tbuckley/cabot-search huggingface dataset:
Abstract 9276: Optimizing Cardiac Progenitor Cell-Sheet Therapy by Adding Endothelial Progenitor Cell Transplantation for Ischemic Cardiomyopathy: An Analysis of Layer-Specific Regional Cardiac Function
Authors: Sokichi kamata, Shigeru Miyagawa, Satoshi Nakatani, Satsuki Fukushima, Atsuhiro Saito, Akima Harada, Atsuhiko Kawamoto, Tatsuya Shimizu, Teruo Okano, Takayuki Asahara, Yoshiki Sawa
Journal: Circulation (2011)

Background: Transplantation of cell-sheet generated by cardiac progenitor cells (CPCs) is a promising therapeutic strategy for ischemic cardiomyopathy (ICM), while potential ischemia in the transplanted area remains to be overcome. Endothelial progenitor cells (EPCs) reportedly induce angiogenesis in the injected territory. Hypothesis: Concomitant EPC injection might enhance the therapeutic effects of CPC cell-sheet in ICM. Methods: Scaffold-free CPC cell-sheet was generated from human primary c-kit + heart-derived cells. ICM model was generated by placing the ameroid ring around the left coronary artery for 4 weeks in swine. They then underwent sham operation, CPC cell-sheet transplantation over the epicardial infarct area, or cell-sheet plus human EPC i.m. injection (n=5 in each), followed by the efficacy assessment for 2 months. Results: Speckle-tracking echocardiography dissected layer-specific regional systolic function by the radial strain. The epicardial radial strain in the infarct area was similarly greater after the CPC sole (19±5%) and the combination (20±5%) than that after the sham (7±1%, P =0.01). In contrast, the endocardial radial strain in the infarct area was greater after the combination (14±2%) than that after the CPC sole (11±2%, P =0.04) or the sham (9±1%, P =0.02), suggesting addition of EPC injection may enhance the functional recovery in the endocardium. Consequently, significant improvement in the left ventricular ejection fraction by the CPC sole therapy (43±5%, P=0.03) compared to the sham (32±4%) was further enhanced by the combination therapy (53±4%, P =0.01), assessed by the multi-detector-raw CT. Consistently, histological findings, including in-situ hybridization with human specific primers, revealed additional EPC injection significantly increased capillaries in the infarct area (272±38/mm 2 vs. 195±32/mm 2 vs. 85±26/mm 2 ) and induced differentiation of transplanted CPCs into the myogenic and endothelial lineages. Conclusion: Transplantation of CPC cell-sheet induced functional recovery in the epicardial infarct area, whereas concomitant EPC transplantation achieved a transmural recovery associated with enhanced neovascularization and possible cardiomyogenic differentiation in ICM.
Association of Inferior Vena Cava Filter Placement for Venous Thromboembolic Disease and a Contraindication to Anticoagulation With 30-Day Mortality
Authors: Tyson E. Turner, Mohammed J. Saeed, Eric Novak, David L. Brown
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Despite the absence of data from randomized clinical trials, professional societies recommend inferior vena cava (IVC) filters for patients with venous thromboembolic disease (VTE) and a contraindication to anticoagulation therapy. Prior observational studies of IVC filters have suggested a mortality benefit associated with IVC filter insertion but have often failed to adjust for immortal time bias, which is the time before IVC filter insertion, during which death can only occur in the control group. <h3>Objective</h3> To determine the association of IVC filter placement with 30-day mortality after adjustment for immortal time bias. <h3>Design, Setting, and Participants</h3> This comparative effectiveness, retrospective cohort study used a population-based sample of hospitalized patients with VTE and a contraindication to anticoagulation using the State Inpatient Database and the State Emergency Department Database, part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, from hospitals in California (January 1, 2005, to December 31, 2011), Florida (January 1, 2005, to December 31, 2013), and New York (January 1, 2005, to December 31, 2012). Data analysis was conducted from September 15, 2015, to March 14, 2018. <h3>Exposure</h3> Inferior vena cava filter placement. <h3>Main Outcomes and Measures</h3> Multivariable Cox proportional hazard models were constructed with IVC filters as a time-dependent variable that adjusts for immortal time bias. The Cox model was further adjusted using the propensity score as an adjustment variable. <h3>Results</h3> Of 126 030 patients with VTE, 61 281 (48.6%) were male and the mean (SD) age was 66.9 (16.6) years. In this cohort, 45 771 (36.3%) were treated with an IVC filter, whereas 80 259 (63.7%) did not receive a filter. In the Cox model with IVC filter status analyzed as a time-dependent variable to account for immortal time bias, IVC filter placement was associated with a significantly increased hazard ratio of 30-day mortality (1.18; 95% CI, 1.13-1.22;<i>P</i> &lt; .001). When the propensity score was included in the Cox model, IVC filter placement remained associated with an increased hazard ratio of 30-day mortality (1.18; 95% CI, 1.13-1.22;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> After adjustment for immortal time bias, IVC filter placement was associated with increased 30-day mortality in patients with VTE and a contraindication to anticoagulation. Randomized clinical trials are needed to determine the efficacy of IVC filter placement in patients with VTE and a contraindication to anticoagulation.
A Biological Signature for Breast Ductal Carcinoma <i>In Situ</i> to Predict Radiotherapy Benefit and Assess Recurrence Risk
Authors: Troy Bremer, Pat W. Whitworth, Rakesh Patel, Jess Savala, Todd Barry, Stephen Lyle, Glen Leesman, Steven P. Linke, Karin Jirström, Wenjing Zhou, Rose-Marie Amini, Fredrik Wärnberg
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Ductal carcinoma in situ (DCIS) patients and their physicians currently face challenging treatment decisions with limited information about the individual's subsequent breast cancer risk or treatment benefit. The DCISionRT biological signature developed in this study provides recurrence risk and predicts radiotherapy (RT) benefit for DCIS patients following breast-conserving surgery (BCS). Experimental Design: A biological signature that calculates an individualized Decision Score (DS) was developed and cross-validated in 526 DCIS patients treated with BCS ± RT. The relationship was assessed between DS and 10-year risk of invasive breast cancer (IBC) or any ipsilateral breast event (IBE), including IBC or DCIS. RT benefit was evaluated by risk group and as a function of DS. Results: The DS was significantly associated with IBC and IBE risk, HR (per 5 units) of 4.2 and 3.1, respectively. For patients treated without RT, DS identified a Low Group with 10-year IBC risk of 4% (7% IBE) and an Elevated Risk Group with IBC risk of 15% (23% IBE). In analysis of DS and RT by group, the Elevated Risk Group received significant RT benefit, HR of 0.3 for IBC and IBE. In a clinicopathologically low-risk subset, DS reclassified 42% of patients into the Elevated Risk Group. In an interaction analysis of DS and RT, patients with elevated DS had significant RT benefit over baseline. Conclusions: The DS was prognostic for risk and predicted RT benefit for DCIS patients. DS identified a clinically meaningful low-risk group and a group with elevated 10-year risks that received substantial RT benefit over baseline.
Abstract 5800: Vorinostat and indole-3-carbinol modulate microRNAs and histone deacetylase activity in subtypes of triple-negative breast cancer
Authors: Beverly Lyn-Cook, Fatemeh NouriEmamzaden, Anfernee Hawkins, George Hammons, Beverly Word
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer is a highly heterogeneous and aggressive subtype of breast cancer. Epigenetic drugs are continuing to emerge as promising therapies for triple-negative breast cancer (TNBC). These drugs, including the one used in this study, vorinostat, a histone deacetylase inhibitor (HDAC), are capable of multiple actions and are considered multifunctional drugs. Epigenetic mechanisms have been shown to play a role in the etiology of this cancer, through modulation of DNA methylation, histone modification or microRNAs. We have shown in this study that vorinostat and indole-3-carbinol (I3C) modulated the expression of microRNAs 221 and 222 differently in basal-like-2 (BL2), MSL, basal-like1 (BL1) and M subtypes of TNBC cells. Additional studies demonstrated that combination of tamoxifen and vorinostat significantly decreased expression of miRNA 221 in TNBC cell lines. MiRNAs are short noncoding RNAs that regulate the function of target genes post-transcriptionally. In addition, breast cancer microarrays further showed modulation of a number of other miRNAs that play a role in cell proliferation, drug resistance, cell invasion and metastasis. MicroRNAs are epigenetic targets for drug development. Using a global HDAC activity assay, it was also shown that subtypes of TNBC cells respond differently to vorinostat and I3C treatment, depending on their HDAC activity. HCC70, an African American cell line and a BL2 subtype, had the highest HDAC activity and its activity was significantly decreased by vorinostat treatment compared to BT549 (M), HCC 1806 (BL2), MCF7 (ER positive) and a basal nonmalignant cell line, MCF10A. Both vorinostat and I3C show great promise alone and in combination as effective agents in triple-negative breast cancer. Histone deacetylase inhibitors and dietary agents are emerging as therapy for triple-negative breast cancer and are currently in clinical trials. Citation Format: Beverly Lyn-Cook, Fatemeh NouriEmamzaden, Anfernee Hawkins, George Hammons, Beverly Word. Vorinostat and indole-3-carbinol modulate microRNAs and histone deacetylase activity in subtypes of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5800.
Primary and metastatic brain tumours in adults: summary of NICE guidance
Authors: Alex Bates, Eva Gonzalez-Viana, Garth Cruickshank, Tom Roques
Journal: BMJ (2018)

### What you need to know

Although primary malignant brain tumours represent only 3% of all cancers, they result in the most life-years lost of any cancer.1 Survival with malignant brain tumours has remained poor despite improvements in diagnosis and management (table 1), and it was believed that survival and quality of life could be improved by standardising care across the country with a guideline. Over 60% of people with primary brain tumours present at and are diagnosed by accident and emergency services rather than by general practitioners or in specialist settings.2 Brain metastases are the most common brain tumour to present in primary care, but other forms of brain cancer are seen.

View this table:

Table 1 
Care requirements for brain tumours by approximate median survival



Although brain tumours are usually managed by specialist teams, primary care and non-specialist teams have an important role in patients’ long term care, particularly when it comes to considering the longer term cognitive, physical, and mental health effects of the tumour and its treatment (table 1).

This article summarises the most recent …
Abstract 19236: Late Outcomes Following Immediate Aortic Repair for Acute Type A Aortic Dissection Complicated by Coma
Authors: Takuro Tsukube, Taro Hayashi, Toshihiro Kawahira, Tomonori Haraguchi, Ritsu Matsukawa, Shuichi Kozawa, Kyoichi Ogawa, Yutaka Okita
Journal: Circulation (2010)

Objectives:  Management of acute type A aortic dissection complicated by coma remains controversial. We previously reported an excellent recovery of consciousness for patients with coma if aortic repair performed within 5 hours from onset of symptoms. This study evaluates the early and late outcomes with this approach.   Methods:  Between 9/03 and 5/10, 132 patients with acute type A aortic dissection were treated surgically, including 22 (16.7%) presented with coma (Glasgow Coma Scale    Results:  Time from onset of symptoms to operating room was 199 (SD 59) minutes. Hospital mortality of the comatose patients who had immediate aortic repair was 5.3% (1/19) and that was equivalent to the mortality of the entire cohort (n = 132: 8.3%). Full recovery of consciousness was achieved in 84% (16/19) in 14 days after repair, and the incidence of coexisted neurological deficits was significantly decreased postoperatively (42%: 8/19). The mean follow-up periods was 34.5 (SD 25.1) months. Cumulative survival rate was 71.8% in 3 years, and ADL independence was achieved in 67% (10/15).   Conclusions:  Early and late outcomes following the strategy of immediate aortic repair, performed within 5 hours from onset of symptoms, for acute type A aortic dissection complicated by coma were satisfactory. Timely surgical repair is strongly recommended.
The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC)
Authors: Julie R. Brahmer, Ramaswamy Govindan, Robert A. Anders, Scott J. Antonia, Sarah Sagorsky, Marianne J. Davies, Steven M. Dubinett, Andrea Ferris, Leena Gandhi, Edward B. Garon, Matthew D. Hellmann, Fred R. Hirsch, Shakuntala Malik, Joel W. Neal, Vassiliki A. Papadimitrakopoulou, David L. Rimm, Lawrence H. Schwartz, Boris Sepesi, Beow Yong Yeap, Naiyer A. Rizvi, Roy S. Herbst
Journal: Journal for ImmunoTherapy of Cancer (2018)

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy - characterized by some benefit but only rare durable responses - was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field.
Photodynamic Therapy: A New Treatment Modality for Rheumatoid Arthritis: Combined Photothermal and Photodynamic Therapy Using Cu<sub>7.2</sub>S<sub>4</sub> Nanoparticles (Adv. Healthcare Mater. 14/2018)
Authors: Yao Lu, Lihua Li, Zefeng Lin, Liping Wang, Lijun Lin, Mei Li, Yu Zhang, Qingshui Yin, Qi Li, Hong Xia
Journal: Advanced Healthcare Materials (2018)

In article 1800013, Qi Li, Hong Xia, and co-workers report a novel treatment modality for rheumatoid arthritis combining photothermal and photodynamic therapy using Cu7.2S9 nanoparticles. The multifunctional nanoparticles can effectively inhibit inflamed synovial invasion and bone erosion under near infrared laser irradiation and prevent from clinical bacterial infection.
Redox Regulation Beyond ROS
Authors: Ralf P. Brandes, Flavia Rezende, Katrin Schröder
Journal: Circulation Research (2018)

B ased on the concept of oxidative stress, reactive oxygen species (ROS) have been incriminated as the drivers behind almost every cardiovascular pathology.Redox alterations are, however, omnipresent bystanders to changes in cellular activity state.Even when ROS levels are altered, their contribution to pathology is not necessarily causal.Researchers should hesitate to engage in global ROS measurements and rather aim on identifying individual molecular targets of redox regulation.
Abstract 16201: Exosomal Y RNA Fragment Alters Macrophage Il-10 Gene Expression And Secretion, Conferring Cardioprotection Following Ischemia/reperfusion Injury
Authors: Linda Cambier, Geoffrey de Couto, Ahmed Ibrahim, Eduardo Marbán
Journal: Circulation (2016)

Background:  Exosomes secreted by cardiosphere-derived cells (CDCs) mediate regeneration and cardioprotection after ischemia/reperfusion (I/R) injury. CDC-secreted exosomes (CDC-exo) reduce infarct size after I/R by delivering bioactive noncoding RNAs to target cells, including macrophages. By previous RNA-sequencing analysis, we identified a unique Y RNA fragment Yb highly enriched in CDC-exo.   Objective:  We sought to clarify the role, if any, of Yb as a mediator of the cardioprotection observed with CDC-exo treatment following I/R.   Methods:  To investigate the role of this specific Y RNA fragment, we directly transfected bone marrow derived-macrophages (BMDMs) with Yb. Gene/protein expression analyses and chromatin immunoprecipitation (ChIP)-sequencing were performed to evaluate transcriptional and epigenetic modifications. Mass spectrometry and RNA pull-down were done to identify protein partners. Potential cytoprotective effects were examined on cardiomyocytes subjected to oxidative stress and cocultured with Yb-primed macrophages. The role of Yb was also assessed  in vivo  in a rat model of I/R injury.   Results:  Yb induced transcription and protein secretion of IL-10 when directly transfected into BMDMs, leading to acetylation of H3K27 at the  Il10  locus as well as promoter activation. These effects underlie an observed increased and sustained release of IL-10 by BMDMs. We identified the ribonucleoprotein HnrpH1 as a critical binding partner of Yb. Moreover, Yb-primed BMDMs were cytoprotective against oxidative stress in cardiomyocytes (24.1±4.8% apoptosis rate  vs.  42.9±6.7% with scramble-primed BMDMs; p=0.0002); this cytoprotection was abrogated by co-incubation with a blocking antibody against IL-10. Intracoronary injection of Yb in rats 10 min post I/R showed scar mass reduction after 48h (Yb: 24.3±2.8 mg; scramble: 67.4±10.9 mg; p   Conclusions:  Yb, a Y RNA-derived fragment highly enriched in CDC-exo, contributes to cardioprotection by increasing  Il10  expression, leading to enhanced IL-10 protein secretion. Yb increases  Il10  expression via promoter activation and epigenetic modifications. Thus, this small noncoding RNA of previously unknown biological activity contributes to the therapeutic effects of CDC-exo.
Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance
Authors: Sabrina Grasse, Matthias Lienhard, Steffen Frese, Martin Kerick, Anne Steinbach, Christina Grimm, Michelle Hussong, Jana Rolff, Michael Becker, Felix Dreher, Uwe Schirmer, Stefan Boerno, Anna Ramisch, Gunda Leschber, Bernd Timmermann, Christian Grohé, Heike Lüders, Martin Vingron, Iduna Fichtner, Sebastian Klein, Margarete Odenthal, Reinhard Büttner, Hans Lehrach, Holger Sültmann, Ralf Herwig, Michal R. Schweiger
Journal: Genome Medicine (2018)

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The major challenge in the treatment of NSCLC patients is intrinsic or acquired resistance to chemotherapy. Molecular markers predicting the outcome of the patients are urgently needed.Here, we employed patient-derived xenografts (PDXs) to detect predictive methylation biomarkers for platin-based therapies. We used MeDIP-Seq to generate genome-wide DNA methylation profiles of 22 PDXs, their parental primary NSCLC, and their corresponding normal tissues and complemented the data with gene expression analyses of the same tissues. Candidate biomarkers were validated with quantitative methylation-specific PCRs (qMSP) in an independent cohort.Comprehensive analyses revealed that differential methylation patterns are highly similar, enriched in PDXs and lung tumor-specific when comparing differences in methylation between PDXs versus primary NSCLC. We identified a set of 40 candidate regions with methylation correlated to carboplatin response and corresponding inverse gene expression pattern even before therapy. This analysis led to the identification of a promoter CpG island methylation of LDL receptor-related protein 12 (LRP12) associated with increased resistance to carboplatin. Validation in an independent patient cohort (n = 35) confirmed that LRP12 methylation status is predictive for therapeutic response of NSCLC patients to platin therapy with a sensitivity of 80% and a specificity of 84% (p < 0.01). Similarly, we find a shorter survival time for patients with LRP12 hypermethylation in the TCGA data set for NSCLC (lung adenocarcinoma).Using an epigenome-wide sequencing approach, we find differential methylation patterns from primary lung cancer and PDX-derived cancers to be very similar, albeit with a lower degree of differential methylation in primary tumors. We identify LRP12 DNA methylation as a powerful predictive marker for carboplatin resistance. These findings outline a platform for the identification of epigenetic therapy resistance biomarkers based on PDX NSCLC models.
In RA, becoming seronegative over the first year of treatment does not translate to better chances of drug-free remission
Authors: Emma C de Moel, Veerle F A M Derksen, Leendert A Trouw, Holger Bang, Yvonne P M Goekoop-Ruiterman, Gerda M Steup-Beekman, Tom W J Huizinga, Cornelia F Allaart, René E M Toes, Diane van der Woude
Journal: Annals of the Rheumatic Diseases (2018)

In rheumatoid arthritis (RA), it is becoming common to attempt to taper or stop medication, aiming for sustained drug-free remission (SDFR). Autoantibody seropositivity is a poor prognostic factor for this treatment goal. However, autoantibody levels may change and patients may become seronegative, sometimes termed ‘immunological remission’.1 Understanding how often this occurs and whether it is favourable for achieving SDFR is important to determine whether becoming seronegative is a meaningful prognostic marker for drug tapering decisions. Furthermore, it will elucidate pathways that lead to long-term resolution of the pathophysiology underlying RA.

To that end, we investigated the relationship between seroconversion and SDFR. In baseline and 1-year serum of 381 patients with seropositive RA, we measured 14 RA-associated autoantibodies by ELISA2: anti-CCP2 IgG, IgM and IgA; rheumatoid factor IgM and IgA; anti-CarP IgG, IgM and IgA; anti-acetylated  lysine vimentin IgG and anti-acetylated ornithine vimentin IgG (Orgentec Diagnostika , Germany); and anti-citrullinated vimentin 59–74 IgG, anti-citrullinated fibrinogen β 36–52 and α 27–43 IgG, anti-citrullinated enolase 5–20 IgG. Patients originated from the IMPROVED study,3 a randomised controlled treat-to-target trial …