tbuckley/cabot-search huggingface dataset:
RBC-Transfusion Dependency Improves the Prognostic Value of the Revised-IPSS in MDS Patients: Analysis of South Australian and Dusseldorf MDS Registries
Authors: Deepak Singhal, Corinna Strupp, Rakchha Chhetri, Monika M Kutyna, L Amilia Wee, Shriram V. Nath, Nicholas Wickham, Chi-hung Hui, James X Gray, David M. Ross, Ian D Lewis, Peter G Bardy, John Reynolds, Luen Bik To, Devendra K Hiwase, Ulrich Germing
Journal: Blood (2016)
Association Between Sacubitril/Valsartan Initiation and Health Status Outcomes in Heart Failure With Reduced Ejection Fraction
Authors: Yevgeniy Khariton, Gregg C. Fonarow, Suzanne V. Arnold, Ann Hellkamp, Michael E. Nassif, Puza P. Sharma, Javed Butler, Laine Thomas, Carol I. Duffy, Adam D. DeVore, Nancy M. Albert, J. Herbert Patterson, Fredonia B. Williams, Kevin McCague, John A. Spertus
Journal: JACC Heart Failure (2019)
Prostaglandin E<sub>2</sub> induces DNA hypermethylation in gastric cancer <i>in vitro</i> and <i>in vivo</i>
Authors: Chi Chun Wong, Wei Kang, Jiaying Xu, Yun Qian, Simson Tsz Yat Luk, Huarong Chen, Weilin Li, Liuyang Zhao, Xiaoming Zhang, Phlip WY Chiu, Enders KW Ng, Jun Yu
Journal: Theranostics (2019)

Rationale: Prostaglandin E2 (PGE2) is a pro-inflammatory eicosanoid up-regulated in gastric cancer (GC).However, its impact on epigenetic dysfunction in the process of gastric carcinogenesis is unknown.In this study, we investigate the role of PGE2 in DNA methylation in gastric epithelium in vitro, in mice, and humans.Methods: PGE2-induced DNMT3B and DNA methylation was determined in gastric cell lines and COX-2 transgenic mice.Effect of COX-2 inhibition on DNA methylation was evaluated in a randomized controlled trial.Efficacy of combined COX-2/PGE2 and DNMT inhibition on GC growth was examined in cell lines and mice models.Results: PCR array analysis of PGE2-treated GC cells revealed the up-regulation of DNMT3B, a de novo DNA methyltransferase.In GC cells, PGE2 induced DNMT3B expression and activity, leading to increased methylated cytosine (5mC) and promoter methylation of tumor suppressive genes (MGMT and CNR1).Consistently, Cox-2 (rate-limiting enzyme for PGE2 biosynthesis) transgenic expression in mice significantly induced Dnmt3b expression, increased 5mC content, and promoted Mgmt promoter methylation.We retrospectively analyzed the 5mC content of 42 patients with intestinal metaplasia (a precancerous lesion of GC) treated with a COX-2 specific inhibitor Rofecoxib or placebo for 2 years, revealing that the COX-2 inhibitor significantly down-regulated 5mC levels (N=42, P=0.009).Collectively, these data indicate that PGE2 is closely related to DNA hypermethylation in vitro and in vivo.Using genome-wide 450K methylation array, we identified chromosomal genes (POT1, ATM and HIST1H2AA) were preferentially methylated by PGE2.Biofunctional work revealed that POT1 functions as a tumor suppressor.Finally, we demonstrated that combinatorial inhibition of COX-2 and DNMT using Celecoxib and Decitabine synergistically inhibited GC growth in vitro and in vivo. Conclusion:This study suggested that PGE2 promotes DNA methylation in GC, and that co-targeting of PGE2 and DNMT inhibits GC.
Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma
Authors: Meredith M. Regan, Lillian Werner, Sumati Rao, Komal Gupte-Singh, F. Stephen Hodi, John M. Kirkwood, Harriet M. Kluger, James Larkin, Michael A. Postow, Corey Ritchings, Mario Sznol, Ahmad A. Tarhini, Jedd D. Wolchok, Michael B. Atkins, David F. McDermott
Journal: Journal of Clinical Oncology (2019)

Outcome measures that comprehensively capture attributes of immuno-oncology agents, including prolonged treatment-free time and persistent treatment-related adverse events (TRAEs), are needed to complement conventional survival end points.We pooled data from the CheckMate 067 and 069 clinical trials of nivolumab and ipilimumab, as monotherapies or in combination, for patients with advanced melanoma. Treatment-free survival (TFS) was defined as the area between Kaplan-Meier curves for two conventional time-to-event end points, each defined from random assignment: time to immune checkpoint inhibitor (ICI) protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was partitioned as time with and without toxicity by a third end point, time to cessation of both ICI therapy and toxicity. Toxicity included persistent and late-onset grade 3 or higher TRAEs. The area under each Kaplan-Meier curve was estimated by the 36-month restricted mean time.At 36 months, many of the 1,077 patients who initiated ICI therapy were surviving free of subsequent therapy initiation (47% nivolumab plus ipilimumab, 37% nivolumab, 15% ipilimumab). The restricted mean TFS was longer for nivolumab plus ipilimumab (11.1 months) compared with nivolumab (4.6 months; difference, 6.5 months; 95% CI, 5.0 to 8.0 months) or ipilimumab (8.7 months; difference, 2.4 months; 95% CI, 0.8 to 4.1 months); restricted mean TFS represented 31% (3% with and 28% without toxicity), 13% (1% and 11%), and 24% (less than 1% and 23%) of the 36-month period, respectively, in the three treatment groups. TFS without toxicity was longer for nivolumab plus ipilimumab than nivolumab (difference, 6.0 months) or ipilimumab (difference, 1.7 months).The analysis of TFS between ICI cessation and subsequent therapy initiation revealed longer TFS without toxicity for patients with advanced melanoma who received nivolumab plus ipilimumab compared with nivolumab or ipilimumab. Regardless of treatment, a small proportion of the TFS involved grade 3 or higher TRAEs.
Factor VIII Activity and Risk of Bleeding in Acquired Hemophilia a: Results from the Gth-AH 01/2010 Study
Authors: Katharina Holstein, Andrea Smith, Paul Knöbl, Christiane Dobbelstein, Wolfgang A. Miesbach, Michael Spannagl, Jürgen Heinz, Ute Scholz, Hermann Eichler, Angela Huth-Kühne, Robert Klamroth, Armin Koch, Andreas Tiede
Journal: Blood (2017)
Functional roles of circular RNAs during epithelial-to-mesenchymal transition
Authors: Bing-Qing Shang, Min-Le Li, Hao-yu Quan, Ping-Fu Hou, Zhong-Wei Li, Su-Fang Chu, Jun-Nian Zheng, Jin Bai
Journal: Molecular Cancer (2019)

Abstract Cancer has become a major health issue worldwide, contributing to a high mortality rate. Tumor metastasis is attributed to the death of most patients. Epithelial-to-mesenchymal transition (EMT) plays a vital role in inducing metastasis. During EMT, epithelial cells lose their characteristics, such as cell-to-cell adhesion and cell polarity, and cells gain motility, migratory potential, and invasive properties to become mesenchymal stem cells. Circular RNAs (circRNAs) are closely associated with tumor metastasis and patient prognosis, as revealed by increasing lines of evidence. CircRNA is a type of single-stranded RNA that forms a covalently closed continuous loop. CircRNAs are insensitive to ribonucleases and are widespread in body fluids. This work is the first review on EMT-related circRNAs. In this review, we briefly discuss the characteristics and functions of circRNAs. The correlation of circRNAs with EMT has been reported, and we discuss the ways circRNAs can regulate EMT progression through EMT transcription factors, EMT-related signaling pathways, and other mechanisms. This work summarizes current studies on EMT-related circRNAs in various cancers and provides a theoretical basis for the use of EMT-related circRNAs in targeted management and therapy.
Carboplatin + pegylated liposomal doxorubicin: activity as 2nd or 3rd line treatment of endometrial carcinoma
Authors: Franco Muggia, Nagasree Seetharamu, Andrea Downey
Journal: Cancer Research (2008)

4486  High-risk stage I and II endometrial carcinoma, and resected stages III and IV are now treated with chemotherapy. In this study, previously treated patients (pts) received carboplatin (C) (AUC5) + pegylated liposomal doxorubicin (PLD), 30 mg/m2 every 3 weeks, a dose found safe by Hamilton et al (ASCO 2003). Single agent PLD had shown activity in pre-treated pts (J Clin Oncol 20:2360, 2003).  Methods: Patients with endometrial/unknown primary (mullerian origin) received C-PLD in 2nd or 3rd line. All had received C-Taxol 1st line. Progression-free survival (PFS 2 or PFS 3 for 2nd or 3rd-line C-PLD, respectively) from start of C-PLD doublet was compared to the PFS after the earlier regimen for each patient; response assessed by imaging studies and/or CA 125.  Results: 11 pts were treated 2004-2007: 6 as 2nd-line and 5 as 3rd-line. C-PLD as 2nd-line will exceed PFS compared to PFS1 in 2 pts (Table 1). As 3rd-line, 2 of 4 had longer PFS3 than PFS2 (Table 2). No grade 3 or 4 toxicities were observed. Skin toxicity was mild.  Table 1  ^pts receiving PLD maintenance every 4-6 weeks *megestrol/tamoxifen in 2nd-line **floxuridine/platinums in 2nd line ^^single agent PLD or Taxol in 2nd line.  Conclusion: Treatment with a platinum/PLD has activity as 2nd-line or 3rd- line treatment of endometrial or unknown primary cancers of probable Mullerian origin
Dutch physician sues FDA for blocking her abortion services in United States
Authors: Owen Dyer
Journal: BMJ (2019)

A Dutch physician and activist known for bringing abortion services to countries with restrictive laws is suing the US Food and Drug Administration over its efforts to stop her online prescription service from reaching US patients.1

Rebecca Gomperts and her company, Aid Access, have claimed in an Idaho federal court that the US regulator seized shipments of mifepristone and misoprostol bound for her patients and stopped their money transfers.

She argues that this violated the equal protection clause of the US’s fifth amendment by placing greater burdens on women in areas where abortion services are thinly spread or restricted by law.

Gomperts was once medical officer …
Don’t Fear the Reaper
Authors: Jules B. Lipoff
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Treatment of relapsed or refractory classical Hodgkin lymphoma with the anti-PD-1, tislelizumab: results of a phase 2, single-arm, multicenter study
Authors: Yuqin Song, Quanli Gao, Huilai Zhang, Lei Fan, Jianfeng Zhou, Dehui Zou, Wei Li, Haiyan Yang, Ting Liu, Quanshun Wang, Fangfang Lv, Haiyi Guo, Liudi Yang, Rebecca Elstrom, Jane Huang, William Novotny, Vivian Wei, Jun Zhu
Journal: Leukemia (2019)

Abstract Prognosis is poor for patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after failure of or who are ineligible for autologous stem cell transplant. We evaluated the efficacy and safety of tislelizumab, an investigational anti-PD-1 monoclonal antibody, in phase 2, single-arm study in Chinese patients with R/R cHL. The primary endpoint was overall response rate as assessed by an independent review committee, according to the Lugano 2014 Classification. Seventy patients were enrolled in the study and received at least one dose of tislelizumab. After median follow-up of 9.8 months, 61 (87.1%) patients achieved an objective response, with 44 (62.9%) achieving a complete response (CR). The estimated 9-month progression-free survival rate was 74.5%. Most common grade ≥3 adverse events (AEs) were upper respiratory tract infection and pneumonitis. Infusion-related reactions occurred in 27 (38.6%) patients, and 27 patients (38.6%) experienced an immune-related AE, the most common of which was thyroid dysfunction. Eleven (15.7%) patients experienced at least one treatment-emergent AE leading to dose interruption or delay. No deaths occurred due to AEs. Treatment of patients with R/R cHL with tislelizumab was generally well tolerated and resulted in high overall response and CR rates, potentially translating into more durable responses for these patients.
Automatic segmentation of prostate MRI using convolutional neural networks: Investigating the impact of network architecture on the accuracy of volume measurement and MRI-ultrasound registration
Authors: Nooshin Ghavami, Yipeng Hu, Eli Gibson, Ester Bonmati, Mark Emberton, Caroline M. Moore, Dean C. Barratt
Journal: Medical Image Analysis (2019)

Convolutional neural networks (CNNs) have recently led to significant advances in automatic segmentations of anatomical structures in medical images, and a wide variety of network architectures are now available to the research community. For applications such as segmentation of the prostate in magnetic resonance images (MRI), the results of the PROMISE12 online algorithm evaluation platform have demonstrated differences between the best-performing segmentation algorithms in terms of numerical accuracy using standard metrics such as the Dice score and boundary distance. These small differences in the segmented regions/boundaries outputted by different algorithms may potentially have an unsubstantial impact on the results of downstream image analysis tasks, such as estimating organ volume and multimodal image registration, which inform clinical decisions. This impact has not been previously investigated. In this work, we quantified the accuracy of six different CNNs in segmenting the prostate in 3D patient T2-weighted MRI scans and compared the accuracy of organ volume estimation and MRI-ultrasound (US) registration errors using the prostate segmentations produced by different networks. Networks were trained and tested using a set of 232 patient MRIs with labels provided by experienced clinicians. A statistically significant difference was found among the Dice scores and boundary distances produced by these networks in a non-parametric analysis of variance (p < 0.001 and p < 0.001, respectively), where the following multiple comparison tests revealed that the statistically significant difference in segmentation errors were caused by at least one tested network. Gland volume errors (GVEs) and target registration errors (TREs) were then estimated using the CNN-generated segmentations. Interestingly, there was no statistical difference found in either GVEs or TREs among different networks, (p = 0.34 and p = 0.26, respectively). This result provides a real-world example that these networks with different segmentation performances may potentially provide indistinguishably adequate registration accuracies to assist prostate cancer imaging applications. We conclude by recommending that the differences in the accuracy of downstream image analysis tasks that make use of data output by automatic segmentation methods, such as CNNs, within a clinical pipeline should be taken into account when selecting between different network architectures, in addition to reporting the segmentation accuracy.
Abstract P315: Beneficial Associations Between Breastfeeding and Cardiopulmonary Fitness: A Life Course Study
Authors: Isabel Ferreira, Tracy L Lim, Colin A Boreham
Journal: Circulation (2019)

In contrast to associations with other cardiometabolic risk factors, the extent to which breastfeeding is associated with cardiorespiratory fitness (CRF) is unclear. Moreover, whether any such association persists throughout the life course has never been investigated before. We have therefore examined the associations between breastfeeding (yes/no, duration) and CRF as estimated from field and laboratory tests and expressed by the level of VO 2 max from late childhood, through adolescence to young adulthood in 892 (50.8% female) participants in the Northern Ireland Young Hearts Project. This is a population-based cohort study conducted in a region with very low rates of breastfeeding within the UK and the western world. Longitudinal data were analyzed with weighted generalized estimating equations, to correct estimates for selective attrition bias (with inverse probability of attrition weights). All estimates were adjusted for the participants age, sex, socio-economic status and important perinatal confounders (birthweight z-scores, gestational age, maternal age and parity, and mode of delivery). Participants’ mean levels of CRF were 45.6±4.9, 43.9±6.9 and 32.8±9.7 mL/kg/min at the ages of 12, 15 and 22 years, respectively. On average, and as compared with participants who were never breastfed (n=746), those who were breastfed (n=146) had significantly higher levels of CRF, from childhood to adulthood: 1.23 mL/min/kg (95%CI: 0.22, 2.24). Further adjustments for potential mediators, i.e. participants’ lifestyle risk factors (physical activity, smoking alcohol and dietary habits) and body size (height) and composition (fat and fat-free masses) during growth, did not appreciably attenuate this association: 1.14 mL/min/kg (95%CI: 0.29, 1.99). Analyses by duration of breastfeeding did not reveal increasing benefits with increasing duration, however: +1.10 and +1.20 mL/kg/min if &lt;=3 and &gt;3 months vs. none, respectively. There were no significant interactions between breastfeeding and participants’ sex or age at the time of CRF assessments, indicating that the decreases in CRF were similar across the different breastfeeding groups, with those who were not breastfed displaying consistently lower levels throughout the longitudinal period. Finally, those who were breastfed had lower lifelong risk of poor CRF as defined according to age and sex-specific reference values of VO 2 max: RR=0.70 (0.49, 0.97) and RR=0.73 (0.51, 0.99) in models adjusted for confounders and potential mediators, respectively. In conclusion, breastfeeding may have lifelong beneficial effects on CRF and thereby cardiovascular health. These findings may have important public health and clinical implications and should reinforce breastfeeding promotion policies, particularly where uptake rates remain low. The mechanisms through which breastfeeding affect CRF need to be further explored though.
Evaluation of the TPO-receptor agonist Eltrombopag in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models.
Authors: Michael Roth, Grace Nevil, Jonathan Benjamin Gill, Wendong Zhang, Beverly A. Teicher, Stephen W Erickson, Gregory Gatto, Malcolm A. Smith, E. Anders Kolb, Richard Greg Gorlick
Journal: Journal of Clinical Oncology (2019)

e22502 Background: Eltrombopag (EP) is a small molecule, thrombopoietin receptor (TPO-R) agonist indicated for the treatment of patients with chronic immune thrombocytopenia and severe aplastic anemia. EP is a polyvalent cation chelator and inhibits leukemia cell proliferation via depletion of intracellular iron. Recent studies show EP inhibits the proliferation of osteosarcoma cells lines via depletion of polyvalent cations. The in vivo effects of EP were studied in osteosarcoma patient derived xenograft models by the Pediatric Preclinical Testing Consortium (PPTC). Methods: The in vivo anticancer effects of EP were assessed in a panel of six osteosarcoma PPTC PDX models with limited MPL mRNA expression (OS2, OS9, OS31, OS33, OS36, OS60). EP was administered at an oral dose of 5 mg/kg/day given for 5 days each week with planned treatment period of 4 weeks. High dose EP (50mg/kg/day) was also tested in 2 PDX models (OS2, OS9) on the same schedule. A control cohort that received vehicle was included for each PDX model. Tumor volumes were measured and responses defined utilizing the PPTC statistical analyses. Results: EP at 5 mg/kg failed to inhibit tumor growth or induce significant differences in event-free survival (EFS) in any of the 6 osteosarcoma PDX models. At the higher dose of 50 mg/kg a significant prolongation in time to event in the EP-treated group was observed, but the effect was small with the ratio of the median time to event for treated versus control animals (EFS T/C) being only 1.2 in the 2 OS PDX models tested. No objective responses were observed with EP at either dose, with all models demonstrating progressive disease. Conclusions: EP did not exhibit significant antitumor activity against the PPTC osteosarcoma PDX panel. However, EP also did not enhance tumor growth. EP’s lack of anti-tumor activity against the OS PDX models suggests leukemia and osteosarcoma cells likely have different dependencies on intracellular polyvalent cations. Given EPs effect on stimulating platelet production, and the demonstration that EP does not stimulate in vivo growth of osteosarcoma, EP may be considered in patients with osteosarcoma as a supportive care agent in supporting platelet recovery.
Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy
Authors: Xiang-Min Tong, Liang Feng, Sreedhar Reddy Suthe, Tian-Hao Weng, Chen-Yu Hu, Yi-Zhi Liu, Zhi-Gang Wu, Ming-Hai Wang, Hang-Ping Yao
Journal: Journal for ImmunoTherapy of Cancer (2019)

Antibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer therapy. Here we describe a humanized antibody recognizing the RON plexin-semaphorin-integrin (PSI) domain with increased drug delivery capability for potential clinical application. Monoclonal antibody PCM5B14 specific to the human and monkey RON PSI domain was generated and characterized by various immunological methods. Humanized antibody H5B14 was created by grafting PCM5B14 complementarity-determining regions into human IgG1/κ acceptor frameworks and conjugated with monomethyl auristatin E and duocarmycin to form two H5B14-based ADCs. Stability of H5B14-based ADCs in human plasma was measured using hydrophobic interaction chromatography. Various biochemical and biological assays were used to determine ADC- regulated RON internalization, cell viability, spheroid formation, and death of cancer stem-like cells. Efficacies of H5B14-based ADCs in vivo were validated using tumor xenograft models. Maximal tolerated doses of H5B14-based ADCs were established in mice. H5B14 was highly specific to the human RON PSI domain and superior over other anti-RON ADCs in induction of RON internalization in various cancer cell lines tested. H5B14-based ADCS had a drug to antibody ratio of ~ 3.70:1 and were stable in human plasma with a minimal dissociation within a 10-day period. Functionally, H5B14-mediated drug delivery decreased cell viability at early stages with an average IC50 at ~ 20 nM in multiple cancer cell lines examined. H5B14-based ADCs also inhibited spheroid formation and caused death of cancer stem-like cells with RON+/CD44+/ESA+ phenotypes. In vivo, H5B14-based ADCs in a single injection inhibited tumor xenograft growth mediated by multiple cancer cell lines. Tumoristatic concentrations calculated from xenograft tumor models were in the range of 0.63 to 2.0 mg/kg bodyweight. Significantly, H5B14-based ADCs were capable of eradicating tumors at variable levels across multiple xenograft models regardless their malignant statuses. Toxicologically, H5B14-based ADCs were well tolerated in mice up to 60 mg/kg. H5B14-based ADCs targeting the RON PSI domain are superior in inducing RON internalization, leading to robust drug delivery and overall inhibition and eradication of tumors in multiple xenograft models. These findings warrant H5B14-based ADCs for clinical trials in the future.