tbuckley/cabot-search huggingface dataset:
MiR-34a to enhance the radiosensitivity of 22RV1 and 22RV1-radiation resistance prostate cancer cell lines.
Authors: John Thoms, Satoko Aoki, Thomas Belbin
Journal: Journal of Clinical Oncology (2019)

74 Background: Radiation therapy (RT) is a standard treatment option for men with prostate cancer (PCa), yet men still fail RT at a rate of up to 50%. MicroRNAs (miRNAs) can influence the tumor RT response, and the abundance or lack of specific miRNAs can alter radiosensitivity through alteration of survival pathway signals. We show that altered expression of miR-34a plays an important role in radiosensitivity. Methods: Both clinical and molecular data from TCGA-PRAD cohort were analyzed. MiR-34a expression was also determined in an independent cohort of 30 patients with PCa treated with RT. An RT resistant subline (22RV1-IRR) from the parental 22RV1 line was generated. MiR-34a expression level was determined in 22RV1, 22RV1-IRR and PrEC cells. 22RV1 and 22RV1-IRR cells were transfected with miR-34a mimics. Stable clones overexpressing miR-34a were generated. The influence of miR-34a on cellular proliferation, migration, clonogenic survival and response to RT was measured using standard assays. Results: Analysis of TCGA-PRAD data showed that low levels of miR-34a was associated with biochemical recurrence (BCR). In our cohort of 30 PCa patients treated with RT, miR-34a was consistently under expressed and associated with BCR. MiR-34a was down regulated in 22RV1 cells compared to PrEC cells and further down regulated in 22RV1-IRR cells. 22RV1 - IRR cells expressed lower levels of TP53, but overexpressed cMYC, BIRC5 (survivin) and E2F3. MiR-34a mimics resulted in a decreased expression of survivin at the mRNA and protein level in 22RV1 and 22RV1-IRR cells. MiR-34a expression was unregulated in response to RT in both cell lines. Survivin and E2F3 expression were down regulated in response to RT in both cell lines. MiR-34a mimics suppressed cell proliferation in 22RV1 and 22RV1-IRR cells. MiR-34a mimics also suppressed cellular migration, by the wound healing assay, in both 22RV1 and 22RV1-IRR cells. Stable clones overexpressing miR-34a were associated with increased radiosensitivity via clonogenic survival assay. Conclusions: Together, these data suggest that low expression of miR-34a is associated with BCR and overexpression of miR-34a enhances radiosensitivity by the downregulation of survivin and E2F3.
Abstract 18252: Washing of Stored Red Cells Prevents Transfusion Related Acute Lung Injury but not Transfusion Associated Coagulopathy
Authors: Nishith N Patel, Hua Lin, Aderoye Abidoye, Michael Wiltshire, Rebecca Cardigan, Kristina Britchford, Veerle Verheyden, Gianni D Angelini, Gavin J Murphy
Journal: Circulation (2012)

Objective To determine if washing of old Red Blood Cell (RBC) units prior to transfusion will prevent transfusion mediated organ dysfunction in our large animal experimental model. Method Adult White-Landrace pigs (50-70kg, n=32) were randomized to either sham procedure or to receive an allogeneic transfusion of 1-, 14- or washed 14-day RBCs. Endpoints included characterization of the RBC storage lesion, serial functional and biochemical measures of lung and renal injury, assessment of platelet function using platelet aggregometry, platelet activation using FACS and coagulation using ROTEM. All pigs were recovered for 24 hours prior to organ harvest. Results Transfused pigs received 1000mls of cross-matched allogenic leucodepleted RBC stored in SAG-M preservative for either 1 or 14 days. Accumulation of toxic metabolites within the supernatant as well as cellular changes showed considerable homology to those measured in SAG-M stored human RBC units. Transfusion of allogeneic porcine RBCs was associated with 24hr RBC survivals of greater than 75% and sustained increases in haematocrit irrespective of age of unit. Despite enhancing oxygen delivery, transfusion of 14-day old RBCs decreased tissue oxygen unloading, caused significant hypoxia and pulmonary hypertension. This was associated with plasma platelet depletion with sequestration into lung parenchyma, platelet dysfunction with decreased aggregation in response to ADP stimulation, coagulopathy and inflammation with increased P-selectin expression in circulating platelets. Washing of aged RBC units prior to transfusion ameliorated TRALI and inflammation, but had no effect on transfusion induced coagulopathy and platelet dysfunction. Data are summarised below. Conclusion Washing of aged RBC units prevents TRALI and should be evaluated in a randomized controlled in patients undergoing cardiac surgery. RBC transfusion mediated coagulopathy is a novel finding which is not affected by washing.
Drawing soldiers out of post-traumatic stress disorder
Authors: Simon R. Hunter
Journal: Military Medical Research (2019)

Art therapies are a broad suite of treatments including drawing, painting and music that can facilitate non-verbal communication through artistic expression. They have been used as adjunctive therapies for a range of mental health conditions. Significant numbers of returning military personnel experience post-traumatic stress disorder (PTSD), and discontinuation of care is a concern. Using drawing-based art therapy as an adjuvant to classical therapies may provide a benefit for such military patients.
Patient centred care for multimorbidity improves patient experience, but quality of life is unchanged
Authors: Rob Cook, Tara Lamont, Rachel Taft
Journal: BMJ (2019)

The study A patient-centred intervention to improve the management of multimorbidity in general practice: the 3D RCT. Salisbury C, Man M-S, Chaplin K, et al. Published in Health Serv Deliv Res 2019;7(5). This study was funded by the National Institute for Health Research Health Services and Delivery Programme (project number 12/130/15). To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000658/patient-centred-care-for-multimorbidity-improves-patient-experience-but-quality-of-life-is-unchanged
School-Associated Youth Homicides
Authors: Bridget Kuehn
Journal: JAMA (2019)

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Evaluation of tumor MET protein expression, <i>MET</i> gene amplification, and HER2 expression in Chinese patients with advanced gastric or gastroesophageal junction (G/GEJ) cancer.
Authors: Rui-hua Xu, Miaozhen Qiu, Yi-xin Zhou, De-Shen Wang, Dong-sheng Zhang, Fenghua Wang, Yu-hong Li, Jacqueline Huang, Hui Zhou, En-Tzu Tang, Zhiqiang Du, Fanny Zhang
Journal: Journal of Clinical Oncology (2015)

4048 Background: Gastric cancer is a disease with high unmet medical needs in China. MET and its ligand, hepatocyte growth factor, are potential targets in G/GEJ cancer. This study evaluated overall survival (OS) according to tumor MET expression, MET gene amplification, and the association between MET and HER2 status in Chinese patients with advanced G/GEJ cancer. Methods: Baseline tumor biopsy samples (formalin-fixed, paraffin-embedded primary tumor) from patients with stage IV unresectable G/GEJ cancer, archived at Sun Yat-Sen University Cancer Center, were assessed for MET and HER2 protein levels and MET and HER2 gene amplification by IHC and FISH, respectively. MET-positive: membrane protein staining in ≥ 25% or ≥ 50% of tumor cells. HER2-positive: IHC 2+ and a confirmatory HER2 FISH-positive result (HER2:centromere 17 ratio ≥ 2.0), or IHC 3+. MET-amplified: MET:centromere 7 ratio > 2.0. We evaluated associations between Kaplan-Meier OS and MET status (log-rank test), MET expression and METgene amplification, and MET and HER2 status (Fisher exact test). Results: Of 289 eligible patients, 271 had evaluable IHC samples, and MET-positive rates were 42.1% and 25.1% by 25% and 50% cutoffs, respectively. Median OS by different levels of MET-positive expression is shown in the Table. Of 183 patients with evaluable FISH samples, 8 (4.4%) were MET-amplified. In 171 patients with IHC and FISH data, MET-positive expression by 25% and 50% cutoffs was associated with MET amplification (P < 0.005, both cutoffs). In 145 patients with MET IHC, FISH, and HER2 data, the HER2-positive rate was 13.8%. Of patients who were MET-positive by 25% and 50% cutoffs, 8/48 (16.7%) and 4/29 (13.8%), respectively, were also HER2-positive. Additionally, 1/8 (12.5%) MET-amplified patients was HER2-positive. Conclusions: MET-positive status was associated with shorter OS in this population of Chinese patients with advanced G/GEJ cancer. MET high expression or MET amplification was not associated with HER2 expression. Patients evaluable for IHC MET-positive MET-negative P value 25% cutoff n 114 157 OS, mo* 10.9 16.0 0.054 50% cutoff n 68 203 OS, mo* 8.3 15.5 < 0.001 *Median
Molecular stratification of high-grade unclassified renal cell carcinoma to improve prognostication and management strategy.
Authors: Yingbei Chen, Renzo G Di Natale, Gowtham Jayakumaran, Mazyar Ghanaat, Julian Marcon, A. Rose Brannon, Hikmat Al-Ahmadie, Samson Fine, Anuradha Gopalan, Sahussapont Joseph Sirintrapun, Satish Tickoo, Maria E. Arcila, Robert J. Motzer, A. Ari Hakimi, Victor E. Reuter
Journal: Journal of Clinical Oncology (2019)

640 Background: Unclassified renal cell carcinoma (uRCC) constitutes a large portion of aggressive non-clear cell RCC with limited response to standard therapy. Clinicopathologic parameters or biomarkers to stratify this heterogeneous group of tumors are currently lacking. In a recently reported analysis of 62 high-grade primary uRCC [“discovery cohort (DC)”], we identified distinct molecular subsets. We aimed to validate this molecular schema in an independent clinical cohort and further delineate the clinicopathologic and molecular features that may refine prognostication and management. Methods: All cases was reviewed by experienced GU pathologists based on the current WHO criteria. Primary (n = 54) or metastatic (n = 21) tumor samples from 75 uRCC patients [“validation cohort (VC)”] were analyzed by a CLIA-approved targeted NGS platform for somatic alterations. 37 had germline testing results available. We performed integrative analysis of both VC and DC. Results: Somatic mutations found in VC were NF2 (24%), SETD2 (13%), SMARCB1 (9%), TP53 (9%), TSC1 (9%), FH (8%), TSC2 (5%), MTOR (5%), EP300 (5%), BAP1 (5%), PBRM1 (5%) and PIK3CA (5%), highly consistent with findings in DC. Germline alterations [ FH (11), SDHB (4), and SMARCB1 (1)] were detected in previously unsuspected patients. Integrative analysis supported the presence of NF2-loss (NF2), hyperactive mTOR-driven (MTOR), FH/SDH-deficient (FH/SDH), and chromatin/DNA damage response (Chrom/DDR) molecular subsets. Univariate analysis of combined DC and VC (n = 137, median f/u 26 mos, death 74%) showed a significantly higher risk associated with NF2 subset than the MTOR group (Table). Clonality analysis confirmed NF2 inactivating mutation as a main driver in the NF2 subset. Rare cases with alterations indicating sensitivity or resistance to immunotherapy were also identified. Conclusions: Molecular features of high-grade uRCC improve risk stratification and provide rationale for distinct management strategies. [Table: see text]
Changes in markers of proliferation, neoangiogenesis and plasminogen activation system in rectal cancer tissue.
Authors: Michail Averkin, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Elena Alekseevna Nikipelova, Larisa Kozlova, Irina Stasio Tavaryan, Natalia D. Cheryarina
Journal: Journal of Clinical Oncology (2015)

e14560 Background: Neoplasm develops and grows being able to produce angiogenic factors stimulating neovascularization. The aim of the study was todetermine levels of some tissue growth factors, fibrinolytic system indices and MMP-3 for specification of the role of their changes in moderately differentiated adenocarcinoma of the rectum. Methods: Levels of growth factors and neoangiogenesis, tissue fibrinolytic system indices and MMP-3 were studied in cytosols of tissue obtained from 73 patients (primary adenocarcinomas, st. III, G2, 47 men and 26 women aged 38-74 years, T1-3N0M0) by the ELISA method using standard test kits. Results: Increase in the content of growth factors VEGF-А, IGF and TGF-β1, the receptor protein VEGF-R, plasminogen activator uPA and metalloproteinases MMP-3 was detected in adenocarcinoma of the rectum. Gender differences in VEGF-А and TGF-β1 content were found. Increase in levels and activity of uPA and MMP-3 only was detected in perifocal zone of the tumor. Changes in EGF content were found neither in adenocarcinoma tissue nor in its perifocal zone. No significant gender differences were observed in tissue fibrinolytic system and MMP-3. Age differences were not found either. Conclusions: Concurrent expression of IGF-I, IGF-II, TGF-β1 and VEGF-А and its receptor in malignant tumor tissue, as well as increased plasmin release from proenzyme and MMP-3 activation is apparently associated with the formation of pathogenic mechanism of vasculature development in moderately differentiated adenocarcinoma of the rectum. Activation of uPA and MMP-3 in perifocal zone of the tumor can serve as an index of its invasive activity. Gender differences in VEGF-А and TGF-β1 content in tumor tissue were observed; significant association between patient gender and levels of IGF, EGF, fibrinolysis indices and MMP-3 was not found.
Abiraterone acetate plus prednisone/prednisolone compared with enzalutamide in metastatic castration resistant prostate cancer before or after chemotherapy: A retrospective study of real-world data (ACES).
Authors: Prantik Das, James Price, Michael Jones, Cristina Martin-Fernandez, Akram Ali, Thangrarajh Mugunthan, Chandrani Mallick
Journal: Journal of Clinical Oncology (2019)

303 Background: Abiraterone acetate (a prodrug of abiraterone, which is a selective inhibitor of androgen biosynthesis) combined with prednisone/prednisolone (AA+P) and enzalutamide (ENZ) (an androgen-receptor–signalling inhibitor) have proven survival benefit in men with metastatic castration resistant prostate cancer (mCRPC) in chemo naïve and prior chemo patients. There have been no studies directly comparing the effectiveness of ENZ to AA+P in mCRPC patients. Methods: A retrospective, survival analysis study of 143 real world mCRPC patients (90 in AA+P and 53 in ENZ group) was conducted. Patients who started their treatment between 1 st February 2012 and 31 st May 2016 were included. The primary endpoint was biochemical progression free survival (PFS). Secondary end points were radiographic progression free survival (rPFS) and overall survival (OS). Data was analysed using Cox proportional hazards models, adjusting for covariates: prior radical or palliative treatment; Gleason score; baseline PSA; age; and chemo naïve or not. Results: After median follow up of 15 months (IQR 7 to 23) 112 events of biochemical progression were observed (71 in AA+P and 41 in ENZ). 41%in AA+P group and 30% patients in ENZ group received prior chemo. The chance of biochemical progression was significantly lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (Hazard Ratio 0.54, 95% CI 0.35 to 0.82, p=0.004. There was a trend implying the chance of rPFS could be higher among ENZ patients than AA+P patients (HR 1.24, 95% CI 0.76 to 2.02, p=0.4). OS is lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (HR 0.91, 95% CI 0.59 to 1.41, p=0.7). 38% of ENZ patients reported fatigue compared to 16% of AA+P patients while hypertension was reported slightly more in AA+P patients than in ENZ patients. Conclusions: This study showed a statistically significant difference in biochemical progression-free survival, favouring ENZ, but no significant difference in radiographic progression-free survival or overall survival.
Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients
Authors: Michael J. Mack, Martin B. Leon, Vinod H. Thourani, Raj Makkar, Susheel K. Kodali, Mark Russo, Samir R. Kapadia, S. Chris Malaisrie, David J. Cohen, Philippe Pibarot, Jonathon Leipsic, Rebecca T. Hahn, Philipp Blanke, Mathew R. Williams, James M. McCabe, David L. Brown, Vasilis Babaliaros, Scott Goldman, Wilson Y. Szeto, Philippe Genereux, Ashish Pershad, Stuart J. Pocock, Maria C. Alu, John G. Webb, Craig R. Smith
Journal: New England Journal of Medicine (2019)

Among patients with aortic stenosis who are at intermediate or high risk for death with surgery, major outcomes are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. There is insufficient evidence regarding the comparison of the two procedures in patients who are at low risk.
Abstract 19542: Relationship Between Ankle-Brachial Index Definitions and Coronary Artery Calcification: The Dallas Heart Study
Authors: Thomas P Koshy, Amit Khera, Colby Ayers, Carlos Timaran, Dharam J Kumbhani
Journal: Circulation (2016)

Introduction: An ankle-brachial index (ABI) is used to screen patients for peripheral arterial disease (PAD), traditionally using the higher of the two foot pressures (dorsalis pedis and posterior ...
Abstract 14337: The Disruption of Natural Killer T Cell Receptor Exacerbates Left Ventricular Remodeling and Failure After Myocardial Infarction in Mice
Authors: Masashige Takahashi, Arata Fukushima, Tsuneaki Homma, Mochamad A Sobirin, Tadashi Suga, Shingo Takada, Tomoyasu Kadoguchi, Yoshihiro Masaki, Takashi Yokota, Shintaro Kinugawa, Hiroyuki Tsutsui
Journal: Circulation (2011)

Background Natural killer T (NKT) cells play an important role in tissue inflammation in various diseases due to their capacity to produce inflammatory cytokines and orchestrate tissue inflammation...
Hypofractionated dose painting IMRT using 20 fractions for intermediate to high-risk localized prostate cancer: Two-year outcome data (BIOPROP20, NCT02125175).
Authors: Isabel Syndikus, Joachim Kwok-Chiu Chan, Thelma Rowntree, Laura Howard, John Staffurth
Journal: Journal of Clinical Oncology (2019)

59 Background: Prostate dose painting (boosting intra-prostatic tumour volumes) may improve biochemical relapse-free survival similar to whole organ dose-escalation without the associated increased toxicity. We present a pre-defined secondary endpoint of 2 year outcome for patients at one of two UK centres in a phase II trial (BIOPROP20) on dose-painting radiotherapy for intermediate to high risk patients treated with 60Gy/20# and concurrent 68Gy boost. Methods: Pinnacle software was used for VMAT planning and boost volumes were outlined by 18 F choline PET/CT and mpMRI. Patients with positive lymph nodes also had concurrent pelvic radiotherapy of 45Gy with boost to 50Gy. Patients were followed up until year 2 with PSA and toxicity scores. Results: Overall 56 patients were treated, 5 with pelvic radiotherapy. Median age and PSA was 67.5 years (range 50 - 77) and 10.0ng/ml (3.9 - 39.4). All patients had tumour volumes &gt; 10mm diameter on pre-biopsy mpMRI. 13 and 43 patients had intermediate and high risk disease. Median % LN risk was 18% (15 - 40). ADT duration was 6 months, 2 years, and 3 years for 42, 5, and 9 patients. At the 2 year follow up review, no grade 3 late toxicity was observed. For prostate only dose painting, grade 2 GU and GI toxicity was noted in 6% and 2% respectively. For prostate and nodal dose painting, no grade 2 toxicity was noted. Median IPSS score was 5 and 9, and median PSA was 0.3 and 0.1, in the two groups respectively. 1 patient had biochemical and metastatic relapse at 18 months (prostate, pelvic nodes and bone metastasis) and 1 patient had died of unrelated disease. Conclusions: Prostate radiotherapy with hypofractionated dose painting schedule of 60Gy/20# with 68Gy boost to intra-prostatic lesions was well tolerated at 2 years follow up. Clinical trial information: NCT02125175. [Table: see text]
Mixed Chimerism and Secondary Engraftment Failure in Allogeneic Transplantation for Aplastic Anemia
Authors: Shinichi Kako, Hirohito Yamazaki, Kazuteru Ohashi, Yukiyasu Ozawa, Shuichi Ota, Yoshinobu Kanda, Tetsuo Maeda, Jun Kato, Ken Ishiyama, Ken-Ichi Matsuoka, Toshihiro Miyamoto, Takahiro Fukuda, Tatsuo Ichinohe, Yoshiko Atsuta, Takehiko Mori
Journal: Blood (2018)
Population pharmacokinetic model for regorafenib: A meta-analysis.
Authors: Joachim Grevel, Isrid Sturm, John T. Lettieri, Jean Smeets
Journal: Journal of Clinical Oncology (2015)

e13580 Background: The multikinase inhibitor regorafenib (REG) has shown clinical efficacy in metastatic colorectal cancer and advanced gastrointestinal stromal tumors. REG is primarily metabolized in the liver to 2 pharmacologically active metabolites, M-2 and M-5. Methods: A popPK model for REG, M-2, and M-5 is based on 14 clinical studies with rich and sparse PK sampling and doses ranging from 10 to 220 mg QD. Covariate effects (formulation, gender, weight, body-mass index [BMI], height, age, ethnic group, baseline kidney and liver function, protein levels, and hematocrit/hemoglobin) were evaluated for their influence on exposure. The popPK model was applied to the PK data of all studies to derive individual exposure estimates for the 902 subjects: Cavp (average concentration in ng/mL of REG over 24h) and Cavtot (average of sum of the molar concentration of REG, M-2, and M-5). Both exposures were estimated after 21 daily doses of 160 mg. Results: The modelled availability of REG in plasma from the oral formulation decreased linearly by 3.9% per 10 mg and was 48% higher after a single dose than after repeated doses > 120 mg. The relative amount of REG metabolized to M-2 increased linearly by 4.0% per 10 mg. The elimination of M-5 decreased linearly by 3.1% per 10 mg. The net result of this nonlinear model was a less than proportional increase in REG and a more than proportional increase in M-2 and M-5, keeping the molar sum exposure almost proportional with dose. Cavp and Cavtot were about 45% lower in healthy volunteers vs cancer patients. Cavp and Cavtot were 11% and 34% higher in females vs males, respectively. Cavp and Cavtot were 11% and 23% lower in Asians vs non-Asians, respectively. Cavtot but not Cavp was 19% lower in patients also taking UGT1A9 inhibitors. Cavp and Cavtot were positively correlated with age, hemoglobin, and plasma albumin. Cavp but not Cavtot increased with BMI. Cavtot but not Cavp decreased with body weight. Simulated patients with extreme covariate combinations were still within the borders of the 90% confidence interval of observed exposures (Cavp 1.2 to 4.7 mg/L, Cavtot 5 to 39 µM). Conclusions: None of the listed covariates or any extreme combinations thereof warrant any dosage adjustments in the absence of compelling clinical reasons.