tbuckley/cabot-search huggingface dataset:
A phase (Ph) II study of the efficacy and safety of the cMET inhibitor capmatinib (INC280) in patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Tawesak Tanwandee, Wattana Sukeepaisarnjaroen, Stephen Lam Chan, SuPin Choo, Guohong Han, Virote Sriuranpong, Hongming Pan, Thomas Cheung Yau, Zhenggang Ren, Jian-Ming Xu, Bin Peng, Takami Saji, Yongjian Sun, Alan Huang, Luigi Manenti, Shukui Qin
Journal: Journal of Clinical Oncology (2016)

4074 Background: Overexpression/activation of cMET occurs in 20‒48% of HCC, and predicts worse survival. Capmatinib (INC280) is a potent, selective cMET inhibitor that causes regression of cMET dysregulated (cMET+) animal solid tumor models at well-tolerated doses. This open-label, single-arm study is evaluating the safety and efficacy of INC280 in pts with cMET+ advanced HCC, who have received no prior systemic therapy (NCT01737827). Methods: The primary endpoint is time to progression (TTP); secondary endpoints are ORR, DCR, PFS, OS, safety and tolerability, and PK. Eligible pts were aged ≥ 18 years, ECOG PS ≤ 2, Child-Pugh A, and had no prior cMET/HGF-targeted therapy. Based on responding pts in preliminary studies, an eligibility criterion was amended to specify that tumors must have high cMET status (IHC 3+, IHC 2+ and cMET gene copy number [GCN] ≥ 5 by FISH, or cMET GCN ≥ 5 and unknown IHC); low cMET status is defined as IHC 2+ and GCN < 5, IHC 1+ and any GCN, or cMET GCN ≥ 5 and IHC 0+. Results: As of September 28, 2015, 36 pts were enrolled: 8 pts in a dose-determining part (INC280 300 mg BID) and 28 pts in Ph II dose-expansion groups (INC280 600 mg BID [capsules], except for one pt who received the wrong dose of 300 mg BID). In expansion pts (8 with high cMET and 20 with low cMET status; 89% male, 57% ECOG PS 0, 57% with distant metastases) median age was 55.5 years (range 34–74). Treatment was discontinued in 24/28 (86%) pts, mainly due to disease progression (54%); treatment is ongoing in 4 (14%) pts. The most common AEs, regardless of causality, were increased AST (39%), nausea (36%), diarrhea (32%), and vomiting (32%). The most common Grade 3/4 AEs, regardless of causality, were increased AST (29%), and hyperbilirubinemia (11%). INC280 PK was similar to that seen in non-HCC pts. Partial responses (PRs) were seen in 3/28 pts (ORR 11%). All responders had high cMET status; there were 3/8 PRs and 1/8 pts had stable disease in the high cMET group (ORR 38%; DCR 50%). Conclusions: Oral INC280 600 mg BID was well tolerated with a manageable safety profile, and showed activity in pts with high cMET status HCC. Confirmation of these initial positive results is warranted to establish the relevance of INC280 in HCC. Clinical trial information: NCT01737827.
Poor FEV1 or DLco on Pre-Transplant PFT Does Not Compromise Outcomes In Patients Undergoing a Reduced-Intensity Allogeneic Progenitor Cell Transplant.
Authors: Manish Sharma, Rima M. Saliba, Muzaffar H. Qazilbash, Grace-Julia Okoroji, Uday Popat, Marcos de Lima, Richard Champlin, Chitra Hosing
Journal: Blood (2010)
Abstract 4658: Activation mechanisms of Integrated Stress Response by inhibition of oncogenic BRAF in melanoma cell lines
Authors: Ikuko Nagasawa, Satomi Tsukahara, Kazuhiro Kunimasa, Akihiro Tomida
Journal: Cancer Research (2016)

Abstract The eIF2α-ATF4 signaling pathway termed “Integrated stress response (ISR)” plays an important role in protecting cells against various cellular stresses such as deprivation of glucose and amino acids, virus infection, and deficiency of heme. Under such stress conditions, eIF2α kinases, including PERK, GCN2, PKR and HRI, phosphorylate eIF2α, resulting in reduction of general protein synthesis while facilitating selective translation of ATF4, a central transcription factor that upregulates expression of stress-induced genes for cellular adaptation. Recently, it was reported that BRAF inhibitor vemurafenib triggers activation of the eIF2α-ATF4 signaling in BRAF-mutant melanoma cell lines; however, activation mechanisms of vemurafenib-induced ISR signaling not fully understood. In this study, we first compared vemurafenib-induced ISR activation in BRAF-mutant and -wild type melanoma cell lines. Consistent with previous studies, vemurafenib activated ISR signaling preferentially in BRAF-mutant cell lines, as determined by phosphorylation of eIF2α and ATF4 expression. We also found that the ISR activation by vemurafenib was impaired by knockdown of BRAF in BRAF-mutant cell lines. These results indicated that existence of mutated BRAF is important for vemurafenib to trigger activation of ISR signaling pathway. We next examined which eIF2α kinase is involved in the ISR signaling activation by vemurafenib. We found that knockdown of GCN2, an eIF2α kinase sensing depletion of amino acids, impaired phosphorylation of eIF2α and ATF4 induction by vemurafenib. In addition, we confirmed that vemurafenib induced phosphorylation of GCN2 on Thr899 that is known to occur in response to amino acids starvation. In agreement with these results, gene expression profiling with ontology analysis revealed that vemurafenib upregulated genes that are involved in amino acids biosynthesis via ISR signaling. Collectively, our results suggested that vemurafenib activated ISR signaling pathway possibly through mimicking amino acid deprivation in BRAF-mutant melanoma cell lines. Citation Format: Ikuko Nagasawa, Satomi Tsukahara, Kazuhiro Kunimasa, Akihiro Tomida. Activation mechanisms of Integrated Stress Response by inhibition of oncogenic BRAF in melanoma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4658.
Abstract 1241: Podophyllotoxin acetate (PA) as an anti-cancer drug candidate regulates various malignancy traits of non-small cell lung cancer
Authors: Jeong Hyun Cho, Wan Gi Hong, Sang-Gu Hwang, Hong-Duck Um, Jong Kuk Park
Journal: Cancer Research (2016)

Abstract Here, we reported that podophyllotoxin acetate (PA) showed various aniti-cancer effects: induction of several cell death pathways, inhibition of γ-ionizing radiation (IR)-induced cancer invasion, chemo-sensitizer effect with topoisomerase (TOP) inhibitors against non-small cell lung cancer (NSCLC) cell lines as follows. (1) Stimulation of cell death via various mechanisms. First, PA dose-dependently induced cell cycle arrest at G2/M phase, as shown by accumulation of the mitosis-related proteins, p21, survivin and aurora B. This arrest was due to the PA-induced inhibition of microtubule polymerization that related to DNA damage (reflected by accumulation of γ-H2AX) resulting induction of intrinsic/extrinsic damage apoptotic pathways. PA also activated the pro-apoptotic ER stress pathway, as evidenced by increased expression levels of BiP, CHOP, IRE1-a, phospho-PERK, and phospho-JNK. Next, PA induced autophagy that reflected the expression of beclin-1, Atg3, Atg5 and Atg7, and the cleavage of LC3. (2) Inhibition of IR-induced cancer invasion. IR increased the invasion/migration of A549 cells, and this effect was decreased by PA treatment that the expressions/activities of matrix metalloprotase (MMP) -2, MMP-9, and vimentin, suggesting that PA could block the IR-induced epithelial-mesenchymal transition (EMT). In this study, we also identified IR-induced new signaling pathway, EGFR - p38/ERK - CREB-1/STAT3 - EMT pathway, that was inhibited by PA. (3) Chemo-sensitizer effect conjugated with TOP inhibitors - etoposide (Eto) and camptothecin (Cpt). Combination Index (CI) values of the combinations showed synergistic effects between PA and topoisomerase inhibitors. Combination with PA and Eto/Cpt promotes disruption of dynamics of actin filaments, which subsequently enhanced apoptotic cell death that accompanied to increased phosphorylation of p38. We also observed these combinations also inhibited activation of CREB-1, synergistically. Therefore, this study indicated that PA functions as a chemosensitizer by enhancing apoptosis through activation of p38/caspases apoptotic axis and suppression of CREB-1.Taken together; these results suggest PA is a new anti-cancer drug candidate that could control several malignancy traits of cancer including uncontrolled cell cycle and IR-induced invasion. Citation Format: Jeong Hyun Cho, Wan Gi Hong, Sang-Gu Hwang, Hong-Duck Um, Jong Kuk Park. Podophyllotoxin acetate (PA) as an anti-cancer drug candidate regulates various malignancy traits of non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1241.
Review: Pneumococcal vaccination is not effective for preventing pneumonia, bacteremia, bronchitis, or mortality
Authors: Jennie Johnstone
Journal: Annals of Internal Medicine (2009)

ACP Journal Club19 May 2009Review: Pneumococcal vaccination is not effective for preventing pneumonia, bacteremia, bronchitis, or mortalityJennie Johnstone, MDJennie Johnstone, MDMcMaster University, Hamilton, Ontario, Canada (J.J.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-150-10-200905190-02004 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationHuss A, Scott P, Stuck AE, et al. Efficacy of pneumococcal vaccination in adults: a meta-analysis. CMAJ. 2009;180:48-58. https://pubmed.ncbi.nlm.nih.gov/19124790Clinical Impact RatingsGIM/FP/GP: Infectious Disease: Pulmonology: References1 Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44:S27-72. [PMID: 17278083] Google Scholar2 Feikin DR, Schuchat A, Kolczak M, et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. Am J Public Health. 2000;90:223-9. Google Scholar3 Centers for Disease Control and Prevention. Recommended Adult Immunization Schedule—United States, 2009. MMWR 2008;57:Q-1-Q-4. www.cdc.gov/mmwr/preview/mmwrhtml/mm5701a8.htm (accessed 22 Apr 2009). Google Scholar4 Moberley SA, Holden J, Tatham DP, et al. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev 2008;1:CD000422. Google Scholar Author, Article, and Disclosure InformationAuthors: Jennie Johnstone, MDAffiliations: McMaster University, Hamilton, Ontario, Canada (J.J.)This article was published at Annals.org on 5 May 2009. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byPneumococcal vaccination in adult solid organ transplant recipients: A review of current evidenceSeroresponses and safety of 13-valent pneumococcal conjugate vaccination in kidney transplant recipients 19 May 2009Volume 150, Issue 10 Page: JC5-4 Keywords Bacteremia Bronchitis Confidence intervals Infectious diseases Mortality Pneumonia Polysaccharides Relative risk Research laboratories Vaccines ePublished: 19 May 2009 Issue Published: 19 May 2009 Copyright & PermissionsCopyright © 2009 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Mutational Profile and Prognostic Relevance of Circulating Tumor Cells in Multiple Myeloma
Authors: Yuji Mishima, Bruno Paiva, Jiantao Shi, Mira Massoud, Salomon Manier, Ludmila Flores, Adriana Perilla-Glen, Yosra Aljawai, Daisy Huynh, Satoshi Takagi, Aldo M Roccaro, Antonio Sacco, Diego Alignani, Maria Victoria Mateos, Joan Bladé, Juan Jose Lahuerta, Paul G. Richardson, Jacob P. Laubach, Robert L. Schlossman, Kenneth C Anderson, Nikhil C. Munshi, Felipe Prosper, Franziska Michor, J.F. San Miguel, Irene M. Ghobrial
Journal: Blood (2015)
Abstract 851: Analysis of cancer-initiating mosaic mutation in germline samples of pediatric cancer patients by next generation sequencing
Authors: Xiaotu Ma, Donald Yergeau, Bhavin Vadodaria, Joy Nakitandwe, John Easton, Sheila Shurtleff, Jinghui Zhang
Journal: Cancer Research (2016)

Abstract A cancer predisposition mutation can occur during post-zygotic stages resulting in a mosaic mutation pattern across tissues. Mosaic germline mutations such as those affecting RB1, TP53 and AKT1 are important for clinical testing. However, it is challenging to detect mosaic mutation by genome-wide sequencing approaches as a mutant allele present at a low fraction in a germline sample can be caused by either tumor-in-normal contamination or mosaicism. Here we propose a two-step analytical approach to distinguish between these two possibilities. The first involves assessing the level of tumor-in-normal contamination using all clonal somatic mutations identified through the analysis of tumor purity and chromosome ploidy. The second step determines the probability of mosaicism for a candidate variant by calculating the binomial probability of its mutant allele fraction (MAF) under the contamination hypothesis. We applied this process to 1,172 paired tumor-normal pediatric cancer samples analyzed by whole-genome or whole-exome sequencing. Six mosaic variants were identified, including three pathogenic TP53 mutations with a mutant allele fractions (MAF) ranging from 0.2 to 0.3, one RB1 mutation in a retinoblastoma case with a MAF of 0.08, one IDH1 p.R132H mutation in an acute myeloid leukemiaý case with a MAF of 0.21, and one mosaic RYR2 p.E1690D mutation in an osteosarcoma case with a MAF of 0.11. At the same time, we were able to reject three candidate TP53 variants caused by contamination with MAFs ranging from 0.06 to 0.33. All predicted mosaic mutations were verified by ultra deep sequencing at 10,000X coverage. This experience demonstrates the feasibility of detecting germline mosaicism from whole-genome or whole-exome sequencing of paired tumor-normal samples and would caution accurate analysis of tumor-in-normal contamination when evaluating candidate germline mosaicism. Citation Format: Xiaotu Ma, Donald Yergeau, Bhavin Vadodaria, Joy Nakitandwe, John Easton, Sheila Shurtleff, Jinghui Zhang. Analysis of cancer-initiating mosaic mutation in germline samples of pediatric cancer patients by next generation sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 851.
A randomized trial of fenretinide in superficial bladder cancer: 20 year follow-up and prognostic significance of VEGF.
Authors: Marilena Petrera, Matteo Puntoni, Sara Campora, Carlotta Defferrari, Rosalba Torrisi, Elsa Garrone, Silvia Bruno, Antonio Curotto, Domenico Marra, Andrea De Censi
Journal: Journal of Clinical Oncology (2015)

e15500 Background: From 1993 to 1994 we conducted a phase IIb chemoprevention trial with the fenretinide (4-hydroxyphenyl retinamide, 4-HPR) in 99 subjects with superficial bladder cancer (SBC) who were randomized to receive either 4-HPR (200 mg/day) or no treatment for 2 years. The modulation of DNA flow-cytometry in urothelial cells obtained from bladder washings was the main endpoint. We found no effect of 4-HPR on DNA content (DeCensi et al. CEB&P 2000). However, DNA aneuploidy exhibited a prognostic effect on PFS and OS after a median of 11.5 years (Puntoni et al., CEB&P 2007). Here we assessed the prognostic effect of circulating VEGF levels in a patient subgroup and updated overall and cancer specific mortality after a median of 20.5 years. Methods: Serum VEGF levels obtained at baseline and at the 12-month visit were measured in 62 patients blinded to treatment allocation. Information on subject’s vital status was ascertained through computer linkage to Genoa Mortality Registry. Kaplan-Meier and Cox regression analyses were used to determine the effect of 4-HPR and the prognostic role of DNA aneuploidy and VEGF. Results: After a median follow-up time of 20.5 years (interquartile range, 20.3-20.8), 54 subjects (55%) deceased, of whom 35 (65%) of any cancer and 14 (26%) of bladder cancer. Neither OS, nor all cancer survival (CS) or bladder cancer survival (BCS) were affected by 4-HPR (log-rank p = .2, .6/.2, respectively). DNA aneuploidy was associated with shorter OS (p = .02), CS (p = .05) and a trend in BCS (p = .09). Subjects with VEGF ≥ 350 pg/mL (5th quintile) at baseline had significantly shorter OS (log-rank p = .01), CS (p = .02) and BCS (p = .008). Multivariate Cox models showed that, in addition to tumor stage (pT1 vs. pTa) and smoking habit (ever vs. never), high VEGF levels ( ≥ 350 vs. < 350 pg/mL) was the only independent prognostic factor for OS (HR = 2.6, 95%CI: 1.1-6.5, p = .03), CS (HR = 3.3, 1.1-9.4, p = .03), and BCS (HR = 11.2, 1.7-76, p = .01). Conclusions: 4-HPR did not affect the long-term outcome of patients with SBC. High serum VEGF level was a significant predictor of death in addition to smoking habit. This biomarker may help to identify a high-risk group who may benefit from a chemoprevention intervention.
Abstract 2559: Genome-wide haplotype association tests identified three candidate loci associated with sporadic colorectal cancer risk in Singapore Chinese
Authors: Peh Yean Cheah, Lai Fun Thean, Yik Ying Teo, Woon-Puay Koh, Jian-Min Yuan, Min Hoe Chew, Choong Leong Tang
Journal: Cancer Research (2016)

Abstract Colorectal cancer (CRC) is one of the most frequent cancers and leading cause of cancer mortality in the developed world. Twin study has attributed about 35% of the etiology of sporadic CRC to genes. Hitherto, more than 20 single nucleotide polymorphism (SNP) loci from genome-wide association studies (GWAS) were associated with CRC risk. Most of these index SNPs however have small effect sizes and often located in gene deserts. Thus they are unlikely to be causal. Haplotype-based methods may offer a more powerful approach to disease gene mapping. We previously performed a GWAS on 2,000 ethnicity-, age-, and gender-matched Singapore Chinese CRC patients and healthy controls using the Affymetrix SNP 6 platform. Sporadic patients were defined as aged 50 or more at the time of surgery and with no dominant family history of CRC. Haplotype block detection was performed in Golden Helix SVS after this SNP6 dataset was filtered for genotype call rate (&amp;gt;95%), Hardy-Weinberg equilibrium in the controls and principal component analysis. Block detection was performed requiring strong linkage disequilibrium between block pairs, minor allelic frequencies (MAF) of SNPs more than 0.01, the maximum number of markers and length of the block at 30 and 160kb respectively. Genome-wide, 73,333 blocks were computed using 336, 466 markers on 22 autosomes. Haplotype frequencies were estimated using the EM algorithm. Chi-Squared and logistic regression with odds ratio tests of haplotype association were performed using these pre-computed blocks on a per-haplotype basis. Three candidate loci at chromosomes 3, 15 and 20, each with 6 to 9 SNPs and sizes ranging from 4 to 15 kb achieved genome-wide significance and encompass potential novel disease genes. These loci are currently being validated in an independent replication panel using the Fluidgm SNPtype assays and pooled analyses will be performed. Citation Format: Peh Yean Cheah, Lai Fun Thean, Yik Ying Teo, Woon-Puay Koh, Jian-Min Yuan, Min Hoe Chew, Choong Leong Tang. Genome-wide haplotype association tests identified three candidate loci associated with sporadic colorectal cancer risk in Singapore Chinese. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2559.
Abstract 2102A: Simultaneous targeting of EGFR and ALK in EML4-ALK positive lung cancer to inhibit tumor cell proliferation and migration
Authors: Chunrong Li, Joseph G. Kern, Shyhmin Huang, Eric A. Armstrong, Lauryn R. Werner, Paul M. Harari
Journal: Cancer Research (2016)

Abstract Approximately 4-7% of non-small cell lung cancers (NSCLC) harbor the EML4-ALK chromosomal rearrangement. ALK has been identified as a molecular driver of cancer and ALK inhibitors have been developed for clinical use. We have confirmed high expression of EGFR in EML4-ALK-positive cell lines (H3122 and H2228). Recognizing the capacity of both EGFR and ALK signaling to regulate tumor cell growth, we investigated the effects of co-inhibition of ALK and EGFR on cell proliferation and migration in EML4-ALK-positive cells in vitro. We also examined the anti-tumor effect of ALK and EGFR inhibitors in xenograft mouse models. Cell proliferation was determined by CCK8 and cell migration was examined by wound healing assay and transwell migration assay. ALK inhibitors (crizotinb, ceritifinib and alectinib) and EGFR inhibitors (erlotinib and gefitinib) were utilized to block ALK and EGFR signaling activity. We confirmed that H3122 and H2228 cells were resistant to EGFR inhibitors in comparison to EML4-ALK negative cell lines H226 and A549. Simultaneous knockdown of ALK and EGFR by siRNA significantly inhibited tumor cell proliferation. Combined inhibition of ALK and EGFR inhibited cell proliferation more potently than single inhibitor treatment alone. In addition, NIH3T3 cells expressing EML4-ALK variants 1, 2 or 3a displayed enhanced ability for cell migration, suggesting a role of EML4-ALK in cell migration. Individual ALK inhibitors and EGFR inhibitors inhibited cell migration. Further, combined ALK and EGFR blockade resulted in a stronger cell migration inhibition than single agent therapy. The combination of ALK inhibitor with EGFR inhibitor was more potent than single target treatment in tumor xenograft growth inhibition. Mechanistic analysis of the co-regulation of cell migration by ALK and EGFR signaling in EML4-ALK positive cells is under investigation. These results identify enhanced inhibitory effects on tumor cell proliferation and migration with simultaneous blockade of ALK and EGFR signaling suggesting that dual targeting may prove more effective than single agent approaches. These findings indicate the potential for therapeutic benefit of co-targeting ALK and EGFR in patients with EML4-ALK positive NSCLC. Citation Format: Chunrong Li, Joseph G. Kern, Shyhmin Huang, Eric A. Armstrong, Lauryn R. Werner, Paul M. Harari. Simultaneous targeting of EGFR and ALK in EML4-ALK positive lung cancer to inhibit tumor cell proliferation and migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2102A.
DMT1-Mutant Erythrocytes Have Shortened Life Span, Accelerated Glycolysis and Increased Oxidative Stress
Authors: Zuzana Zidova, Pavla Pospisilova, Renata Mojzikova, Katarina Kapralova, Dalibor Dolezal, Vladimir Divoky, Monika Horvathova
Journal: Blood (2013)