tbuckley/cabot-search huggingface dataset:
Role of cellular apoptosis in the modulation of benzo[a]pyrene-DNA adducts in human hepatoma cells.
Authors: Guo-dong Zhou, Molly Richardson, Inayat Fazili, Bhagavatula Moorthy, Kirby Donnelly
Journal: Cancer Research (2007)

4266   Polycyclic aromatic hydrocarbons (PAH) including benzo[a]pyrene (BP) are environmental carcinogens that undergo metabolic activation by cytochrome P450 (CYP) enzymes to reactive metabolites that are capable of forming DNA adducts, which could in turn lead to mutations in critical genes, eventually resulting in cancer. DNA adducts can be removed by DNA repair processes and damaged cells can be eliminated by apoptosis. These protective processes are inevitably less than perfect, and, in fact, PAH-DNA adducts accumulate over time. Retinoids are a group of compounds that regulate cell growth and differentiation. Many studies have shown that retinoic acid (RA) plays an important role in inducing cell apoptosis. In this study we have tested the hypothesis that levels of carcinogen DNA adducts can be diminished by eliminating damaged cells through enhancing apoptosis. Human hepatoma (HepG2) cells were used in this study. The levels of DNA adducts were analyzed by  32 P-postlabeling assay. Cellular apoptosis was analyzed with Annexin V-FITC Apoptosis Detection Kit. Our results showed that the levels of total DNA adducts in HepG2 cells treated with BP (2 µM) + RA (1 µM) were significantly reduced compared to those treated with BP only. Mean RAL values for BP+RA and BP group were 427.70±46.26 and 632.48±69.77 in 10 9  nucleotides (P=0.038), respectively. The levels of BP-dG adduct were also diminished in BP+RA group (362.06±49.00) compared to BP group (516.63±55.08), P=0.046. In order to understand the mechanism of attenuation of DNA adducts, further experiments were carried out. Cells were treated with BP for 24 h to initiate DNA adduct formation, following which the medium containing BP was removed, and fresh medium containing 1 µM RA was added. The cells were harvested 24 h after RA treatment (BP/RA). Control group was treated with BP for 24 h, but RA was replaced with DMSO (BP/DMSO). Interestingly, the levels of total DNA adducts were decreased in the BP/RA group (390.46±34.19) than those in the BP/DMSO group (543.70±32.82), P=0.319. Analysis of cell apoptosis showed an increase in BP+RA group, compared to BP only or RA only group. Our results also demonstrated that BP elicited significant induction of CYP1A1 and 1A2 enzyme activities. Co-treatment of the cells with RA did not significantly alter the inducibility of CYP1A1/1A2 by BP, suggesting that attenuation of BP-DNA adducts by RA was not primarily due to its effects on CYP1A expression. In conclusion, our results suggest a mechanistic link between cellular apoptosis and DNA adduct formation, phenomena that play important roles in BP-mediated carcinogenesis. Furthermore, these results help in the understanding of the mechanisms of carcinogenesis, especially in relation to the chemopreventive properties of nutritional apoptosis inducers .  (Supported by P30-ES09106, P42-ESO4917 and ES 009132).
Abstract 12911: Metformin Preserves ATP Concentration, Attenuates Action Potential Shortening, and Prevents Ventricular Fibrillation During Low-flow Ischemia in Normal Hearts
Authors: Gregory G Schwartz, Li Lu, Shuyu Ye, Clifford R Greyson
Journal: Circulation (2015)

Introduction: Metformin (MET) is the most common drug used to treat type 2 diabetes, in part because it is believed to reduce cardiovascular mortality. However, it is unknown whether MET provides protection from ischemic ventricular fibrillation (VF) in the normal heart. In a region of ischemic myocardium, reduced energy charge causes ATP-sensitive potassium channels to open, shortening the action potential (AP). The resulting dispersion of AP duration and refractoriness may predispose to VF. We determined effects of MET on myocardial ATP concentration, AP, and VF during regional ischemia in metabolically normal pigs. Methods: Normal domestic pigs were treated with a clinically relevant dose of MET (30 mg/kg/d, n=25) for 2-3 weeks and compared with untreated controls (CTL, n=23). Under anesthesized, open-chest conditions, phospho-AMP activated protein kinase (pAMPK, Thr172) was measured in myocardial biopsies taken before ischemia (n=8 each group). Low-flow ischemia was induced by 50% LAD flow reduction. [ATP] was measured in myocardial biopsies at 15 min ischemia (MET n=8, CTL n=7). Monophasic AP was recorded at baseline and at 15 min ischemia. Survival free of VF was observed during 90 min of ischemia and 45 min reperfusion. Results: pAMPK was 85% greater in MET than in CTL (p&lt;0.001), establishing a myocardial effect of MET prior to ischemia. MET had no effect on non-ischemic AP duration. At 15 min ischemia, [ATP] was higher in MET than CTL (4.1 vs 3.5 μmol/g, p=0.039), with less AP shortening from baseline in MET (4±2%) than in CTL (13±2%, p&lt;0.001). Survival free of VF was greater in MET pigs than CTL (Figure). Conclusions: Chronic treatment with a clinically relevant dose of MET activates AMPK, preserves [ATP] and prevents AP shortening during ischemia, and diminishes the propensity for ischemic VF in metabolically normal pigs. Based on these findings, MET may have therapeutic utility beyond type 2 diabetes, extending to ischemic protection of the normal heart.
In vitro and in vivo anti-B cell lymphoma activities of TRU-016
Authors: C. G. Cerveny, L. Grosmaire, C. Nilsson, R. Bader, A. Wahl, L. Kicknosway, A. Simon, W. Brady, M. Kennedy, P. Baum
Journal: Journal of Clinical Oncology (2008)

3074 Background: TRU-016, a CD37-specific, small modular immunopharmaceutical (SMIP) compound, was designed to deplete human B cells. TRU-016 was created by humanizing SMIP-016, a mouse/human chimeric protein previously demonstrated to kill human B cells in vitro via two distinct mechanisms and have antitumor activity against human B cell tumors in xenograft models. Here we report a comparison of the activities of the chimeric and humanized molecules as well as the antitumor activity of TRU-016 in a xenograft model in which CD20- directed treatment fails. Methods: Binding of the CD37-specific molecules to B cells was determined by flow cytometry. Direct cytotoxicity mediated by the anti-CD37 molecules was assessed when cell-bound and cross-linked. ATP release or flow cytometry assays were used to measure cell viability or apoptosis. The ability of the CD37-specific molecules to promote Fc-dependent cell mediated cytotoxicity (FcDCC) was assessed by the release of 51Cr from labeled target cells incubated with human PBMC and either SMIP-016 or TRU- 016. Antitumor activity of the CD37-specific molecules was tested in immunodeficient mice bearing subcutaneous human B cell tumor xenografts and included comparison of TRU-016 and rituximab activities in a model with DOHH2 xenografts. Results: TRU-016 and SMIP-016 were indistinguishable in terms of their ability to bind to and kill CD37+ cells. In addition, TRU-016 and SMIP-016 had similar and significant antitumor activity in mice bearing Ramos or Daudi tumor xenografts. Finally, although TRU-016 and rituximab each had antitumor activity in mice bearing DOHH2 xenografts, the response was durable only in mice treated with TRU-016. Conclusions: TRU- 016, a humanized CD37-specific SMIP compound, showed significant antitumor activity against human B cell tumors in several subcutaneous xenograft models, including a model in which CD20-directed treatment failed. Therefore, TRU-016 may be a promising therapeutic agent for patients with B cell lymphoma and leukemia who fail or relapse with current standard of care. No significant financial relationships to disclose.
GEMOX as first-line chemotherapy in advanced pancreatic cancer (APC): A monoinstitutional experience
Authors: M. Di Marco, E. Nobili, R. Di Cicilia, G. Brandi, S. Bertolini, E. Derenzini, S. Dell’Arte, R. Casadei, L. Calculli, G. Biasco
Journal: Journal of Clinical Oncology (2007)

15179 Background: To date, gemcitabine (GEM) remains the cornerstone of chemotherapy (CHT) for APC. According to GERCOR and GISCAD phase III trials the combination of GEM and oxaliplatin (GEMOX) has proven superior to GEM alone in terms of response rate (RR), time to progression (TTP) and clinical benefit rate (CBR). Methods: We conducted a retrospective analysis on 19 patients (pts) affected with histologically-confirmed APC, in order to determine the impact of GEMOX as first-line chemotherapy in terms of objective responses (OR) and TTP, using the Kaplan-Meier method. Among the 19 pts considered there were 15 males and 4 females (median age at diagnosis of 60.84 yrs; ECOG 0–2). The staging, according to AJCC criteria, was: IIB in 1 case, III in 5 cases and IV in the 13 remaning cases. The only metastatic site was the liver (in 13/19 pts). Ten of the 19 pts underwent surgical treatment prior to CHT: 2 radically resected (R0) subsequently treated with GEMOX after recurrence, 4 with positive margins (R1) and 4 surgically palliated. All pts received GEM 1000 mg/m2/d1 + oxaliplatin 100 mg/m2/d2 every 2 weeks. The median number of cycles was 5.89. Results: Among the 19 pts, 3 had a partial response (PR, 15.69%), 6 had stable disease (SD, 31.57%); no complete response was observed and 10 pts had progressive disease (PD, 52.63%). The overall disease control rate (DCR: PR + SD) was 47.37% while the OR were 15.69%. The median survival observed was 9.03 months (95% C.I. 5.15–12.91) and the median TTP was 6.13 months (95% C.I. 2.81–9.46). The main toxicities were: leucopenia, piastrinopenia, diarrhoea, nausea, fever and peripheral neuropathy; 3 pts discontinued the treatment due to grade 3–4 neurotoxicity. Conclusions: In our experience GEMOX gives an improved control of APC in terms of OR and TTP, with acceptable toxicity. The OS is in accordance to literature as well as the other data. No significant financial relationships to disclose.
Phase I and pharmacokinetics study of a novel anti-CD20 antibody, RO5072759 (GA101), in Japanese patients (Pts) with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) pretreated with rituximab.
Authors: K. Tobinai, M. Ogura, K. Hatake, Y. Kobayashi, M. Mori, T. Uchida, T. Suzuki, Y. Terui, M. Yokoyama, T. Hotta
Journal: Journal of Clinical Oncology (2010)

e18552 Background: GA101 is the first fully humanized and glycoengineered type II monoclonal anti-CD20 antibody. Previously, GA101 monotherapy has shown similar safety to rituximab and promising efficacy in relapsed or refractory pts with B-NHL and B-cell chronic lymphocytic leukemia (B-CLL) in Europe and Canada. The present study evaluated the safety, biomarkers, pharmacokinetics (PK) and efficacy of GA101 in 12 Japanese pts. Methods: A flat dose of GA101 was administered IV on days 1, 8 and 22, and then every 3 wk, for a total of 9 infusions. The dose was escalated using a 3+3 design. Full PK sampling was performed in cycles 1 and 8, trough serum GA101 was monitored, and the peripheral CD19+ B-cell count was examined as a biomarker. Results: 12 pts (8 FL, 1 NMZL, 1 MALT, 2 CLL/SLL) were treated at doses from 200 to 2,000 mg. GA101 was well tolerated and there were no dose-limiting toxicities. The adverse events were mostly G1 or G2 infusion-related reactions (IRR). These IRR were mainly pyrexia and chills during the first infusion, and occurred less often during subsequent infusions. Two pts had G3 IRR at the first infusion, but the symptoms resolved within 9 hr with supportive treatment. Two pts had drug-related ≥G3 neutropenia on day 1 of cycle 3 and so were withdrawn. One pt had transient G3 thrombocytopenia. Peripheral B-cell depletion was rapid and sustained in all pts (median follow-up period after last infusion: 20 wk). Plasma drug concentration showed dose-dependent increase, although there was considerable inter- and intra-patient variability. Levels of exposure to GA101 (PK results) were comparable to those found in non-Japanese pts. The efficacy of 2 CR, 5 PR and 5 SD was observed in both low and high dose levels. Conclusions: These results suggest that GA101 is well tolerated and has encouraging efficacy in Japanese B- NHL pts pretreated with rituximab. The dose for subsequent trials was considered to be the same as overseas. Further investigation of GA101 treatment in B-NHL pts is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chugai Pharma Chugai Pharma Chugai Pharma
Combined modality treatment of lymphedema using the Reid Sleeve and the BioCompression/Optiflow System
Authors: A. Hafner, R. Robinson, L. Massa, J. Maddox, C. Hoskins, S. Morgan, T. Reid
Journal: Journal of Clinical Oncology (2005)

592 Background: The objective of this study is to evaluate the effectiveness of combined modality treatment of lymphedema using the Reid Sleeve and the BioCompression/Optiflow System. Methods: 35 patients (16 upper extremity/19 lower extremity) with refractory lymphedema were enrolled on a study using the Reid Sleeve in combination with the BioCompression/Optiflow system. The patients wore the Reid Sleeve at night. During the daytime, the patients used the BioCompression pump with the Reid Sleeve Optiflow insert for 2 sessions of 60 minutes. Results: Among patients with upper extremity edema, the reduction in lymphedema increased steadily during treatment and was 24.7, 53.8 and 80.2% at 4, 12 and 28 weeks. The volume reduction at these times was 2310, 2753 and 4047 cubic centimeters. Linear regression analysis demonstrates a highly significant (p<0.001) reduction in arm edema during the course of treatment. A plateau phase occurred between weeks 4 and 8. For the patients with leg edema, the average reduction at 4 weeks was 9143 cubic centimeters followed by a period of relatively stable lymphedema until week 12 with an average decrease in lymphedema of 1486 cubic centimeters between weeks 12 and 16. Linear regression analysis demonstrates a significant (p<0.02) decrease in leg edema. The plateau phase may represent a tissue repair phase that occurs with effective resolution of residual lymphedema. Subsequent reductions in lymphedema can occur following tissue healing. The plateau phase appears to be more protracted among patients with more serious lymphedema such as patients with leg edema. Conclusions: The Reid Sleeve used in combination with the BioCopression/Optiflow system provides effective management for lymphedema Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Peninsula Medical Peninsula Medical
Carcinogenicity of Isosters of Epoxides and Lactones: Aziridine Ethanol, Propane Sultone, and Related Compounds&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: B L Van Duuren, S Melchionne, R Blair, B M Goldschmidt, C Katz
Journal: JNCI Journal of the National Cancer Institute (1971)

Thirteen compounds of low molecular weight were tested for carcinogenic activity by lifetime subcutaneous injection in ICR/Ha Swiss mice. The compounds tested were epoxides, their nitrogen or sulfur analogs, a polymeric aldehyde, and an acetal. The compounds were selected for bioassay on the basis of their chemical reactivity and the relationship of chemical structure to carcinogenic activity. Two of these compounds, propane sultone (1-propanesulfonic acid-3-hydroxy-γ-sultone) and aziridine ethanol (β-hydroxy-1-ethylaziridine), induced sarcomas and other tumors at the injection site. Propane sultone injections resulted in 21/30 mice with tumors (12 sarcomas, 1 carcinoma, 7 adenoacanthomas, and 1 papilloma) at the site of injection; aziridine ethanol administration resulted in 10/30 mice with sarcomas at the injection site. The following compounds induced a low incidence of tumors at the injection site: 3,4-epoxysulfolane, 1,2-epoxybutyronitrile, 3,4-dihydroxy-3-cyclobutene-1,2-dione, ethyl-2,3-epoxybutyrate, tetramethyl-1,3-cyclobutanedione, perchloro-2-cyclobutene-1-one, and polymeric dialdehyde. The following compounds were inactive when injected subcutaneously: 3-sulfolene, 3,4-epoxybutanal diethyl-acetal, 5,6-epoxyhexanal diethylacetal, and N,N-dimethylformamide dimethylacetal. The incidences of distant tumors were the same for test and control groups.
Abstract 8785: CYT387, a Novel Jak1/Jak2 Inhibitor, Prevents Progression of Pulmonary Arterial Hypertension in the Rat Monocrotaline Model
Authors: Lawrence S Zisman, Ritu Jain, Jaye Chin-Dusting, Karen Andrews, Naomi Court, Emmanuelle Fantino, Michelle Farrugia, Christopher J Burns
Journal: Circulation (2010)

Introduction: The JAK/STAT pathway has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). Hypothesis: This study tested the hypothesis that CYT387 (N-(cyanomethyl)-(4-...
Poor Risk Metastatic Renal Cell Carcinoma (Mrcc) Patients are not a Homogeneous Group: a New Stratificating Model in the Era of Targeted Therapy
Authors: F.M. Guida, M. Santoni, U. De Giorgi, M. De Tursi, G. Procopio, S. Pignata, L. Galli, G. Di Lorenzo, G. Badalamenti, A. Felici, P. Marchetti, R. Iacovelli, F. Longo, M. Maruzzo, F. Massari, C. Suarez, M. Aieta, S. Cascinu, M. Milella, D. Santini
Journal: Annals of Oncology (2014)
Primary chemotherapy of brain metastasis in small-cell lung cancer.
Authors: J S Lee, W K Murphy, B S Glisson, H M Dhingra, P Y Holoye, W K Hong
Journal: Journal of Clinical Oncology (1989)

Fourteen patients with brain metastases from previously untreated small-cell lung cancer (SCLC) were treated with three courses of systemic chemotherapy as an initial mode of treatment. Whole brain irradiation was given concurrently with the fourth course of chemotherapy. The chemotherapy consisted of cyclophosphamide, 600 mg/m2 intravenously (IV) on day 1; doxorubicin, 50 mg/m2 IV on day 1; vincristine, 1.5 mg IV days 1 and 5; and etoposide, 60 mg/m2 IV days 3 through 5; all repeated every 3 weeks with dosage adjustments. There were ten men and four women, with a median age of 59 years (range, 47 to 75). Six patients had multiple brain lesions, and the brain was the sole site of distant metastasis in four patients. Three patients were inevaluable for response in the brain, as two died early and the third dropped out of the trial too soon. Brain lesions responded to chemotherapy in nine (one complete remission [CR], eight partial remissions [PR]) of 11 (82%) evaluable patients, and objective responses in the extracranial lesions were documented in nine (one CR, eight PR) of 12 (75%) evaluable patients. Median survival was 34 weeks (range, 1 to 93), and two patients are still alive. Toxicity was significant, with severe granulocytopenia (less than 500/microL) and thrombocytopenia (less than 50,000/microL) observed in 85% and 15% of patients, respectively. Six patients had major infectious complications, which resulted in septic deaths in two. However, there was no deterioration of neurologic status during the initial phase of treatment with chemotherapy. We conclude that systemic chemotherapy alone can induce objective regression of metastatic brain lesions in patients with previously untreated SCLC.
Response to tositumamab and 131 I-tositumomab in follicular lymphoma based on the Follicular Lymphoma International Prognostic Index (FLIPI)
Authors: S. E. Pal, E. S. Winer, B. Higgins, A. Dungy, F. Foss
Journal: Journal of Clinical Oncology (2005)

6629 Background: Bexxar (tositumamab and 131 I-tositumomab) demonstrated efficacy in treatment of relapsed follicular lymphoma. Prior analyses showed that predictive factors of durable response have not been elucidated. Solal-Celigny et al. recently validated a novel prognostic scoring system, the Follicular Lymphoma International Prognostic Index (FLIPI), as a predictor of outcome and survival in patients with follicular lymphoma. We applied the FLIPI score to our series of patients treated with Bexxar to determine whether FLIPI was predictive of response or survival. Methods: From April 1999 to November 2001, 24 follicular lymphoma patients were treated on the Bexxar Expanded Access Study at Tufts New England Medical Center. Patients were dosed with 450 mg of tositumomab and a total body exposure of 75 cGy with 131-I tositumomab. Response and survival were determined by the Kaplan-Maier method and results compared by the log rank methods. Results: Twenty-four patients were enrolled. The median prior therapies were 3. The overall response was 75%, with 61% of responders achieving CR. Median progression free survival (PFS) of responders was 22.6 months, compared to 4 months with their last therapy; 17 responders had a remission inversion. Median overall survival was not reached at 44 months in the responders and was 23 months in non-responders (p=0.001). Twenty patients eventually relapsed and 14 deaths occurred during the study period. Ten patients had a high FLIPI score, 9 had intermediate FLIPI score and 4 had a low FLIPI score. One patient was could not be assessed. The patients with high FLIPI scores had an inferior survival (19.8 months) compared to those with intermediate scores (42+ months). Median response duration was lower (11.5 months) in the high risk group compared to the intermediate risk group (38.9 mo, p < 0.003). The response duration in the low FLIPI group (n=4) was 51 months. Conclusions: Our results demonstrate that the FLIPI score is strongly predictive of response. In patients with a high FLIPI, the remission inversion and the response duration of 11.5 months after Bexaar may be meaningful given that the overall survival in this population was 5 years. No significant financial relationships to disclose.
Phase I trial of fenretinide (4-HPR) intravenous emulsion for hematologic malignancies
Authors: A. Mohrbacher, M. Gutierrez, A. J. Murgo, S. Kummar, C. P. Reynolds, B. J. Maurer, S. Groshen, L. Vergara, A. S. Yang
Journal: Journal of Clinical Oncology (2007)

13007 Background: 4-HPR is a retinoid cytotoxic for cancer cell lines. In clinical trials, oral capsule 4-HPR had limited bioavailability and activity. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase bioavailability. The objectives of this phase I trial were to determine a maximally tolerated dose (MTD) of ILE 4-HPR, and to assess toxicities, pharmacokinetics (PK), and preliminary response data. Methods: We used an accelerated titration Simon design 2 dose escalation schema with 100% increase in ILE 4-HPR per dose level tested until moderate toxicity was observed in 2 patients or DLT in one. Ten dose levels were planned with a starting dose of 80 mg/m2/day (continuous i.v. x 5 days q 3 weekly), increasing until Dose level 10 at 1,810 mg/m2. A De-escalation to 1,240 mg/m2/day Dose level 9 was added when DLT was observed in 2 patients at 1,810 mg/m2 dose level 10. Results: To date, 11 patients have been enrolled. At dose level 10 (1,810 mg/m2/day), 2 pts experienced a DLT of grade IV hypertriglyceridemia with grade 2 pancreatitis. A de-escalation to dose level 9 (1,280 mg/m2/day) has enrolled 4 pts, 1 had grade IV hypertriglyceridemia; enrollment is ongoing. We observed a transient response in a patient with NHL at 320 mg/m2 and a continued partial response in one patient with NHL on dose level 10 (1,810 mg/m2). PK showed a linear relationship of dose to plasma level, with steady-state levels of 54 μM (1,280 mg/m2)and 62 μM (1,810 mg/m2). Conclusions: ILE 4-HPR was given via continuous infusion to a dose of 1,810 mg/m2/day x 5 days. 1 patient with NHL had a transient partial response and a second patient with chemotherapy-refractory NHL had a partial response sustained on treatment for &gt; 6 months. The DLT of hypertriglyceridemia is likely related to the intralipids delivered. Enrollment continues at a dose of 1,280 mg/m2/day. ILE 4- HPR can be safely administered and obtained plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR, with clinical activity in hematologic malignancies. No significant financial relationships to disclose.