tbuckley/cabot-search huggingface dataset:
Class I HDAC inhibitors inhibit the retention of BRCA1 and 53BP1 at the site of DNA damage.
Authors: Takayo Fukuda, Wenwen Wu, Maiko Okada, Ichiro Maeda, Yasuyuki Kojima, Ryosuke Hayami, Yasuo Miyoshi, Koichiro Tsugawa, Tomohiko Ohta
Journal: Journal of Clinical Oncology (2015)

e13552 Background: BRCA1 and 53BP1 antagonistically regulate homology-directed repair (HDR) and non-homologous end-joining (NHEJ) of DNA double-strand breaks (DSBs). The histone deacetylase inhibitor (HDACi) trichostatin A directly inhibits the retention of 53BP1 at DSB sites by acetylating histone H4 (H4ac), which interferes with 53BP1 binding to dimethylated histone H4 Lys20 (H4K20me2). Conversely, we recently found that the retention of the BRCA1/BARD1 complex is also affected by another methylated histone residue, H3K9me2, which can be suppressed by the histone lysine methyltransferase inhibitor (HKMTi) UNC0638. Methods: We investigate the effects of the Class I HDACis MS-275 and FK228 compared to UNC0638 on histone modifications and the DNA damage response by immunoblotting, immunofluorescence microscopy, DR-GFP HDR reporter assay and clonogenic survival assay. Results: In addition to H4ac, the HDACis induce H3K9ac and inhibit H3K9me2 at doses that do not affect the expression levels of DNA repair genes. By contrast, UNC0638 selectively inhibits H3K9me2 without affecting the levels of H3K9ac, H3K56ac or H4ac. Reflecting their effects on histone modifications, the HDACis inhibit ionizing radiation-induced foci (IRIF) formation of BRCA1 and BARD1 as well as 53BP1 and RIF1, whereas UNC0638 suppresses IRIF formation of BRCA1 and BARD1 but not 53BP1 and RIF1. Although HDACis suppressed HDR, they did not cooperate with the poly(ADP-ribose) polymerase inhibitor olaparib to block cancer cell growth, possibly due to simultaneous suppression of NHEJ pathway components. Conclusions: These results suggest the mechanism by that HDACis inhibit both the HDR and NHEJ pathways, whereas HKMTi inhibits only the HDR pathway; this finding may affect the chemo-sensitizing effects of the inhibitors.
PCI患者のための血小板凝集測定におけるVASP指数とVerifyNowTM(P2Y12アッセイ)のアベイラビリティ
Authors: Nakata Tomoyuki, Nishikawa Masakatsu, Sawai Toshiki, Tamaru Satoshi, Hoshino Kozo, Tanigawa Takashi, Miyahara Masatoshi, Nakamura Mashio, Nakatani Ataru, Wada Hideo, Itoh Masaaki
Journal: Circulation (2010)
Integrated Analysis Of CRLF2 Signaling In Acute Lymphoblastic Leukemia Identifies Polo-Like Kinase 1 As a Therapeutic Target
Authors: Tai-Chung Huang, Shubhada Shashikant Bharne, Jevon Cutler, Jun Zhong, David M. Weinstock, Jeffrey W. Tyner, Curt I. Civin, Akhilesh Pandey
Journal: Blood (2013)
Polymorphisms of the <i>MATP/SLC45A2</i> gene and susceptibility to melanoma in the French population
Authors: N. Soufir, M. Guedj, A. Bourrillon, C. Combadieres, V. Descamps, N. Dupin, P. Wolkenstein, C. Lebbe, N. Basset- Seguin, P. Saiag, B. Grandchamp
Journal: Journal of Clinical Oncology (2008)

11040 Background: Loss-of-function variants in the melanocortin 1 receptor gene (MC1R) are low penetrant melanoma predisposing alleles. Methods: A cohort comprising 1,019 patients affected by melanoma (MelanCohort) and 1,466 Caucasian controls skin cancer-free were studied. Ten polymorphisms, including five functional MC1R alleles (R151C, R160W, D294H, R142H, D84E), two non-synonymous SLC45A2 variants (L374F and E272K), and three intronic OCA2 variants previously shown to be strongly associated with eye color (rs7495174, rs4778241 and rs4778138) were genotyped. Genotype, allele, haplotype and diplotype frequencies were compared in the two groups using Fisher’s exact test and odds ratio calculations Results: As expected, MC1R variants were closely associated with melanoma risk (P-value < 2.20×10-16). Interestingly, the SLC45A2 variants L374F and E272K were also significantly and strongly associated with melanoma (respectively, P-value × 2.12×10-15, OR × 0.35 [0.26–0.46], and P-value = 1.10×10-6 OR × 0.40 [0.27–0.59]). MC1R and SLC45A2 variants had additive effects on melanoma risk, and after adjusting for clinical risk factors, the risk was persistent, even though both genes were strongly associated with pigmentation. Conclusions: Future studies may show whether genetic information could provide a useful complement to physical examination in predicting melanoma risk. No significant financial relationships to disclose.
A prospective evaluation of cell free DNA (cfDNA) genotyping and circulating tumor cells (CTC) in <i>EGFR</i> mutant NSCLC patients (pts) treated with erlotinib.
Authors: Masahiko Yanagita, Cloud Paweletz, Allison O'Connell, David Michael Jackman, Yanan Kuang, Geoffrey R. Oxnard, Pasi A. Janne
Journal: Journal of Clinical Oncology (2015)

11068 Background: Genotype directed therapy is now standard of care for advanced NSCLC pts. However, adequate tumor tissue for comprehensive genotyping remains a challenge. Recent research suggests that CTC capture or cfDNA analysis allows for non-invasive diagnosis and monitoring of treatment. This prospective trial was designed to quantify the predictive value of CTC and cfDNA analyses of EGFR-mutant NSCLC pts treated with first-line erlotinib. Methods: TKI naïve EGFR mutant NSCLC pts were enrolled in a phase II trial of erlotinib treatment. Paired blood for cfDNA and CTC analysis was collected at baseline prior to therapy and every 2 months during follow ups. Plasma genotyping was performed by ddPCR for EGFR19del, L858R, T790M while CTCs were isolated by CellSearch and analyzed by IF and MET-FISH. Repeat biopsies at progression were performed when feasible. Results: Between 2/10 and 1/15, 60 EGFRmutant pts (L858R:17, 19del:38, other:5) were enrolled. As of 1/15, 44 patients have discontinued therapy (39 for RECIST progression; 5 for adverse events). Blood was available for cfDNA analysis on 53 and 33 pts at baseline and progression respectively, and EGFR mutations were detected in 25/53 pts (47.1 %, median: 57 copies/mL plasma, range: 2-1649) and 10/33 pts (30.3% median, 71 copies/mL plasma, range: 5-2530). Blood was available for CTC analysis on 47 and 33 pts and CTCs were detected in 17/47 pts (36.1%, median: 3 CTCs/7.5 mL blood, range: 1-1145) at baseline and 15/33 pts (45.4%, median: 6 CTC/7.5 mL blood, range: 1-328) at progression. METamplification was identified in CTCs of 2 pts. For 18 pts with detectable cfDNA at baseline and > = 3 follow up blood draws, treatment reduced cfDNA levels to non-detectable for > = 4 months in 83.3 % (15/18). In contrast, for 17 pts with detectable CTCs at baseline, CTCs continued to be intermittently detected on treatment in 58.9% (10/17) of pts. Conclusions: cfDNA and CTCs are complementary non-invasive assays for EGFRmut NSCLC although the low yield of CTCs may preclude genotyping. Serial cfDNA monitoring may be a better predictor of treatment efficacy than CTCs. Funding: R01-CA135257, P50-CA090578, Conquer Cancer Foundation, Genentech
Continuous Treatment with Lenalidomide and Low-Dose Dexamethasone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma in Asia: Subanalysis of the First Trial
Authors: Jin Lu, Jae Hoon Lee, Shang-Yi Huang, Lugui Qiu, Je-Jung Lee, Ting Liu, Sung-Soo Yoon, Kihyun Kim, Zhi Xiang Shen, HyeonSeok Eom, Wenming Chen, Chang-Ki Min, Hyo Jung Kim, Jeong Ok Lee, Jae Yong Kwak, Wai Yiu, Guang Chen, Annette Ervin Haynes, Cyrille Hulin, Thierry Facon
Journal: Blood (2015)
RhoB supports c-Myc turnover by a GSK-3-dependent mechanism
Authors: Minzhou Huang, James Duhadaway, George C. Prendergast
Journal: Cancer Research (2005)

2598  RhoB is a ubiquitous member of the Rho family of small GTPases that control cytoskeletal actin organization in cells. However, unlike other family members RhoB has features of a negative modifier or suppressor gene in cancer. The mechanisms RhoB uses to inhibit cancer cell proliferation are not well understood. Recent studies have linked RhoB to trafficking of important cell regulators, such as Akt, which through its regulation of GSK-3 has an important role in controlling the stability of the c-Myc oncoprotein. c-Myc stabilization may be a root feature of human tumorigenesis, as it phenocopies the essential contribution of SV40 small T antigen in human cell transformation. Here we present evidence that RhoB directs efficient turnover of c-Myc in E1A+Ras-transformed murine fibroblasts (ER MEFs) and MMTV-c-myc-transformed mouse mammary epithelial cells (mycMMECs). Mechanistic analyses indicated that RhoB supports efficient nuclear accumulation of GSK-3 and GSK-3-mediated phosphorylation of c-Myc at T58, the critical site for ubiquitination and subsequent degradation of c-Myc located within the Myc Box 1 region. Targeted deletion of RhoB restricted the nuclear localization of GSK-3, reduced phosphorylation of T58, and stabilized c-Myc. These effects were not associated with changes in the level, phosphorylation, or localization of Akt in ER-MEFs, however, we observed differences in phosphorylation and localization of the Akt-related kinase SGK that also regulates GSK-3. Studies in mycMMECs suggest that RhoB attenuation stimulates actin fiber formation, decreases apoptotic sensitivity, and increases anchorage-independent proliferation. Indeed, preliminary work suggests that RhoB is haploinsufficient with regard to these properties. Importantly, the effects of RhoB loss in mycMMECs were associated with Akt activation as well as with diminution of GSK-3-mediated turnover of the c-Myc protein. Taken together, our findings suggest that that RhoB may limit cell proliferation by promoting GSK-3-mediated turnover of c-Myc. Precise control of RhoB may be crucial for limiting proliferation and facilitating apoptosis, in support of an hypothesized role for RhoB as a negative modifier or anti-progression gene.
Meta-analyses of randomized trials assessing the interest chemotherapy in advanced gastric cancer
Authors: P. Rougier, K. Oba
Journal: Journal of Clinical Oncology (2008)

4563 Background: Advanced or recurrent stomach cancer remains an incurable disease. Several drugs and different combinations of chemotherapy (CT) have been investigated but very often with small sample sizes making definitive conclusions difficult. Recently docetaxel showed a significant overall survival (OS) benefit. The GASTRIC project is an individual patient data (IPD)-based meta-analysis in the advanced disease setting to quantify the potential benefit of various chemotherapies including FU derivatives, anthracyclines, platinum salts, taxanes, or irinotecan. Methods: All randomized trials closed to patient accrual before the end of 2004 were included. Trials with neoadjuvant or adjuvant treatment were excluded. The primary endpoint was OS, the secondary endpoint progression-free-survival. The logrank test, stratified by trial, was used to compare treatment arms. Data collection was initiated in January 2007. Results: Fifty-four eligible randomized trials (8,248 patients) were identified. To date, IPD from 17 trials (3,106 pts) with a median follow-up of 8.1 months were available for OS. No statistically significant difference was observed between anthracycline-based regimens versus any other CT (7 RCTs, 1,501 pts, HR = 0.94, 95% CI = 0.84 - 1.06, p = 0.31), between irinotecan-based regimens versus any other CT (3 RCTs, 550 pts, HR = 0.89 p = 0.36), or between platinum-based regimens versus any other CT (7 RCTs, 1,677 pts, HR= 0.98, p = 0.59). However, significant heterogeneity was detected in the last comparison (p < 0.01). Only taxane-based regimens showed an OS benefit over any other CT (HR = 0.82, 95% CI = 0.68 - 0.99, p = 0.03, 3 RCTs, 572 pts). Conclusions: IPD-based meta-analysis represents one of the highest levels of evidence. Our results, based on partial data, suggest a benefit in favor of taxane-based regimens, mainly driven by a trial of cisplatin + 5-FU with and without docetaxel. No significant financial relationships to disclose.
Liposomal Amphotericin B (L-AMB) as Initial Therapy for Invasive Filamentous Fungal Infections (IFFI): A Randomized, Prospective Trial of a High Loading Regimen vs. Standard Dosing (AmBiLoad Trial).
Authors: Oliver A. Cornely, Johan Maertens, Mark Bresnik, Raoul Herbrecht
Journal: Blood (2005)
A randomized multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3).
Authors: Tom Samuel Waddell, Ian Chau, Yolanda Barbachano, David Gonzalez de Castro, Andrew Wotherspoon, Claire Saffery, Gary William Middleton, Jonathan Wadsley, David Raymond Ferry, Wasat Mansoor, Tom David Lewis Crosby, Fareeda Y Coxon, David Smith, Justin S. Waters, Timothy Iveson, Stephen Falk, Sarah Slater, Alicia Frances Clare Okines, David Cunningham
Journal: Journal of Clinical Oncology (2012)

LBA4000 Background: EGFR overexpression occurs in 27-50% of esophagogastric adenocarcinomas (OGA), and correlates with poor prognosis. The REAL3 trial evaluated the addition of the anti-EGFR antibody panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in advanced OGA. Methods: Patients with untreated, metastatic or locally advanced OGA were randomised to EOC (E 50mg/m2, O 130mg/m2, C 1250mg/m2/day) or mEOC+P (E 50mg/m2, O 100mg/m2, C 1000mg/m2/day, P 9mg/kg). Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response rate (RR), toxicity, and biomarker evaluation. Response was evaluated by RECIST after 4 and 8 cycles. Following IDMC review in October 2011 trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. Results: 553 patients were recruited (EOC 275, mEOC+P 278), with median follow-up 5.0 and 5.2 months respectively. Median OS was 11.3 months with EOC compared to 8.8 months with mEOC+P (HR 1.37: 95% CI 1.07-1.76, p=0.013). Median PFS was 7.4 and 6.0 months respectively (HR 1.22: 95% CI 0.98-1.52, p=0.068), with RR being 42% compared to 46% (odds ratio 1.16: 95% CI 0.81-1.57, p=0.467). mEOC+P was associated with ↑ G3/4 diarrhoea (17% vs 11%), skin rash (14% vs 1%) and thrombotic events (12% vs 7%), but ↓ haem toxicity (&gt;G3 neutropenia 14% vs 31%). In the mEOC+P arm, OS was significantly improved in patients with G1-3 rash (77%, n=209) on treatment compared to those without (23%, n=63); median OS 10.2 vs 4.3 months (p&lt;0.001), with similar significant improvements seen in RR and PFS. Biomarker analysis in the first 200 patients has not identified other predictive markers associated with P therapy. Multivariate analysis for OS in these patients demonstrated a negatively prognostic role for KRAS mutation (HR 2.1: 95% CI 1.10-4.05, p=0.025) and PIK3CA mutation (HR 3.2: 95% CI 1.01-10.40, p=0.048). Conclusions: Addition of P to EOC chemotherapy was associated with worsening of OS in an unselected advanced OGA population. This may be in part due to lowered doses of O and C in the mEOC+P regimen. Outcomes in patients treated with P varied by grade of skin toxicity.
Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube
Authors: Mark A. Eckert, Shawn Pan, Kyle M. Hernandez, Rachel M. Loth, Jorge Andrade, Samuel L. Volchenboum, Pieter Faber, Anthony Montag, Ricardo Lastra, Marcus E. Peter, S. Diane Yamada, Ernst Lengyel
Journal: Cancer Discovery (2016)

Abstract Accumulating evidence has supported the fallopian tube rather than the ovary as the origin for high-grade serous ovarian cancer (HGSOC). To understand the relationship between putative precursor lesions and metastatic tumors, we performed whole-exome sequencing on specimens from eight HGSOC patient progression series consisting of serous tubal intraepithelial carcinomas (STIC), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases. Integration of copy number and somatic mutations revealed patient-specific patterns with similar mutational signatures and copy-number variation profiles across all anatomic sites, suggesting that genomic instability is an early event in HGSOC. Phylogenetic analyses supported STIC as precursor lesions in half of our patient cohort, but also identified STIC as metastases in 2 patients. Ex vivo assays revealed that HGSOC spheroids can implant in the fallopian tube epithelium and mimic STIC lesions. That STIC may represent metastases calls into question the assumption that STIC are always indicative of primary fallopian tube cancers. Significance: We find that the putative precursor lesions for HGSOC, STIC, possess most of the genomic aberrations present in advanced cancers. In addition, a proportion of STIC represent intraepithelial metastases to the fallopian tube rather than the origin of HGSOC. Cancer Discov; 6(12); 1342–51. ©2016 AACR. See related commentary by Swisher et al., p. 1309. This article is highlighted in the In This Issue feature, p. 1293
Mechanistic and clinical analysis of Sperm associated antigen 5 (SPAG5) as a novel prognostic, predictive, actionable gene in Breast Cancer (BC).
Authors: Tarek M. A. Abdel-Fatah, Dong-Xu Liu, Devika Agarwal, Roslin Russell, Oscar M Rueda, Paul M Moseley, Andrew R. Green, Abhik Mukherjee, Jorge Reis-Filho, Carlos Caldas, Ian O. Ellis, Graham Ball, Steve Y.T. Chan
Journal: Journal of Clinical Oncology (2015)

1040 Background: Clinicopathological implications of SPAG5 were investigated in BC. Methods: SPAG5 copy number changes and gene expression were investigated in 1980 cases of BC (METABRIC cohort) and validated in multicentre databases (n = 3500). SPAG5 protein expression was evaluated in three primary BC cohorts (n = 2250) with 20-year-median follow-up. The response to chemotherapy (CT) was investigated in two cohorts in whom pathological complete response (pCR) was the primary endpoint: a) Multicentre phase II trial (NCT00455533; n = 295) received doxorubicin/cyclophosphamide followed by 1:1 randomisation to ixabepilone or paclitaxel and b) 250 BC treated with neoadjuvant-anthracycline (AC). BC cell lines with high (+) and low (-) SPAG5 expressions were tested for CT sensitivity. Results: 10-20% of BC showed gain/amplification of SPAG5 locus at Ch17q11.2. SPAG5 gain/amplification and mRNA+ were significantly associated with: TP53 mutation; PAM50 Her2; PAM50 Basal; PAM50 LumB and integrative molecular clusters 1, 5, 9 and 10 (p < 0.0001). SPAG5 gain/amplification, mRNA+ and protein+ were associated with poor survival and were independent prognostic factor (p < 0.0001). In the clinical trial, SPAG5 mRNA+ was associated with higher pCR (OR = 2.3, 95% CI = 1.2-4.2, p = 0.008), especially among ER- BC (OR = 2.8, 95% CI = 1.3-5.9, p = 0.007). Patients with SPAG5-mRNA+ in the ixapeblone arm achieved higher pCR in all patients (OR = 3.0, 95% CI = 1.3-7.1, p = 0.01) and ER- cases (OR = 4.2, 95% CI = 1.3-13.0, p = 0.01). In the paclitaxel arm there was no statistical association between pCR and SPAG5 mRNA level. SPAG5-protien+ was shown to be an independent predictor for pCR (OR; 2.4; 95% CI = 1.6-3.9, p < 0.001). In in vitro cell line models, SPAG5+ expression was linked to cell response to CT drugs, irrespective of ER and TP53 status. For instance, T47D and BT549 cell lines with SPAG5+ expression were sensitive to Doxorubicin and knocking-down of SPAG5 made cells resistant to CT agents. Conclusions: SPAG5 is a novel amplified gene on ch17.q11 and is an independent prognostic factor. SPAG5 could help in the selection of patients who will benefit from AC-CT. and its interaction with TP53 need to be explored.
Conformal high-dose external radiation therapy (CHERT) alone for medically inoperable non-small cell lung cancer (MILC)
Authors: J. J. Urbanic, A. Turrisi, A. Sharma, G. Silvestri, P. Nietert, T. Williams, K. Vanek, C. Sherman, R. Harley
Journal: Journal of Clinical Oncology (2004)

7228 Background: Treatment options are limited for patients with MILC. This is a review of patients with MILC treated with CHERT. Methods: 36 patients with MILC treated between 1998 and 2002. All had a pathologic diagnosis of non-small cell lung cancer (NSCLC); all unresectable [poor pulmonary function (23 patients), prior cancer (10 patients - other lung, 4 lobectomies, 1 wedge, esophageal, and colon cancer), 2 other co-morbidities, 1 refused surgery]. Six had more than one primary tumor; 4 concurrently treated (1 small cell with concurrent chemotherapy). The median age was 69 years. Lesion size was < 3cm, 25; 3 – 5cm, 12 lesions; and > 5cm, 5. All had CT scans of the chest; no mediastinoscopy; staged as N0, 34 and N1,2. Radiation was once daily (6–18MV). Median dose was 80.5 Gy/35 fx/2.3 Gy/fx. Target volume included tumor and nodes measuring 1.0cm or larger; margin was the clinical target within a 90–95% isodose line. The mean treatment volume was 42.7 cm3. Results: Thirty-five completed treatment; median length of follow-up 11.5 months. 17 deaths, 12 patients died of NSCLC (71%), 4 died of co-morbid illness (24%), and 1 died of small cell lung cancer. Median survival 21.9 months (95% CI: 18.0–29.8). Six patients alive with disease; 13 alive disease free with follow up between 3 and 49 months. Of 42 lesions, local failure (LF) occurred in 11 patients (26%); 2 (5%) failed concomittantly in regional lymph nodes. No isolated nodal recurrences. Distant tumor progression 7 patients (20%), of these 5 patients had distant progression without local failure. Three patients (8%) had a significant pulmonary toxicity. Two are grade 5 toxicity (both had prior lobectomies). Conservatively 6% treatment mortality in an extremely high risk population. Conclusions: CHERT to 80.5 Gy in 2.3 Gy fractions was tolerated. Treatment related death was rare, isolated to patients with prior lobectomies. LF in 26% despite inattention to motion. Most mortality was related to lung cancer, notco-morbidity. A dose of 80.5 Gy in 7 weeks is supported with single lesions, conservative volumes, and no prior lobectomy. Local failure dominates and higher effective doses should be explored. No significant financial relationships to disclose.