tbuckley/cabot-search huggingface dataset:
Paclitaxel enhances antibody-dependent cell-mediated cytotoxicity of trastuzumab by a rapid recruitment of natural killer cells in Her-2 overexpressing breast cancer
Authors: D. Miura, K. Yoneyama, Y. Furuhata, H. Kawabata
Journal: Journal of Clinical Oncology (2007)

3503 Background: One of the important mechanisms that trastuzumab (TZ) inhibits the growth of Her-2 overexpressing breast cancer cells is the activation of a host tumor response via antibody-dependent cell-mediated cytotoxicity (ADCC). Although paclitaxel (PTX) has a synergistic effect in combination with TZ, whether the ADCC is enhanced by PTX is less known. We questioned whether adding PTX to TZ enhances ADCC and also investigated kinetics of effector cells in ADCC. Methods: Twenty-eight patients with Her-2 overexpression, 9 received the combination of (4mg/kg as a loading and 2 mg/kg weekly) and PTX (80 mg/m 2 weekly) and 19 did monotherapy of TZ, were studied. Using blood samples (mononuclear cells) taken before and 10 minutes after administrations, ADCC and the number of effector cells including NK cell, monocyte, and CD64+ cell were compared in each case (after/before). ADCC was analyzed by 51 Cr releasing assay using SK-BR-3 cell line and the fractions of NK cells (both CD16+(FcγRIII) and CD56+) and CD64+(FcγRI) cells were analyzed by flow cytometry. Results: ADCC levels increased in + 9% (mean) after TZ monotherapy and + 120% (p&lt;0.05) after the combination of TZ and PTX. All 9 patients in combination had enhancements in ADCC levels. As regards effector cells, NK cells increased in + 51% after TZ alone and in + 112% (p&lt;0.05) after the combination. No significant changes were found in monocytes (+ 39%) and CD64+ cells (+ 53%) after TZ, however monocytes decreased in - 40% (p&lt;0.05) and also CD64+ in - 24% after the combination. Conclusions: Adding PTX to TZ significantly enhanced ADCC, which level was twice as strong as TZ monotherapy, by a rapid recruitment of NK cells. This may reflect that a combination of TZ and PTX has a strong synergistic effect than we expected in Her- 2 overexpressing breast cancer. No significant financial relationships to disclose.
Cognitive gadgets and cognitive priors
Authors: Gian Domenico Iannetti, Giorgio Vallortigara
Journal: Behavioral and Brain Sciences (2019)

Some of the foundations of Heyes' radical reasoning seem to be based on a fractional selection of available evidence. Using an ethological perspective, we argue against Heyes' rapid dismissal of innate cognitive instincts. Heyes' use of fMRI studies of literacy to claim that culture assembles pieces of mental technology seems an example of incorrect reverse inferences and overlap theories pervasive in cognitive neuroscience.
Validating the Cancer and Aging Research Group (CARG) toxicity prediction tool in older men receiving chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) and extending it to androgen receptor targeted agents.
Authors: Shabbir M.H. Alibhai, Henriette Breunis, Richard William Gregg, Aaron Richard Hansen, Padraig Richard Warde, Narhari Timilshina, George Tomlinson, Anthony M. Joshua, Neil Eric Fleshner, Urban Emmenegger
Journal: Journal of Clinical Oncology (2019)

11510 Background: Multiple treatment options are available for mCRPC. Being able to predict toxicity risk for different treatments in older adults can aid treatment decision-making and supportive care. The CARG tool is a promising toxicity risk prediction tool for chemotherapy, but has not been specifically validated in the mCRPC setting for either chemotherapy or androgen receptor targeted agents. We prospectively evaluated the ability of the CARG tool to predict risk of clinically relevant grade 2 and grade 3+ toxicity of treatment with chemotherapy (CHEMO) and abiraterone or enzalutamide (A/E) in older adults with mCRPC. Methods: Men age 65+ were enrolled in this prospective observational study at 3 academic centres, Princess Margaret Cancer Centre, Sunnybrook Health Sciences Centre, and Kingston Health Sciences Centre in Ontario, Canada. All grade 2 and grade 3+ toxicities were documented during cycle 1 of CHEMO or in the first 3 months of A/E via structured interviews and chart review. Lab abnormalities were documented only if resulting in emergency room visits, requiring treatment, or affecting subsequent oncologic treatment. Toxicity was rated using the Common Terminology Criteria for Adverse Events version 4. Logistic regression was performed to identify predictors of toxicity. Results: 64 men starting CHEMO (primarily docetaxel 60-75 mg/m^2, mean age 73y) and 59 men starting A/E (mean age 76y) were included. Clinically important grade 2 toxicities occurred in 86% and 70% of CHEMO and A/E patients, respectively. Grade 3+ toxicities occurred in 48% and 25% of CHEMO and A/E patients, respectively. The CARG tool was predictive of grade 3+ toxicities with CHEMO, which occurred in 22%, 53%, and 71% of low, moderate, and high risk groups (p = 0.017). However, the CARG tool was not predictive of grade 2 toxicities with CHEMO, or grade 2 or 3+ toxicities with A/E (Table). Conclusions: We provide external validation of the CARG tool in predicting grade 3+ toxicity in older men with mCRPC undergoing CHEMO. Grade 2 toxicities are very common with both CHEMO and A/E, and grade 3+ toxicity occurs in 1 in 4 older men on A/E. Additional efforts to identify men at higher risk of toxicity from various mCRPC treatments are warranted. [Table: see text]
Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53
Authors: Maximiliane Schuldner, Bastian Dörsam, Olga Shatnyeva, Katrin S Reiners, Andriy Kubarenko, Hinrich P Hansen, Florian Finkernagel, Katrin Roth, Sebastian Theurich, Andrea Nist, Thorsten Stiewe, Annette Paschen, Gero Knittel, Hans C Reinhardt, Rolf Müller, Michael Hallek, Elke Pogge von Strandmann
Journal: Theranostics (2019)

Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive. Methods: Here, we investigated the role of the chaperone Bcl2-associated anthogene 6 (BAG6, synonym Bat3) for the formation of pro- and anti-tumor EVs. EVs collected from wildtype cells and BAG6-deficient cells were characterized by mass spectrometry and RNAseq. Their tumorigenic potential was analyzed using the B-16V transplantation mouse melanoma model. Results: We demonstrate that EVs from B-16V cells inhibit lung metastasis associated with the mobilization of Ly6Clow patrolling monocytes. The formation of these anti-tumor-EVs was dependent on acetylation of p53 by the BAG6/CBP/p300-acetylase complex, followed by recruitment of components of the endosomal sorting complexes required for transport (ESCRT) via a P(S/T)AP double motif of BAG6. Genetic ablation of BAG6 and disruption of this pathway led to the release of a distinct EV subtype, which failed to suppress metastasis but recruited tumor-promoting neutrophils to the pre-metastatic niche. Conclusion: We conclude that the BAG6/CBP/p300-p53 axis is a key pathway directing EV cargo loading and thus a potential novel microenvironmental therapeutic target.
Systemic therapy in advanced cutaneous squamous cell carcinoma (CSCC): The Roswell Park experience.
Authors: Anthony Jarkowski, Ryan B Hare, Peter Loud, Jospeh J. Skitzki, John Michael Kane, Kilian Salerno May, Nathalie Zeitouni, Jill Nestico, Karen L Vona, Adrienne E. Groman, Nikhil I. Khushalani
Journal: Journal of Clinical Oncology (2012)

e19041 Background: Treatment of locally advanced unresectable (LAU) or metastaticCSCC (mCSCC) is sub-optimal with a paucity of robust data on systemic therapy. Platinum or fluorouracil-based chemotherapy is commonly used. This retrospective study aimed to evaluate the efficacy and outcomes of patients (pts) with LAU or mCSCC treated with systemic therapy. Methods: Records ofpts with CSCC treated with systemic therapy from Jan ‘01 – Jan ‘11 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon Rank Sum test for ordinal responses and Pearson Chi-square test for categorical responses. Survival was calculated by the Kaplan-Meier method. Results: Of 28 pts identified, 25 pts (M:F – 18:7), median age 66 yrs (39, 85) had required data for final analysis. 11 pts (44%) had facial primary tumors (including 7 of the external ear). 19 pts (76%) had LAU and 6 pts had mCSCC. 17 pts (68%) received multi-agent 1st-line chemotherapy (CT). 72%, 76% and 48% pts received platinum, taxane or cetuximab respectively as part of their regimens. 14 pts got 2nd line therapy and 4 pts received concurrent radiation therapy. Partial response (PR) was 44% and 24% pts had stable disease (SD) for a disease control rate of 68%. With a median follow-up of 42.8m, the median progression-free (PFS) and overall survival (OS) were 5.5m (2.3, 13.2) and 10.9m (5.3, 21.3) respectively; 3-yr OS was 22%. Pts with WHO response had improved PFS (20.8m; 4.4, NR; p&lt;.0001) and OS (37.5m; 10.3, NR; p=.0003) compared to pts with SD/PD (PFS 2.7m; OS 5.9m). Use of platinum-based therapy significantly improved PFS and OS, while taxanes and cetuximab had no impact in this small cohort. 91% (n=10) of pts who had a PR received a platinum drug. There was no difference in PFS or OS between face and non-face primary site CSCC and multi-agent versus single agent therapy. Conclusions: Platinum-based therapy remains a standard option in advanced CSCC management. Agents to improve response rates are needed and future trials should address the role of other therapies in CSCC, including novel targeted and CT combinations.
MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas
Authors: Yifu Song, Li Zhang, Yang Jiang, Tianhao Hu, Di Zhang, Qiao Qiao, Run Wang, Minghao Wang, Sheng Han
Journal: Theranostics (2019)

Background: Glioblastoma (GBM) is highly proliferative and resistant to radio-chemotherapy.Loss of tumor suppressor gene TP53 function frequently occurs at protein level in GBMs.This inhibition is often mediated by other components within the p53 signaling axis, including MDM2, whose binding protein (MTBP) plays an important role in the regulation of MDM2 and p53 activity.We investigated the role of MTBP in the biology of TP53-wildtype (TP53wt) GBMs.Methods: MTBP expression was examined in TCGA and REMBRANDT datasets.MTBP was silenced or overexpressed in TP53wt GBM cells and glioma stem cells (GSCs).The effects on cell viability, apoptosis, and clonogenicity were assessed.The transcriptional regulation of MTBP was investigated.Results: Upregulation of MTBP was correlated with the Classical molecular subtype, and it predicted poor survival.In TP53wt GBM cells, the protein levels of MTBP were positively associated with those of MDM2 but negatively correlated with those of p53.MTBP knockdown promoted apoptosis and inhibited clonogenicity, while overexpression of this protein enhanced tumorigenicity in vitro and in vivo.The pro-survival effect of MTBP depended on the activity of MDM2 and p53.MTBP was transcriptionally regulated by c-myc, thereby forming a positive regulatory loop.Finally, MTBP silencing increased the sensitivity of TP53wt GSCs to radiation and TMZ treatment in vitro and in vivo.Conclusion: MTBP regulates the cell survival and treatment sensitivity of TP53wt GBMs through MDM2-dependent post-translational modification of p53.MTBP-targeting treatments are potentially useful in increasing patients' survival.
<i>AACR Cancer Progress Report 2019</i>: Transforming Lives Through Innovative Cancer Science
Authors: Rajarshi Sengupta, Karen Honey
Journal: Clinical Cancer Research (2019)

The American Association for Cancer Research (AACR) is proud to announce the release of the AACR Cancer Progress Report 2019 . This ninth edition of the annual report details how research discoveries are the backbone of progress across the spectrum of cancer care. The full report, and all eight
Combination therapy with CpG oligodeoxynucleotide and imatinib can reverse the drug resistance when applied alone through promoting BAX activation and overcoming BCR-ABL1-independent PI3K/AKT activation.
Authors: Ling Bai, Wei Chen, Wei Li, Lei Zhou, Chao Niu, Jingtao Chen, Wei Han, Jiuwei Cui
Journal: Journal of Clinical Oncology (2019)

e18502 Background: Philadelphia chromosome is an independent prognostic factor in B-cell acute lymphoblastic leukemia (B-ALL). Due to the emergence of TKIs resistance such as imatinib, new methods are yet to be explored. Toll-like receptor 9 (TLR9) agonists have been used in many cancers as immune adjuvants, due to the immune effects as well as direct effects. However, the effect of TLR9 agonists on Ph(+) B-ALLs remain unknown. Methods: Expression levels in primary B-ALL cells from 41 patients in our hospital were determined by real-time quantitative PCR and correlated to clinicopathological factors. WST-1 cell viability assay and flow cytometry were used to confirm the biological behaviors of proliferation, cell cycle arrested, apoptosis, and surface molecules expression in Ph(+) B-ALL cell line. GST pull-down, western blot, and relevant inhibitors were used to detect the mechanism of the monotherapy and combination therapy. All data were analyzed using SPSS 24.0 software. Results: Expression of TLR9 in 19 patients with Ph chromosome was higher than that in 22 patients with the normal chromosome (Median: 0.10 vs. 0.03, P= 0.047). Sup-B15, one of imatinib resistance Ph(+) B-ALL cell line, showed no proliferation suppression, no cell cycle arrested and no apoptosis after CpG 685 stimulation. However, the combination use of CpG 685 and imatinib significantly increased apoptotic cells and upregulated the expression of CD40, MHC class Ⅰ and PD-L1. By comparing the downstream signaling pathway of TLR9 in B-ALL cell lines, Sup-B15 also promoted apoptosis through P38/P53/BAX signaling pathway as other B-ALLs. After imatinib pre-treatment, the inhibition of BAX activation by BCR-ABL kinase as well as C-MYC was exposed, and the resistance of CpG 685 was reversed. In addition, CpG 685 downregulated miR-21, further upregulated PTEN, and ultimately reversed the drug resistance of imatinib which caused by BCR-ABL1-independent AKT phosphorylation in Ph(+) B-ALL. Conclusions: The combinational use of imatinib and CpG 685 to treat B-ALL cells can reverse the drug resistance when applied alone. This method can not only kill Ph(+) B-ALL directly, but also increase the immunogenicity and enhance the recognition by CD8 + T cells. Besides, due to the increasing of PD-L1, adding PD-L1 antibody with imatinib and CpG ODNs in Ph(+) B-ALL warrants more data before moving into clinical practice.
Abstract 13725: Oxidative Stress Accelerates Senescence and Reduces Life Span but Does Not Alter Cardioprotection in Mice Over-expressing H11kinase/hsp22
Authors: Didier Morin, Romain Long, Lydie Laure, Christophe Depre, Stephen F Vatner, Dorothy E Vatner, Geneviève Derumeaux, Alain Berdeaux, Bijan Ghaleh
Journal: Circulation (2014)

H11 kinase/Hsp22 (H11K) is a small heat shock protein which provides powerful cardioprotection, i.e., reduction by 80% of infarct size expressed as a fraction of area at risk following 45 min coronary occlusion/4 hr reperfusion when over-expressed in a cardiac-specific transgenic (TG) mouse model. The goal of this investigation was to determine if these protective mechanisms would also enhance longevity and be effective in protecting from age-related myocardial dysfunction. Surprisingly, TG mice showed a reduction of 48% in their mean life span as compared to wild type (WT). The mechanism of premature death was most likely cardiac as left ventricular ejection fraction was reduced in one year old TG mice (49% vs 74% in WT, p&lt;0.01), left ventricular cavity was dilated and cardiac hypertrophy was increased by 58%, all compatible with severe dilated cardiomyopathy. At the molecular level, hearts from TG mice showed a significant increase in reactive oxygen species, oxidized/reduced glutathione ratio, NADPH and xanthine oxidase activities, Nox2 expression associated with an increase in p16, p19 mRNA, β-galactosidase positive cells and telomerase activity. Subgroups of WT and TG mice were also treated with the antioxidant tempol (100 mg/kg/d) from weaning to their sacrifice. Chronic tempol treatment abolished oxidative stress, reduced cardiac hypertrophy, extended life span (+31%) and prevented aging markers (p16, p19 mRNA, β-galactosidase positive cells) in TG mice. The marked reduction in infarct size with ischemia/reperfusion noted above, observed in 10-12 weeks old mice, remained unchanged after tempol in TG mice and was not abolished with aging. Thus, this is the first demonstration that the mechanisms mediating reduced longevity such as increased oxidative stress do not reduce cardioprotection in H11K TG mice, and conversely, the mechanisms mediating powerful cardioprotection against ischemic stress are ineffective in maintaining normal cardiac function with aging.
A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe
Authors: Jeffrey V. Lazarus, Mattias Ekstedt, Giulio Marchesini, Jillian Mullen, Katja Novak, Juan M. Pericàs, Elena Roel, Manuel Romero-Gómez, Vlad Ratziu, Frank Tacke, Helena Cortez-Pinto, Quentin M. Anstee
Journal: Journal of Hepatology (2019)

Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and has become an important field of biomedical inquiry. We aimed to determine whether European countries have mounted an adequate public health response to NAFLD and non-alcoholic steatohepatitis (NASH).In 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively.None of the 29 participating countries had written strategies or action plans for NAFLD. Two countries (7%) had mentions of NAFLD or NASH in related existing strategies (obesity and alcohol). Ten (34%) reported having national clinical guidelines specifically addressing NAFLD and, upon diagnosis, all included recommendations for the assessment of diabetes and liver cirrhosis. Eleven countries (38%) recommended screening for NAFLD in all patients with either diabetes, obesity and/or metabolic syndrome. Five countries (17%) had referral algorithms for follow-up and specialist referral in primary care, and 7 (24%) reported structured lifestyle programmes aimed at NAFLD. Seven (24%) had funded awareness campaigns that specifically included prevention of liver disease. Four countries (14%) reported having civil society groups which address NAFLD and 3 countries (10%) had national registries that include NAFLD.We found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries.We conducted a survey on non-alcoholic fatty liver disease with experts in European countries, coupled with data extracted from official documents on policies, clinical guidelines, awareness, and monitoring. We found a general lack of national policies, awareness campaigns and civil society involvement, and few epidemiological registries.
Dual-Energy Computed Tomography Detection of Cardiovascular Monosodium Urate Deposits in Patients With Gout
Authors: Andrea Sabine Klauser, Ethan J. Halpern, Sylvia Strobl, Johann Gruber, Gudrun Feuchtner, Rosa Bellmann-Weiler, Guenter Weiss, Hannes Stofferin, Werner Jaschke
Journal: JAMA Cardiology (2019)

The prevalence of gout has increased in recent decades. Several clinical studies have demonstrated an association between gout and coronary heart disease, but direct cardiovascular imaging of monosodium urate (MSU) deposits by using dual-energy computed tomography (DECT) has not been reported to date.To compare coronary calcium score and cardiovascular MSU deposits detected by DECT in patients with gout and controls.This prospective Health Insurance Portability and Accountability Act-compliant study included patients with gout and controls who presented to a rheumatologic clinic from January 1, 2017, to November 1, 2018. All consecutive patients underwent DECT to assess coronary calcium score and MSU deposits in aorta and coronary arteries. In addition, cadavers were assessed by DECT for cardiovascular MSU deposits and verified by polarizing microscope. Analysis began in January 2017.Detection rate of cardiovascular MSU deposits using DECT in patients with gout and control group patients without a previous history of gout or inflammatory rheumatic diseases.A total of 59 patients with gout (mean [SD] age, 59 [5.7] years; range, 47-89 years), 47 controls (mean [SD] age, 70 [10.4] years; range, 44-86 years), and 6 cadavers (mean [SD] age at death, 76 [17] years; range, 56-95 years) were analyzed. The frequency of cardiovascular MSU deposits was higher among patients with gout (51 [86.4%]) compared with controls (7 [14.9%]) (χ2 = 17.68, P < .001), as well as coronary MSU deposits among patients with gout (19 [32.2%]) vs controls (2 [4.3%]) (χ2 = 8.97, P = .003). Coronary calcium score was significantly higher among patients with gout (900 Agatston units [AU]; 95% CI, 589-1211) compared with controls (263 AU; 95% CI, 76-451; P = .001) and also significantly higher among 58 individuals with cardiovascular MSU deposits (950 AU; 95% CI, 639-1261) compared with 48 individuals without MSU deposits (217 AU; 95% CI, 37-397; P < .001). Among 6 cadavers, 3 showed cardiovascular MSU deposits, which were verified by polarizing light microscope.Dual-energy computed tomography demonstrates cardiovascular MSU deposits, as confirmed by polarized light microscopy. Cardiovascular MSU deposits were detected by DECT significantly more often in patients with gout compared with controls and were associated with higher coronary calcium score. This new modality may be of importance in gout population being at risk from cardiovascular disease.