tbuckley/cabot-search huggingface dataset:
Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer
Authors: Valeria Santoro, Ruochen Jia, Hannah Thompson, Anke Nijhuis, Rosemary Jeffery, Konstantinos Kiakos, Andrew R. Silver, John A. Hartley, Daniel Hochhauser
Journal: JNCI Journal of the National Cancer Institute (2015)

The antibody cetuximab, targeting epidermal growth factor receptor (EGFR), is used to treat metastatic colorectal cancer (mCRC). Clinical trials suggest reduced benefit from the combination of cetuximab with oxaliplatin. The aim of this study was to investigate potential negative interactions between cetuximab and oxaliplatin. Thiazolyl blue tetrazolium bromide (MTT) assay and Calcusyn software were used to characterize drug interactions. Reactive oxygen species (ROS) were measured by flow cytometry and real-time polymerase chain reaction oxidative stress arrays identified genes regulating ROS production. Chromatin immunoprecipitation (ChIP) measured signal transducer and activator of transcription 1 (STAT-1) binding to dual oxidase 2 (DUOX2) promoter. SW48, DLD-1 KRAS wild-type cell lines and DLD-1 xenograft models exposed to cetuximab, oxaliplatin, or oxaliplatin + cetuximab (control [saline]; n = 3 mice per treatment group) were used. Statistical tests were two-sided. Cetuximab and oxaliplatin exhibited antagonistic effects on cellular proliferation and apoptosis (caspase 3/7 activity reduced by 1.4-fold, 95% confidence interval [CI] = 0.78 to 2.11, P = .003) as opposed to synergistic effects observed with the irinotecan metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38). Although both oxaliplatin and SN-38 produced ROS, only oxaliplatin-mediated apoptosis was ROS dependent. Production of ROS by oxaliplatin was secondary to STAT1-mediated transcriptional upregulation of DUOX2 (3.1-fold, 95% CI = 1.75 to 2.41, P < .001). Inhibition of DUOX2 induction and p38 activation by cetuximab reduced oxaliplatin cytotoxicity. Inhibition of STAT1 and DUOX2-mediated ROS generation by cetuximab impairs p38-dependent apoptosis by oxaliplatin in preclinical models and may contribute to reduced efficacy in clinical settings. Understanding the rationale for unexpected trial results will inform improved rationales for combining EGFR inhibitors with chemotherapeutic agents in future therapeutic use.
Abstract 15775: Cyclosporin-a Mediated Inhibition of Nrf2 Nuclear Localization and Reduction in Superoxide Activity is Rescued by Tert-Butylhydroquinone in Human Coronary Artery Endothelial Cells
Authors: Arash Ghashghai, Andrzej Chruscinski, Amelia Mociornita, Liza Grosman-Rrimon, Carolina Alba, Spencer Lalonde, Laura Tumiati, Vivek Rao
Journal: Circulation (2012)
Prognostic nonimplication of glutathione S-transferase polymorphisms in breast cancer: Meta-analysis of ghosts and lessons to be learned.
Authors: A. Valachis, D. Mauri, N. P. Polyzos, C. Neophytou, C. Lythras, N. A. Patsopoulos
Journal: Journal of Clinical Oncology (2010)

e13667 Background: Glutathione S-transferases (GSTs) enzymes catalyse the conjugation of glutathione to many substrates including chemotherapeutic agents. However, 3 polymorphisms in GSTP1, GSTT1, and GSTM1 genes decrease GST enzyme activity. It has been hypothesized that the presence of these polymorphisms may influence cancer patients survival. The strength of this association is unclear and studies present contradictory results. Aim: To review literature of GSTM1, GSTT1, and GSTP1 polymorphisms in breast cancer survival, and perform meta-analysis wherever applicable. Methods: We searched MEDLINE and ISI (September 2009) for studies evaluating the associations of GSTM1, GSTT1, GSTP1 polymorphisms and breast cancer survival. From each study we extracted Hazard Ratio (HR) and all necessary data to impute it. We meta-analysed HRs and standard errors assuming random effects model. Results: Search strategy yielded 523 studies, 10 fulfilled inclusion criteria. Included studies had heterogeneous clinical settings (type and duration of treatment, stage of breast cancer), number of covariates and median follow up periods. Meta-analysis: Overall Survival summary HR were 0.74 (95%CI:0.58–0.93) for presence of GSTM1 allele, 0.93 (95%CI:0.58–1.51) for GSTT1 allele; 1.06 (95%CI: 0.88–1.27) for Ile/Val, and 0.87 (95%CI:0.52–1.45) for Val/Val carriers of GSTP1 polymorphism. Statistical heterogeneity was evident in almost all polymorphisms [GSTM1=24% (95% CI:0-68%), GSTT1=39% (95% CI:0-78%), GSTP1 Ile/Val=0% (95% CI:0–75%), GSTP1 Val/Val=52%(95%-CI: 0–82%)]. Conclusions: Although the research question of the role of GST polymorphisms in breast cancer survival has been around for many years, the methodological and clinical heterogeneity of respective literature is limiting factor. Many studies reported insufficiently their results and/or had methodological caveats. Respective literature is heterogeneous and many time of questionable value, even for studies published in high impact factor journals. Thereafter, despite survival differences could be shown for the presence of GSTM1 allele, reliable conclusions cannot be based on current evidence. No significant financial relationships to disclose.
Radiomodifying responses of vitamin E and epigallocatechin gallate supplementation during irradiation of implanted tumors
Authors: B. D. Lawenda, D. E. H. Smith, A. Niemierko, L. Xu, J. R. Silverstein, K. D. Held, J. S. Loeffler, R. K. Jain, J. B. Blumberg
Journal: Journal of Clinical Oncology (2004)

9601 Background: Dietary antioxidants may play an antagonistic role during radiation treatment (RT). Antioxidants such as vitamins C and E show radioprotective effects on normal cells in vitro but limited evidence in this regard is available in healthy tissue or tumor cells in vivo. Methods: Syngeneic, murine breast carcinoma (MCa-4) cells were implanted in hind legs of C3H mice. Vitamin E (VE) or epigallocatechin gallate (EGCG, derived from green tea extract) were fed at 500 and 658 mg/kg diet, respectively, for 4 wk until tumors reached 8 mm. Three tumor control dose 50 (TCD50) assays (N=48 mice/assay) were performed to quantify the radiomodifying effect of the antioxidants. Tumor growth data were collected prior to and after RT. Tissue concentrations of VE and EGCG were analyzed by HPLC. Tissue reactions were recorded for 90 d following RT. Angiogenesis specific gene arrays were used to analyze expression in tumor and cultured tumor cells. Results: A 4% increase in TCD50 was observed in mice fed either VE or EGCG supplemented diets relative to the control diet, though these changes were not statistically significant (P=0.30 and 0.20, respectively). The gamma-50 (slope) was 6.2 for control and 3.5 for both experimental arms (P=0.20). Prior to RT, tumor growth was 10% slower in the EGCG group compared to controls (P=0.002). VE concentration in the tumor was twice that of surrounding muscle (382 vs. 189 pmole/mg) but only slightly (4%) slowed tumor growth (P=0.24) prior to RT. There were fewer RT-related soft-tissue reactions (loss of irradiated limb below the tumor) in the EGCG (9.8%) and VE (7.1%) groups compared to control (23.8%) at P=0.09 and 0.04, respectively. EGCG increased VEGF and MMP gene expression in stromal tissue but decreased it in the tumor. Conclusions: TCD50 and gamma-50 were modestly increased in mice fed diets supplemented with VE or EGCG, but these changes were not statistically significant. EGCG significantly inhibited tumor growth rate. Adverse RT-related soft tissue reactions occurred less frequently with antioxidant supplementation, particularly with VE. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Harvard Medical School/Osher Institute; Goldman Philanthropic Partnerships
Improved outcomes in advanced stage uterine carcinosarcoma (mixed mullerian tumor [MMT])
Authors: D. M. O'Malley, C. Nagel, L. A. Cantrell, L. Havrilesky, M. Liotta, A. Alvarez Secord, A. Nickles, D. E. Cohn, A. Wallace, P. Rose, P. Gehrig
Journal: Journal of Clinical Oncology (2009)

5518 Background: There is currently no consensus regarding the management of advanced stage uterine MMT. In an effort to better define postoperative treatment modalities and their associated outcomes, we retrospectively reviewed factors that influence progression and survival. Methods: A retrospective, multi-institution study of women diagnosed from 1997–2007 was performed. Post-operative treatment included either observation (OBS), RT (brachytherapy, whole pelvic, or combination), chemotherapy (CT) alone or with RT (CT+RT). The majority of chemotherapy regimens included carboplatinum/paclitaxel, Ifosfamide/cisplatin, cisplatin/adriamycin, Data collected included time to recurrence, overall survival and sites of recurrence. Statistics included t-test, ANOVA and Kaplan Meier. Results: 119 patients were identified with late stage uterine MMT. 81 had stage III disease and 38 had stage IV disease. The median age at diagnosis was 67 years (range: 30–86). 70 (59%) were Caucasian and 48 (40%) were African-American. 116 (87%) were optimally debulked and their survival further analyzed. 18 (15%) were observed and 9 of these patients recurred. This group had the poorest median progression free survival (PFS) of 3.4 months. The majority (N = 50, 49%) of late stage patients underwent adjuvant CT with a median PFS of 13.3 months and median OS of 15.6 months. Of these patients 33 (66%) recurred. 18 (17 %) patients underwent RT alone with a median PFS of 12.4 months and OS of 14.9 months. 14 (78%) of these patients recurred. 20 patients (19%) underwent a combination of CT and RT and 11 (55%) experienced recurrences . The combination therapy group had the longest median PFS of 14.3 months and OS of 17.2 months (p = 0.27). Conclusions: Chemotherapy had become the standard therapy for advanced stage MMT however the addition of radiation has not been established. Patients diagnosed with advanced stage MMT can achieve long-term DFS in a minority of patients (33%) treated with chemotherapy. We showed that the addition of radiation to adjuvant chemotherapy showed a slight improvement over chemotherapy alone yet the optimal therapy has yet to be defined. This retrospective review highlights the need for prospective trials of new therapeutic agents and treatment regimens for women with advanced stage uterine MMT. No significant financial relationships to disclose.
Characeteristics and outcome of neonates with a healthcare-associated bloodstream infection in a NICU over a 10-year period (2002-2011)
Authors: Evelien Verstraete, Geert Claeys, Isabel Leroux-Roels, Dirk Vogelaers, Piet Vanhaesebrouck, Stijn Blot
Journal: Intensive Care Medicine (2013)
Cell Lines Derived from Human Ovarian Carcinomas: Growth Stimulation by Gonadotropic and Steroid Hormones&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: W E Simon, M Albrecht, M Hänsel, M Dietel, F Hölzel
Journal: JNCI Journal of the National Cancer Institute (1983)

Carcinoma cell lines established from 5 patients with advanced tumors of ovarian location were characterized by karyotypes and growth properties in serum-free medium. In early passages of the cultivation, the growth of cell lines derived from tumors of fairly differentiated histology was stimulated by human follicle-stimulating hormone or human chorionic gonadotropin-human luteinizing hormone. Cells obtained from poorly differentiated carcinomas were unresponsive to gonadotropins. The proliferation of cell lines derived from a malignant clear cell carcinoma and from the ovarian metastasis of an advanced mammary carcinoma was enhanced by cortisol. The results imply that hormonal factors in concentrations physiologically occurring in human serum may support the in vivo growth of ovarian tumors.
Polycomb-mediated chromatin compaction weathers the STORM
Authors: Iain Williamson, Wendy A. Bickmore, Robert S. Illingworth
Journal: Genome biology (2016)

A recent super-resolution imaging study by Boettiger et al. elegantly demonstrates that three epigenetically defined, and functionally disparate, chromatin states have distinct folding characteristics in Drosophila nuclei.
Emerging roles of Nrf2 signal in non-small cell lung cancer
Authors: Yijun Tian, Qian Liu, Xuelian He, Xun Yuan, Yuan Chen, Qian Chu, Kongming Wu
Journal: Journal of Hematology & Oncology (2016)

Non-small cell lung cancer (NSCLC) causes considerable mortality in the world. Owing to molecular biological progress, treatments in adenocarcinoma have evolved revolutionarily while those in squamous lung cancer remain unsatisfied. Recent studies revealed high-frequency alteration of Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-like factor 2 (Keap1/Nrf2) pathway within squamous lung cancer, attracting researchers to focus on this particular pathway. In NSCLC patients, deregulated Nrf2 signal is recognized as a common feature at both DNA and protein level. Emerging associations between Nrf2 and other pathways have been elucidated. MicroRNA was also implicated in the regulation of Nrf2. Agents activating or antagonizing Nrf2 showed an effect in preclinical researches, reflecting different effects of Nrf2 during tumor initiation and progression. Prognostic evaluation demonstrated a negative impact of Nrf2 signal on NSCLC patients' survival. Considering the importance of Nrf2 signal in NSCLC, further studies are required in the future.
How different are epidemiology and treatment of cancer persistent pain (PP) and breakthrough pain (BTP) in elderly patients (pts)? Results of a French prospective survey
Authors: M. Di Palma, R. Duclos, C. Tessier
Journal: Journal of Clinical Oncology (2007)

19520 Background: Efforts have been made in the recent years to improve pain care in cancer pts, especially for elderly ones Methods: We conducted a national survey in France in order to evaluate the actual situation. Data were collected from 100 cancer centers and analyzed using SAS software. Only adult pts treated for cancer pain, with their treatment initiated less than 8 days before study, were considered. Comparisons were made considering pts under and over 70 years old Results: Epidemiology: 793 pts were included, 565 being under 70 years old (mean 54), 228 over 70 years old (mean 76). There were more men in the elder group (67% vs 54%, this being explained by some differences in tumor type (more prostate cancer). Proportion of metastatic pts was not different (78 vs 79%) but metastatic sites were not the same, especially bone mets (70 vs 55%). Fewer pts were currently treated with chemo or radiotherapy in the elder group. Median WHO performance status was worse in elderly pts (3 vs 2). Characteristics of pain: Of note, characteristics of PP and BTP (pain location, nociceptive or neuropathic pain, intensity for PP and BTP, number of BTP episodes) were not different between the 2 groups. Pain treatment: Almost all the pts received opioids in both groups for PP and BTP, while elder pts were treated less frequently with specific drugs for neuropathic pain (antidepressant and anti-epileptic), and psychological support was less likely offered to them (36 vs 48%) Conclusions: Characteristics of PP and BTP in cancer pts are not influenced by pts age. Progresses have been made as elder pts receive opioids as often as younger ones, but improvements are still needed concerning the treatment of neuropathic pain and psychological support in elderly pts. No significant financial relationships to disclose.
E1201: An Eastern Cooperative Oncology Group (ECOG) randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/RT or irinotecan/cisplatin/RT in endoscopy with ultrasound (EUS) staged adenocarcinoma of the esophagus
Authors: L. Kleinberg, M. E. Powell, A. Forastiere, S. Keller, P. Anne, A. B. Benson
Journal: Journal of Clinical Oncology (2007)

4533 Background: E1201 included operable esophageal adenocarcinoma, staged II-IVa by EUS. Endpoints were pathologic complete response (pCR), toxicity, and tolerability of these two experimental regimens. pCR was used as a surrogate endpoint. As previously reported, the pCr rates indicated that these regimens did not meet criteria for further study based on a target of 45% against the null hypothesis of 25% for standard therapy. This report contains details of toxicity, tolerability of adjuvant chemotherapy, and prognostic value of EUS staging. Materials/Methods: 90 eligible pts enrolled. Arm A was Cisplatin (C) 30mg/m 2 and Irinotecan (I) 50 mg/m 2 on days (d) 1,8,22,29 of 45 Gy RT/5 weeks. Post-op therapy was C 30 mg/m 2 and I 65 mg/m 2 d 1, 8 q21 days x 3. Arm B therapy was C 30 mg/m 2 and Paclitaxel (P) 50 mg/m 2 1 hour infusion d 1,8,15, 22, 29 with RT. Postoperative therapy was C 75 mg/m 2 and P 175 mg/m 2 day 1 q21 days x 3. Results: Of all eligible patients, 83% (38/46) and 70% (31/44) had a complete resection with negative margins and 6/46 (15%) (95% CI = 5%, 26%) and 7/44 (16%) (95% CI = 7%, 30%) had pCR on arm A and B respectively. Confirmed EUS staging was available for 71 pts, Path CR rate was 3/19(16%) for stage T 2- 3 N 0 M 0 and 7/52(14%) for stages T 1–3 N 1 M 0 or T 1–3 N 0- 1 M 1a . The incidence of ≥ grade 3 hematology toxicity, dysphagia, and diarrhea during neoadjuvant therapy were 20 (43%), 6 (13%), 4 (9%) for arm A (n TOX =47) and 18 (39%), 9 (20%), and 1 (23%) for arm B (n TOX =46). Zero, one, two and three cycles of adjuvant chemotherapy were received by 26%, 20 %, 5% and 49% of operated patients in arm A (n=41) and 36%, 14%, 3%, and 47% in arm B (n=36). Two of 77 (3%) operated patients died within 30 days of surgery. Conclusions: The low pCR rates suggest that neither regimen is likely to advance treatment of esophageal/GEJ adenoca over preoperative cisplatin/5-FU/RT and therefore do not warrent pursuing. EUS stage did not appear to influence response rate with these regimens. Moreover, these regimens are associated with significant toxicity and, as with other regimens, only a minority of patients were able to receive the planned adjuvant therapy. Survival follow-up continues. No significant financial relationships to disclose.
Effect of genetic polymorphisms on toxicity and survival in advanced non-small cell lung cancer (NSCLC) patients (pts) treated with carboplatin (CBDCA) and pemetrexed disodium regimen
Authors: V. Ludovini, L. Crinò, L. Pistola, I. Floriani, M. Meacci, R. Chiari, D. Garavaglia, F. R. Tofanetti, M. Mare, D. Giuffrida, S. Gori
Journal: Journal of Clinical Oncology (2009)

e19028 Background: Identification of genetic polymorphisms which influence chemotherapy outcome may help towards individually optimized therapy. We investigated the influence of ten single nucleotide polymorphisms (SNPs) of 7 genes (P53 Arg72Pro (G/C); XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); ERCC1 Asn118Asn (C/T); GARFT C/G, GARFT C/T, DHFR C/G, DHFR A/G, TS 5’UTR, TS 3’UTR involved with metabolism of CBDCA and Alimta regimen in pts with advanced NSCLC. Methods: Genomic DNA was extracted from whole blood samples using the QIAamp DNA estraction kit on Biorobot EZ1 (Qiagen). Polymorphisms were detected with TaqMan-probe based assays using the 7300 Real-Time PCR system (Applied Biosystems, Foster City, CA) or PCR followed by RFLP. The results of SNPs were assessed by Cox model for survival/PFS &amp; logistics regression for response/toxicity. Results: We performed a retrospective analysis in 57 advanced pretreated (2 nd or 3 th line) NSCLC pts treated with CBDCA(AUC=5) + Alimta (500 mg/m 2 ). Median age was 59 years (range 26–79), M/F:63/37%; Adeno/Squa/other Ca:65/20/15%; ECOG PS:0–1/2–3:96/4%. Overall response rate was 38.6%, stable disease 38.6% and disease progression 21.1%. At median follow-up of 7.9 months, 10 pts (17.5%) died, 47 pts (82.5%) are alive. The median progression free survival (PFS) was 7.4 months, the median survival time not reached. P53 Pro72Pro was significantly associated with shorter survival (HR 5.5, 95%CI 1.01–30.5, p=0.04) when compared to P53 Arg72Arg. None of the analyzed polymorphisms was related to response to therapy. No associations were found between the analyzed polymorphisms and toxicity considered either as the maximum observed grade, or as sum of each toxicity pattern grade, probably due to low number of events observed for toxicity within this data set. Conclusions: P53 Pro72Pro may be associated with shorter survival in pts with advanced NSCLC. Further studies are warranted to validate this finding. Genotype-related differences in common toxicities and in response to therapy were not observed. The small sample size limits interpretation of these data. No significant financial relationships to disclose.
Specific Cytotoxicity In Vitro by T-Cell-Enriched Lymphocyte Subpopulations From Rats Bearing Chemically Induced But Not Spontaneous Tumors2
Authors: Margot Zöller, Siegfried Matzku
Journal: JNCI Journal of the National Cancer Institute (1980)

Effector cells from inbred BD X and WAB rats bearing either spontaneously arising or chemically induced tumors were cytotoxic for target cells of both kinds of tumor. The level of cytotoxicity of tumor-bearing animals regularly surmounted that of natural cytotoxicity observed in age-matched untreated controls. These findings were obtained by a visual-countin microcytotoxicity assay (48 hr) and by a 51Cr label assay (12 hr). Cytotoxicity by tumor-bearing rat effectors was directed against the homologous tumor target cell line, different tumor cells of the same inbred rat strain, tumor cells derived from allogeneic rats, and fetal fibroblasts, but not against adult fibroblasts. Separation of lymphocytes by rosetting with sheep red blood cells (SRBC) loaded with either antiimmunoglobulin or anti-SRBC or with anti-SRBC and complement revealed that cross-reactive cytotoxiciy was confined to a non-T effector cell population, which was observed with lymphocytes from rats bearing either chemically induced or spontaneous tumors. Cytotoxicity directed exclusively against the tumor of the lymphocyte donors was exerted by the T-cell-enriched fraction. This element was completely absent in lymphocytes from animals bearing spontaneous tumors, but it was detected in lymphocytes from donors with chemically induced (immunogenic) tumors.
Immune and inflammatory responses in induced sputum (IS) in Anderson Fabry disease (AFD), COPD and healthy volunteers
Authors: Nadia Shafi, Derralynn Hughes, Atul Mehta, Colette Smith, Marc Lipman
Journal: European Respiratory Journal (2011)

AFD is an X-linked lysosomal storage disorder caused by mutations of the GLA gene. Reduced enzyme results in accumulation of storage material, leading to multi-organ pathology including airflow obstruction. Given the association between intra-cellular lipid and disease, we hypothesised subjects with pulmonary AFD would have detectable changes in airway immune/inflammatory cell profiles.

Methods: AFD and COPD subjects matched for GOLD stage plus healthy age/sex matched volunteers underwent lung function testing and sputum induction.

IS cells were stained with combinations of CD3, CD4, CD8, CD16 & CD56 antibodies and examined using flow cytometry for T cell populations including NKT cells, thought to be relevant to AFD immuno-pathology.

Results: 46% of AFD patients had evidence of airflow obstruction (AO+).The% of total T cells in IS in AFD AO+ was greater than AFD AO- (p<0.01), and similar to COPD patients. AFD AO- had lower T cell% than seen in COPD (p<0.01). Other T cell populations including NKT cells were similar between groups.

View this table:

T cell populations from IS





Conclusion: Sputum T cell profiles in AFD and airways obstruction are similar to those of COPD whilst AFD AO- are more like healthy volunteers. This suggests a role for T cells in AFD lung disease.