tbuckley/cabot-search huggingface dataset:
Abstract 15230: MiR-30e Reduces Osteogenic Differentiation of Bone Marrow Derived Mesenchymal Stem Cells by Repressing IGF2 Expression
Authors: Wen Ding, Jihe Li, Reldy Riveron, Roberto Vazquez-Padron, Samirah Gomes, Joshua Hare, Lina Shehadeh
Journal: Circulation (2013)

Objective: In atherosclerosis, activation of an osteogenic transcriptional program in de-differentiated mesenchymal-like smooth muscle cells contributes substantially to the initiation of aortic calcification. MiR-30e was recently reported as the most downregulated miR in the aortas of atherogenic APOE-/- mice. To assess a causal link of deficient miR-30e, we tested the hypothesis that overexpression of miR-30e would inhibit osteogenic differentiation of bone marrow derived mesenchymal stem cells (MSCs).

Method and Results: Using qPCR and Elisa respectively, we confirmed that the expression of the mRNA and protein for the osteogenic marker osteopontin (OPN) was upregulated (p<.01) in aortas of 6 mo old APOE-/- mice (n=9) relative to wild type controls (n=4). In MSCs transduced with lentivirus for miR-30e or a scrambled (scr) control, microarrays and qPCR showed repression (p<.05) of an osteogenic profile including Opn, Igf2, Runx2, Bmp4, Dpt, and Dcn genes. At 2 wk osteogenic differentiation, this osteogenic gene expression panel was dramatically enhanced in the MSCs but reduced (p<.05) by miR-30e, with a decrease (p<.05) in OPN protein levels. Secreted IGF2 protein was decreased in the MSCs over-expressing miR-30e at 1wk osteogenic differentiation. Electron microscopy after 2wk osteogenic differentiation showed a marked morphological difference in the miR-30e stables versus controls. MiR-30e oligos with 2’Fluoro-modification also significantly decreased the above osteogenic panel together with Alp1 transcripts, in a dose-dependent manner. MiR-30e reduced (p<.01) proliferation of MSCs at Days 2, 4, and 5 post plating. Inhibiting miR-30e in MSCs using antimiR-30e oligos followed by microarrays and qPCR showed over-expression of Igf2 transcripts suggesting that Igf2 could be a primary target of miR-30e-driven osteogenic repression. Double luciferase assay showed binding of miR-30e to the 3’UTR of Igf2 (p=.00001) and positive control Runx2 (p=.01) but not Opn.

Conclusion: miR-30e represses the osteogenic potential of MSCs by targeting IGF2, and its dowregulation may be a proximate cause of the initiation of atherosclerosis. The miR-30e pathway represents a potentially powerful and important clinical target in vascular diseases.
Evaluating the Erythrocyte Sedimentation Rate
Authors: Andrew J. Hale, Daniel N. Ricotta, Jason A. Freed
Journal: JAMA (2019)

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Epigenomic Reordering Induced by Polycomb Loss Drives Oncogenesis but Leads to Therapeutic Vulnerabilities in Malignant Peripheral Nerve Sheath Tumors
Authors: John B. Wojcik, Dylan M. Marchione, Simone Sidoli, Anissa Djedid, Amanda Lisby, Jacek Majewski, Benjamin A. Garcia
Journal: Cancer Research (2019)

Abstract Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with recurrent loss-of-function alterations in polycomb-repressive complex 2 (PRC2), a histone-modifying complex involved in transcriptional silencing. To understand the role of PRC2 loss in pathogenesis and identify therapeutic targets, we conducted parallel global epigenomic and proteomic analysis of archival formalin-fixed, paraffin-embedded (FFPE) human MPNST with and without PRC2 loss (MPNSTLOSS vs. MPNSTRET). Loss of PRC2 resulted in increased histone posttranslational modifications (PTM) associated with active transcription, most notably H3K27Ac and H3K36me2, whereas repressive H3K27 di- and trimethylation (H3K27me2/3) marks were globally lost without a compensatory gain in other repressive PTMs. Instead, DNA methylation globally increased in MPNSTLOSS. Epigenomic changes were associated with upregulation of proteins in growth pathways and reduction in IFN signaling and antigen presentation, suggesting a role for epigenomic changes in tumor progression and immune evasion, respectively. These changes also resulted in therapeutic vulnerabilities. Knockdown of NSD2, the methyltransferase responsible for H3K36me2, restored MHC expression and induced interferon pathway expression in a manner similar to PRC2 restoration. MPNSTLOSS were also highly sensitive to DNA methyltransferase and histone deacetylase (HDAC) inhibitors. Overall, these data suggest that global loss of PRC2-mediated repression renders MPNST differentially dependent on DNA methylation to maintain transcriptional integrity and makes them susceptible to therapeutics that promote aberrant transcription initiation. Significance: Global profiling of histone PTMs and protein expression in archival human MPNST illustrates how PRC2 loss promotes oncogenesis but renders tumors vulnerable to pharmacologic modulation of transcription. See related commentary by Natarajan and Venneti, p. 3172
Success or Failure of High-Flow Nasal Oxygen Therapy: The ROX Index Is Good, but a Modified ROX Index May Be Better
Authors: Habib M. R. Karim, Antonio M. Esquinas
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

The ROX index was calculated for Sp O 2 of 95% and respiratory rates of 20-40 breaths/min using a range of FI O 2 values from 0.4 to 1.0.The gray area indicates ROX values below a cutoff point of 4.88 (1).Respiratory rates in oxygen-dependent patients are expected to be increased.The figure reveals that the ROX index is unlikely to drop below 4.88 with FI O 2 values of up to 0.5, and it would be under the cutoff point with FI O 2 values of 0.8 or higher for the anticipated range of respiratory rates.FI O 2 values of 0.5 and 0.8 are marked with interrupted vertical lines.If Sp O 2 is under or above 95%, all of the presented curves of the calculated ROX will shift slightly downward or upward, respectively.The index is very simple and has the potential to become a routine parameter in clinical practice when supplemental oxygen is used with NHF therapy.The presented figure may help to predict when a patient is expected to fail and could be considered for escalation of care.
QIM19-141: SOAR (Survivors Overcoming and Achieving Resilience)
Authors: Bianshly Rivera Rivero, Sonya Pflanzer, Diane Riccardi, Smitha R. Pabbathi
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: There are 4 components of survivorship care: prevention, surveillance, interventions, and coordination between oncology and primary care/specialists. As part of the initial visit in Moffitt’s survivorship program, we provide a comprehensive and personalized care plan to our patients with a focus on wellness. We understand the transition from active treatment into the extended phase of survivorship can be fraught with many unexpected physical, emotional, psychological, and social challenges, yet this could also be a critical period where survivors are uniquely positioned to adopt healthy and resilient behaviors. We want to help patients be empowered through knowledge from interactive and multidisciplinary classes and we aim at improving their quality of life. Methods: We created an 8-week curriculum customized and designed for breast cancer survivors by experts in nutrition, social work, physical therapy, yoga, arts in medicine, and survivorship medicine with utilization technique–driven live food demonstrations. The core message of the series is further echoed and instilled by use of weekly journaling and guidance on how to practice the techniques following each class. Results: We completed one 8-week course. 15 patients were enrolled in the program; of these 9–12 participants consistently presented to the sessions. Sessions consisted in education regarding nutrition, emotional health, exercise, mindfulness, and medical management after completing cancer treatment. To further determine the impact of sessions, we are measuring change in health-related quality of life through the RAND-36 questionnaire with a precourse survey and a postcourse survey. As we continue our sessions and our patient population increases, we expect to have substantial data to report on the impact of this curriculum. Conclusions: It is estimated that there are more than 3.1 million women in the United States with history of breast cancer. Development of a multidisciplinary program focused in comprehensive care for breast cancer survivors may improve quality of life. These techniques can positively impact the transition from active treatment and position survivors to be better managers of their wellness.
Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial
Authors: Vicky Makker, Drew Rasco, Nicholas J Vogelzang, Marcia S Brose, Allen L Cohn, James Mier, Christopher Di Simone, David M Hyman, Daniel E Stepan, Corina E Dutcus, Emmett V Schmidt, Matthew Guo, Pallavi Sachdev, Robert Shumaker, Carol Aghajanian, Matthew Taylor
Journal: The Lancet Oncology (2019)
Re: A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2–10 ng/ml at Initial Biopsy
Authors: Fumihiko Urabe, Takahiro Ochiya, Shin Egawa
Journal: European Urology (2019)
Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients
Authors: Bixia Tang, Xieqiao Yan, Xinan Sheng, Lu Si, Chuanliang Cui, Yan Kong, Lili Mao, Bin Lian, Xue Bai, Xuan Wang, Siming Li, Li Zhou, Jiayi Yu, Jie Dai, Kai Wang, Jinwei Hu, Lihou Dong, Haifeng Song, Hai Wu, Hui Feng, Sheng Yao, Zhihong Chi, Jun Guo
Journal: Journal of Hematology & Oncology (2019)

JS001, a humanized IgG4 monoclonal antibody against the programmed death-1 (PD-1) receptor, blocks the interaction of PD-1 with its ligands and promotes T cell activation in preclinical studies. This phase I study is designed to evaluate the safety, tolerability, and clinical activity of JS001 in advanced melanoma or urologic cancer patients who are refractory to standard systemic therapy. In the dose escalation cohorts, subjects initially received a single-dose, intravenous infusion of JS001, and were followed for 28 days followed by multi-dose infusions every 2 weeks. In the dose expansion cohorts, subjects received multi-dose infusions every 2 weeks. Clinical response was evaluated after each 8-week treatment cycle according to RECIST v1.1 criteria. Thirty-six subjects diagnosed with advanced melanoma (n = 22), urothelial cancer (UC) (n = 8), or renal cell cancer (RCC) (n = 6) were enrolled. Melanoma subjects included 14 acral and 4 mucosal subtypes. JS001 was well tolerated, and no dose-limiting toxicity was observed. By the safety data cutoff date, 100% of subjects had treatment-related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 36%. Among all 36 subjects, 1 confirmed complete response (acral melanoma), 7 confirmed partial responses (2 acral melanoma, 1 mucosal melanoma, 2 UC, and 2 RCC), and 10 stable disease were observed, for an objective response rate of 22.2% (95% CI, 10.1 to 39.2), and a disease control rate of 50.0% (95% CI, 32.9 to 67.1). Clinical responses were correlated with PD-L1 expression on tumor cells, the presence of tumor infiltrating lymphocytes (TIL), baseline tumor volume, ECOG performance status, serum LDH levels, high percentage of activated CD8+ T cells and CD3− CD16+ CD54+ NK cells in the peripheral blood as well as tumor mutational burden (TMB). JS001 was well tolerated and demonstrated promising anti-tumor activity in UC and RCC as well as in previously underexplored acral and mucosal melanoma subtypes. Subjects with an immune-active profile in the tumor microenvironment or in peripheral blood responded favorably to JS001 treatment. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on acral and mucosal melanoma subtypes, representative of the regional disease epidemiology. Clinical Trial ID: NCT02836795 , registered July 19, 2016, retrospectively registered.
CLO19-036: Folate Receptor alpha Expression in Metastatic Triple-Negative Breast Cancer (TNBC)
Authors: Thorunn Helgason, Senthil Damodaran, Kenneth R. Hess, W. Fraser Symmans, Stacy L. Moulder
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Folate receptor alpha (FRα) is a glycosyl phosphatidylinositol (GPI)-anchored cell surface protein that binds and internalizes folate, which is a cofactor required for DNA/RNA synthesis and cell growth and proliferation. There is a marked up-regulation of FRα in many solid tumors; in contrast, FRα has a minimal expression in adult normal tissue. Mirvetuximab soravtansine is an antibody drug conjugate (ADC) consisting of a maytansinoid, N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4), conjugated to an anti-FRα antibody, M9346A. Once bound to the FRα and internalized, the anti-mitotic agents are released and inhibit tubulin polymerization and microtubule assembly, leading to cell death. Here we report the expression of FRα+ on residual tumor samples in metastatic TNBC. Methods: 68 patients (Pts) with stage IV TNBC underwent prescreening to determine if residual tumor tissue expressed FRα. Formalin fixed paraffin embedded (FFPE) samples were sent to Ventana Translational Diagnostics CAP/CLIA Laboratory for analysis using an in-house developed assay, Ventana OptiView DAB Detection kit, and the Ventana BenchMark Ultra automated slide stainer. FRα expression was evaluated by board certified pathologists using a scoring scale 1+ (low), 2+ (medium), and 3+ (high). For the purposes of study entry, FRα expression on cell surface was required to be low, defined as &gt;25% of cells having 1+ expression. Results: 12% (8/68) of evaluated TNBCs had moderate to high rates of FRα expression. The median age of pts screened for FRα was 53 years. Moderate to high FRα expression rates were more common in Black and Asian patients (Table 1). Conclusion: Our prospective study has demonstrated that moderate to high expression of FRα in metastatic TNBC is 12%, which is lower than previously reported. An ongoing phase II study will determine efficacy for mirvetuximab soravtansine in advanced TNBC. Acknowledgement: This study was approved and funded in part by the NCCN Oncology Research Program from general research support provided by ImmunoGen, Inc.
Abstract 17141: Functional Evaluation of Heart Failure With Mid-Range vs Preserved Ejection Fraction by Exercise Gas Exchange Analysis and Stress Echocardiography
Authors: Marta Barletta, Francesco Bandera, Maria Chiara Palumbo, Maria Pia Del Corral, Martina Evangelista, Eleonora Alfonzetti, Marco Guazzi
Journal: Circulation (2017)

Introduction:  HF patients’ classification has been recently reviewed, with the new-born HF with mid-range ejection fraction class (HFmrEF; EF 40-49%), supposed to have its own clinical and pathophysiology picture.   Hypothesis:  We aimed to evaluate whether HFmrEF patients exhibit distinctive echocardiographic and functional phenotype in comparison to HF with preserved EF population (HFpEF; EF ≥ 50%).   Methods:  We performed simultaneously combined exercise stress echocardiography and cardiopulmonary test in 57 HF patients, divided in two cohorts: HFpEF (24 pts: 20 F and 4 M; age 72 + 9) and HFmrEF (33 pts: 12 F and 21 M; age 65,58 + 8,61). Thirty individuals were considered as control group (14 F and 16 M; age 52 + 17).   Results:  HF groups had enlarged LA (HFpEF p = 0.002; HFmrEF p  rest  p = 0,026;  peak  p = 0,044). TAPSE was reduced in HFmrEF, compared to HFpEF ( rest  p = 0.002;  peak  p = 0.038) and controls ( rest  and  peak  p  rest  HFpEF p = 0.003, HFmrEF p  peak  HFpEF and HFmrEF p  2  slope - p = 0.002).   Conclusions:  HFmrEF revealed more pronounced degree of ventricular remodeling, suggesting a progressive evolution from HFpEF. Moreover, HFmrEF had a worse functional profile as suggested by impaired ventilatory efficiency and inability to generate adequate CO at rest, and to improve it during stress test.
Microenvironment regulation of VEGF alternative splicing in malignancy
Authors: Ana Paula Elias, Sergio Dias
Journal: Cancer Research (2007)

1368  The vascular endothelial growth factor (VEGF) has several isoforms that are distinguished due to the presence or absence of heparin-binding domains: VEGF 121, VEGF 145, VEGF 165 and VEGF 189. Although the relative contribution of the VEGF isoforms has been studied in angiogenesis, little is known about the signals/mechanisms that regulate their production. In the present study, we sought to define how external signals play a role in such process, and chose an organ where metabolic changes and angiogenic pathways are crucial: endometrium.  We used an endometrial cell line (RL-95) cultured in varying pH, hormones, glucose and CoCl2. The VEGF isoforms production, activation of signaling pathways and the pattern of SR proteins were analyzed by real time RT-PCR and western blotting. When placed in pH 5,5 for 8 hours we can see an inversion of VEGF isoforms pattern expression. With regards to the signaling pathways involved, AKT and ERK appear largely unaffected by pH stimulation, while p38 and Junk stress pathways shows a modest increase. Using specific inhibitors for these pathways we demonstrate that p38 is the pathway responsible for the VEGF isoforms inversion in acidic pH.  Serine/arginine rich (SR) proteins, that are described to be involved in alternative splicing, are also up-regulated in pH5,5. To investigate the specific SR proteins involved in VEGF splicing, we used siRNA to block separately some SR proteins that have binding domains in VEGF, and determined the net effects of this approach in VEGF isoform expression. SRp20 and SRp40 knockdown blocked the effects of pH stimulation. In detail, there was a change in VEGF isoforms pattern by downregulation of VEGF 145 and 189 or VEGF 121, 145 and189 respectively, in cells treated with siRNA for these SR proteins.  Since microenvironmental changes, like acidosis, occur during the process of malignant transformation we determine VEGF isoforms pattern in different samples of human endometrial adenocarcinomas. Samples of more aggressive adenocarcinomas show an increased VEGF 121/165 ratio, which may be indicative of selective changes in the tumor microenvironment that result/select more aggressive/angiogenic tumor types. We postulate that the change of VEGF isoforms observed in acidic conditions may represent the adaptation of tumors to changes in the microenvironment, namely by activating angiogenic signaling pathways, through different VEGF isoforms production.
Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study
Authors: Maria C Magnus, Allen J Wilcox, Nils-Halvdan Morken, Clarice R Weinberg, Siri E Håberg
Journal: BMJ (2019)

Abstract Objectives To estimate the burden of miscarriage in the Norwegian population and to evaluate the associations with maternal age and pregnancy history. Design Prospective register based study. Setting Medical Birth Register of Norway, the Norwegian Patient Register, and the induced abortion register. Participants All Norwegian women that were pregnant between 2009-13. Main outcome measure Risk of miscarriage according to the woman’s age and pregnancy history estimated by logistic regression. Results There were 421 201 pregnancies during the study period. The risk of miscarriage was lowest in women aged 25-29 (10%), and rose rapidly after age 30, reaching 53% in women aged 45 and over. There was a strong recurrence risk of miscarriage, with age adjusted odds ratios of 1.54 (95% confidence interval 1.48 to 1.60) after one miscarriage, 2.21 (2.03 to 2.41) after two, and 3.97 (3.29 to 4.78) after three consecutive miscarriages. The risk of miscarriage was modestly increased if the previous birth ended in a preterm delivery (adjusted odds ratio 1.22, 95% confidence interval 1.12 to 1.29), stillbirth (1.30, 1.11 to 1.53), caesarean section (1.16, 1.12 to 1.21), or if the woman had gestational diabetes in the previous pregnancy (1.19, 1.05 to 1.36). The risk of miscarriage was slightly higher in women who themselves had been small for gestational age (1.08, 1.04 to 1.13). Conclusions The risk of miscarriage varies greatly with maternal age, shows a strong pattern of recurrence, and is also increased after some adverse pregnancy outcomes. Miscarriage and other pregnancy complications might share underlying causes, which could be biological conditions or unmeasured common risk factors.
Whole-Body Blood Pool Metastatic Superscan (Bone Hunger Pattern)
Authors: Sara Shakeri, Somayeh Khosravi, Ghasemali Divband, Ramin Sadeghi, Susan Shafiei
Journal: Clinical Nuclear Medicine (2019)

We presented a 61-year-old man's surprising Tc-MDP whole-body blood pool superscan pattern with early unexpected generalized bone uptake. He complained of weakness and undesired weight loss with anemia and elevated erythrocyte sedimentation rate. As a malignancy workup in a patient without obvious suspicious origin, a whole-body Tc-MDP bone scan was requested. This unusual tracer distribution on blood pool imaging was very similar to the whole-body delayed scan except for visible kidneys.
Maintenance therapy for teeth and implants
Authors: Andrea Mombelli
Journal: Periodontology 2000 (2019)

Abstract Maintenance care is mandatory for the long‐term success of periodontal and implant treatment. As it is frequently necessary to treat recurrent or persisting disease, maintenance therapy goes beyond a true prophylaxis. During this lifelong therapy, both the patient and the dental team need to be working closely together. It is imperative to combine efforts to have the build‐up of biofilm under control during maintenance and to reduce, as much as possible, the influence that risk factors may play in plaque accumulation as well as in the tissue inflammatory response. Guidelines to evaluate periodontal tissue response are described, and a maintenance protocol is outlined. The management of residual pockets is stressed, and a variety of treatment approaches are considered and evaluated. How to evaluate peri‐implant tissues during maintenance is discussed, as is the protocol of the cumulative interceptive supportive therapy.