cytotoxic drugs that have well-demonstrated efficacy in advanced colorectal cancer. Most recently, targeted biological agents [i.e., antibodies against the epidermal growth factor receptor and vascular endothelial growth factor] have become essential components of the palliative medical treatment of colorectal cancer. Proof of efficacy of these agents in advanced disease has led to the initiation of several trials testing epidermal growth factor receptor and vascular endothelial growth factor antibodies in the adjuvant setting. Although definitive results of ongoing adjuvant studies will not be available for 2 to 3 years, some oncologists might already inappropriately consider the use of these targeted agents as a component of adjuvant therapy in selected patients. Whether the results obtained in advanced colorectal cancer can be readily translated into a projected efficacy in early-stage colon cancer, however, is unclear. In addition, the long-term safety of biological agents in potentially surgically cured patients has not yet been established. This review discusses the potential caveats and concerns associated with the uncritical use of targeted agents as adjuvant therapy before their safety and efficacy in this setting has been indisputably established in definitive phase III trials.
Mental Disorder in Elderly Suicides: A Case-Control Study
Authors: Margda Wærn, Bo S. Runeson, Peter Allebeck, Jan Beskow, Eva Rubenowitz, Ingmar Skoog, Katarina Wilhelmsson
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The authors’ goal was to study the importance of different psychiatric disorders in relation to suicide in individuals 65 years old or older. METHOD: The psychological autopsy approach was used to study 85 cases of suicide among subjects who were 65 years old or older; 153 living comparison subjects from the same age group who were randomly selected from the tax register were interviewed face-to-face. Retrospective axis I diagnoses were made according to DSM-IV on the basis of interview data and medical records. RESULTS: Ninety-seven percent of the suicide victims fulfilled criteria for at least one DSM-IV axis I diagnosis, compared with 18% of the living comparison subjects. Recurrent major depressive disorder was a very strong risk factor for suicide, as was substance use disorder. An elevated risk was also associated with minor depressive disorder, dysthymic disorder, psychotic disorder, single-episode major depressive disorder, and anxiety disorder. Comorbid axis I disorders were observed in 15 (38%) of the 39 elderly subjects with major depressive disorder who had committed suicide. CONCLUSIONS: Although recurrent major depressive disorder was the mental disorder most strongly associated with suicide, the findings of this study suggest that elderly individuals who commit suicide represent a heterogeneous group with regard to mental disorders, implying a need for differentiated prevention strategies.
CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis
Authors: T. Inoue, S. Fujishima, E. Ikeda, O. Yoshie, N. Tsukamoto, S. Aiso, N. Aikawa, A. Kubo, K. Matsushima, K. Yamaguchi
Journal: European Respiratory Journal (2004)

Pulmonary fibrosis is caused by various known and unknown aetiologies, but the key pathogenic mechanisms are still ill-defined. Chemokines are a large family of chemotactic cytokines that play pivotal roles in various inflammatory diseases. In the present study, the roles of chemokines in a rat model of radiation pneumonitis/pulmonary fibrosis were examined. Accumulation of inflammatory cells and pneumonitis were observed on day 28, and diffuse alveolar wall thickening with extensive fibrosis was observed on day 56. In addition to the previously reported CCL2 (macrophage chemoattractant protein‐1) induction, selective upregulation of CCL22 (macrophage-derived chemokine) and CCL17 (thymus and activation-regulated chemokine) were demonstrated for the first time in the irradiated lung tissues. Immunohistochemically, it was demonstrated that CCL22 and CCL17 were localised primarily to alveolar macrophages, whereas their receptor CC chemokine receptor 4 (CCR4) was detected on alveolar lymphocytes and macrophages. On further analysis of bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and sarcoidosis, elevated levels of CCL22, but not of CCL17, were observed in the idiopathic pulmonary fibrosis patients. Since these two chemokines play pivotal roles in various type‐2 T‐helper cell-dominant diseases, it was speculated that CCL22, and probably CCL17, are involved in the pathophysiology of radiation pneumonitis/pulmonary fibrosis and idiopathic pulmonary fibrosis through the recruitment of CC chemokine receptor 4‐positive type‐2 T‐helper cells and alveolar macrophages. This study was supported, in part, by grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (both Tokyo, Japan).
miRNA Processing and Human Cancer: DICER1 Cuts the Mustard
Authors: Amin Bahubeshi, Marc Tischkowitz, William D. Foulkes
Journal: Science Translational Medicine (2011)

Numerous studies have implicated microRNAs (miRNAs) in cancer initiation and progression. In contrast, only recently has attention been focused on the pathway that generates these regulatory molecules. The identification of neoplasia-associated germline mutations in DICER1 has focused translational research on components of the miRNA processing pathway. Deciphering of the many links between miRNA processing perturbations and cancer will likely provide insights into mechanisms of cancer control.
Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma
Authors: Thinle Chodon, Begoña Comin-Anduix, Bartosz Chmielowski, Richard C. Koya, Zhongqi Wu, Martin Auerbach, Charles Ng, Earl Avramis, Elizabeth Seja, Arturo Villanueva, Tara A. McCannel, Akira Ishiyama, Johannes Czernin, Caius G. Radu, Xiaoyan Wang, David W. Gjertson, Alistair J. Cochran, Kenneth Cornetta, Deborah J.L. Wong, Paula Kaplan-Lefko, Omid Hamid, Wolfram Samlowski, Peter A. Cohen, Gregory A. Daniels, Bijay Mukherji, Lili Yang, Jerome A. Zack, Donald B. Kohn, James R. Heath, John A. Glaspy, Owen N. Witte, David Baltimore, James S. Economou, Antoni Ribas
Journal: Clinical Cancer Research (2014)

It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy.A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation.A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells.Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.
High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?
Authors: S Berardi, F Lodato, A Gramenzi, A D'Errico, M Lenzi, A Bontadini, M C Morelli, M R Tame, F Piscaglia, M Biselli, C Sama, G Mazzella, A D Pinna, G Grazi, M Bernardi, P Andreone
Journal: Gut (2006)

<b>Background:</b> Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. <b>Methods:</b> 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. <b>Results:</b> In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a "probable autoimmune hepatitis" (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). <b>Conclusions:</b> De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.
Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation
Authors: Hiroshi Kuriyama, Shizuya Yamashita, Iichiro Shimomura, Tohru Funahashi, Masato Ishigami, Katsumi Aragane, Kouji Miyaoka, Tadashi Nakamura, Kaoru Takemura, Zhiwei Man, Kiyotaka Toide, Natsuki Nakayama, Yoji Fukuda, Marie C. Lin, John R. Wetterau, Yuji Matsuzawa
Journal: Hepatology (1998)

The liver plays a central role in lipoprotein metabolism. In particular, very-low density lipoprotein (VLDL) is assembled in the hepatocytes and secreted into the blood circulation. The VLDL is then catabolized to low-density lipoprotein by lipoprotein lipase and hepatic triglyceride lipase. Obese subjects, especially those with visceral fat accumulation, are frequently associated with hyperlipidemia, non-insulin-dependent diabetes mellitus (NIDDM), and hypertension. The mechanism of hyperlipidemia in visceral fat obesity has not yet been elucidated. Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model of NIDDM, characterized by obesity with visceral fat accumulation, hyperlipidemia, and late-onset insulin resistance. To elucidate the mechanism of hyperlipidemia observed in OLETF rats, we focused on the production of VLDL by the liver and investigated hepatic messenger RNA (mRNA) levels of microsomal triglyceride transfer protein (MTP), acyl-coenzyme A synthetase (ACS), and apolipoprotein B (apo B), which play important roles in VLDL synthesis and secretion. In 6-week-old OLETF rats, in which insulin resistance had not been manifested, visceral fat weight was already higher and portal free fatty acid (FFA) and VLDL-triglyceride levels were elevated compared with the control rats. Hepatic ACS activity and mRNA levels, and MTP mRNA levels were also increased in OLETF rats, whereas apo B mRNA levels were similar; these results suggest that the enhanced expression of both ACS and MTP genes associated with visceral fat accumulation before developing insulin resistance may be involved in the pathogenesis of hyperlipidemia in obese animal models with NIDDM.
Promoter Hypermethylation of <b> <i>FANCF</i> </b>
Authors: Gopeshwar Narayan, Hugo Arias-Pulido, Subhadra V. Nandula, Katia Basso, Dorcas D. Sugirtharaj, Hernan Vargas, Mahesh Mansukhani, Jeannine Villella, Larissa Meyer, Achim Schneider, Lutz Gissmann, Matthias Dürst, Bhavana Pothuri, Vundavalli V. V. S. Murty
Journal: Cancer Research (2004)

Abstract Patients with advanced stage invasive cervical cancer (CC) exhibit highly complex genomic alterations and respond poorly to conventional treatment protocols. In our efforts to understand the molecular genetic basis of CC, we examined the role of Fanconi Anemia (FA)-BRCA pathway. Here, we show that FANCF gene is disrupted by either promoter hypermethylation and/or deregulated gene expression in a majority of CC. Inhibition of DNA methylation and histone deacetylases induces FANCF gene re-expression in CC cell lines. FANCF-deregulated CC cell lines also exhibit a chromosomal hypersensitivity phenotype after exposure to an alkylating agent, a characteristic of FA patients. We also show the involvement of BRCA1 gene by promoter hypermethylation or down-regulated expression in a small subset of CC patients. Thus, we have found inactivation of genes in the FA-BRCA pathway by epigenetic alterations in a high proportion of CC patients, suggesting a major role for this pathway in the development of cervical cancer. Thus, these results have important implications in understanding the molecular basis of CC tumorigenesis and clinical management in designing targeted experimental therapeutic protocols.
Edema Control by Cediranib, a Vascular Endothelial Growth Factor Receptor–Targeted Kinase Inhibitor, Prolongs Survival Despite Persistent Brain Tumor Growth in Mice
Authors: Walid S. Kamoun, Carsten D. Ley, Christian T. Farrar, Annique M. Duyverman, Johanna Lahdenranta, Delphine A. Lacorre, Tracy T. Batchelor, Emmanuelle di Tomaso, Dan G. Duda, Lance L. Munn, Dai Fukumura, A. Gregory Sorensen, Rakesh K. Jain
Journal: Journal of Clinical Oncology (2009)

Recent clinical trials of antivascular endothelial growth factor (VEGF) agents for glioblastoma showed promising progression-free and overall survival rates. However, available clinical imaging does not separate antitumor effects from antipermeability effects of these agents. Thus although anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice.We treated mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis and proliferation, and circulating angiogenic biomarkers.We show by intravital microscopy that cediranib significantly decreased tumor vessel permeability and diameter. Moreover, cediranib treatment induced normalization of perivascular cell coverage and thinning of the basement membrane, as mirrored by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation -- as measured by MRI and by dry/wet weight measurement of water content -- but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage infiltration and significant but minor changes in tumor cell proliferation and apoptosis. Systemically, cediranib increased plasma VEGF and placenta growth factor levels, and the number of circulating CXCR4(+)CD45(+) cells. However, by controlling edema, cediranib significantly increased survival of mice in the face of persistent tumor growth.Anti-VEGF agents may be able to improve survival of patients with glioblastoma, even without inhibiting tumor growth.
Acute haemolytic anaemia after inhalation of amyl nitrite
Authors: T. D Graves, S. Mitchell
Journal: Journal of the Royal Society of Medicine (2003)

commonly misdiagnosed—especially as melanocytic naevus, basal cell carcinoma, seborrhoeic keratosis or lentigo.5 In a study comparing the ability of general practitioners and dermatologists to discriminate pigmented lesions the general practitioners made an exact diagnosis of melanoma in 50% of the cases compared with the dermatologists’ 84%.6 Any changing or atypical mole or non-healing skin lesion should be referred urgently to a dermatologist or to a surgeon with a special interest in pigmented lesions.
Inverse relationship between vertebral fractures and spine osteoarthritis in postmenopausal women with osteoporosis
Authors: C Roux, J Fechtenbaum, K Briot, C Cropet, S Liu-Léage, C Marcelli
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Background:</h3> Although the coexistence of osteoarthritis and osteoporosis is considered as uncommon, it has been suggested that, in postmenopausal women, disc space narrowing increases the risk of vertebral fracture. The aim of this study was to check this hypothesis in postmenopausal women with osteoporosis. <h3>Objective:</h3> We analysed the relationship between vertebral fractures and spine osteoarthritis in 410 postmenopausal women with osteoporosis: in this population both disc space narrowing and osteophytes are inversely related to vertebral fractures. <h3>Patients and methods:</h3> This study is based on baseline data collected in a multicentre, prospective and 6-month longitudinal observational study. 410 postmenopausal women (74±5 years) were enrolled who had consulted for back pain, and had osteoporosis (according to WHO definition). Spine <i>x</i>-rays were performed according to standardised procedures. Vertebral fractures were evaluated from T4 to L4 using the Genant's semiquantitative method; osteoarthritis was evaluated by scoring osteophytes and disc space narrowing at all levels of the thoracic and lumbar spine, and by a qualitative assessment of facet joint arthritis. <h3>Results:</h3> The prevalence of vertebral fractures was 52.4%. At least one osteophyte, one disc space narrowing and one facet arthritis were present in 90.2, 64.6 and 77.8% of patients respectively. There was an inverse association between vertebral fractures and osteoarthritis: odds ratios adjusted for age and weight (95% CI) were 0.38 (0.17–0.86), p = 0.02 and 0.27 (0.16–0.46), p&lt;10<sup>−4</sup> for the presence of at least one osteophyte, and of at least three disc space narrowings respectively. In a cluster analysis, it was possible to identify a subgroup of patients without any disc space narrowing, and another subgroup with all patients having at least one disc space narrowing; the proportion of patients having more than three vertebral fractures was 25.2 and 15.9% in these two clusters respectively. <h3>Conclusions:</h3> Disc space narrowing and osteophytes are associated with a decreased vertebral fracture prevalence in postmenopausal women with osteoporosis.
Prediction of Stage, Grade, and Survival in Bladder Cancer Using Genome-wide Expression Data: A Validation Study
Authors: Martin Lauss, Markus Ringnér, Mattias Höglund
Journal: Clinical Cancer Research (2010)

To evaluate performances of published gene signatures for the assessment of urothelial carcinoma.We evaluated 28 published gene signatures designed for diagnostic and prognostic purposes of urothelial cancer. The investigated signatures include eight signatures for stage, five for grade, four for progression, and six for survival. We used two algorithms for classification, nearest centroid classification and support vector machine, and Cox regression to evaluate signature performance in four independent data sets.The overlap of genes among the signatures was low, ranging from 11% among stage signatures to 0.6% among survival signatures. The published signatures predicted muscle-invasive and high-grade tumors with accuracies in the range of 70% to 90%. The performance for a given signature varied considerably with the validation data set used, and interestingly, some of the best performing signatures were not designed for the tested classification problem. In addition, several nonbladder-derived gene signatures performed equally well. Large randomly selected gene signatures performed better than the published signatures, and by systematically increasing signature size, we show that signatures with >150 genes are needed to obtain robust performance in independent validation data sets. None of the published survival signatures performed better than random assignments when applied to independent validation data.We conclude that gene expression signatures with >150 genes predict muscle-invasive growth and high-grade tumors with robust accuracies. Special considerations have to be taken when designing gene signatures for outcome in bladder cancer.
Trastuzumab-Resistant HER2-Driven Breast Cancer Cells Are Sensitive to Epigallocatechin-3 Gallate
Authors: Sean F. Eddy, Susan E. Kane, Gail E. Sonenshein
Journal: Cancer Research (2007)

Abstract Overexpression of the epidermal growth factor receptor family member HER2 is found in ∼30% of breast cancers and is a target for immunotherapy. Trastuzumab, a humanized monoclonal antibody against HER2, is cytostatic when added alone and highly successful in clinical settings when used in combination with other chemotherapeutic agents. Unfortunately, HER2 tumors in patients develop resistance to trastuzumab or metastasize to the brain, which is inaccessible to antibody therapy. Previously, we showed that the green tea polyphenol epigallocatechin-3 gallate (EGCG) inhibits growth and transformed phenotype of Her-2/neu–driven mouse mammary tumor cells. The different modes of action of EGCG and trastuzumab led us to hypothesize that EGCG will inhibit HER2-driven breast cancer cells resistant to trastuzumab. We studied trastuzumab-resistant BT474 human breast cancer cells, isolated by chronic trastuzumab exposure, and JIMT-1 breast cancer cells, derived from a pleural effusion in a patient who displayed clinical resistance to trastuzumab therapy. EGCG treatment caused a dose-dependent decrease in growth and cellular ATP production, and apoptosis at high concentrations. Akt activity was suppressed by EGCG leading to the induction of FOXO3a and target cyclin-dependent kinase inhibitor p27Kip1 levels. Thus, EGCG in combination with trastuzumab may provide a novel strategy for treatment of HER2-overexpressing breast cancers, given that EGCG can cross the blood-brain barrier. [Cancer Res 2007;67(19):9018–23]