tbuckley/cabot-search huggingface dataset:
Angiogenesis polymorphisms profile in the prediction of clinical outcome of advanced HCC patients receiving sorafenib: Combined analysis of VEGF and HIF-1.
Authors: Luca Faloppi, Mario Scartozzi, Marco D'Anzeo, Maristella Bianconi, Gianluca Svegliati Baroni, Nicola Silvestris, Andrea Casadei Gardini, Gianluca Masi, Riccardo Giampieri, Michela Del Prete, Samuele De Minicis, Alessandra Mandolesi, Antonio Benedetti, Stefano Cascinu
Journal: Journal of Clinical Oncology (2014)

e15140 Background: Tumour cells adapt to hypoxic microenvironment via the activation of numerous molecules, among which hypoxia inducible factor 1 (HIF-1) is the most important. HIF-1 plays a crucial role in tumour angiogenesis triggering the transcription of several genes including the vascular endothelial growth factor (VEGF). Currently the therapeutic stronghold of advanced hepatocellular carcinoma (HCC) is the antiangiogenetic TKIs sorafenib. The overexpression of HIF-1 in HCC is associated with tumour angiogenesis, invasion, metastasis, treatment resistance and poor prognosis. In our previous report polymorphisms (SNPs) CC+CG>GG of rs2010963 and TT+CT>CC rs4604006 of VEGF have been shown to predict clinical outcome in HCC patients treated with sorafenib. Methods: From a large database a preliminary analysis on 90 HCC patients receiving sorafenib was conducted to assess the role of HIF-1 SNPs in determining the clinical outcome in this setting. Tumour histologic samples were tested for 8 different HIF-1 SNPs. Patients progression free survival (PFS) and overall survival (OS) were analysed. Results: At univariate analysis CC>AA+AC of rs1951795, TT>CC+CT of rs10873142, AA+AG>GG of rs12434438 SNPs were statistically significant for PFS and OS. At multivariate analysis rs1951795 of HIF-1, rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors (Table). Conclusions: This investigation on HIF-1 SNPs, following our previous discoveries on VEGF and its receptors, may represent a clinical tool to identify patients with favourable response to sorafenib, presumably related to a more efficient control of tumour growth. Genotype Univariate analysis Multivariate analysis SNPs PFS OS p PFS OS mo p mo p mo p HR IC HR IC HIF-1a rs1951795 CC 6.8 0.0271 16.1 0.0174 0.0332 0.33 0.12-0.91 0.0182 0.20 0.10-0.76 AA+AC 3.0 12.6 rs10873142 TT 6.7 0.0427 16.0 0.0247 ns ns CC+TT 3.4 12.7 rs12434438 AA+AG 6.1 0.0181 14.7 0.0225 ns ns GG 2.6 10.6 VEGF-A rs2010963 CC+CG 6.9 0.0096 17.0 0.0016 0.0279 0.63 0.37-1.05 0.0248 0.50 0.28-0.91 GG 4.0 9.0 VEGF-C rs4604006 TT+TC 10.1 0.0043 22.0 0.0334 0.0022 0.42 0.24-0.73 0.0335 0.50 0.27-0.94 CC 4.3 13.0
Lipid Peroxidation Drives Renal Cyst Growth In Vitro through Activation of TMEM16A
Authors: Rainer Schreiber, Björn Buchholz, Andre Kraus, Gunnar Schley, Julia Scholz, Jiraporn Ousingsawat, Karl Kunzelmann
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement The chloride channels cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) drive cyst enlargement in polycystic kidney disease (PKD), ultimately leading to kidney failure. The mechanisms for channel activation, however, are poorly understood. The authors show for the first time that peroxidation of plasma membrane phospholipids activates renal TMEM16A; this facilitates calcium signaling and activation of the calcium-sensitive adenylate cyclase ADCY1, which further stimulates CFTR. The antioxidant idebenone significantly delays cyst enlargement as does ferrostatin-1, suggesting activation of ferroptosis, an apoptosis-independent regulated cell death pathway during PKD. These findings show a strong effect of reactive oxygen species on cyst progression via lipid peroxidation. Inhibition of lipid peroxidation and blockade of TMEM16A are potential novel therapeutic approaches to delay cyst development in PKD. Background Transepithelial chloride − secretion, through the chloride channels cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1), drives cyst enlargement in polycystic kidney disease (PKD). Polycystic kidneys are hypoxic, and oxidative stress activates TMEM16A. However, mechanisms for channel activation in PKD remain obscure. Methods Using tissue samples from patients with autosomal dominant PKD, embryonic kidney cultures, and an MDCK in vitro cyst model, we assessed peroxidation of plasma membrane phospholipids in human and mouse polycystic kidneys. We also used electrophysiologic Ussing chamber and patch clamp experiments to analyze activation of TMEM16A and growth of renal cysts. Results Peroxidation of phospholipids in human and mouse kidneys as well as MDCK cysts in vitro is probably due to enhanced levels of reactive oxygen species. Lipid peroxidation correlated with increased cyst volume as shown in renal cultures and MDCK cysts in three-dimensional cultures. Reactive oxygen species and lipid peroxidation strongly activated TMEM16A, leading to depletion of calcium ion stores and store-operated calcium influx. Activation of TMEM16A- and CFTR-dependent chloride secretion strongly augmented cyst growth. Exposure to scavengers of reactive oxygen species, such as glutathione, coenzyme Q10, or idebenone (a synthetic coenzyme Q10 homolog), as well as inhibition of oxidative lipid damage by ferrostatin-1 largely reduced activation of TMEM16A. Inhibition of TMEM16A reduced proliferation and fluid secretion in vitro . Conclusions These findings indicate that activation of TMEM16A by lipid peroxidation drives growth of renal cysts. We propose direct inhibition of TMEM16A or inhibition of lipid peroxidation as potentially powerful therapeutic approaches to delay cyst development in PKD.
A meta-analysis of prevalence rates and moderating factors for cancer-related post-traumatic stress disorder.
Authors: Gareth Abbey, Simon BN Thompson, Tamas Hickish, David Heathcote
Journal: Journal of Clinical Oncology (2014)

e20557 Background: Systematic reviews highlight a broad range of PTSD prevalence estimates in cancer survivors. This meta-analysis was conducted to provide a general prevalence estimate of significant PTSD symptoms and full diagnoses to facilitate the psychological aftercare of cancer survivors. Methods: A systematic literature search of studies using samples of cancer survivors using validated clinical interviews and questionnaires to assess the prevalence of cancer-related PTSD (k=25, n=4189). Prevalence point estimates were calculated for each assessment method using random-effects meta-analysis. Mixed-effects meta-regression and categorical analyses were used to investigate study-level moderator effects. Results: Studies using the Posttraumatic Stress Disorder Checklist – Civilian Version (PCL-C) yielded lower event rates using cut-off (7.3%, 95% CI=4.5-11.7, k=10) than symptom cluster (11.2%, 95% CI=8.7-14.4, k=9). Studies using the Structured Clinical Interview (SCID) yielded low rates for lifetime (15.3%, 95% CI=9.1-25, k=5) and current PTSD (4.8%, 95% CI=2.7-8.3, k=10). There was substantial between-study heterogeneity (I2=54-86%). Studies with higher-staged samples yielded significantly higher rates with PCL-C cluster scoring (p=.05), and when assessing current cancer-related PTSD on the SCID (p=.05). The effect of mean age on current PTSD prevalence met significance on the SCID (p=.05). SCID lifetime prevalence rates decreased with time post-treatment (R2= .56, p<.05). Conclusions: The cancer experience may be sufficiently traumatic as to induce PTSD in a minority of cancer survivors. Post-hoc analyses suggest that cancer survivors who are younger, are diagnosed with more advanced disease, and recently completed treatment, may be at greater risk of PTSD. More research is needed to investigate vulnerability factors for PTSD in cancer survivors.
Safety analysis of a phase II randomized trial of carboplatin (C), paclitaxel (P), bevacizumab (B) with or without cixutumumab (CX) in patients (pts) with advanced nonsquamous, non-small cell lung cancer (NSCLC).
Authors: Athanassios Argiris, Ju-Whei Lee, Joseph W. Leach, Joan H. Schiller
Journal: Journal of Clinical Oncology (2014)

e19018 Background: CX is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type receptor 1 (IGF1R) that can potentially reverse resistance and enhance treatment efficacy. E3508 was designed to evaluate the addition of CX to CPB, a reference Eastern Cooperative Oncology Group (ECOG) regimen. Safety concerns with increased grade 5 events reported in another ECOG trial (E4508) with CX prompted this analysis. Methods: Bevacizumab-eligible pts with recurrent or stage IV non-squamous NSCLC and ECOG performance status (PS) of 0-1 were equally randomized to receive either P 200 mg/m² IV over 3 hours, day 1, followed by C AUC = 6.0, IV over 30 min, day 1, B 15 mg/kg IV over 30-60 min, every 21 days to a maximum of 6 cycles followed by B maintenance until progression or unacceptable toxicity (arm A) or same CPB plus CX 6 mg/kg IV over 1 hour, days 1, 8, and 15 during CPB and B maintenance (arm B). The primary endpoint was PFS. After an interim toxicity evaluation in the first 37 pts, the study proceeded to enroll 175 pts (short of the original goal of 180 because of discontinuation of sponsorship). Results: Of 175 pts randomized, 165 started protocol treatment (83 in arm A and 82 in arm B) and were analyzed. ECOG PS 0, 55% arm A; 54% arm B; adenocarcinoma, 93% arm A; 86% arm B. Median number of cycles delivered was 7 (range 1-34) and 6 (1-43) for arms A and B. Common treatment-related grade 3/4 (%) toxicities in arm A vs B were: neutropenia, 17/16 vs 16/37 (p=0.012); febrile neutropenia, 0/0 vs 7/0 (p=0.014); infection (any) with neutropenia, 1/0 vs 4/5 (p=0.034); thrombocytopenia, 4/5 vs 16/7 (p=0.011); anemia, 7/0 vs 12/0 (non-significant (NS)); fatigue, 6/0 vs 20/1 (p=0.006), hyperglycemia; 0/0 vs 10/1 (p=0.002); peripheral sensory neuropathy, 4/0 vs 5/0 (NS); nausea, 5/0 vs 11/0 (NS ); hypertension, 13/0 vs 18/0 (NS); thromboembolic event, 7/1 vs 5/0 (NS); bleeding 0/0 vs 1/0 (NS). There was 1 grade 5 event per arm (intracranial hemorrhage in arm A and lung hemorrhage in arm B). Conclusions: The addition of CX to CPB increased toxicities, including febrile neutropenia and fatigue, but without an increase in treatment-related deaths.
Parents should decide when children’s screen time is too high, says first UK guidance
Authors: Ingrid Torjesen
Journal: BMJ (2019)

There is not enough evidence to conclude that screen time is harmful to the health of children and young people or advise on how much screen time is too much, says the first guidance on children’s screen time to be published in the UK.1

The guidance from the Royal College of Paediatrics and Child Health is informed by a comprehensive review of the evidence, published in BMJ Open ,2 on the impact of screen time on the physical and mental health of children and young people.

Max Davie, officer for health promotion at the college, said: “We couldn’t find any …
Predicting GBM response to targeted therapeutics using simulation with ex vivo validations.
Authors: Sandeep C. Pingle, Zeba Sultana, Pengfei Jiang, Rajesh Mukthavaram, Ying Chao, Taher Abbasi, Shweta Kapoor, Ansu Kumar, Shahabuddin Usmani, Ashish Agrawal, Shireen Vali, Santosh Kesari
Journal: Journal of Clinical Oncology (2014)

2041 Background: The unique signature of a patient’s tumor implies that a one-size-fits-all treatment approach will likely fail. This necessitates a rationally designed personalized therapeutic approach employing N=1 segmentation. To predict clinical responses to targeted drugs, we (1) employed predictive modeling and validated this retrospectively (2) used patient tumor profiling data to create simulation avatars (3) screened drugs prospectively and predicted response for patient-derived cell lines (4) validated outcomes ex-vivo in patient lines. Methods: Human patient-derived glioblastoma (GBM) samples were cultured and characterized using histopathologic and integrated genomic analyses. Using these data, we created simulation avatars of patient lines. Responses of patient-derived GBM lines to erlotinib, sorafenib and dasatinib were used as alignment datasets. The predictive simulation-based approach from Cellworks provides a comprehensive representation of GBM disease physiology, incorporating signaling and metabolic networks with an integrated phenotype view. This model predicts clinical outcomes based on phenotype and biomarker assays. We prospectively screened ten drugs across eight patient profiles and validated their responses ex vivo. Results: We evaluated the ability of the simulation model to predict drug responses, using results from a recent study by Garnett et al. Of the gene mutation-drug response associations reported in this study, we predicted 22 of the 25 associations tested (>85% correlation). Importantly, we predicted the sensitivity of patient-derived GBM lines to various targeted therapeutic agents; more than 75% predictions matched our experimental ex vivo results. Conclusions: There is an unmet need for individualization of cancer treatment. Use of innovative simulation technology to predict responses to drugs may provide a way to stratify patients for clinical trials. This study validates our in silico model for predicting sensitivity of patient cells to targeted therapeutics. By accurately predicting responses a priori, the in silico model enables personalizing cancer therapy and promises to improve clinical management.
Promising Clinical Efficacy and Toxicity Profile of Isatuximab Based Regimens for Treatment of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: A Systematic Review
Authors: Zunairah Shah, Madeeha Shafqat, Faiza Jamil, Mustafa Nadeem Malik, Abdul Rafae, Shehroz Aslam, Anum Qureshi, Maryam Sadiq, Muhammad Abu Zar, Ahmad Kamal, Insija Ilyas Selene, Sharoon Samuel, Rida Riaz, Midhat Lakhani, Faiz Anwer
Journal: Blood (2018)
TMX2: A potential biomarker or a predictive marker in breast cancer?
Authors: Ioannis Papasotiriou, Panagiotis Apostolou, Maria Toloudi, Marina Chatziioannou, Georgia Mimikakou, Eleni Kourtidou, Ioanna Vlachou
Journal: Journal of Clinical Oncology (2014)

e22077 Background: Thioredoxin is a class of proteins that participates in redox reactions. The reaction oxygen species (ROS) are important for cell signaling and homeostasis, as abnormal regulation is involved in cell proliferation and carcinogenesis. Carcinogenesis is resulted of many mutations that caused by ROS-related oxidation of DNA and contribute to genome instability. Cancer stem cells (CSCs) may generate tumors through the stem cell processes (self-renewal and differentiation into multiple cell types). The present study aims to find the contribution of thioredoxin and particularly of thioredoxin-related transmembrane protein 2 (TMX2) in a wide range of sample types including cancer, non-cancer (normal), embryonic stem cells (ESCs) as well as CSCs. Methods: Human established human cancer cells as well as cancer stem cell lines (ECACC, CelProgen), representing breast, colon and lung cancer, have been used. Whole genome gene expression microarrays have been performed for the above samples as well as for RNA extracted from CSCs that derived from breast patients’ samples. These samples were evaluated by using specific gene and protein stemness markers. The data were evaluated with qPCR by using specific primers for TMX2. A relative quantification was performed according to Livak method, by using 18SrRNA as housekeeping gene. Results: The microarray data indicated that TMX2 was over-expressed in almost all cancer samples but the level was higher in breast cancer. The qPCR data confirmed all the above. In addition, the gene expression was 10-16 times higher in all breast patients’ CSCs, 5-10 times higher in established breast cancer cell lines, while in colon and lung cancer and CSCs was only up to 2 times higher. Conclusions: The thioredoxin and thioredoxin-related proteins are involved in redox regulation, an important process for maintaining homeostasis. The above experimental data indicated that TMX2, exhibits high levels of gene expression in breast cancer and specifically in breast CSCs, while the levels are lower in colon and lung cancer. Thereby, TMX2 may be used as a specific biomarker for breast cancer and breast CSCs. Further studies, in more samples, are needed to demonstrate all the above, so that it can be used at clinical level.
Preclinical in vitro and in vivo evaluation of antitumor activity of poly (ADP-ribose) polymerase inhibition and trastuzumab combined therapy in HER2-overexpressing breast cancer.
Authors: Ignacio Tusquets, Jetzabel Garcia-Parra, Alba Dalmases, Beatriz Morancho, Oriol Arpi, Silvia Menendez, Mohammad Ali Sabbaghi, Sandra Zazo, Cristina Chamizo, Juan Madoz, Pilar Eroles, Sonia Servitja, Jose Yelamos, Ana Lluch, JoaquÃƒÂn Arribas, Federico Rojo, Ana Rovira, Joan Albanell
Journal: Journal of Clinical Oncology (2014)

622 Background: PARP inhibitors have provided promising results in BRCA deficient breast cancer, but not in unselected patient populations. Two lines of research in this field are needed: identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies. Methods: We tested PARP inhibition, alone or combined with the anti-HER2 antibody trastuzumab on HER2 positive breast cancer. We used two PARP inhibitors in clinical development, olaparib and rucaparib, as well as genetic downmodulation of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX foci and comet assay. Finally, in vivo anti-tumor effect of olaparib and trastuzumab was examined in subcutaneously implanted BT474 cells in nude mice. Results: In a panel of four HER2 overexpressing cell lines, but not in non-HER2 overexpressing breast cancer cell lines, both olaparib and rucaparib significantly decreased cell growth and enhanced anti-tumor effects of trastuzumab. Similar results were observed in cells with genetic downmodulation of PARP-1. Combined treatment with olaparib and trastuzumab resulted in increased DNA damage in vitro. In in vivoexperiments using the HER2 overexpression BT474 xenograft model, the combined treatment resulted in enhanced growth inhibition, as well as reduced tumor cell proliferation, increased DNA damage and apoptosis. Conclusions: Taken together, our results show that in HER2 overexpressing breast cancer, PARP inhibition has antitumor effects and significantly increases trastuzumab activity, which makes this novel combination a promising strategy for further development.
Impact of Prophylaxis Usage on Bleeding Rates Among Persons with Hemophilia A: Evidence from Longitudinal Analyses in the USA
Authors: Michael B. Nichol, Randall Curtis, Yuchen Ding, Elmar R. Aliyev, Marion A. Koerper, Mimi Lou, Megan M. Ullman, Duc Quang Tran, Judith Baker, Brenda Riske, Joanne Wu
Journal: Blood (2018)
Genomics of Limited-Stage Diffuse Large B-Cell Lymphoma Developing Late Relapse: Analysis of Gene Alterations in Paired Primary and Late Relapsed Tumors By Target Sequencing
Authors: Tomotaka Suzuki, Suguru Fukuhara, Junko Nomoto, Satoshi Yamashita, Akiko Miyagi Maeshima, Yuta Ito, Shunsuke Hatta, Sayako Yuda, Shinichi Makita, Wataru Munakata, Tatsuya Suzuki, Dai Maruyama, Hirokazu Taniguchi, Toshikazu Ushijima, Koji Izutsu, Kensei Tobinai, Yukio Kobayashi
Journal: Blood (2018)
Adoption of hypofractionated radiotherapy for early-stage invasive breast cancer after publication of randomized trials.
Authors: Ronald C. Chen, Aaron David Falchook, Laura H. Hendrix, Reshma Jagsi
Journal: Journal of Clinical Oncology (2014)

6522 Background: Large randomized trials have established the non-inferiority of shorter courses of “hypofractionated” radiotherapy to the whole breast (HyRT) vs conventional courses using smaller daily doses (CRT). HyRT is more convenient and less costly, so we sought to document its uptake as randomized trial evidence accumulated. Methods: In SEER-Medicare, we identified 15,781 women with pT1-2, node negative breast cancer who received lumpectomy followed by external beam RT from 2004-10. Number of RT treatments was obtained from Medicare claims, and grouped into partial breast RT (PBI, ≤12 treatments), HyRT (13-24), or CRT (≥25). We evaluated patterns and correlates of HyRT receipt on bivariable and multivariable analyses. Results: HyRT steadily increased after 2006 (3.6%): 5.3% (2007), 9.3% (2008), 13.7% (2009-10), with corresponding decrease in CRT from 92.6% to 83.5%. HyRT was more common in older women in all T-stage subgroups (4.0-5.9% for age 66-69 vs 6.0-8.2% age 76-79 vs 11.6-13.3% for age 80+). Multivariable analysis showed increased HyRT in recent years; in patients with older age, smaller tumors (T1a-b), increased comorbidity; and in regions with higher educational levels (Table). Conclusions: HyRT use increased in a low-risk population-based sample of older US women with publication of randomized trials, but overall use (13.7%) of this cost-saving approach remained low. Logistic regression for receipt of HyRT (vs. CRT; PBI excluded). OR (95% CI) p-value RT year (REF=2004)* 2005 1.0 (.7-1.4) .98 2006 1.0 (.7-1.4) .96 2007 1.5 (1.1-2.0) <.01 2008 2.8 (2.2-3.7) <.01 2009-10 4.4 (3.4-5.6) <.01 Age (yrs) (REF=66-69) 70-75 1.1 (.9-1.3) .47 76-79 1.5 (1.2-1.9) <.01 80+ 2.8 (2.4-3.4) <.01 Path stage (REF=T1a-b) T1c .91 (.8-1.0) .18 T2 .77 (.63-.93) <.01 Tumor grade (REF=1-2) 3 1.1 (.96-1.3) .16 Laterality (REF=right) Left 1.0 (.88-1.1) .97 NCI comorbidity (REF=0) >0 1.2 (1.1-1.4) <.01 Regional education quartile (REF=Q1) Q2 .74 (.61-.90) .<.01 Q3 .76 (.61-.94) .01 Q4 (worst) .58 (.45-.75) <.01 Covariates: race (ns), urban/rural (ns), marital status, SEER region. *Canadian trial published 5-yr results in 2002 & long-term results in 2010; UK START trials published 2008.
Long-term outcomes of tumor-bearing autografts treated with liquid nitrogen for reconstruction after tumor removal.
Authors: Norio Yamamoto, Kentaro Igarashi, Toshiharu Shirai, Katsuhiro Hayashi, Hideji Nishida, Hiroaki Kimura, Akihiko Takeuchi, Shingo Shimozaki, Takeshi Kato, Yu Aoki, Takashi Higuchi, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2014)

e21508 Background: In 1999, we developed and clinically applied an original biological reconstruction technique using tumor-bearing autografts treated with liquid nitrogen. The purpose of this study was to assess the long-term outcome of frozen autografts treated by liquid nitrogen in a clinical setting by examining the outcomes of reconstructions in a series of patients with bone and soft tissue sarcoma. Methods: 36 cases with an average follow-up period of 101 months (range 61–163) were enrolled in this study. The reconstruction methods used were: osteoarticular graft (n = 16), intercalary graft (n = 13), and composite graft with prosthesis (n = 7). Results: No tumor recurrence was observed following frozen autografting. Frozen autografts survived in 29 of the 36 cases, and 5- and 10-year survival rates were 86.1% and 80.6 %, respectively. Seven of the 16 osteoarticular grafts failed because of fracture or infection, but all composite and intercalary grafts survived. Postoperative function was excellent in 26 patients (72.2%), good in 7 (19.4%), and fair in 3 (8.3%) according to the functional evaluation system of Enneking. Conclusions: Especially, the long-term outcomes of frozen autografting for composite and intercalary grafts are quite satisfactory and thus represent an outstanding limb salvage surgical method in bone and soft tissue sarcoma.
Safety Analysis of Intra-Patient Dose- Study of Crenolanib Maintenance Therapy in Patients with FLT3 Mutant AML Following Allogeneic Hematopoietic Stem Cell Transplant
Authors: Betul Oran, Stefan O. Ciurea, David Marin, Jessica M McCarty, Qaiser Bashir, Sairah Ahmed, Amanda L. Olson, Uday Popat, Yago Nieto, Partow Kebriaei, Elizabeth J. Shpall, Trishala Agrawal, Richard E Champlin
Journal: Blood (2018)