tbuckley/cabot-search huggingface dataset:
Neddylation in glioblastomas
Authors: Sheila Mansouri, Gelareh Zadeh
Journal: Neuro-Oncology (2015)

Protein degradation is a highly regulated process that is required for maintaining cellular homeostasis, and its deregulation is associated with development of a number of diseases including cancer. Neddylation is a posttranslational modification that involves conjugation of the ubiquitin-like protein NEDD8 (neural precursor cell expressed, developmentally downregulated) to target proteins such as oncoproteins and tumor suppressors to regulate their functions through a cascade of enzymes including NEDD8-activating enzyme (E1), NEDD8-conjugating enzyme (E2), and NEDD8 ligases (E3). 1 As such, the neddylation pathway presents an attractive oncogenic target for development of anticancer therapies. The main cellular substrates for neddylation include components of the Cullin-RING E3 ligase (CRL), which is the largest multicomponent ubiquitin ligase family regulating the turnover of multiple tumor suppressor proteins such as p21, p27, and NF-Kappa-B Inhibitor Alpha, among others (Fig. 1A). 2 In an elegant study, Hua et al systematically investigated the effectiveness of the NAE inhibitor, MLN4924, against glioblastoma (GBM) in vitro and in vivo. MLN4924 is a newly developed small molecule inhibitor of the neddylation pathway that specifically inhibits NAE by binding to its active site and hindering its enzymatic activity. 3 Several other groups have shown that treatment of cancer cells with MLN4924 results in induction of DNA damage response, cell cycle arrest, apoptosis, or senescence. 4,5 MLN4924 is currently under investigation in several phase 1/2 clinical trials for multiple solid tumor types and hematologic malignancies. 6 The ability of MLN4924 to cross the blood-brain barrier, its low toxicity, and clinical efficacy in other cancers suggests that this drug is an attractive treatment against GBM. Analysis of overall survival of GBM patients, as well as correlation with expression of global protein neddylation, indicated that higher global protein neddylation correlates with poor patient survival. They also found that GBM tumors generally express higher levels of NEDD8 and neddylation enzymes such as NAE1/UBA3 and UBC12 compared with adjacent normal brain tissue, with recurrent GBM tumors displaying even
Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors
Authors: Saoirse O. Dolly, Andrew J. Wagner, Johanna C. Bendell, Hedy L. Kindler, Lee M. Krug, Tanguy Y. Seiwert, Marjorie G. Zauderer, Martijn P. Lolkema, Doris Apt, Ru-Fang Yeh, Jill O. Fredrickson, Jill M. Spoerke, Hartmut Koeppen, Joseph A. Ware, Jennifer O. Lauchle, Howard A. Burris, Johann S. de Bono
Journal: Clinical Cancer Research (2016)

Abstract Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases. Experimental Design: Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed. Results: Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of &amp;gt;25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas). Conclusions: Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874–84. ©2016 AACR.
Mefloquine for malarial prophylaxis in military personnel
Authors: Nithya J Gogtay, Robin E Ferner
Journal: BMJ (2015)

Not the first choice

The British Army adopted mefloquine (Lariam) as its preferred drug for chemoprophylaxis against malaria in 1993. Treatment doses of mefloquine had already been reported to cause an acute brain syndrome.1 In 1996, army doctors reported a private soldier who, after six doses of mefloquine prophylaxis, saw the Grim Reaper standing behind the chaplain, heard incoherent voices, and was admitted to a psychiatric hospital2; more reports followed. A health minister explained reassuringly that the increase in reports was “not unexpected.”3 Twenty years later, we are still uncertain how safe mefloquine is, and the media have focused attention on whether the drug should still be used for chemoprophylaxis by British troops, a group with limited autonomy. The UK defence authorities are under renewed pressure to rethink their policy.4 

The threat of malaria remains real, with over 1500 imported cases each year in the United Kingdom and several deaths. The key to malaria prophylaxis is to prevent bites by using suitable clothing, bed nets, …
Significantly higher pathological complete remission (PCR) rate following neoadjuvant therapy with trastuzumab (H), paclitaxel (P), and anthracycline-containing chemotherapy (CT): Initial results of a randomized trial in operable breast cancer (BC) with HER/2 positive disease
Authors: A. U. Buzdar, K. Hunt, T. Smith, D. Francis, M. Ewer, D. Booser, E. Singletary, T. Buchholz, A. Sahin, G. N. Hortobagyi
Journal: Journal of Clinical Oncology (2004)

520 Background: In patients (pts) with metastatic BC, trastuzumab [Herceptin (H)] in combination with CT results in higher response rates, longer control of disease, and superior survival. The objective of this study was to determine whether the addition of H to CT in the neoadjuvant setting could increase PCR rate in pts with HER/2 positive disease. Methods: 42 pts with HER/2-positive disease (IHC 3+ or FISH +) with operable BC were randomized to 4 cycles of P followed by 4 cycles of FEC, or the same CT with simultaneous weekly H at 2 mg/kg for 24 weeks.The primary objective was to demonstrate a 20% improvement in PCR (assumed 21% to 41%) with addition of H to CT. At the end of CT±H, pts had definitive surgery. The planned sample size was 164 pts. Results: Prognostic factors were similar in the two groups. After 34 pts had completed therapy, the trial's Data Monitoring Committee stopped the trial for superiority of CT + H. PCR rates were 25% and 67%, respectively, for CT alone (n=16) and CT + H (n=18) (P=0.02). Additional results are included in the table. Fever during neutropenia occurred in 9 and 11 pts, respectively, in CT alone and CT + H. Of those, 3 pts in each subgroup were hospitalized. Decrease in cardiac ejection fraction (>10%) was observed in 6 and 4 pts, respectively, in CT and CT + H. No pts had clinical CHF or other clinically relevant cardiac toxicity. Troponin-T levels remained normal in all pts. The trial was stopped by an independent DMC based on a Bayesian predictive probability of 0.95 that the trial would conclude a significant benefit for CT+H if completed to originally planned 164 pts. Conclusions: Despite the small sample size, these data indicate that adding H to CT as utilized in this trial significantly increased PCR without clinical CHF. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech
FOLFIRI plus bevacizumab (B) as neoadjuvant treatment for potentially resectable colorectal cancer patients (pts) with liver metastasis: A phase II trial.
Authors: Guglielmo Nasti, Alessandro Ottaiano, Carmen Romano, Francesco Izzo, Paolo Delrio, Vittorio Albino, Pasqualina Giordano, Maria Carmela Piccirillo, Gennaro Daniele, Secondino Lastoria, Corradina Caraco, Cecilia Arrichiello, Elisabetta De Lutio, Piera Maiolino, Fabiana Tatangelo, Rosario Vincenzo Iaffaioli
Journal: Journal of Clinical Oncology (2012)

e14130 Background: Irinotecan-based chemotherapy plus B was shown to be effective and safe in both first- and second-line treatment for metastatic colorectal cancer (mCRC) pts.We designed this trial to assess whether the combination of FOLFIRI + B given to untreated, potentially resectable mCRC pts was feasible and active. Methods: Phase II, single arm trial with 1-year progression-free rate (PFR) as primary end-point. A sample size of 39 pts was calculated to detect a 70% ± 12% 1-year PFR. The treatment was FOLFIRI q2w (irinotecan 180 mg/m2, leucovorin 200 mg/m2, 5FU 2400 mg/m2 iv in 46 hrs) plus B 5mg/kg q2w. Last cycle before surgery was without B. Potentially resectable, untreated mCRC pts, with liver as unique site of metastases, were eligible. Normal organ function and no contraindications to B were required. Pts were reevaluated for surgery after 6 cycles. PET-Scan were performed at baseline and at the second cycle. Results: Overall 39 pts were enrolled. Median age was 58 (range 30-75), male/female were 24/15. Twenty seven pts (69.2%; 95%CI 52.4% – 83.0%) were progression-free at 1-year. Thirty seven pts (94.9%) underwent surgery. One complete and 22 partial responses were observed (response rate 59.0%; 95% CI 42.1% – 74.4%); 5 pts had disease progression (4 resectable and 1 unresectable). Early PET-scan was assessed according PERCIST criteria [Wahl RL, J Nucl Med 2009] in 29 pts and showed metabolic response (SUV-max decrease &gt; 30%) in 17 (58.6%; 95% CI: 38.9%- 76.5%).Severe toxicity includes grade 3 neutropenia (3 pts, 7.7%) and grade 3 diarrhea (1 pt, 2.6%). Other toxicities include grade 1-2 diarrhea (15.4%), grade 2 nausea (7.8%), grade 2 leucopenia (5.1%), grade 2 asthenia (5.1%), grade 1 anemia (2.6%), grade 2 thrombosis (2.6%). Overall, 16 pts out of 37 experienced surgical complications (43.2%; 95%CI 27.1% - 60.5%): biliary leak (11 pts, 29.7%), biliary fistula (1 pt, 2.7%), other complications (4 pts, 10.8%). All complications were reversible. No peri-operative bleeding was observed. Conclusions: The trial yielded its primary aim and shows that FOLFIRI plus B is feasible and active as neo-adjuvant treatment in patients with resectable liver metastases of CRC.
Influence of Age on Susceptibility of Mice to the Development of Lymphoid Tumors after Irradiation&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/xref&gt;
Authors: H S KAPLAN
Journal: JNCI Journal of the National Cancer Institute (1948)

Journal Article Influence of Age on Susceptibility of Mice to the Development of Lymphoid Tumors after Irradiation Get access Henry S. Kaplan Henry S. Kaplan radiologist National Cancer Institute, National Institute of Health, Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 9, Issue 1, August 1948, Pages 55–56, https://doi.org/10.1093/jnci/9.1.55 Published: 01 August 1948 Article history Received: 20 May 1948 Published: 01 August 1948
Hepatitis B core-related antigen levels are associated with response to entecavir and peginterferon add-on therapy in hepatitis B e antigen–positive chronic hepatitis B patients
Authors: M.J.H. van Campenhout, W.P. Brouwer, G.W. van Oord, Q. Xie, Q. Zhang, N. Zhang, S. Guo, F. Tabak, A. Streinu-Cercel, J. Wang, S.D. Pas, M.J. Sonneveld, R.J. de Knegt, A. Boonstra, B.E. Hansen, H.L.A. Janssen
Journal: Clinical Microbiology and Infection (2016)
Criterion validity of Medicare chemotherapy claims in breast and lung cancer patients
Authors: E. B. Lamont, J. E. Herndon, J. C. Weeks, I. C. Henderson, R. Lilenbaum, R. L. Schilsky, N. A. Christakis
Journal: Journal of Clinical Oncology (2005)

6022 Background: We sought to determine the accuracy with which an administrative data source, Medicare claims data, captures chemotherapy use in elderly Medicare beneficiaries with cancer. Methods: In this criterion validation study, we merged gold-standard clinical trial data pertaining to 175 elderly cancer patients treated on two Cancer and Leukemia Group B (CALGB) breast and lung cancer trials (i.e., CALGB #9344 (n=45) and CALGB #9730 (n=130)) with temporally coincident ambulatory and inpatient Medicare health insurance claims data from Centers for Medicare and Medicaid Services (CMS). We then compared the data sources to determine test characteristics (i.e., sensitivity and specificity) of Medicare claims for chemotherapy administration. Results: The crude sensitivity for CMS claims for chemotherapy administration among the cohort during the study period was high at 0.91 (95% CI: 0.86, 0.95). Individual chemotherapy agents had similarly high sensitivities: carboplatin (0.81, 95% CI: 0.70–0.89), cyclophosphamide (0.91, 95% CI: 0.79–0.98), doxorubicin (0.91, 95% CI: 0.79–0.98) and paclitaxel (0.87, 95% CI: 0.79–0.92). Agent specific specificities were each 1.00. For 86% of lung cancer patients, CMS data measured the correct number of cycles of paclitaxel chemotherapy to within one cycle (58% patients had same number of cycles in both data sources, 27% had one less cycle in CMS data than in CALGB data, and 1% had one more cycle in CMS data than in CALGB data). Conclusions: This study suggests that administrative Medicare claims data are a valid source of information regarding chemotherapy administration to elderly Medicare beneficiaries with cancer and thus may be appropriate for use in observational studies of the risks, benefits, and patterns of use of anti-cancer therapy in the elderly. No significant financial relationships to disclose.
Assessment of epidermal growth factor receptor (EGFR) and K-ras mutation status in cytologic stained smears of non-small cell lung cancer (NSCLC) patients.
Authors: M. D. Lozano, A. Gurpide, J. I. Echeveste, A. Del Barrio, J. L. Perez-Gracia, L. M. Seijo, J. Zulueta, J. M. López-Picazo, I. Gil-Bazo, S. Martin-Algarra
Journal: Journal of Clinical Oncology (2010)

7560 Background: EGFR and K-ras mutations can help to guide treatment selection in NSCLC patients. Mutation status is routinely assessed in biopsy samples. Yet, lung cancer diagnosis relies to a large extent on cytological specimens which frequently are the only tumor samples available. We assessed EGFR and K-ras mutations in Papanicolau stained slides and cytological samples from NSCLC patients. Methods: DNA was extracted from cytological samples obtained by fine-needle aspiration (FNA) performed by bronchoscopy or ultrasound-guided endoscopy or from biological fluids. PCR and direct sequencing of exons 18-21 of EGFR gene and exon 2 of K-ras gene were performed using an ABI PRISM 310XL. Clinical activity of EGFR TKI was assessed and when biopsies were available, EGFR mutations were also determined in such samples. Results: From January 2007 to November 2009, 140 cytological samples were analyzed. DNA was extracted from: Papanicolau stained smears (111; 79%), cell block (9; 6%), fresh samples (9; 6%), ThinPrep (6; 4%) and body cavity fluids (5; 4%). Cytological diagnosis was: adenocarcinoma (101; 72%); other (39; 28%). EGFR mutations were found in 26 of 140 samples (19%) and K-Ras mutations in 14 of 126 (11%). In EGFR mutated cases, DNA was obtained from stained smears in 23 cases (88%), pleural fluid in 2 (8%) and cell block in 1 (4%). Response rate to EGFR tyrosine-kinase inhibitors in patients harbouring mutations was 75%. Paraffin-embedded tissue was also available from 12 patients. Mutation status of those samples showed 100% concordance with the cytology results. Conclusions: Assessment of EGFR and K-ras mutation status in cytological samples is feasible and their results and clinical applicability are similar to those obtained from biopsies. This technique allows extending the benefits of individualized treatment selection to NSCLC patients in which tumor biopsies are not available. No significant financial relationships to disclose.
Expression of cyclooxygenase-2 mRNA (COX2-mRNA) in peripheral blood (PB) of head and neck cancer patients (HNC) and healthy controls (HC)
Authors: J. J. Grau, J. Carles, M. Monzó, R. Palmero, R. Artells, J. Domingo-Domenech, A. Navarro, M. Amat, X. Fabregat, P. Gascon
Journal: Journal of Clinical Oncology (2004)

5521 Background: Overexpression of COX2 has been described in tissues of several tumors in contrast to normal tissues, and has been correlated with invasiveness, prognosis and survival. We analysed the expression of COX2-mRNA in PB cells in HNC patients (pts) and in HC and its relationship with outcome and progression free survival (PFS). Methods: Sixty blood samples were obtained from 43 consecutive HNC pts and 17 HC. Two ml of PB were analyzed for COX2-mRNA with quantitative real time protein chain reaction (PCR) and compared with b-actin as a house-keeping gene. HNC pts were grouped according to their outcome (favourable or unfavourable) and as bulky or non bulky (over or less than 6 cm in diameter). PB exams were performed before treatment in 29 pts or during treatment in other 14 pts. Results: Mean age was 59 (range 41–78) and 41 (range 25–59) for HNC and HC respectively. In HNC, primary was in oropharynx (10), oral cavity (10), hypopharynx (12), larynx (11). Bulky tumors were in 13 pts and non bulky in other 30 pts. Treatment consisted of surgery only (4), concomitant chemoradiotherapy (20), chemotherapy followed by curative surgery (4) or palliative chemotherapy (15). COX2-mRNA levels were higher in pts with unfavorable outcome than in those with favorable outcome. Both were higher than HC. Mean (range) were 6.8 (2.5–20), 1.2 (0.2–2.1), and 0.74 (0.33–1.5) respectively. In bulky tumors, 8 had unfavorable outcome (7 of them had COX2-mRNA higher than 6). Among 26 chemotherapy pts which COX2-mRNA was performed before treatment, in those with level 1 or less no relapse or progression was observed (n=7), and PFS was significantly better than those with level over 1 (n=19) (p=0.0138). Conclusions: COX2-mRNA level in PB cells are higher in HNC than in controls and it correlates with tumor size and outcome. These findings strongly suggest the use of this parameter as a future tumor marker. No significant financial relationships to disclose.
Abstract 18273: Cardiomyocytes Inhibit the Growth of Lung and Breast Cancer Cells but Fail to Abrogate the Proliferation of Melanoma Cells
Authors: Laura Graciotti, Toru Hosoda, Fumihiro Sanada, Giulia Borghetti, Christian Arranto, Fiorenza Valeriani, Ewa Wybieralska, Barbara Ogorek, Marcello Rota, Polina Goichberg, Piero Anversa, Annarosa Leri
Journal: Circulation (2014)

The adult heart is an organ resistant to primary cancer formation and secondary metastatic invasion. Rhabdomyosarcomas are rare and the majority of primary tumors are benign and restricted to the a...
Abstract 91: Pathogenicity of Naturally Produced Fragments of Cardiac Myosin Binding Protein C and Their Effects on Heart Function and Failure
Authors: Md. Abdur Razzaque
Journal: Circulation Research (2012)

Background: Myosin binding protein C (MyBP-C) is a thick filament protein consisting of 1274 amino acid residues (149kD) and mutations in the cardiac isoform (cardiac MyBP-C; cMyBP-C) are responsible for a substantial proportion (20-35%) of identified cases of familial hypertrophic cardiomyopathy (FHC). Recently we found a 40kD fragment is produced from cMyBP-C when the heart is stressed, using a stimulus such as ischemia reperfusion injury. This fragment can be detected in both the mouse and human heart and appears to be stable. Its ability to interfere with normal cardiac function is unexplored. Methods and Results: To understand the potential pathogenicity of the 40kd fragment in vivo, we generated cardiac myocyte-specific transgenic mice (TG) using a Tet-Off inducible system to permit controlled expression in cardiomyocytes. When 40kD protein expression is induced by crossing the responder animals with tetracycline transactivator (tTA) mice, the double TG mice show protein expression and, subsequently, sarcomere dysgenesis and altered cardiac geometry. The double transgenic heart fails between 3 to 17 weeks of age. Expression, the fragment in cardiomyocytes led to development of significant cardiac hypertrophy with myofibrillar disarray and fibrosis. Subsequent analyses showed that MEK-ERK hypertrophic signaling pathways were activated. To determine the role of this pathway in the pathogenic response being generated, we subjected an experimental cohort of animals to treatment with the MAPK/ERK kinase inhibitor U0126 during pregnancy. The drug effectively improved heart function and prolonged survival as compared to the untreated control cohort. Conclusions: The data show that a 40kD fragment of cMyBP-C, which is generated during the development of heart disease in both the mouse and human, is a pathogenic fragment whose presence leads to hypertrophic cardiomyopathy and heart failure. Blockade of the MEK-ERK pathway was effective therapeutically in decreasing morbidity and increasing lifespan in the face of continued synthesis of the fragment.
Dimethylcarbamyl Chloride, a Multipotential Carcinogen&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: B. L. van Duuren, B. M. Goldschmidt, C. Katz, I. Seidman
Journal: JNCI Journal of the National Cancer Institute (1972)

Dimethylcarbamyl chloride, an industrial chemical related to urethan, was carcinogenic to ICR/Ha Swiss mice by application to skin and by subcutaneous injection. After 385 days on test, application to skin caused a 68% incidence of tumors; of these, 46% were papillomas and 22% carcinomas. Subcutaneous injection resulted in a 72% incidence of local sarcomas. There was a low incidence, 8%, of papillary tumors of the lung by subcutaneous injection and 4% by application to skin. No lung tumors were seen in the control groups not treated. It is suggested that dimethylcarbamyl chloride is a direct-acting acylating carcinogen and that its active form is the cation (CH3)2N⊕C = O.
Spatiotemporal T790M Heterogeneity in Individual Patients with EGFR-Mutant Non–Small-Cell Lung Cancer after Acquired Resistance to EGFR-TKI
Authors: Akito Hata, Nobuyuki Katakami, Hiroshige Yoshioka, Reiko Kaji, Katsuhiro Masago, Shiro Fujita, Yukihiro Imai, Akihiro Nishiyama, Tadashi Ishida, Yoshihiro Nishimura, Yasushi Yatabe
Journal: Journal of Thoracic Oncology (2015)
Soy Isoflavones Promote Radioprotection of Normal Lung Tissue by Inhibition of Radiation-Induced Activation of Macrophages and Neutrophils
Authors: Lisa M. Abernathy, Matthew D. Fountain, Shoshana E. Rothstein, John M. David, Christopher K. Yunker, Joseph Rakowski, Fulvio Lonardo, Michael C. Joiner, Gilda G. Hillman
Journal: Journal of Thoracic Oncology (2015)