tbuckley/cabot-search huggingface dataset:
Differential anti-vascular effects of mTOR or VEGFR pathway inhibition: A rational basis for combining RAD001 and PTK787/ZK222584
Authors: Terence M. O’Reilly, Jeanette M. Wood, Littlewood-Evans Amanda, Anne Boulay, Christian R. Schnell, Sini Patrizia, Michael Maira, Georg Martiny-Baron, Heidi A. Lane
Journal: Cancer Research (2005)

3038  The potent antiproliferative/antitumor compound RAD001 (everolimus) is an mTOR pathway inhibitor in phase II cancer clinical trials. The mTOR pathway is involved in regulation of proangiogenic factor production by tumors and modulation of VEGFR signaling in endothelial cells. The antiangiogenic effects caused by RAD001 were examined, using tumors derived from cell lines considered sensitive (B16/BL6 melanoma, 0.7 nM IC50) or resistant (KB-31 epidermoid 1.8 μM IC50) to RAD001 in vitro. At 5 mg/kg/d, p.o., RAD001 elicited potent antitumor activity in mouse tumor models (T/C: B16/BL6, 24% in primary tumors [P] and 9% in lymph node metastases [M]; KB-31 26%) despite sub-optimal drug exposure in the resistant models (tumor Cmax ∼106 nM). RAD001 treatment reduced tumor vascularization (versus controls, B16/BL6 P, ∼50%, M, ∼65%, and KB-31, ∼54%), and also reduced plasma and tumor VEGF levels, and These effects of RAD001 on angiogenic processes may explain its activity against tumors formed by cells resistant to mTOR inhibition. Comparison of the anti-angiogenic effects of RAD001 with those of PTK787/ZK222584 [PTK787] (a potent, selective small molecule inhibitor of VEGFR tyrosine kinase in phase III clinical trials), indicated overlapping effects on VEGF-induced endothelial cell proliferation but not endothelial cell migration consistent with an integral role of the mTOR pathway in the VEGFR proliferative signaling. The two agents differed in their effects on vascular permeability (significantly reduced by PTK787, while RAD001 was without effect) and the vessel-associated smooth muscle cell population (absence in RAD001-treated tumors, but only reduced in PTK787-treated tumors). Combining RAD001 (1 mg/kg/d and PTK787 100 mg/kg/d) produced profound antitumor effects in the RAD001-sensitive B16/BL6 model (T/C: P 2%, M 9%) as compared with single agents (T/C: RAD001, P 45%, M 33% and PTK787 38% for both P and M). This also occurred with tumors from the RAD001-resistant KB-31 line (T/C, RAD001, 47%, PTK787 61%, combination 31%). In the B16/BL6 model, the combination potently inhibited tumor VEGF and tumor vascularization as compared with single agents. The differential effects of mTOR and VEGFR inhibition on antiangiogenic processes likely contribute to the drug combination effects. Hence, the combination of RAD001 and PTK787 holds strong promise for the treatment of human cancers.
Circulating-free DNA (cfDNA) as biomarker of taxane resistance in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Edoardo Francini, Fang-Shu Ou, Justin Rhoades, Eric G. Wolfe, Edward O'Connor, Gavin Ha, Gydush Gregory, Kaitlin Kelleher, Rupal Satish Bhatt, Steven P. Balk, Christopher Sweeney, Viktor Adalsteinsson, Mary-Ellen Taplin, Atish Dipankar Choudhury
Journal: Journal of Clinical Oncology (2020)

174 Background: Docetaxel (D) and cabazitaxel (C) are standard chemotherapies for mCRPC. A reliable biomarker predictive of resistance to D or C is yet to be identified. We aimed to assess the association between genetic amplification of the multidrug resistance transporter ABCB1 (ABCB1 amp) and primary resistance (RES) to D or C for mCRPC, using cfDNA. Methods: A cohort (A) of 136 patients (pts) with at least 1 plasma sample drawn and stored within 1 year prior to starting D for mCRPC (2002-2014) and a cohort (B) of 42 pts with at least 1 plasma sample from within 1 year prior to starting C for mCRPC (2010-2016) were identified from the Dana-Farber Cancer Institute IRB approved database. Whole genome sequencing (WGS) at 0.1x coverage, termed ultra-low pass WGS (ULP-WGS), was performed on cfDNA extracted from the selected samples (1000μL/subject) and sequencing data were analyzed using a tool called ichorCNA to identify cases with sufficient tumor DNA content (&gt;7%) for accurate detection of copy number alterations (CNAs) including ABCB1 amp. Primary objective was the association between ABCB1 amp and RES to D or C. RES was defined as lack of response (no PSA50 decline or radiologic response per RECIST criteria 1.1, within 4 months from treatment start). Odds ratio (OR) was used to compare odds of RES to D or C for pts with ABCB1 amp and P-values were calculated by Fisher’s exact test. Results: Of the selected 178 pts, 66 had tumor fraction &gt;7%: 45 pts in cohort A and 21 in cohort B. No significant association was noted between ABCB1 amp and RES to D (P=0.7123; OR=1.600) or C (P=1.000; OR=1.0606). RES was observed in 26 pts (57.8%) of cohort A and 18 (85.7%) of cohort B. ABCB1 amp was found in 9 pts (20%; 95% CI, 9.6-34.6) in group A and 6 of them (66%) had RES to D. ABCB1 amp rate among D-resistant men was 23.1% (95% CI, 9.0-43.7). In group B, 2 pts (9.5%; 95% CI, 1.2-30.4) had ABCB1 amp and both of them had RES to C. ABCB1 rate among C-resistant pts was 11.1% (95% CI, 1.4-34.7). Conclusions: In this study, ABCB1 amp using cfDNA did not show statistically significant correlation with RES to D or C for pts with mCRPC. Future studies including ABCB1 amp in a suite of putative biomarkers and larger sample size may aid drawing definitive conclusions.
STAT3 activation promotes angiogenesis in human breast cancer cells
Authors: Sateesh Kunigal, Sajani Lakka, Norman Estes, Roger Geiss, Meena Gujrati, Jasti Rao
Journal: Cancer Research (2008)

439  Overexpression of vascular endothelial growth factor (VEGF) is associated with angiogenic phenotype and poor prognosis in a variety of human cancers, including breast cancer. However, the precise mechanism underlying VEGF overexpression in breast cancer remains unknown. Previous studies show that signal transducer and activator of transcription 3 (STAT3) is constitutively activated in breast tumors; this activation is significantly associated with aggressive phenotypes of breast cancer. In the present study, we investigated the role of STAT3 activation on VEGF production and tumor angiogenesis in breast tumors both in vitro and in vivo. Transfection with constitutively activated STAT3 increased STAT3 activation, which in turn, enhanced breast metastasis. In contrast, blockade of STAT3 activation by transfection with siRNA for STAT3 suppressed breast tumor growth in animal models. Furthermore, altered STAT3 activity profoundly affected breast tumor angiogenesis in vivo, tumor cell invasion in vitro, and the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2) in vivo and in vitro. Finally, STAT3 activity transcriptionally regulated the promoter activity of bFGF as well as VEGF and MMP-2 in human cancer cells. These results indicate STAT3 activation plays an important role in the dysregulated expression of bFGF, VEGF and MMP-2 as well as in the angiogenic and invasive processes utilized by cancer cells_all of which contribute to metastasis. Therefore, STAT3 activation may present a novel target in the treatment of human breast cancer.
Endoscopic Ultra Sound-guided RadioFrequency Ablation (EUSRFA) as focal treatment for pancreatic metastases from renal cell carcinoma: A monocentric experience.
Authors: Brice Chanez, Fabrice Caillol, Jean-Philippe Ratone, Erwan Bories, Christian Pesenti, Geraldine Pignot, Serge Brunelle, Jochen Walz, Jeanne Thomassin, Naji Salem, Marc Giovannini, Gwenaelle Gravis
Journal: Journal of Clinical Oncology (2020)

695 Background: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are rare but associated with long survival. The usual management of PM is surgery or tyrosine kinase inhibitor (TKI) with sides effects. Endoscopic radiofrequency ablation (EUSRFA) is an innovative approach to focally treat deep metastasis and could be a relevant technic to control PM from RCC. Methods: This analysis addressed the local control and toxicity in patients treated by EUSRFA for progressive PM from RCC. EUSRFA was done with a linear EUS scope and a 19 G needle delivering short ablation time. Response was assessed by CT-scan using both size and contrast enhancement of the PM treated every 2 to 3 months. Results: 8 pts from Paoli-Calmettes Institute (France) were treated between May 2017 and August 2019. Age was 70.5y [61-75], 5/8 female, ECOG 0-1 (100%). The median time from diagnosis to PM was 14.5 years [9.35-22.18], median number of PM was 2 [1-3], 6/8 was documented by histology and all were classified as progressive before EUSRFA. PM localizations was: head in 40%, body 40% and average size was 14 mm [4 - 35]. 75% of pts (6/8) had other mRCC spread, 5/8 had received systemic treatment and 2 were on therapy at EUSRFA time. 3 pts had EUSRFA as the only treatment for RCCm. We performed 18 EUSRFA procedures over 16 PM. Patient received in median 2 EUSRFA sessions [1-3]. Follow up of 22.4 months [2.3-42.6], 50% of treated PM was evaluated as complete response, 17.5% as partial response and 20% as stable disease at the last CT-scan evaluation. 2 pts were considered as progressive disease and PM focal control was 87.5%. One patient treated with TKI during EURFA developed a paraduodenal abscess 2 months after EUSRFA. Another patient with biliary prothesis developed hepatic abscesses few days after EUSRFA. No other acute side effects were experienced. Interestingly, all PM treated with diameter of &lt; 20mm was locally control versus only 75% of PM&gt; 20mm. Conclusions: Though larger studies have to corroborate our data, EUSRFA is feasible and displays a good local control for PM. It could be a valuable option, less morbid than pancreas resection, for well selected patients with progressive PM.
Ube2v1 Positively Regulates Protein Aggregation by Modulating Ubiquitin Proteasome System Performance Partially Through K63 Ubiquitination
Authors: Na Xu, James Gulick, Hanna Osinska, Yang Yu, Patrick M. McLendon, Kritton Shay-Winkler, Jeffrey Robbins, Katherine E. Yutzey
Journal: Circulation Research (2020)

Compromised protein quality control can result in proteotoxic intracellular protein aggregates in the heart, leading to cardiac disease and heart failure. Defining the participants and understanding the underlying mechanisms of cardiac protein aggregation is critical for seeking therapeutic targets. We identified Ube2v1 (ubiquitin-conjugating enzyme E2 variant 1) in a genome-wide screen designed to identify novel effectors of the aggregation process. However, its role in the cardiomyocyte is undefined.
Impact of time to antibiotic therapy on clinical outcome in patients with bacterial infections in the emergency department: implications for antimicrobial stewardship
Authors: P. Nauclér, A. Huttner, C.H. van Werkhoven, M. Singer, P. Tattevin, S. Einav, T. Tängdén
Journal: Clinical Microbiology and Infection (2020)

BackgroundRapid initiation of antibiotic treatment is considered crucial in patients with severe infections such as septic shock and bacterial meningitis, but may not be as important for other infectious syndromes. A better understanding of which patients can tolerate a delay in start of therapy is important for antibiotic stewardship purposes.ObjectivesTo explore the existing evidence on the impact of time to antibiotics on clinical outcomes in patients presenting to the emergency department (ED) with bacterial infections of different severity of illness and source of infection.SourcesA literature search was performed in the PubMed/MEDLINE database using combined search terms for various infectious syndromes (sepsis/septic shock, bacterial meningitis, lower respiratory tract infections, urinary tract infections, intra-abdominal infections and skin and soft tissue infections), time to antibiotic treatment, and clinical outcome.ContentThe literature search generated 8828 hits. After screening titles and abstracts and assessing potentially relevant full-text papers, 60 original articles (four randomized controlled trials, 43 observational studies) were included. Most articles addressed sepsis/septic shock, while few studies evaluated early initiation of therapy in mild to moderate disease. The lack of randomized trials and the risk of confounding factors and biases in observational studies warrant caution in the interpretation of results. We conclude that the literature supports prompt administration of effective antibiotics for septic shock and bacterial meningitis, but there is no clear evidence showing that a delayed start of therapy is associated with worse outcome for less severe infectious syndromes.ImplicationsFor patients presenting with suspected bacterial infections, withholding antibiotic therapy until diagnostic results are available and a diagnosis has been established (e.g. by 4–8 h) seems acceptable in most cases unless septic shock or bacterial meningitis are suspected. This approach promotes the use of ecologically favourable antibiotics in the ED, reducing the risks of side effects and selection of resistance.
Consistency of patient versus investigator reporting of symptomatic adverse events (AEs) in international trials.
Authors: Elaine Chang, Yutao Gong, Chana Weinstock, Daniel L. Suzman, Amna Ibrahim, Julia A. Beaver, Paul Gustav Kluetz
Journal: Journal of Clinical Oncology (2020)

38 Background: FDA approved 3 androgen receptor inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on global randomized trials with control arms of placebo + ADT. Despite similar enrolled populations, grade 1 or higher investigator-reported, Common Terminology Criteria for Adverse Events (CTCAE)-graded fatigue ranged 11-25% in the placebo arms. We sought to characterize variability in investigator-reported, CTCAE-graded fatigue across geographic regions and compare this with the variability in patient-reported fatigue. Methods: Data from patients receiving ≥ 1 placebo dose were reviewed from control arms of 3 nmCRPC double-blind, placebo-controlled trials submitted to FDA. We determined worst grade clinician-reported (ClinRO) CTCAE fatigue, and most severe fatigue reported by patient-reported outcome (PRO) for each patient at any time during treatment or within 30 days of last dose in each trial by geographic region: North America/Western Europe (NAWE) versus rest of the world (ROW). We compared variability in fatigue rates to those of a more objective AE, CTCAE-defined anemia. Results: NAWE enrollment comprised 46-75% of placebo cohorts. Median age was comparable across trials and regions. ClinRO CTCAE fatigue was higher in NAWE (15-33%) compared to ROW (8-14%) in each of the 3 placebo cohorts (see Table). Rates of PRO fatigue varied by region (50-73% in NAWE compared to 42-59% in ROW), and the regional differential was present at baseline. Anemia rates were similar in NAWE and ROW in each trial ( &lt; 5%) per CTCAE. Conclusions: CTCAE reporting of fatigue, a subjective symptom, was inconsistent across sites. Anemia, an objective AE, was more consistently reported. ROW investigators less frequently reported fatigue compared to NAWE investigators. Reasons for this are unclear, but could include cultural and language factors. PRO fatigue was relatively consistent across trials and regions. These results should be interpreted with caution, as we acknowledge the limitations of cross-trial comparison.[Table: see text]
Real‐world evidence of subcutaneous allergoid immunotherapy in house dust mite‐induced allergic rhinitis and asthma
Authors: Marek Jutel, Bernd Brüggenjürgen, Hartmut Richter, Christian Vogelberg
Journal: Allergy (2020)

Abstract Background The objective of this study was to analyze the effectiveness of allergen immunotherapy (AIT) with an allergoid in the treatment of house dust mites (HDM)‐induced allergic rhinitis and/or asthma based on recent real‐life data. The outcomes were measured using asthma incidence and consumption of corresponding medications as the indicator of persisting symptoms. Methods In this retrospective cohort analysis of a German longitudinal prescription database, patients who received at least two relevant mite AIT prescriptions in two different successive seasonal cycles were compared with non‐AIT patients who received at least three symptomatic allergic rhinitis (AR) prescriptions in successive mite seasons. Study endpoints included AR progression, asthma progression, asthma occurrence, and therapy adherence. We used multivariate regression analyses to estimate the effects of AIT, adjusting for relevant variables. Results This study included 2350 patients receiving a mite allergoid and 64 740 control patients. After up to 6 years of follow‐up, patients treated with mite allergoid required significantly fewer AR and asthma prescriptions (59.7% vs 10.8%) than the control group, and the probability of asthma development was significantly lower. The adherence of patients receiving allergoid was 63.8% at the end of the second year and 38.6% at the end of the third year. Conclusions This real‐world evidence confirms the good efficacy of subcutaneous AIT with HDM mite allergoid in the treatment of allergic rhinitis and/or asthma. Up to 6 years of follow‐up revealed significant effects in allergic rhinitis by measuring the number of AR medications and demonstrating significant reductions in asthma medications.
Comprehensive targeted gene profiling to determine the genomic signature likely to drive progression of high-grade nonmuscle invasive bladder cancer to muscle invasive bladder cancer.
Authors: Abedalrhman Alkhateeb, Govindaraja Atikukke, Lisa Porter, Bre-Anne Fifield, Dora Cavallo-Medved, Julianna Facca, Yasser El-Gohary, Tianmin Zhang, Osamah Hamzeh, Luis Rueda, Sindu Mary Kanjeekal
Journal: Journal of Clinical Oncology (2020)

568 Background: Bladder cancer is the fifth most common cancer and eighth leading cause of cancer related-death in North America. It can present as non-muscle invasive bladder cancer (NMIBC) and/or muscle invasive bladder (MIBC). Although genomic profiling studies have established that low-grade NMIBC and MIBC are genetically distinct, high-grade NMIBC can recur and progress to MIBC [ Knowles, M.A. and C.D. Hurst, 2015]. Low grade, non-invasive bladder cancers are characterized by activating mutations in fibroblast growth factor receptor 3 (FGFR3), HRAS or other pathways of receptor kinase activation. High-grade disease, which is often becomes invasive, is characterized by inactivation of TP53 and Rb pathways [Kim, J., et al.]. Finding a subtype of invasive carcinoma with FGFR3 mutation may suggest an alternate pathway by which low grade, non-invasive pathology could transform into invasive disease [Knowles, M.A. and C.D. Hurst, 2015]. Methods: In this study, using a total of 30 bladder cancer (NMIBC and MIBC) patient samples from Windsor Regional Hospital Cancer Program, we performed comprehensive targeted gene sequencing to identify single nucleotide variants, small insertions / deletions, copy number variants and splice variants in over 500 common tumor genes panel. Results: Preliminary data from our study correlates with previously published mutation landscape for NMIBC and MIBC, and includes mutations in EGFR, FGFR3, FGFR4, PIK3CA, CDK6, ALK, JAK, as well as RET. While mutations in AKT1, BRCA1, CCND1, ERBB2, FGFR1, FGFR2, HRAS, and MET appear to be prevalent in NMIBC, mutations in IDH1 and MAP2K2 appear to be more common in MIBC. Three of the samples used in the study are from patients who progressed from high-grade NMIBC to MIBC. Conclusions: Therefore, have the genomic profiling performed at these two stages, which provides a unique ability to identify the potential “genomic triggers” for the transition.
Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies
Authors: Steven P. Treon, Lian Xu, Maria Luisa Guerrera, Cristina Jimenez, Zachary R. Hunter, Xia Liu, Maria Demos, Joshua Gustine, Gloria Chan, Manit Munshi, Nicholas Tsakmaklis, Jiaji G. Chen, Amanda Kofides, Romanos Sklavenitis-Pistofidis, Mark Bustoros, Andrew Keezer, Kirsten Meid, Christopher J. Patterson, Antonio Sacco, Aldo Roccaro, Andrew R. Branagan, Guang Yang, Irene M. Ghobrial, Jorge J. Castillo
Journal: Journal of Clinical Oncology (2020)

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including MYD88 (95%-97%), CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%). Deletions involving chromosome 6q are common in patients with mutated MYD88 and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type MYD88 WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of MYD88 and CXCR4 mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by MYD88 and/or CXCR4 mutation status. The mutation status of both MYD88 and CXCR4 can be used for a precision-guided treatment approach to WM.
85P Prognostic Impact of Brca1 and Aldh1 Expression in Sporadic Breast Cancer
Authors: M. Ksiazkiewicz, A.J. Zaczek, B. Seroczynska, J. Skokowski, J. Szade, M. Welnicka-Jaskiewicz, P. Nastaly, N. Bednarz-Knoll
Journal: Annals of Oncology (2012)
Significance of distinct specifically enriched missense TP53 mutations in prostate cancer.
Authors: Irina Vasilevskaya, Jennifer McCann, Christopher McNair, Neermala Poudel Neupane, Peter Gallagher, Karen E. Knudsen
Journal: Journal of Clinical Oncology (2020)

377 Background: The most common TP53 alterations are missense mutations occurring in the DNA binding domain. The majority of missense p53 mutants (mut-p53) demonstrate oncogenic gain-of-function (GOF) abilities, irrespective of wild-type p53 presence, and thus contribute to a more aggressive disease. In prostate cancer (PCa), characterized by comparatively low overall mutational burden, TP53 is frequently mutated in both primary and advanced disease. Despite significant progress made in the field, detailed mechanisms of GOF in PCa remain undefined due to differing features of p53 mutants. Methods: Analysis of available datasets was performed to assess TP53 mutational status in PCa patient samples and its correlation with the clinical outcome. Using hormone therapy sensitive and CRPC cells, a panel of cell lines was generated to model the two most frequently occurring mutations in the presence or absence of wild-type TP53, as occurs clinically. CHIP-seq, gene expression arrays, and in vitro and in vivo biological assays were performed to interrogate the significance of mut-p53 in PCa. Results: In PCa, missense mutations are significantly associated with decreased progression-free and overall survival. In PCa patient samples these mutations most commonly occur at the R273 residue, demonstrating specific enrichment when compared to other cancers, with R273C alteration being the most frequent. Using our cell panel, CHIP-seq data revealed an expansion of the p53 cistrome upon expression of R273C and R273H mutants in a manner distinct from p53 stabilization in the presence of wt-p53. Moreover, analysis of the TP53 missense mutant-sensitive transcriptomes demonstrated differential gene expression between these mutants, related to the expression of wild-type TP53 in those cells. Finally, R273C and R273H p53 mutants elicited context dependent effects on canonical p53 functions, thereby modulating distinct downstream biological outcomes. Conclusions: These data expand our knowledge of the underlying mechanisms by which distinct gain-of-function p53 mutants affect prostate cancer, and can lead to identification of novel therapeutic targets to improve clinical outcomes in PCa patients harboring these mutations.