tbuckley/cabot-search huggingface dataset:
Adjuvant gemcitabine for high-risk breast cancer (BC) patients: Final survival results of the randomized phase III SUCCESS-A study.
Authors: Wolfgang Janni, Andreas Schneeweiss, Lothar Haeberle, Peter A. Fasching, Harald Leo Sommer, Mahdi Rezai, Joern Hilfrich, Hans Tesch, Georg Heinrich, Helmut Forstbauer, Thomas W. P. Friedl, Fabienne Schochter, Susanne Albrecht, Bernadette Jaeger, Julia Kathrin Jueckstock, Klaus Friese, Werner Lichtenegger, Matthias W. Beckmann, Brigitte Kathrin Rack
Journal: Journal of Clinical Oncology (2014)

1010 Background: Gemcitabine (G) has shown to have a relevant single agent efficacy and to improve chemotherapy response to taxanes in advanced BC patients. Aim of this study was to evaluate the effect of G on disease free survival (DFS) in high risk adjuvant BC patients. Methods: This is a phase III, randomized, open label trial of FEC-Doc vs. FEC-DocG (3 cycles of FEC (500/100/500 mg/m²) followed by 3 cycles of docetaxel (Doc; 100mg/mg²) every three weeks (q3w) vs. 3 cycles of FEC followed by 3 cycles of G (1,000 mg/m² d1,8) and Doc (75 mg/m²) q3w). Key inclusion criteria: stage N1 or T2–T4 or grade 3 or age ≤ 35 or hormone receptor (ER/PR) negative. Key exclusion criteria: locally recurrent/metastatic disease; prior systemic therapy or radiotherapy for current BC. Strata for randomization: nodal, ER/PR, menopausal and HER2 status and grading. Primary and secondary study aims were DFS and overall survival (OS). Survival rates were estimated by the Kaplan-Meier method. Cox regression models were fitted to estimate unadjusted hazard ratios (HRs). Further exploratory analyses investigated treatment differences within patient subgroups. Results: 3,754 patients were randomized to FEC-Doc (n=1898) or FEC-DocG (n=1856). Median observation time was 5.3 ys with 456 (238 vs. 218; FEC-Doc vs. FEC-DocG) events for DFS and 269 (140 vs. 129) events for OS. Mean age was 53.5 ys and 58.7% were ≥ T2, 66.1% were nodal positive, 29.3% ER and PR negative and 23.5% HER2 positive. 5-year DFS rate was 0.87 for both randomization arms and 5-year OS was 0.93 for both arms. HRs for DFS and OS were 0.93 (95%CI: 0.78-1.12; p=0.46) and 0.94 (95%CI: 0.74-1.19; p=0.60). Further analyses, accounting for age, body mass index, tumour stage, grading, lymph node status, tumor type, hormone receptor and HER2neu status, did not generate any hypothesis for subgroup-specific efficacy. Conclusions: AdjuvantGemcitabine does not improve the efficacy of FEC-Doc chemotherapy for high risk breast cancer patients. With regard to the risk-benefit ratio, we do not recommend adjuvant Gemcitabine for the adjuvant treatment of high risk breast cancer patients. Future analyses will report on circulating tumor cells, serum markers and pharmacogenomics. Clinical trial information: 2005-000490-21.
Pretreatment characteristics and early indicators of long-term efficacy of cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (rmSCCHN).
Authors: Ulrich Keilholz, Maren Knoedler, Ines Redlich, Thomas Christoph Gauler
Journal: Journal of Clinical Oncology (2013)

e17015 Background: Cetuximab has established activity in rmSCCHN as a single agent as well as in conjunction with chemotherapy. Combination treatment protocols lead to significant toxicity. It would be of interest to identify pretreatment characteristics and early indicators of long-term cetuximab efficac. Methods: rmSCCHN patients were analysed, who participated in trials of chemotherapy plus cetuximab, followed by cetuximab maintenance. Patients were stratified into two groups of long term exposure (LTE) and short term exposure (STE) of cetuximab using 6 months as cut-off. Factors considered for analysis included age, sex, performance status, smoking behavior, primary tumor site, time from primary to treatment for rm-disease, number of chemotherapy cycles received, response, toxicity, and reason for treatment discontinuation. Results: In 2 institutions, 61 patients were enrolled in 5 clinical trials between 2008 and 2011. Cetuximab was administered in standard dose and schedule until disease progression or unacceptable toxicity. 27 patients received cetuximab &lt;6 mo (STE, median 1.5 mo) and 34 &gt;6 mo (LTE, median 9 mo). Patients with LTE as compared to STE only differed in 2 characteristics: oral/oropharyngeal primary (56% vs. 41%) and median chemotherapy cycles received (6 vs. 2). Comparing LTE to STE, treatment discontinuation during the chemotherapy phase was due to toxicity in 14 vs. 37% or death in 4 vs. 15%. Median OS in LTE vs. STE was 18 vs. 4 mo. Conclusions: LTE was associated with a huge improvement of OS. Toxicity of chemotherapy was a relevant factor for early discontinuation of combination treatments, limiting the overall efficacy of cetuximab. Results may be improved by further intensification of the already implemented proactive toxicity management, but also by development of less toxic chemotherapy schedules.
Trends of Classification, Incidence, Mortality, and Survival of MDS Patients in Switzerland Between 2001 and 2012
Authors: Nicolas Bonadies, Anita Feller, Alicia Rovo, Axel Ruefer, Sabine Blum, Bernhard Gerber, Georg Stuessi, Rudolf A. Benz, Nathan Cantoni, Andreas Holbro, Schmidt Adrian, Thomas Lehmann, Matthias Wilk, Volker Arndt
Journal: Blood (2016)
Phase I Trial of the Oral Poly (ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888, V) Combined Wtih Topoecan (T) and Carboplatin (C) for Adults with Relapsed and Refractory Acute Leukemias
Authors: Judith E. Karp, Keith W Pratz, Mark R. Litzow, Jiuping Ji, Alice Chen, Michelle Rudek, Scott H. Kaufmann
Journal: Blood (2010)
Abstract B26: Epigenetic master regulator EPC1 is a decisive factor for E2F1 to silence cell death and activate metastatic gene signatures in response to DNA damage
Authors: David Engelmann, Yajie Wang, Vijay Alla, Deborah Goody, Shailendra K. Gupta, Alf Spitschak, Brigitte M. Pützer
Journal: Cancer Research (2016)

Abstract The transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Recently, it has been shown that aberrant E2F1 expression often detectable in advanced-stage metastatic and chemoresistant cancers contributes essentially to malignant progression and characterizes the aggressive potential of a tumor. Conceptually, this requires a subset of malignant cells capable of evading apoptotic death through anticancer drugs. The molecular mechanism by which the pro-apoptotic activity of E2F1 is antagonized is widely unclear. Here we report a novel function for enhancer of polycomb homolog 1 (EPC1) in DNA damage protection. Depletion of EPC1 potentiates E2F1-mediated apoptosis in response to genotoxic treatment and abolishes tumor cell motility. We found that E2F1 directly binds and activates the EPC1 promoter and EPC1 vice versa physically interacts with bifunctional E2F1 to modulate its transcriptional activity in a target gene-specific manner. Remarkably, nuclear-colocalized EPC1 activates E2F1 to upregulate the expression of anti-apoptotic survival genes such as BCL-2 or Survivin and inhibits death-inducing targets including p27 and Bim. Mechanistically, we observed that EPC1 is required for recruitment of Tip60, a subunit of the NuA4 acetyltransferase complex, to E2F sites of the Bcl-2 promoter, causing increased activating histone acetylation levels. In contrast, ablation of EPC1 removes the PRC2 component EZH2 from the p27 promoter, resulting in decreased histone methylation for E2F1-mediated gene activation. In this scenario, EPC1 acts as a crucial bridging factor to connect E2F1 with essential components of the chromatin remodeling complexes Nu4A and PRC2. The uncovered cooperativity between EPC1 and E2F1 triggers a gene signature in advanced cancers that predicts metastatic behavior and poor patient survival. These findings unveil a novel oncogenic function of EPC1 for inducing the switch into tumor progression-relevant gene expression that may help to set novel therapies. This work was supported by German Cancer Aid, Dr. Mildred Scheel Stiftung (109801 to B.M.P. and D.E.) and German Federal Ministry of Education and Research (BMBF) as part of the eBio:SysMet project (0316171 to B.M.P.). Note: This abstract was not presented at the conference. Citation Format: David Engelmann, Yajie Wang, Vijay Alla, Deborah Goody, Shailendra K. Gupta, Alf Spitschak, Brigitte M. Pützer. Epigenetic master regulator EPC1 is a decisive factor for E2F1 to silence cell death and activate metastatic gene signatures in response to DNA damage. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B26.
Abstract P294: Higher Obesity Duration and Severity are Associated with Progression to Metabolic Syndrome From Metabolically Healthy Obesity: Discrete Time Survival Evidence From the Multi-Ethnic Study of Atherosclerosis
Authors: Morgana Mongraw-Chaffin, Meredith C Foster, Rita R Kalyani, Dhananjay Vaidya, Gregory L Burke, Mark Woodward, Cheryl A Anderson
Journal: Circulation (2016)

While the health risks of obesity compared to normal weight have been well studied, the cumulative risk associated with chronic obesity remains unknown. Specifically, debate continues about the importance of recommending weight loss for those who have metabolically healthy obesity. We therefore hypothesized that longer duration of obesity combined with greater severity of obesity is associated with progression to incident metabolic syndrome. We used complementary log-log models of discrete time survival to metabolic syndrome with clustered robust variance for time varying obesity severity and duration in 2,748 Multi-Ethnic Study of Atherosclerosis participants with obesity (BMI≥30kg/m 2 ) at any visit. Participants who developed metabolic syndrome before obesity were excluded. We defined obesity duration as the number of visits with measured obesity and obesity severity as the WHO levels I-III based on BMI. We defined metabolic syndrome using Adult Treatment Panel III criteria modified to exclude waist circumference. We assessed whether participants exhibited individual heterogeneity in their risk for metabolic syndrome using a random effects complementary log-log model. We specified an a priori sensitivity analysis to determine if the results were similar in those younger or older than 70 years. Higher obesity severity and duration were independently associated with incident metabolic syndrome (Table 1). Including random intercepts in the model, while statistically significant, did not attenuate other associations. Estimates for duration were stronger for those under 70 years when compared to those 70 and older (age interaction p=0.039). While there is significant individual heterogeneity in risk, both duration and severity of obesity are associated with incident metabolic syndrome, suggesting that metabolically healthy obesity is a transient state in the pathway to metabolic risk. Weight loss should be recommended to all individuals with obesity, including those who are currently metabolically healthy. Table 1. Metabolic syndrome hazard ratios and 95% confidence intervals from complementary log-log models of discrete time survival by obesity duration and severity in MESA participants with measured obesity at any visit (n=2,748) * All models include age, gender, and race/ethnicity, and indicator variables for study visit (visits 1-5) ** All models, except for the random effects model, use robust variance clustered on participant ID *** Metabolic syndrome is defined as 2 or more of the following: 1. Triglyceride level ≥150mg/dL 2. HDL cholesterol &lt;40mg/dL in men and &lt;50mg/dL in women 3. Systolic blood pressure ≥130mmHG or diastolic blood pressure ≥85mmHG or use of blood pressure medications 4. Fasting glucose ≥100mg/dL or use of medications for diabetes
Experience in Second Line TKI Treatment in 6 Million Region of Russia (St-Petersburg and Leningrad region).
Authors: Kudrat Abdulkadirov, Elza Lomaia, Alla Abdulkadirova, Vasiliy Shuvaev, Vera Udalieva, Elena Usacheva, Elena Machulaitene, Irina Zotova, Ekaterina Poznyak, Elena Koryagina, Natalia Ilina, Tatiana Shneider, Svetlana Stepanova, Ekaterina Romanova, Eugenia Salamatova, Elena Goryunova, Natalija Lazorko, Irina Martinkevich, Andrey Zaritskey
Journal: Blood (2009)
Clock genes expression in breast cancers (BC) from patients (pts) treated with neoadjuvant chemotherapy (NAC) in a randomized multicenter phase II trial.
Authors: Sylvie Giacchetti, Ida Iurisci, Guillaume Meurice, Patricia de Cremoux, Suzette Delaloge, Frederique Spyratos, Jacqueline Lehmann- Che, Etienne Brain, Michel E. Marty, Bernard Asselain, Jean-Yves Pierga, Francis Levi
Journal: Journal of Clinical Oncology (2014)

e11528 Background: Circadian clocks control cellular metabolism and proliferation. Circadian disruption could affect BC development and treatment efficacy. Purpose: To determine the relevance of 17 core clock genes as prognostic factors and their predictive value for pathological complete response (pCR) to NAC and disease-free survival. Methods: Tumor biopsies from 189 BC pts in a randomized Phase II trial were available for DNA microarrays (Pierga, BCRT, 2010; De Cremoux, Breast 2013). Transcriptome was determined with Affymetrix chip. Three metagenes were identified using Non negative Matrix Factorization. Genes recapitulating a metagene were defined by r > 0.7 (Pearson). Principal component analysis (PCA) discriminated groups according to clock genes expression. Differential analysis using LIMMA’s package scrutinized clock genes according to BC characteristics, pCR and DFS. Results: No clock gene expression was correlated to the metagenes. PCA did not discriminate any group according to individual clock genes. The activating regulatory loop (Bmal1, Clock and Npas2) discriminated 2 groups regarding the first principal component: a homogeneous one, mostly represented by non triple negative BC (144 pts), and a heterogenous group related to TNBC (45 pts). Dec1 was highly expressed in ER+ BC, and underexpressed in TN and mutated P53. Cry2, Per2, and Dec1 were underexpressed in BC achieving pCR (Table). BC relapses within 12 months were associated with NPAS2 overexpression Conclusions: Circadian clock genes displayed different expression according to BC characteristics and response to chemotherapy, suggesting their potential relevance for BC prognosis and control. Expression of clock genes according to BC features and pCR. Clock genes ER+ vs. ER- Grade 1+ 2 vs. 3 HER2 +++ vs - TN vs. NTN P53 mut vs. wt pCR yes vs. no Per2 1.50 (***) 1.48 (**) -1.79 (***) -1.48 (*) -1.47 (*) Clock 1.15 (*) -1.22 (*) Cry2 1.27 (***) 1.41 (***) -1.33 (***) -1.29 (*) Dec1 2.23 (***) -2.36 (***) -2.22 ( *) -2.26 (**) CSNK1δ -1.20 (**) -1.36 (**) 1;25 (*) NPAS2 -1.39 (**) 1.43 (**) Reverb α 1.43 (*** ) -1.4 (***) CSNK1ε 1.6 (***) -1.32 (*) (fold change;*p <10-2; ** p< 10-3; p***< 10-4)
Mesencephalic astrocyte-derived neurotrophic factor reduces cell apoptosis via upregulating HSP70 in SHSY-5Y cells
Authors: Hui Sun, Ming Jiang, Xing Fu, Qiong Cai, Jingxing Zhang, Yanxin Yin, Jia Guo, Lihua Yu, Yun Jiang, Yigang Liu, Liang Feng, Zhiyu Nie, Jianmin Fang, Lingjing Jin
Journal: Translational Neurodegeneration (2017)

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a new candidate growth factor for dopaminergic neurons against endoplasmic reticulum stress (ER stress). HSP70 family, a chaperon like heat shock protein family, was proved to be involved in the MANF induced survival pathway in 6-OHDA treated SHSY-5Y cells. However, the ER stress relative transcriptome, in MANF signaling cascades is still investigated. The involvement of HSP70, a 70kd member of HSP70 family, need further to be verified. The cell apoptosis was assayed by MTT, TUNEL staining and western blot of cleaved Caspase-3. The differentially expressed genes in SHSY-5Y cells under different conditions (control, 6-OHDA, 6-OHDA + MANF) were investigated by RNA-seq. Expression of HSP70 was further confirmed by real-time PCR. RNAi knockdown for HSP70 was performed to investigate the role of HSP70 in the MANF signaling pathway. MANF inhibits 6-OHDA-induced apoptosis in SHSY-5Y cells. Six ER stress relative genes (HSP70, GRP78, xbp-1, ATF-4, ATF-6, MAPK) were found enriched in 6-OHDA + MANF treatment group. HSP70 was the most significantly up-regulated gene under 6-OHDA + MANF treatment in SHSY-5Y cells. RNAi knockdown for HSP70 inhibits the protective effects of MANF against 6-OHDA toxicity in SHSY-5Y cells. MANF exerts a protective role against 6-OHDA induced apoptosis in SHSY-5Y cells via up-regulating some ER stress genes, including HSP70 family members. The HSP70 expression level plays a key role in MANF-mediated survival pathway.
Abstract 194: Characterization of Arrhythmogenic Dilated Cardiomyopathy Caused by Novel Filamin C Splice Variant in a Zebrafish Model
Authors: Rene L Begay, Teisha J Rowland, Charles A Tharp, August Martin, Sharon L Graw, Gianfranco Sinagra, Daniela Miani, Dobromir B Slavov, Neil Stafford, Mary E Sweet, Francesca Brun, Kenneth L Jones, Katherine Gowan, Luisa Mestroni, Deborah M Garrity, Matthew R Taylor
Journal: Circulation Research (2015)

Although dilated cardiomyopathy (DCM) is a serious and frequent genetic cause of heart failure, only 30-40% of cases can be attributed to a known DCM gene mutation. To identify and confirm additional disease genes involved in DCM, we performed whole exome sequencing in two multigenerational families with DCM, both from the same geographic region of Italy, and found a novel splice variant in the gene encoding filamin-C (FLNC). Previously characterized mutations in FLNC had been primarily linked to skeletal muscle disease, although none of the affected family members displayed skeletal myopathy. To confirm and further characterize the arrhythmogenic DCM phenotype observed in family members, we performed embryonic knockdown experiments using morpholino (MO) treatment in zebrafish (Danio rerio) targeting the FLNC ortholog, filamin Cb (flncb). Following MO injection into 1-2 cell stage zebrafish embryos, 63.4% (78 of 123) of viable flncb MO-injected embryos displayed a cardiac phenotype at 72 hours post fertilization (hpf) (vs. 17.0% [30 of 177] of control MO-injected embryos; p≤0.001). Increases in mortality were observed, with 20.8% (54 of 260) of flncb MO-injected embryos surviving at 7 days post fertilization (vs. 65% [162 of 249] of control embryos; p≤0.001). The flncb MO-injected embryos demonstrated pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction. The flncb MO-injected embryos additionally demonstrated a lower mean stroke volume than controls (0.076 vs. 0.181 nl; p=0.015), a reduced mean cardiac output (10.8 vs. 25 nl/min; p=0.02), and an increase in the fraction of retrograde blood flow over the cardiac cycle (0.42 vs. 0.03; p=0.027). Overall, this flncb MO treatment recapitulated a DCM phenotype similar to the state caused by the human splicing variant, supporting haploinsufficiency as the mechanism leading to DCM in these families. Our findings suggest that approaches to augment endogenous filamin C protein levels may represent a viable treatment strategy that warrants exploration in future studies.
In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs
Authors: Maxim Bez, Dmitriy Sheyn, Wafa Tawackoli, Pablo Avalos, Galina Shapiro, Joseph C. Giaconi, Xiaoyu Da, Shiran Ben David, Jayne Gavrity, Hani A. Awad, Hyun W. Bae, Eric J. Ley, Thomas J. Kremen, Zulma Gazit, Katherine W. Ferrara, Gadi Pelled, Dan Gazit
Journal: Science Translational Medicine (2017)

Microbubble-enhanced, ultrasound-mediated BMP-6 gene delivery to endogenous progenitor cells induces rapid and efficient repair of critical-sized, nonunion bone fractures in mini-pigs.
Self‐Assembled Nanoparticles from Phenolic Derivatives for Cancer Therapy
Authors: Yunlu Dai, Junling Guo, Ting‐Yi Wang, Yi Ju, Andrew J. Mitchell, Thomas Bonnard, Jiwei Cui, Joseph J. Richardson, Christoph E. Hagemeyer, Karen Alt, Frank Caruso
Journal: Advanced Healthcare Materials (2017)

Therapeutic nanoparticles hold clinical promise for cancer treatment by avoiding limitations of conventional pharmaceuticals. Herein, a facile and rapid method is introduced to assemble poly(ethylene glycol) (PEG)-modified Pt prodrug nanocomplexes through metal-polyphenol complexation and combined with emulsification, which results in ≈100 nm diameter nanoparticles (PtP NPs) that exhibit high drug loading (0.15 fg Pt per nanoparticle) and low fouling properties. The PtP NPs are characterized for potential use as cancer therapeutics. Mass cytometry is used to quantify uptake of the nanoparticles and the drug concentration in individual cells in vitro. The PtP NPs have long circulation times, with an elimination half-life of ≈18 h in healthy mice. The in vivo antitumor activity of the PtP NPs is systematically investigated in a human prostate cancer xenograft mouse model. Mice treated with the PtP NPs demonstrate four times better inhibition of tumor growth than either free prodrug or cisplatin. This study presents a promising strategy to prepare therapeutic nanoparticles for biomedical applications.
STUDIES ON THE ETIOLOGY OF RABBIT POX
Authors: Louise Pearce, Paul D. Rosahn, Ch'uan-K'uei Hu
Journal: The Journal of Experimental Medicine (1936)

The white mouse, the guinea pig, the calf, and probably the rat, were found to be susceptible to infection with the virus of rabbit pox. Serial transmission of the virus in mice by brain to brain passage was characterized by a fatal outcome usually on the 5th or 6th day after inoculation. Infection of the guinea pig was accomplished by intratesticular injection and the virus was continued to the 2nd passage in this species. Guinea pigs developed a well marked cutaneous reaction from the intradermal injection of both rabbit and guinea pig tissue virus. Active virus was demonstrated in the testicles of rats 8 days after intratesticular injection by rabbit subinoculation. In the calf inoculation of the scarified skin was followed by the development of large papular lesions with marked hemorrhage and necrosis. The results of the investigations on the etiology of rabbit pox and of the experimentally induced infection reported in this and the four preceding papers (1-4) are discussed with special reference to the relation of pox virus to other viruses and of rabbit pox to other pock diseases.