tbuckley/cabot-search huggingface dataset:
Predictive value of a gene signature evaluated in multiple chemotherapy regimens for breast cancer.
Authors: M. Fournier, K. Martin
Journal: Journal of Clinical Oncology (2010)

545 Background: Approximately 12,800 U.S. women present with locally advanced breast cancer each year. Primary (or neoadjuvant) chemotherapy is a treatment to shrink a large tumor to a size that allows it to be removed with breast conserving surgery. A woman who would otherwise need a mastectomy (surgical removal of the breast) may instead elect to receive primary chemotherapy and breast- conserving lumpectomy. Unfortunately, primary chemotherapy has a low response rate (30%-50%) and a significant negative impact on a patient's quality of life. If a tumor does not respond to primary chemotherapy, a mastectomy may be necessary after all. Currently, there is no widely used clinical test to determine before treatment if a given tumor will respond. We have developed a signature of 22 genes whose expression pattern accurately predicts response to primary chemotherapy in breast cancer. This 22-gene signature was discovered by a unique approach using an in vitro model of normal breast epithelial cell differentiation. Here we present data showing that the 22-gene signature predicts response to multiple chemotherapies. Methods: We performed analysis of two published microarray datasets to test whether the 22- gene signature would be predictive of response to primary chemotherapy by hierarchical clustering, Fischer's exact tests, and ROC analysis. The dataset of Chang et al. includes 24 breast cancer core biopsies (Lancet. 2003;362:362-369) and Hess et al. includes 133 fine-needle aspirates from breast cancer patients (JCO. 2006;24:4236-4244) taken before primary treatment with docetaxel or combination treatment respectively and response was assessed after chemotherapy. Results: The 22-gene signature accurately predicted chemotherapy response in both independent datasets (ROC p = 0.0001; Fisher's Exact p < 0.0001). ROC analysis values for sensitivity and specificity showed that the 22-gene signature was superior to clinical parameters and other published gene signatures. Conclusions: This gene signature has the potential to fill the existing need for an in vitro diagnostic to provide accurate personalized information to guide primary chemotherapy treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bioarray Therapeutics Inc. Bioarray Therapeutics Inc. Bioarray Therapeutics Inc. Bioarray Therapeutics Inc.
Stemness and reprogramming in liver cancer
Authors: Snorri S. Thorgeirsson
Journal: Hepatology (2015)

1Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of HealthBethesdaMD *ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:Snorri S. Thorgeirsson, M.D., Ph.D.Laboratory of Human CarcinogenesisCenter for Cancer Research, National Institutes of Health37 Convent Drive, MSC 4262, Building 37, Room 4128BBethesda, MD 20892‐4262E‐mail: [email protected].
Propylene glycol-embodying deformable liposomes as a novel drug delivery carrier for vaginal fibrauretine delivery applications
Authors: Wei-Ze Li, Xu-Liang Hao, Ning Zhao, Wen-Xia Han, Xi-Feng Zhai, Qian Zhao, Yu-E Wang, Yong-Qiang Zhou, Yu-Chuan Cheng, Yong-Hua Yue, Li-Na Fu, Ji-Lei Zhou, Hong-Yu Wu, Chun-Jing Dong
Journal: Journal of Controlled Release (2016)
Phase 1b Study Of Everolimus (RAD001), a mTORC1 Inhibitor In Combination With Rituximab (R), In Patients With Relapsed Or Refractory Indolent CD20+ Lymphomas Or Transformed Aggressive CD20+ Lymphomas
Authors: Vincent Ribrag, Lionel Karlin, Louis Terriou, Thomas Gastinne, Valérie Camara-Clayette, Steven Le Gouill, Franck Morschhauser, Herve Tilly, Bertrand Coiffier
Journal: Blood (2013)
Combination of PKC412 and sirolimus in a metastatic patient with PDGFRA-D842V gastrointestinal stromal tumor (GIST)
Authors: E. Palassini, E. Fumagalli, P. Coco, C. Piovesan, P. Dileo, R. Bertulli, P. G. Casali
Journal: Journal of Clinical Oncology (2008)

21515 Background: The exon 18 PDGFRA-D842V mutation is the most common PDGFRA mutation in GIST. This mutation appears to be resistant to imatinib, but preclinical data have reported its sensitivity to PKC412, a multitarget protein kinase inhibitor. The combination of mammalian target of rapamycin (mTOR) inhibitor and imatinib has been previously explored in imatinib-resistant GIST, based on the involvement of AKT/mTOR pathway in GIST oncogenic signalling mechanisms. We report on the use of PKC412 and sirolimus, an mTOR inhibitor, in a patient with a PDGFRA-D842V metastatic GIST, progressing on PKC412 as a single agent. Methods: In January 2002, a 54 year-old woman with a PDGFRA-D842V GIST arising from the omentum was treated with surgery. In April 2007, following multifocal peritoneal recurrence, imatinib 400 mg/day was started. After 3 months, it was interrupted due to progressive disease, with hemoperitoneum. In July 2007, PKC412 100 mg/day was started, on a named individual basis. After 6 weeks, CT scan showed progressive disease according to Choi's criteria. In August 2007, sirolimus 2 mg/day was added to PKC412. Results: After 4 weeks of combined treatment, a stable disease according to Choi's and RECIST criteria was observed. It was maintained at 11 weeks. Plasma concentrations of sirolimus have been monitored (range 9–15 ng/mL). Treatment is ongoing, in the lack of severe or unexpected toxicities. Conclusions: In this patient, progressing on PKC412, a stable disease was obtained by adding sirolimus to the latter. Nevertheless, potential drug-drug interaction of this formerly unexplored combination, through CYP3A4 common metabolic pathway, would require for any future cases formal DLT and reciprocal drug level assessment within a proper clinical trial setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis
Abstract 2026: G0S2 functions as a tumor suppressor gene through inhibition of c-Myc
Authors: Christina Y. Yim, David J. Sekula, Sarah J. Freemantle, Ethan Dmitrovsky, Michael J. Spinella
Journal: Cancer Research (2015)

Abstract G0/G1 switch gene 2 (G0S2) is a direct retinoic acid target gene that is widely expressed in diverse organs and has been reported to have a role in adipose lipolysis by negatively regulating adipose triglyceride lipase (ATGL). G0S2 is also commonly silenced by DNA methylation in a variety of solid tumors including glioma, head and neck and lung cancers, and G0S2 induction is associated with retinoic acid-mediated clinical remissions in acute promyelocytic leukemia. This evidence suggests that G0S2 may possess tumor suppressor activity although definitive proof and mechanistic details are lacking. We now clearly demonstrate using G0S2 null immortalized mouse embryonic fibroblasts (MEFs) that G0S2 can function to oppose oncogene-induced transformation. G0S2 null MEFs were readily transformed with H-RAS or EGFR while wild-type MEFs were not. Importantly, re-introduction of G0S2 reversed H-RAS transformation of G0S2 null MEFs. Although G0S2 is a known regulator of fat metabolism through attenuating ATGL activity, we found that G0S2 repression of oncogene-induced transformation was independent of ATGL inhibition. Detailed microarray analysis demonstrated that G0S2 knockout alone upregulated gene signatures associated with transformation, proliferation and Myc transcriptional responses. G0S2 knockout also induced c-Myc expression at the transcript and protein level. Finally, transient and stable shRNA-mediated repression of c-Myc completely abrogated oncogene-induced transformation of G0S2 null MEFs. Taken together, these findings indicate that G0S2 can function as a tumor suppressor by opposing Myc. Studies to elucidate the mechanism underlying G0S2 regulation of Myc are ongoing. Understanding the functions and mechanisms of this novel tumor suppressor pathway may lead to new pharmacologic strategies for many cancers where G0S2 is silenced. Citation Format: Christina Y. Yim, David J. Sekula, Sarah J. Freemantle, Ethan Dmitrovsky, Michael J. Spinella. G0S2 functions as a tumor suppressor gene through inhibition of c-Myc. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2026. doi:10.1158/1538-7445.AM2015-2026
Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract.
Authors: J D Khandekar, P J Elson, W D DeWys, R E Slayton, D T Harris
Journal: Journal of Clinical Oncology (1985)

From October 1978 to October 1981, 135 patients with disseminated transitional cell carcinomas of the urinary tract, with either measurable or evaluable disease, were randomized to receive either cis-diamminedichloroplatinum (DDP) or cyclophosphamide (CTX), Adriamycin (ADR) (Adria Laboratories, Columbus, Ohio), and DDP (CAD). DDP was given at a dose of 60 mg/m2, CTX at 400 mg/m2, and ADR at 40 mg/m2 intravenously every three weeks. Patients over the age of 65 and those with prior radiation received 75% of the dose initially. The dose was escalated if only mild toxicity developed. Of the patients on the CAD arm, 34% developed grade 3 or 4 hematologic toxicity, as compared to 3% in patients on the DDP therapy. Of the 93 patients with measurable disease, 48 received DDP. Seventeen percent had a partial or complete remission, as compared to 33% of the 45 patients on the CAD arm (P = .09). The crude median survival of patients on DDP was 6.0 months as compared to 7.3 months in patients receiving CAD (P = .17). We conclude that the CAD combination is more toxic than DDP with, at best, very marginal benefit in survival.
Phase I dose escalation and safety study of a semi-solid matrix (SSM) formulation of oral irinotecan and capecitabine tablets in patients with advanced solid tumors
Authors: A. I. B. Benson, E. Rubin, S. Beers, P. Mucci-Lorusso, W. Vermuelen, L. Denis, L. Compton, D. Pavlov, M. L. Rothenberg
Journal: Journal of Clinical Oncology (2004)

2042 Background: Oral irinotecan has the potential to safely and conveniently achieve protracted exposure of cycling tumor cells to SN-38 (irinotecan's active metabolite). The maximum tolerated dose (MTD) of irinotecan SSM was 60 mg/m2/day x 5 (Proc ASCO 22:130, 2003 (#521). This study evaluates the MTD, dose-limiting toxicities (DLT), of oral irinotecan SSM capsules administered Day 1–5 followed by Day 6–14 oral capecitabine. Methods: Sequential groups of pts received oral irinotecan once daily for 5 consecutive days followed by capecitabine for 9 consecutive days Q3W. MTD is defined as the highest dose level at which less than 2/3 or 2/6 pts experience DLT. 11 additional pts were treated at the MTD. Results: 21 pts with solid tumors (median age=53.5, range 28–78; M/F=10/11; ECOG PS 0/1/2=5/12/3) received starting doses of irinotecan 40 (n=18), and 50 (n=3) mg/m2/d in combination with a fixed dose of capecitabine 800 mg/m2/bid. During dose escalation segment, DLTs were observed in 2/3 pts at 50 mg/m2 (G3 diarrhea (2), dehydration and nausea). Grade 3 /4 toxicities are listed below* Two PRs (colon cancer) and 11 SDs (colon (2), adrenocortical (2), pancreatic (2) lung (2), hepatocellular (1) fibrosarcoma (1), and malignant melanoma (1)) were observed. 6 patients had PD and 2 were not evaluable for response. 4 patients are still receiving treatment. Conclusions: The recommended phase II dose for SSM oral irinotecan is 40 mg/m2/daily for 5 days followed by capecitabine 800 mg/m2/bid for 9 days every 3 wks. From our previous study, we know that this dose and schedule maintains cytotoxic plasma SN-38 drug concentrations continuously over a 5-day period in each 3-week cycle. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer; Roche; Vertex Pfizer Alza; Pfizer; Roche Pfizer (originally by Pharmacia)
Cost-effectiveness analysis of the EORTC 24971 (TAX 323) trial comparing docetaxel plus cisplatin and 5-fluorouracil versus standard treatment (cisplatin and 5-fluorouracil) as induction chemotherapy followed by radiation therapy in locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN)
Authors: J. Jansen, J. B. Vermorken, D. Boote, F. Joulain, A. Parthan
Journal: Journal of Clinical Oncology (2007)

6090 Background: The phase III EORTC 24971 clinical trial (TAX 323) showed that induction chemotherapy followed by radiation therapy increases time to progression and improves outcomes in unresectable SCCHN patients. [Remenar et al. ASCO 2006; Abs 5516] Induction chemotherapy with cisplatin/5-FU (PF) is a standard regimen for patients with locally advanced SCCHN. The economic impact of adding docetaxel to cisplatin/5-FU (TPF) in this setting was assessed using a Markov state-transition model. Methods: The Markov model includes four health states (based on WHO criteria for measuring objective response): stable, response, progression, and death. Efficacy data from the TAX 323 clinical trial were used to derive transition probabilities between the health states. Adverse event rates were also derived from TAX 323. Data for resource utilization and costs for the UK were derived from the literature and from an advisory board of clinicians. In order to calculate quality adjusted life years (QALYs), utilities were derived by mapping the global score on the Health Related Quality of Life Questionnaire Core-30 (QLQ-C30) to the EQ-5D. Results: Patients survived longer in the TPF arm versus PF (2.5 vs. 2.0 years). Total costs for TPF and PF were £31,203 and £26,944, respectively. The incremental discounted cost per QALY gained for TPF versus PF was £9,859/QALY, which is below the £20,000 cost-effectiveness threshold suggested by NICE as a guide to the acceptability of a technology. Conclusion: Docetaxel, when given as induction chemotherapy in combination with cisplatin/5-FU, is cost-effective compared with PF in locally advanced unresectable SCCHN patients. Treating SCCHN patients with TPF followed by radiation represents good value for money based on the results of the analysis. No significant financial relationships to disclose.
Abstract 10999: CHADS2 and CHA2DS2-VASc scores are Predictive of Adverse Cardiovascular Outcomes in All Patients, Not Just Those With a Diagnosis of AF: an Analysis of the 2010 Patients From the MOST Trial
Authors: Taya Glotzer, Gervasio Lamas, Anne S Hellkamp, Kerry L Lee
Journal: Circulation (2013)

Currently, CHADS2 and CHA2DS2-VASc scores (C-scores) are tallied only for patients (pts) who already have a diagnosis of atrial fibrillation (AF). We hypothesized that these scores are predictive o...
Early phase I results of recombinant immunotoxin HA22 in patients with B-cell leukemia
Authors: I. Pastan, W. H. Wilson, M. Stetler-Stevenson, P. Noel, D. J. Fitzgerald, R. J. Kreitman
Journal: Journal of Clinical Oncology (2008)

3039 Background: HA22 is a 63 kDa recombinant anti-CD22 immunotoxin containing the variable domains of the anti-CD22 Mab RFB4 connected to truncated Pseudomonas exotoxin. HA22 is a mutant form of BL22, which induced CR in 61% of patients with CdA-pretreated hairy-cell leukemia (HCL), and partial or marginal response (PR or MR) in chronic lymphocytic leukemia (CLL). BL22 is much more cytotoxic for HCL compared to CLL ex vivo; the median IC50 is 4.3 ng/ml in 33 patients with HCL vs 430 ng/ml in 70 patients with CLL (p < 0.0001). Compared to BL22, HA22 contains THW replacing SSY in the CDR3 domain of the variable heavy domain, which improves binding affinity to CD22 by 15-fold. CLL cells from 17 patients are a median of 8-fold more sensitive to HA22 than to BL22. Methods: Patients with HCL and CLL were treated on 2 separate multicenter phase I protocols. Eligibility required at least 2 prior standard therapies and a medical indication for treatment including either disease-related cytopenias, symptoms or increasing tumor burden. Patients were treated with HA22 by 30 min infusion every other day for 3 doses (QOD x3), with cycles repeated every 28 days. Dose-escalation in each trial required 0 of 3 or 1 of 6 patients with dose limiting toxicity (DLT) by cycle 2 day 10, or by cycle 1 day 28 if patients were followed without DLT and not retreated. Neutralizing antibodies in the serum and active HA22 in the plasma were quantified by cytotoxicity assays using CD22+ Raji cells. Results: Nine HCL and 11 CLL patients received HA22 at 5, 10, or 20 ug/Kg QOD x3, with no DLT. High levels of neutralizing antibodies were observed in 1 (14%) of 7 HCL and 0 of 7 CLL patients evaluated. In 13 of 14 evaluable patients, peak plasma levels were higher with the 3rd than with the 1st dose (median 1.8-fold, range 0.9–11-fold, p < 0.0001), either due to rapidly decreasing tumor burden or clearing of soluble CD22. The median half-life with the 3rd dose of HA22 was 66 min (range 23–121 min). Despite low dose levels, patients with HCL responded with 1 (20%) CR and 4 (80%) PR in 5 evaluable patients. Patients with CLL have had decreases in circulating CLL cells. Conclusions: HA22 at early dose levels is active in HCL and without significant toxicity in both HCL and CLL. There is no evidence of increased toxicity due to the increased binding of HA22 to CD22. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medimmune
Molecular mechanisms of colicin evolution.
Authors: M A Riley
Journal: Molecular Biology and Evolution (1993)

This review explores features of the origin and evolution of colicins in Escherichia coli. First, the evolutionary relationships of 16 colicin and colicin-related proteins are inferred from amino acid and DNA sequence comparisons. These comparisons are employed to detail the evolutionary mechanisms involved in the origin and diversification of colicin clusters. Such mechanisms include movement of colicin plasmids between strains of E. coli and subsequent plasmid cointegration, transposition- and recombination-mediated transfer of colicin and related sequences, and rapid diversification of colicin and immunity proteins through the action of positive selection. The wealth of information contained in colicin sequence comparisons makes this an ideal system with which to explore molecular mechanisms of evolutionary change.
Why We Need Nonpharmacologic Approaches to Manage Chronic Low Back Pain in Older Adults
Authors: M. Carrington Reid, Anthony D. Ong, Charles R. Henderson
Journal: JAMA Internal Medicine (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Precise Correction of Disease Mutations in Induced Pluripotent Stem Cells Derived From Patients With Limb Girdle Muscular Dystrophy
Authors: Soeren Turan, Alfonso P Farruggio, Waracharee Srifa, John W Day, Michele P Calos
Journal: Molecular Therapy (2016)

Limb girdle muscular dystrophies types 2B (LGMD2B) and 2D (LGMD2D) are degenerative muscle diseases caused by mutations in the dysferlin and alpha-sarcoglycan genes, respectively. Using patient-derived induced pluripotent stem cells (iPSC), we corrected the dysferlin nonsense mutation c.5713C>T; p.R1905X and the most common alpha-sarcoglycan mutation, missense c.229C>T; p.R77C, by single-stranded oligonucleotide-mediated gene editing, using the CRISPR/Cas9 gene-editing system to enhance the frequency of homology-directed repair. We demonstrated seamless, allele-specific correction at efficiencies of 0.7-1.5%. As an alternative, we also carried out precise gene addition strategies for correction of the LGMD2B iPSC by integration of wild-type dysferlin cDNA into the H11 safe harbor locus on chromosome 22, using dual integrase cassette exchange (DICE) or TALEN-assisted homologous recombination for insertion precise (THRIP). These methods employed TALENs and homologous recombination, and DICE also utilized site-specific recombinases. With DICE and THRIP, we obtained targeting efficiencies after selection of ~20%. We purified iPSC corrected by all methods and verified rescue of appropriate levels of dysferlin and alpha-sarcoglycan protein expression and correct localization, as shown by immunoblot and immunocytochemistry. In summary, we demonstrate for the first time precise correction of LGMD iPSC and validation of expression, opening the possibility of cell therapy utilizing these corrected iPSC.
Germline methylation of the MSH2 promoter as a cause of Hereditary Non-Polyposis Colorectal Cancer
Authors: Tsun Leung Chan, Siu Tsan Yuen, Judy W. C. Ho, Yee Wai Chan, Annie S. Y. Chan, Emily M. S. Chan, Suet Yi Leung
Journal: Cancer Research (2005)

2760  Promoter methylation mediated silencing of the DNA mismatch repair gene, MLH1, has been observed mostly as a somatic event in sporadic colorectal cancer (CRC) but rare Hereditary Non-Polyposis colorectal cancer (HNPCC) patients with germline methylation of MLH1 promoter have been reported. So far methylation of MSH2 promoter has never been observed in CRC. We have identified a family who satisfied Bethesda criteria 3, with two siblings who developed CRC at the age of 30 and 40 years respectively, and a third sibling who developed adenocarcinoma-in-situ of the endometrium at the age of 43 years. Both CRCs displayed loss of MSH2 protein by immunohistochemistry and available CRC tissue from one case demonstrated high level microsatellite instability (MSI-H). Analysis for MSH2 mutation by protein-truncation test and exon-by-exon sequencing revealed no germline mutation but presence of a somatic MSH2 mutation with retention of heterozygosity in the cancer tissue of the index patient. Methylation of the MSH2 promoter, however, was found by methylation-specific PCR in the cancer tissue, which were further confirmed by direct bisulphite genomic sequencing. Similar analysis of a batch of MSI-H CRC with MSH2 protein loss did not reveal the presence of any methylated products. Furthermore, analysis of the constitutional DNA extracted from the blood and normal colonic mucosae in the index patient and her 5 siblings all showed the presence of the methylated MSH2 promoter products. Haplotype analysis using microsatellite markers within and flanking the MSH2 gene in these 6 siblings revealed 3 haplotypes in total, with all siblings sharing a single common haplotype that is associated with cancer development in three siblings so far. Our results suggest that germline methylation of MSH2 promoter co-segregate with a single MSH2 haplotype and this is associated with a high risk of development of HNPCC-related cancers. Further study for potential alteration in the DNA structure flanking the MSH2 gene in this family may reveal novel mechanisms for epigenetic germline inheritance.