tbuckley/cabot-search huggingface dataset:
Identification of novel HER2 splice variants in breast cancer
Authors: A. M. Borras, A. Rogers, Y. Kuang, L. Flores, R. Distel, I. E. Krop
Journal: Journal of Clinical Oncology (2008)

22010 Background: De novo and acquired resistance of HER2+ breast cancer (HBC) totrastuzumab (T) is an important clinical problem, yet the molecular basis underlying resistance is not well understood. Mutations in the T binding domain of HER2 and a splicing variant of HER2 lacking exon 16 (del16) have been identified in small studies and postulated to play a role in T resistance. To identify additional mutations and splice variants in HER2, we utilized a sensitive mismatch detection assay to systematically screen the entire HER2 cDNA for such alterations. Methods: Total RNA was isolated from cell lines and frozen primary breast cancer samples and cDNA synthesized using oligo-(dT)20 primers. Seven sets of HER2-specific primers were used to PCR amplify the entire coding region of HER2 cDNA. Using Transgenomic WAVE HPLC, deletions were resolved by size, and point mutations were identified by Surveyor endonuclease. Fractions from peaks of interest were collected for subsequent Sanger sequencing. Results: 18 breast cancer cell lines, 11 primary HBC samples, and 8 normal breast controls were analyzed. No point mutations were identified. However, in addition to the previously described del16 transcript, several novel splice variants were observed in cell lines and primary HBC, including transcripts with deletion of exons 4–7 of the extracellular domain, and transcripts with deletion of exons 20–23 (del20–23) encoding the kinase domain. All of these variants were in-frame. To determine the relevance of these splice variants, we generated T-resistant clones of the cell lines BT-474, MDA-MB453, SKBR3, and ZR75–1. In all T-resistant cell lines except the SKBR3, the level of the del20–23 transcript was markedly lower than that of the parental cell line. Conclusions: In contrast to a previous report, we did not detect mutations in HER2 in a limited survey of HBC samples using a highly sensitive assay. However, several novel splice variants were identified. The expression of del20–23, lacking the kinase domain, was downregulated in T-resistant cell lines, suggesting that this variant may modulate HER2 signaling and T resistance. Functional studies of the protein encoded by this variant are warranted. No significant financial relationships to disclose.
Abstract 13762: Sedentary Behavior and Physical Activity Are Differentially Associated with Fat Deposition in Older Adults
Authors: Britta Larsen, Matthew Allison, Eugene Kang, Sarah Saad, Gail A Laughlin, Maria Rosario Araneta, Elizabeth Barrett-Connor, Christina L Wassel
Journal: Circulation (2012)

Background:  Physical activity is robustly cardioprotective. Recent studies, however, suggest that sedentary behavior, specifically time spent sitting, predicts greater cardiovascular morbidity and mortality, and does so independently of physical activity levels. This association is only partially explained by BMI and body composition, suggesting mechanisms other than general increased adiposity, such as location of fat deposition, may be involved. Objective: To explore the independent associations of physical activity and sedentary behavior with fat deposition among older community-dwelling adults in the Rancho Bernardo study.   Methods:  Participants were 504 adults (26% Caucasian men, 32% Caucasian women, 23% African American women, and 19% Filipino women) with a mean age of 65 years. Weekly physical activity hours and daily sitting hours were measured by self-report. Areas of pericardial, intra-thoracic, visceral, and intermuscular fat were measured using computed tomography (CT) scans of abdominal and chest regions. Reported physical activity and sitting hours were entered simultaneously into multivariate regression models to determine independent associations with each area of fat deposition.   Results:  After adjusting for age, sex, race/ethnicity, BMI, and cardiovascular risk factors, each additional hour of weekly physical activity predicted 2.54 cm2 less visceral fat and 0.34 cm2 less intermuscular fat (for both p    Conclusions:  Sitting time and physical activity have distinct, independent associations with the location of fat deposition in older adults. Common inflammatory markers did not mediate these associations. The positive association between sitting and pericardial fat could partially explain the link between sitting and coronary heart disease.
대한간학회지 제8차 춘계학술대회 초록집 : 포스터 전시 ; 자가면역성 간질환 환자에서 스테로이드의 장기치료 효과
Authors: 홍성필 ( Hong Seong Pil ), 전재윤 ( Jeon Jae Yun ), 문병수 ( Mun Byeong Su ), 이관식 ( Lee Gwan Sig ), 한광협 ( Han Gwang Hyeob ), 문영명 ( Mun Yeong Myeong ), 박영년 ( Park Yeong Nyeon )
Journal: Clinical and Molecular Hepatology (2002)
Normal Sister Chromatid Exchange and Cell Cycle Progression in Cultured Lymphocytes From Patients With Malignant Lymphoma&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: P E Crossen, P H Fitzgerald, B M Colls
Journal: JNCI Journal of the National Cancer Institute (1981)

Twenty patients with malignant lymphoma were examined; all but 2 were untreated or had not recently received therapy. Sister chromatid exchange (SCE) and cell progression through to the third mitotic cycle after phytohemagglutinin stimulation did not differ according to lymphoma type or disease stage, and the lymphoma group as a whole did not differ from 20 normal controls. These findings are contrary to other recent studies of SCE in malignant lymphoma. The only patient who had received recent chemotherapy had the highest SCE score and a greatly accelerated cell cycle response.
Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells
Authors: Dongwon Choi, Swapnika Ramu, Eunkyung Park, Eunson Jung, Sara Yang, Wonhyeuk Jung, Inho Choi, Sunju Lee, Kyu Eui Kim, Young Jin Seong, Mingu Hong, George Daghlian, Daniel Kim, Eugene Shin, Jung In Seo, Vicken Khatchadourian, Mengchen Zou, Wei Li, Roger De Filippo, Paul Kokorowski, Andy Chang, Steve Kim, Ana Bertoni, Tania Weber Furlanetto, Sung Shin, Meng Li, Yibu Chen, Alex Wong, Chester Koh, Jan Geliebter, Young-Kwon Hong
Journal: Cancer Research (2015)

Abstract Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 reexpression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression Cancer Res; 76(3); 582–93. ©2015 AACR.
Suicide among cancer patients.
Authors: P Periman
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.6.2292 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9626242 Suicide among cancer patients. P PerimanxP PerimanSearch for articles by this author https://doi.org/10.1200/JCO.1998.16.6.2292 PDF "Suicide among cancer patients.." Journal of Clinical Oncology, 16(6), p. 2292© 1998 by American Society of Clinical Oncology
Abstract 320: Long-term Atorvastatin, But Not Pravastatin, Treatment Leads To Repressed Mitochondrial Gene Expression And Altered Cardiac Ultrastructure
Authors: Alice Zemljic-Harpf, Joseph C Godoy, Ingrid R Niesman, Jan M Schilling, Anna Schwarz, Elizabeth K Asfaw, Erika A Alvarez, Nancy D Dalton, Piyush M Patel, Brian P Head, John C Drummond, David M Roth, Georgios Kararigas, Hemal H Patel
Journal: Circulation Research (2014)

Statins reduce low-density lipoprotein cholesterol (LDL-C) and decrease cardiovascular events. Although statins are generally well tolerated, the FDA warns that statins may induce skeletal muscle side effects, cognitive changes and increased fasting glucose levels. Skeletal muscle biopsies from patients with statin myopathy have revealed defects in mitochondrial ultrastructure. Impaired mitochondrial function has been postulated as a key cause of statin-induced myopathy and hepatotoxicity. Long-term statin effects on cardiac muscle are currently unknown. Wild type mice received atorvastatin, pravastatin or vehicle daily for seven months by oral gavage. Atorvastatin and pravastatin reduced LDL-C compared to vehicle. Echocardiography at two-week intervals showed no differences in %FS, %EF, circumferential fiber shortening and ventricular wall thicknesses between atorvastatin, pravastatin and vehicle treated mice. After seven months of atorvastatin, pravastatin or vehicle administration cardiac muscles (n=21-29) were analyzed, and only atorvastatin treated hearts revealed: A) swollen and misaligned mitochondria and accumulation of protein aggregates by transmission electron microscopy (n=4, each), and B) repression of mitochondrial and endoplasmatic reticulum related genes by genome-wide expression profiling. In cultured ventricular myocytes, atorvastatin, but not pravastatin; 1) down-regulated survival pathways via inhibition of ERK1/2T202/Y204, AktSer473 and mTOR signaling (p70 S6 kinaseThy421/Ser4240 and S6 RPSER 235/236), 2) reduced protein expression of caveolin-1, dystrophin, epithermal growth factor receptor and insulin receptor β, 3) decreased RhoA activation, and 4) induced apoptosis. LDL-C reduction by atorvastatin, but not pravastatin, was associated with a repression of mitochondrial and endoplasmic reticulum related genes, an accumulation of protein aggregates, and swollen mitochondria. This is the first report demonstrating that long-term atorvastatin treatment causes adverse effects on cardiac muscle with preserved cardiac function. Whether these changes predispose atorvastatin treated hearts to contractile dysfunction after hemodynamic stress needs further investigation.
A Cancer Research UK phase I study evaluating safety, tolerability, and biological effects of chimeric anti-CD40 monoclonal antibody (MAb), Chi Lob 7/4.
Authors: P. W. Johnson, N. M. Steven, F. Chowdhury, J. Dobbyn, E. Hall, M. Ashton-Key, E. Hodges, C. H. Ottensmeier, A. Williams, M. Glennie
Journal: Journal of Clinical Oncology (2010)

2507 Background: Expression of CD40 on a range of malignancies and the role of CD40 signaling in antigen presentation make it an attractive target for MAb therapy. Potential mechanisms of action for agonistic anti-CD40 include direct cytotoxic effects on tumor cells, recruitment of immune effectors and conditioning of antigen-presenting cells (Schultze and Johnson. Lancet, 1999. 354:1225). Preclinical studies showed anti-CD40 can eradicate lymphoma in immunocompetent hosts, inducing rapid CD8+ T-cell responses independent of CD4+ T-cell help. The response provided protection against re-challenge without further treatment. Notably, therapeutic activity improved when animals with a higher tumor burden were treated. (French et al Nat Med. 1999. 5:548). We have made an agonistic IgG1 chimeric anti-CD40 MAb, Chi Lob 7/4. The affinity is 0.2 nM, comparable to the parent murine MAb (0.1 nM). The aims of the study are to establish maximum tolerated dose (MTD), toxicity profile, biologically-active dose and pharmacokinetics, identify dose limiting toxicity and propose a dose for phase II evaluation. Methods: Eligible patients (pts) have histologically proven CD40+ solid tumors or diffuse large B-cell lymphoma resistant to conventional therapy. Chi Lob 7/4 is given by intravenous infusion weekly for 4 doses starting at 0.5 mg/dose. Planned dose escalation is in cohorts of 3 pts until MTD or biological effect, defined as reduction of peripheral blood CD19+ B-cells to 10% or less of baseline. Nineteen patients have been recruited to the dose escalation study, reaching 160 mg/dose. An expanded cohort at this dose will test efficacy in different tumor types. Enzyme linked immunosorbant assays were developed and validated to quantitate Chi-Lob 7/4 in serum and test for anti-chimeric MAb responses. Pharmacodynamic assessments include quantitation of T-, NK-, and B-cell numbers and activation in peripheral blood by flow cytometry, measurement of a panel of cytokines in plasma by Luminex technology, enumeration, and phenotypic assessment of human plasmacytoid and myeloid dendritic cells by a novel 6 color flow cytometry panel. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CancerResearch UK CancerResearch UK
Activity of the multi-tyrosine kinase inhibitor sunitinib in neuroblastoma tumors.
Authors: R. Calero, R. Serrano, L. Avendaño, E. Poblet, A. Ocana
Journal: Journal of Clinical Oncology (2010)

e13640 Background: Neuroblastoma (NB) is the most commonly diagnosed extracranial solid malignancy during infancy. Although curable in its early stages, metastatic tumors are associated with a bad prognosis and a poor survival. Receptor tyrosine kinases have been associated with oncogenic transformation in many human tumors. Sunitinib is multityrosine kinase inhibitor (c-kit, PDGFR and VEGFR) that has shown antitumor activity in some solid tumors. It was our intention to evaluate the antitumor activity of the multityrosine kinase inhibitor sunitinib in NB in order to identify novel therapeutic options of treatment. Methods: Here, we tested the antitumor activity of sunitinib, using cancer cell lines and in vivo xenografted mouse models. MTT proliferation, apoptosis assays and biochemical experiments were performed to investigate the molecular bases of the action of sunitinib alone or in combination with standard chemotherapy. Results: Sunitinib exhibited a potent antitumor activity in vitro (IC50 0.8-2.6 μM) in a representative panel of NB cell lines (SH-SY5Y, SK-N-BE2 and SK-N-AS). It also showed a high therapeutic index when tested in the non-transformed cells 293T and MCF10A. When combined with chemotherapies (cisplatin and doxorubicin) used for the treatment of NB tumors sunitinib was synergistic at very low doses (0.1 μM). Sunitinib induced cell cycle arrest and stimulates apoptosis at different doses. Mechanistically sunitinib inhibited several receptor tyrosine kinase proteins and the downstream PI3-AKT pathway. In vivo xenograft studies revealed a significant antitumor activity of sunitinib compared with the control group in two types of cells lines (SH-SY5Y, p=0.02 and SK-N-BE, p=0.08). Sunitinib demonstrated an anti-angiogenic effect in vivo with a reduction of markers associated with angiogenesis (factor VIII). Conclusions: Sunitinib demonstrates antitumor activity in several in vitro and in vivo models. Theses results support the development of sunitinib in clinical studies alone or in combination with chemotherapy. No significant financial relationships to disclose.
A Transgenic Mouse Model of Hemoglobin S Antilles Disease
Authors: R.A. Popp, D.M. Popp, S.G. Shinpock, M.Y. Yang, J.G. Mural, M.d.P. Aguinaga, P. Kopsombut, P.D. Roa, E.A. Turner, E.M. Rubin
Journal: Blood (1997)
Acute Lymphoblastic Leukemia in Infants
Authors: Ching-Hon Pui, William E. Evans
Journal: Journal of Clinical Oncology (1999)

Article Tools EDITORIAL Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1999.17.2.438 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10080582 Acute Lymphoblastic Leukemia in Infants Ching-Hon PuixChing-Hon PuiSearch for articles by this author , William E. EvansxWilliam E. EvansSearch for articles by this author Show More St. Jude Children's Research Hospital, University of Tennessee, Memphis, TN https://doi.org/10.1200/JCO.1999.17.2.438 First Page Full Text PDF Figures and Tables © 1999 by American Society of Clinical Oncology
Characterization of Monoclonal Antibodies to Human Melanoma-Associated Antigens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: K Imai, A K Ng, S Ferrone
Journal: JNCI Journal of the National Cancer Institute (1981)

The hybridomas No. 165.28T, No. 473.54S, and No. 653.25N derived from the fusion of myeloma cells with splenocytes from mice immunized with cultured human melanoma cells secreted monoclonal antibodies recognizing antigenic determinants maximally expressed on cultured human melanoma cells and freshly explanted melanoma cells. Monoclonal antibody No. 376.74T reacted also with carcinoma cell lines but with a significantly lower titer. Rosette inhibition assay showed that these antigenic determinants were expressed on antigenic structures, which are not associated with beta 2 microglobulin and histocompatibility antigens. Two monoclonal antibodies recognized the same or closely associated antigenic determinants, and the remaining two monoclonal antibodies reacted with distinct antigenic determinants. All four monoclonal antibodies could mediate antibody-dependent cellular cytotoxicity of cultured melanoma cells, but none could mediate complement-dependent cytotoxicity.
The Cause of G2-Arrest in Chinese Hamster Ovary Cells Treated With Anticancer Drugs2
Authors: Arelli P. Rao, Potu N. Rao
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article The Cause of G2-Arrest in Chinese Hamster Ovary Cells Treated With Anticancer Drugs Get access Arelli P. Rao, Arelli P. Rao Search for other works by this author on: Oxford Academic PubMed Google Scholar Potu N. Rao Potu N. Rao Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 57, Issue 5, November 1976, Pages 1139–1143, https://doi.org/10.1093/jnci/57.5.1139 Published: 01 November 1976 Article history Received: 13 January 1976 Accepted: 27 April 1976 Published: 01 November 1976
Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA).
Authors: S. A. Wells, B. G. Robinson, R. F. Gagel, H. Dralle, J. A. Fagin, M. Santoro, E. Baudin, J. R. Vasselli, J. Read, M. Schlumberger
Journal: Journal of Clinical Oncology (2010)

5503 Background: VAN is a once-daily oral inhibitor of RET, VEGFR, and EGFR signaling. VAN 300 mg/day has previously shown antitumor activity in a phase II study of patients (pts) with advanced hereditary MTC. Methods: Eligible pts had unresectable measurable, locally advanced or metastatic MTC (hereditary or sporadic). The primary objective was to determine if VAN prolonged PFS versus placebo (P), as determined by independent central RECIST assessments. Secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), biochemical response (changes in serum calcitonin [CTN] and carcinoembryonic antigen [CEA]) and overall survival (OS). Results: Between Dec 2006 and Nov 2007, 331 pts (mean age 52 yrs; 57% male; 90% sporadic; 95% metastatic; RET mutation status: Pos 56%; Neg 2%; Unknown 41%) were randomized 2:1 to VAN (n=231) or P (n=100). Pt characteristics were similar in both arms. At data cutoff (July 2009), median follow-up was 24 mths; 48% pts randomized to VAN continued blinded treatment, 37% pts progressed, 15% were dead. Statistically significant PFS prolongation was observed for VAN vs P (HR 0.45, 95% CI 0.30–0.69); statistically significant advantages for VAN were also seen for ORR, DCR and biochemical response (Table). The adverse event (AE) profile was similar to previous VAN studies. Common AEs (any grade) more frequent with VAN included diarrhea (56% vs. 26%), rash (45% vs. 11%), nausea (33% vs. 16%), hypertension (32% vs. 5%), and headache (26% vs. 9%). Dosing was reduced in 35% (VAN) vs. 3% (P) pts. Conclusions: This study met its primary objective of significant PFS prolongation with VAN vs. P. VAN is the first therapy to demonstrate efficacy in a phase III trial in pts with advanced MTC, a disease for which there is no standard effective therapy. PFS HR 0.45 95% CI 0.30–0.69 p = 0.0001 Median PFS: not reached (VAN); 19.8 mths (P) ORR Odds ratio = 5.4 95% CI 2.99–10.79 p < 0.0001 DCR (>24 wks) Odds ratio = 2.64 95% CI 1.48–4.69 p = 0.001 Biochemical response CTN Odds ratio = 54.1 95% CI 21.6–181.7 p < 0.0001 CEA Odds ratio = 50.3 95% CI 15.4–309.4 p < 0.0001 OS* HR 0.89 99.98% CI 0.28–2.85 p = 0.712 HR <1 favors VAN; odds ratio >1 favors VAN*OS data immature—final OS analysis when 50% pts dead. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Amgen, AstraZeneca, Bayer, Eisai, Exelixis, Genzyme Genzyme AstraZeneca, Eisai, Genzyme Genzyme Genzyme
Reasons for late diagnostics of lung cancer in pulmonary tuberculosis patients
Authors: N.V. Yatskevich, L.K. Surkova, V.P. Kurchin, M.I. Dziusmikeyeva
Journal: European Respiratory Journal (2012)

The aim of this study was to find out reasons for late diagnostics of lung cancer (LC) in pulmonary tuberculosis (TB) pts have been admitted and treated in the RRPC for pulmonology and tuberculosis in 2006-2011.

Methods. Data of 6 pts with TB and peripheral LC (grA) (3m,3w, age 66±4), 11 pts with TB and central LC (grB) (8m,3w, age 64±3) were examined. X-ray, HRCT, sputum microscopy, cytology had been performed in all pts. Bronchoscopy had been performed in 4 pts of grA, 9 pts of grB, lobectomy-in 1 pts of grA.

Results. LC has been diagnosed during bronchoscopy by morphological investigation of tissue sampling in 2 (50%) pts of grA, 9 (100%) pts of grB, during lobectomy by morphological investigation of tissue sampling in 1 pts of grA, by sputum cytology in 1 pts of grA, in 1 pts of grB. In 1 (17%) pts of grA, 4 (36,4%) pts of grB have been found IB stage of LC, in 3 (27,2%) pts of grB-IIIA stage of LC, in 5 (83%) pts of grA, in 4 (36,4%) pts of grB-IV stage of CL. LC in TB pts have been diagnosed in 1 week-16 months (1 week-1 month-in 8 (47%), in 2 months-in 2 (12%), in 3 months-in 2 (12%), in 4 months-in 3 (17%), in 6 months-in 1 (6%), in 16 months-in 1 (6%) pts). The reasons for late diagnosis of LC since detection of X-ray changes in TB pts were incorrect interpretation of X-ray data, delaying using of invasive methods of investigation-in 6 (50%), late health-care seeking-in 1 (8%), pts severity, delaying using of invasive methods of investigation-in 2 (17%), did not carrying out invasive methods of investigation-in 3 (25%) pts.

Conclusions. LC in TB pts has been diagnosed late in 12 (71%) pts. The main reason for late diagnostics of LC in TB pts is delaying using of invasive methods of investigation.