tbuckley/cabot-search huggingface dataset:
Combination effects of resveratrol and 5-fluorouracil on human colon cancer cells
Authors: Jason Chan, Ronald Phoo, Shazib Pervaiz, Shao Chin Lee
Journal: Clinical Cancer Research (2007)

A14  We have recently reported that resveratrol (RSV) evokes apoptosis of colon cancer cells even in the absence of p53. In the present study, we demonstrated that 5-fluorouracil (5-FU) similarly elicited apoptosis in the colon cancer cells, although significantly abrogated in the absence of p53. We proceeded to evaluate the combination effect of RSV and 5-FU by calculating combination indices (CI). Combination of higher dose RSV (200 µM) with 5-FU produced synergistic effects on the cancer cells, independent of p53 status (p53+/+: CI(IC50) = 0.715 and CI(IC70) = 0.768; p53-/-: CI(IC50) = 0.67 and CI(IC70) = 0.719). Notably, RSV (200 µM) significantly enhanced sensitivity to 5-FU by 7.9 and 4.5 folds over IC50 in p53+/+ and p53-/- cells, respectively. In contrast, antagonistic interactions were observed for lower dose RSV (25 or 50 µM) in combination with 5-FU, depending on the p53 status and effect levels. The p53+/+ cell sensitivity to 5-FU was decreased by approximately 10-25% in the presence of lower dose RSV. The interactions of 5-FU with RSV (25 or 50µM) in p53+/+ cells were antagonistic at lower effect levels but were additive at higher effect levels (CI(IC50) = 1.16 and CI(IC70) = 1.04). The former observation was also made with 5-FU and RSV (50 µM) in p53-/- cells, as the interaction of 5-FU with RSV (50 µM) in combination progressively changed from antagonism to synergism with increasing effect levels. The effects of RSV on 5-FU-evoked apoptosis were associated with alterations in cell cycle profiles. Specifically, co-exposure to lower dose RSV and 5-FU resulted in G1-arrest in p53+/+ cells, which was not observed with either agent alone. In conclusion, RSV exhibited converse effects on 5-FU-induced apoptosis, depending on the dose combination in addition to p53 status. These results would facilitate the pharmacological development of RSV as a chemotherapeutic agent in 5-FU-based combination chemotherapy in colon cancer.
Comparison of BEAMing assays and competitive approaches in the detection of main alteration of RAS in circulating DNA of non small-cell lung cancer (NSCLC) and metastatic colon cancer. Manuscript 2016.
Authors: Jessica Garcia, Julien Forestier, Eric Dusserre, Claire Rodriguez-Lafrasse, Valérie Cheynet, Anne-Sophie Wozny, Carole Ferraro Peyret, Karen Brengel-Pesce, Marielle Guillet, Marion Chauvenet, Marie Brevet, Sebastien Couraud, Thomas Walter, Lea Francoise Payen
Journal: Journal of Clinical Oncology (2017)

e23056 Background: A number of RAS mutations confer resistance to anti-EGFR therapies routinely used in the treatment of colon cancer. The objective of this study was to evaluate the pertinence of analyzing circulating-free plasma DNA (cfDNA) as an indicator of the mutational status of a tumor, in order to use liquid biopsies instead of invasive and painful tumor biopsies during tumor progression. Methods: A cohort of 24 lung and 25 colon cancer patients was constituted in the Hospices Civils of Lyon. Liquid biopsy plasma samples were collected at diagnosis (colon cancer) and during tumor progression (lung cancer) for the purpose of the current study. KRAS and NRAS somatic alterations were quantified using three different technologies: the Droplet Digital polymerase chain reaction (ddPCR) from BioRad, the BEAMing Digital PCR from Sysmex Inostics, and the NGS NextSeq 500 by Illumina with the Accel-Amplicon 56G Oncology Panel from SWIFT BIOSCIENCES. Results: We observed a high level of sensitivity and specificity with the BEAMing technology, which provided us with excellent matches, around 96% and 73%, between solid and liquid biopsies taken at diagnosis (colon cancer) or during tumor progression (lung cancer), respectively. Indeed, when examining cfDNA from patients displaying one of the KRAS or NRAS mutations, 11 of the 13 mutations were confirmed using this technology, whereas only 5-6 matched the initial NGS status, using the two other technologies. The detection threshold was estimated at 1% for samples containing at least 0.8 ngctDNA/µL for the multiplex screening ddPCR from BioRad and for the 56G Oncology Panel from SWIFT BIOSCIENCES. The threshold was lower, at 0.03%, in samples containing only 0.25 ng ctDNA/µL for the BEAMing technology, which includes a PCR pre-amplification step. Conclusions: The advantage of the Illumina NGS technology is the larger coverage of longer gene regions, and thus the detection of more genetic mutations. Finally, the BEAMing technology enabled us to follow the appearance and disappearance of somatic alterations, with a very high level of sensitivity.
Clusters of Childhood Mixed Phenotype Acute Leukemia Diagnosed By Nation-Wide Immunophenotyping in Japan
Authors: Takao Deguchi, Nobutaka Kiyokawa, Kentaro Ohki, Yoshiko Hashii, Atsushi Manabe, Souichi Adachi, Akiko M. Saito, Keizo Horibe, Yoshihiro Komada
Journal: Blood (2016)
Changes in serum alkaline phosphatase levels to predict response to ixazomib-based therapy in patients with newly diagnosed multiple myeloma.
Authors: Nidhi Tandon, Martha Lacy, Francis Buadi, Nelson Leung, Ronald S. Go, David Dingli, Prashant Kapoor, Morie A. Gertz, Yi Lin, Angela Dispenzieri, Matthew Drake, Yi Lisa Hwa, Amie Fonder, Miriam Hobbs, Suzanne R. Hayman, Steven R. Zeldenrust, John Anthony Lust, Wilson I. Gonsalves, S.Vincent Rajkumar, Shaji Kumar
Journal: Journal of Clinical Oncology (2016)

8053 Background: Proteasome inhibitors (PI) decrease levels of Wnt pathway inhibitor dickkopf-1 to increase canonical Wnt signaling, resulting in increased osteoblast differentiation & increases in serum alkaline phosphatase (sALP) levels in multiple myeloma (MM) patients. However, it remains uncertain whether the rise in sALP is related to PI therapy or clinical myeloma response. We retrospectively analyzed data from 2 previous clinical trials to investigate the value of change in sALP to predict response to the PI Ixazomib (Ixa) in newly diagnosed MM (NDMM) patients. Methods: MC1382 (NCT01864018; phase I/II; 51 pts) & MC058E (NCT00478218; phase II; 53 pts) recruited adults with NDMM who had ECOG PS ≥2 & adequate hematological & organ function. Subjects received either Ixa (4 mg days 1, 8, 15) or Lenalidomide (Len; 25 mg days 1-21) with cyclophosphamide (400 mg/m2 with Ixa & 300 mg/m2 with Len;days 1, 8, 15 ) & dexamethasone (40 mg days 1, 8, 15, 22) (ICd & RCd respectively). Responses were evaluated according to International Myeloma Working Group (IMWG) response criteria. Levels of sALP were analyzed at baseline & after every cycle (C) until end of C4. Results: In the ICd group, median age was 66 yrs (41-90); 54.9 % were male & 45.1%/35.3%/15.7% were Revised International Staging System (RISS) I/II/III. In the RCd group, median age was 71 yrs (45-90); 54.7% were male & 26.4%/ 58.5%/9.4% were RISS I/II/III. Outcomes are shown in the Table. Using logistic regression analysis, the rise in sALP was significantly associated with ≥PR after C1 (p = 0.01) & C2 (p = 0.03) but not after C3 (p = 0.13) & C4 (p = 0.54) in the ICd group. However, no such association was seen in the RCd group (p = 0.44 after C1). Conclusions: The increase in sALP is a predictor of subsequent response in NDMM after Ixa therapy but not after Len therapy. The changes are most pertinent at the end of C1 & indicate a possible anabolic effect on bone metabolism specific to PI. ICd (n = 51) RCd (n = 53) Median Baseline sALP U/L 73 (26-163) 73 (35-303) Median sALP rise after C1 % 19.2 (-23.2 to 395.3) 18.6 (-63 to 119.4) C2 % -4.1 (-34.8 to 118.8) 6.3 (-68.3 to 79.2) C3 % -9.6 (-48.4 to 107.7) 0 (-69.6 to 260.9) C4 % -16.1 (-49.7 to 92.5) -10.6 (-73.9 to 64.1)
Predictors of Overall Survival (OS) in Patients with Multiple Myeloma (MM) Initiating First- and Second-Line Treatment in the Czech Republic
Authors: Roman Hájek, Jarkovsky Jiri, Bouwmeester Walter, Treur Maarten, DeCosta Lucy, Campioni Marco, Brozova Lucie, Gonzalez-McQuire Sebastian
Journal: Blood (2016)
Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer
Authors: Johanna Kondelin, Alexandra E. Gylfe, Sofie Lundgren, Tomas Tanskanen, Jiri Hamberg, Mervi Aavikko, Kimmo Palin, Heikki Ristolainen, Riku Katainen, Eevi Kaasinen, Minna Taipale, Jussi Taipale, Laura Renkonen-Sinisalo, Heikki Järvinen, Jan Böhm, Jukka-Pekka Mecklin, Pia Vahteristo, Sari Tuupanen, Lauri A. Aaltonen, Esa Pitkänen
Journal: Cancer Research (2017)

Abstract Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8. Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. Cancer Res; 77(15); 4078–88. ©2017 AACR.
A study of the pharmacokinetics of 5-FU when S-1 was administered orally as an adjuvant agent in gastric cancer patients
Authors: H. Matsumoto, T. Hirai, Y. Hirabayashi, H. Kubota, H. Murakami, M. Higashida, Y. Kawabe, A. Urakami, K. Yamashita, T. Tsunoda
Journal: Journal of Clinical Oncology (2007)

15024 Background: S-1 is an effective oral anti-cancer drug which is formulation of 5-FU, and it is widely used for gastric cancers in Japan. However, the compliance of S-1 treatment is not satisfactory due to its side effects. We hypothesized that the plasma concentration of 5-FU could be verified individually, because the drug is administered orally. Therefore, we investigated the pharmacokinetics of 5-FU when it was administered orally in the form of S-1. Methods: The plasma concentration of 5-FU after S-1 oral administration for adjuvant chemotherapy was measured in 22 advanced gastric cancer patients (Stage II or III). Total gastrectomy was performed in 12 patients and distal gastrectomy was performed in 10 patients. All patients were given S-1 (80mg/m2) orally at 8:00 and 20:00, daily. Blood samples were collected at 10:00, 12:00, 14:00 and 16:00 on the 7th day after S-1 administration and we measured 5-FU concentration of plasma. Results: Pharmacokinetic parameters of plasma concentration of 5-FU were as follows: C max , 157.92 ± 42.9 ng/ml; T max , 2.36 ± 0.79 h; T 1/2 , 2.90 ± 2.36 h; and AUC 0–8 ,731.8 ± 236.4 ng ·h/ml in all patients given the usual dosage. The plasma concentration of 5-FU was quite different between patients. The difference of C max and AUC was 3∼ 4 times. The AUC 0- 8 in the total gastrectomy patients (752.6± 273.3 ng·h/ml) was higher than that in distal gastrectomy patients (714.5±211.7 ng·h/ml), however this difference did not reach significance. Adverse events of more than grade 3 were observed in 7 patients. AUC 0–8 of 4 of 7 patients were more than 800 ng·h/ml and those of 2 other patients were more than 750 ng·h/ml. The patients with high AUC 0–8 levels had a tendency to show more severe adverse events. Conclusions: We conclude that physicians should pay close attention to individual differences in the plasma concentration of 5-FU in postoperative gastric cancer patients when this drug is given orally as S- 1. No significant financial relationships to disclose.
Male Gender Increases the Risk of Liver Fibrosis in Patients with Thalassemia Major Independent of Iron Overload
Authors: Murtadha K. Al-Khabori, Said Al Busaifi, Al Ghaliya Al Omairi, Moez Hassan, Humoud Al Dhuhli, Umaima Al Ajmi, Sarah Al Rahbi, Shahina Daar
Journal: Blood (2016)
Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis
Authors: Albanus O. Moguche, Munyaradzi Musvosvi, Adam Penn-Nicholson, Courtney R. Plumlee, Helen Mearns, Hennie Geldenhuys, Erica Smit, Deborah Abrahams, Virginie Rozot, One Dintwe, Søren T. Hoff, Ingrid Kromann, Morten Ruhwald, Peter Bang, Ryan P. Larson, Shahin Shafiani, Shuyi Ma, David R. Sherman, Alessandro Sette, Cecilia S. Lindestam Arlehamn, Denise M. McKinney, Holden Maecker, Willem A. Hanekom, Mark Hatherill, Peter Andersen, Thomas J. Scriba, Kevin B. Urdahl
Journal: Cell Host & Microbe (2017)
Second-line chemotherapy exposure in a German cancer society certified lung cancer center: Single-center experience of 4 years and relevance for maintenance therapy.
Authors: Frank Griesinger, Regina Prenzel, Volker Halbfass, Douglas Scriba, Anne Christina Lueers, Kay Willborn
Journal: Journal of Clinical Oncology (2014)

e19097 Background: One of the strongest rationale for maintenance therapy in NSCLC is the fact that exposure to 2nd line therapy is only 40-60% in clinical trials in specialized treatment centers. Even with follow-up intervals of 6 weeks, the 2nd line treatment rate does not seem to increase. We analyzed the exposure of patients with stage IV NSCLC in one German Cancer Society certified Lung Cancer Center since certification, as long term follow-up data are available. Methods: All primary lung cancer cases stage IV in the lung cancer center were analyzed based on the documentation files between 2009 and 2013. Patients were followed between 1st and 2nd line therapy every 6-8 weeks according to S3 guidelines. Results: 267 patients were diagnosed with NSCLC IV (UICC7), or had systemic relapse of localized disease and were treated with 1st line therapy for metastatic disease. Of these, 168 (63%) received 1st line combination therapy with Carboplatin, 57 (21%) with Cisplatin, 29 (11%) with TKI 1st line therapy (data of patients with mutations not further discussed here) and 13 (5%) with platin-free single agent therapy. 42 (16%) of all patients received maintenance therapy, most of them with bevacizumab. Of 228 patients, 188 (82%) progressed after 1st line therapy or 1st line and maintenance therapy. 105/156 (67%) of non-maintenance therapy patients received 2nd line therapy, 51 patients (32%) did not. Of 27 patients receiving maintenance therapy and requiring 2nd line therapy, 24 (89%) received 2nd line therapy. Survival analyses showed substantial differences regarding overall survival (median survival 25 (maintenance and 2nd line) vs. 14 (1st and 2nd line) months) but no relevant differences regarding progression free survival on 2nd line (median 2 months). Conclusions: In a certified lung cancer center and stringent follow-up every 6 to 8 weeks, 1/3 of patients do not receive 2nd line therapy. The application of maintenance therapy raised the chances of receiving 2nd line therapy and increased overall survival whereas progression free survival was not affected. These data suggest that maintenance therapy should be considered for patients after 1st line therapy.
Regulation of JNK kinase signaling modules by Rho activated kinase, ROCK1
Authors: Pat P. Ongusaha, Young-Bum Kim, Hank H. Qi, Roger Davis, Sam W. Lee
Journal: Cancer Research (2006)

4923  Vitis amurensis Rupr. (Vitaceae) has long been used in Chinese/Oriental herbal medicine for the treatment of cancer, but its active compounds and mechanisms of action have not been well studied. To this end, we isolated from its root heyneanol A (HA), which is a tetramer of resveratrol (RES), and aimed to establish the in vivo anti-tumor activity of HA using the Lewis Lung Carcinoma (LLC) model and the involvement of apoptotic and anti-angiogenic activities for such effect. Furthermore, we sought to elucidate the cellular and molecular processes that mediate the apoptosis and anti-angiogenesis effects using cell culture models. We used RES as a reference compound for comparison of the anti-tumor efficacy and mechanisms. To test the in vivo efficacy for inhibiting tumor growth, we administered HA and RES by daily i.p. injection to C57BL/6 mice that were subcutaneously inoculated with LLC cells. HA dose-dependently decreased tumor growth without any adverse effect on body weight and seemed more potent than RES. The tumor inhibitory effects were accompanied by a marked increase in tumor cell apoptosis as detected by cleaved caspase 3 and TUNEL assays and decreased tumor cell proliferation index and tumor microvessel density. These data support apoptosis and anti-angiogenesis as two key mechanisms for mediating the anti-tumor effects. Mechanistically, treatment of LLC cells in cell culture with HA or RES significantly increased apoptotic cells. Both HA and RES activated caspase 9 and 3, caused PARP cleavage, which were completely blocked by a pan caspase inhibitor, Z-VAD-FMK. In addition, HA and RES suppressed the bFGF-induced proliferation and differentiation of HUVECs without apparent cytotoxicity. Furthermore, HA and RES inhibited the binding of bFGF to its receptor in a concentration-dependent manner and HA and RES inhibited bFGF-induced vascularization of Matrigel plugs in vivo. Together, the results support HA as an active anti-cancer compound that induces caspase-mediated cancer cell apoptosis and inhibits tumor angiogenesis, rivaling the potency of its monomer, RES.
Rentabilité diagnostique et thérapeutique de l'entéroscopie à double ballon: résultats d'une série prospective de 100 patients
Authors: T Maniere, B Landi, V Pacault, B Boboc, M Simon, M Bensoussan, A de Leusse, JM Canard, F Bloch, R Jian, C Cellier
Journal: Endoscopy (2006)

L'entéroscopie double-ballon (EDB) est une technique récente d'exploration de l'intestin grêle. Nous rapportons notre expérience en termes de rentabilité diagnostique et thérapeutique et de morbidité chez les 100 premiers patients explorés dans notre centre.
Incidence and risk of hand foot skin reaction (HFSR) in patients receiving regorafenib for cancer: A meta-analysis.
Authors: Viswanath Reddy Belum, Shenhong Wu, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2013)

e14713 Background: Regorafenib (BAY 73-4506) is a potent oral multi-kinase inhibitor with targeted activity against (VEGFR) -1,-2, and -3, TIE-2, FGFR-1, PDGFR-α/β and ret, c-Kit, raf-1 kinases. Currently it is approved for treatment in previously treated patients with metastatic colorectal cancer (mCRC) and in locally advanced gastrointestinal stromal tumors (GIST), and is being explored in other cancers. We conducted a meta-analysis to ascertain the incidence and risk of HFSR, a commonly reported AE. Methods: Our search was performed on electronic databases (PubMed, Scopus, Web of Knowledge) and the ASCO website for presented abstracts. We searched for studies published until December 2012. Eligible Phase II-III clinical trials utilizing a 160mg dose of Regorafenib were included in the analysis. Relative risk (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: In these trials, regorafenib was investigated in mCRC, gastrointestinal stromal tumor (GIST), and renal cell carcinoma (RCC). A total of 1,078 patients were analyzed. The overall incidence of all-grade and high-grade HFSR was 60.5% (95% CI: 48.3–71.6%) and 20.4% (95% CI: 15.4–26.6%), respectively. The relative risks of all-grade and high-grade HFSR to regorafenib monotherapy in comparison with controls were increased for all-grade (RR=5.40, 95% CI: 3.76-7.76, p&lt;0.001) and high-grade (RR=41.99, 95% CI: 5.88–299.93, p&lt;0.001) HFSR. The incidence of the HFSR based on tumor type was 62.9% (95% CI: 46.9–76.5%) for mCRC, 69.5% (95% CI: 29.7–92.5%) for GIST and 46.6% (95% CI: 42.3–51.0%) for RCC, which was not very significant (p=0.08) suggesting that tumor type does not seem to influence the incidence of HFSR in patients treated with regorafenib. Conclusions: The incidence and risk of developing HFSR is highest with regorafenib, when compared to other multikinase inhibitors (e.g. sorafenib, sunitinib, pazopanib, axitinib). This toxicity warrants further investigation and evidence-based management strategies, in order to ensure adherence and most favorable clinical outcome.
Myeloid deprived suppressor cell to mediate the prognostic value of neutrophil for advanced hepatocellular carcinoma patients.
Authors: Xing Li, Ai-Hua Lei, Yan-Fang Xing, Zhi-Huan Lin, Ying-fen Hong, Qiang Xiao, Min Dong, Qu Lin, Xiang-yuan Wu, Jie Zhou
Journal: Journal of Clinical Oncology (2016)

e15597 Background: Myeloid Deprived Suppressor Cell (MDSC) has been raised to be a novel target for multiple cancers. However, target agents on MDSC has not displayed promising efficacy. One of the critical reasons shall be less optimal patient selection. In the present study, we aimed to identify optimal advanced hepatocellular carcinoma (aHCC) patients for MDSC targeted therapy. Methods: In the present study, a series of 55 aHCC patients and 20 healthy donors were analyzed investigating frequencies of both monocytic MDSC (M-MDSC; defined as HLA-DRnegCD14posCD33posCD11bpos) and G-MDSC (defined as HLADRnegCD14negCD33posCD11bposCD15pos) in peripheral blood mononuclear cells (PBMC). Then, the association between MDSC and routing blood cell counts were analyzed to identify the possible predictors of MDSC level. Then, the prognostic value of the predictors was determined in retrospective database of 255 aHCC patients. Results: As a result, we found that G-MDSC level (median 5.55%, range 0.60-26.7%) was increased in HCC patients compared to healthy donors (median 1.55%, range 0.60-4.7%). M-MDSC level was also higher in a group (median 1.95%, range 0.006-13.7%) than the healthy control (median 0.55%, range 0.001-1.67%). Then the association of MDSC with routing blood cell counts was detected. And the neutrophils counts was positively associated with G-MDSC level (r2= 0.091, p = 0.011) and M-MDSC level (r2= 0.138, p = 0.002). Furthermore, univariate analysis by Cox regression revealed that neutrophils were associated with unfavorable overall survival (OS) (p = 0.000, HR 1.057, 95% CI 1.032-1.084). Then, neutrophils were integrated into cancer of the liver Italian program (CLIP) score system to determine its independence in prognostic value, since CLIP was the most accepted prognostic system for aHCC patients. The result showed that neutrophil count was a independent unfavorable prognostic factor for aHCC patients) (p = 0.000, HR 1.055, 95% CI 1.025-1.086). Conclusions: In summary, the present study indentified neutrophils counts was a predictor of MDSC level in aHCC patients. And, patients with higher neutrophils count level might be the optimal patient subgroup for MDSC targeted therapy.