tbuckley/cabot-search huggingface dataset:
Contribution of Implanted, Genetically Modified Muscle Progenitor Cells Expressing BMP-2 to New Bone Formation in a Rat Osseous Defect
Authors: Rodolfo E. De La Vega, Consuelo Lopez De Padilla, Miguel Trujillo, Nicholas Quirk, Ryan M. Porter, Christopher H. Evans, Elisabeth Ferreira
Journal: Molecular Therapy (2017)

Because muscle contains osteoprogenitor cells and has a propensity to form bone, we have explored its utility in healing large osseous defects. Healing is achieved by the insertion of muscle fragments transduced with adenovirus encoding BMP-2 (Ad.BMP-2). However, it is not known whether the genetically modified muscle contributes osteoprogenitor cells to healing defects or merely serves as a local source of BMP-2. This question is part of the larger debate on the fate of progenitor cells introduced into sites of tissue damage to promote regeneration. To address this issue, we harvested fragments of muscle from rats constitutively expressing GFP, transduced them with Ad.BMP-2, and implanted them into femoral defects in wild-type rats under various conditions. GFP+ cells persisted within defects for the entire 8 weeks of the experiments. In the absence of bone formation, these cells presented as fibroblasts. When bone was formed, GFP+ cells were present as osteoblasts and osteocytes and also among the lining cells of new blood vessels. The genetically modified muscle thus contributed progenitor cells as well as BMP-2 to the healing defect, a property of great significance in light of the extensive damage to soft tissue and consequent loss of endogenous progenitors in problematic fractures. Because muscle contains osteoprogenitor cells and has a propensity to form bone, we have explored its utility in healing large osseous defects. Healing is achieved by the insertion of muscle fragments transduced with adenovirus encoding BMP-2 (Ad.BMP-2). However, it is not known whether the genetically modified muscle contributes osteoprogenitor cells to healing defects or merely serves as a local source of BMP-2. This question is part of the larger debate on the fate of progenitor cells introduced into sites of tissue damage to promote regeneration. To address this issue, we harvested fragments of muscle from rats constitutively expressing GFP, transduced them with Ad.BMP-2, and implanted them into femoral defects in wild-type rats under various conditions. GFP+ cells persisted within defects for the entire 8 weeks of the experiments. In the absence of bone formation, these cells presented as fibroblasts. When bone was formed, GFP+ cells were present as osteoblasts and osteocytes and also among the lining cells of new blood vessels. The genetically modified muscle thus contributed progenitor cells as well as BMP-2 to the healing defect, a property of great significance in light of the extensive damage to soft tissue and consequent loss of endogenous progenitors in problematic fractures.
The significance of minimal residual disease (MRD) in relapsed childhood B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) protocol AALL0433.
Authors: Glen Lew, Xiaomin Lu, Rochelle Yanofsky, Susan R. Rheingold, James Whitlock, Scott D Gulig, Meenakshi Devidas, Michael Pulsipher, Caroline Aimee Hastings, Naomi Joan Winick, William L. Carroll, Michael J. Borowitz, Stephen Hunger
Journal: Journal of Clinical Oncology (2014)

10014 Background: Relapsed childhood B-ALL has a poor prognosis. Few risk factors beyond immunophenotype, timing, and site of relapse are known to affect outcome. MRD is a powerful predictor of outcome in newly diagnosed ALL, but its significance after relapse is less clear. We report an analysis of MRD and outcome from the AALL0433 protocol for childhood B-ALL with intermediate-risk relapse. Methods: AALL0433 is a Phase 3 study of intermediate-risk relapsed childhood B-ALL, defined as CNS/testicular relapse <18 mo. or bone marrow (BM)/combined relapse >36 mo. from diagnosis. Therapy is based upon the AALL01P2 / 9412 platforms. BM MRD was measured by flow cytometry at end-induction; results were blinded to investigators. Only matched family donor SCT was allowed on protocol. 271 eligible patients were enrolled. Outcome by treatment received remains blinded at this time. Results: The 3-yr. EFS/OS for the entire cohort of 271 patients were 60.7 ± 4.6% and 71.3 ± 4.3%, respectively. All 29 patients with isolated extramedullary relapse had MRD <0.01% at end-induction. Further analyses focused on patients with BM/combined relapse (n=242). The 3-yr. EFS/OS for this group of patients was 62.8 ± 4.8% and 73.6 ± 4.4%, respectively. 175 patients had available end-induction MRD data: 84 patients had MRD levels <0.01%, 28 were between 0.01-0.1%, and 63 had MRD > 0.1%. These three groups had 3-yr. EFS of 83.4 ± 5.4%, 70.4 ± 12.8%, and 40.9 ± 8.4% respectively (p=0.001), and 3-yr. OS of 88.5 ± 4.6%, 83.0 ± 10.3%, and 56.2 ± 9.0%, respectively (p = 0.0019). An MRD cutoff of 0.1% provided the best discriminator of outcome, with 3-yr. EFS 80.2 ± 5.2% vs. 40.9 ± 8.4%, and 3-yr. OS of 87.1 ± 4.3% vs. 56.2 ± 9.0% for those below (n=112) or above (n=63) this cutoff. Conclusions: Preliminary efficacy of the AALL0433 platform for intermediate-risk relapse of childhood B-ALL is encouraging. An end-induction MRD cutoff of 0.1% was the best predictor of outcome for patients with late BM/combined relapse. Because of the major survival difference at the 0.1% MRD cutoff, it will be used to stratify late BM relapse patients to receive chemotherapy vs. SCT in the next COG relapsed ALL trial. Clinical trial information: NCT00381680.
First prospective multicenter real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis
Authors: J. Garcia Foncillas, J. Tabernero, E. Aranda Aguilar, M. Benavides, C.J. Camps, R. López, C. Montagut, A. Anton Torres, G. Lopez Vivanco, E. Diaz Rubio, F. Rojo, A. Vivancos
Journal: Annals of Oncology (2017)
A phase I study of the bispecific antibody T-cell engager GBR 1302 in subjects with HER2-positive cancers.
Authors: Martin Wermke, Helmuth Schmidt, Hildegard Nolte, Sebastian Ochsenreither, Jonathan Back, Yacine Salhi, Eliel Bayever
Journal: Journal of Clinical Oncology (2017)

TPS3091 Background: GBR 1302, a bispecific antibody based on Glenmark’s BEAT platform, is designed to recruit cytotoxic T-cells (independent of their specificity) to HER2-positive cancer cells where they are activated by the CD3e-specific domain of the molecule. Preclinically, GBR 1302 has demonstrated potent killing of HER2-positive human cancer cells (HER2 3+ or 2+ by IHC HercepTest), as well as growth suppression of the trastuzumab-resistant cell line JIMT-1. In contrast, the GBR 1302 concentration required to kill primary cardiomyocytes with normal HER2 levels was up to 1000 times greater than the concentration needed to kill HER2 3+ tumor cell lines. This study will determine safety and tolerability of GBR 1302 monotherapy in subjects with HER2-positive cancers. Methods: Part 1 (dose-finding) of this ongoing phase 1 study (NCT02829372) is enrolling adults with progressing HER2-positive solid tumors for which no standard treatment is available. Intravenous GBR 1302 is given every 2 weeks in 28-day cycles at escalating doses (Table). Each of the first 4 cohorts includes a single subject; subsequent cohorts enroll subjects using a standard 3+3 design. Primary endpoints are: maximum tolerated dose (MTD) of GBR 1302; and relationship of GBR 1302 with the incidence, nature, and intensity of adverse events. After Cycle 1, subjects continue GBR 1302 treatment until disease progression or unacceptable toxicity. Part 2 (expansion) will treat subjects at the MTD to further evaluate anti-tumor activity, as well as safety and pharmacokinetics. Due to the known cardiotoxic potential of classic HER2-targeting strategies, this study incorporates a rigorous serological and echocardiographic surveillance schedule. The effects of GBR 1302 on the adaptive immune system will also be studied at cellular and serological levels in translational research. Clinical trial information: NCT02829372. [Table: see text]
SUMO1 modification of KHSRP regulates tumorigenesis by preventing the TL-G-Rich miRNA biogenesis
Authors: Haihua Yuan, Rong Deng, Xian Zhao, Ran Chen, Guofang Hou, Hailong Zhang, Yanli Wang, Ming Xu, Bin Jiang, Jianxiu Yu
Journal: Molecular Cancer (2017)

MicroRNAs (miRNAs) are important regulators involved in diverse physiological and pathological processes including cancer. SUMO (small ubiquitin-like modifier) is a reversible protein modifier. We recently found that SUMOylation of TARBP2 and DGCR8 is involved in the regulation of the miRNA pathway. KHSRP is a single stranded nucleic acid binding protein with roles in transcription and mRNA decay, and it is also a component of the Drosha-DGCR8 complex promoting the miRNA biogenesis. The in vivo SUMOylation assay using the Ni2+-NTA affinity pulldown or immunoprecipitation (IP) and the in vitro E.coli-based SUMOylation assay were used to analyze SUMOylation of KHSRP. Nuclear/Cytosol fractionation assay and immunofluorescent staining were used to observe the localization of KHSRP. High-throughput miRNA sequencing, quantantive RT-PCR and RNA immunoprecipitation assay (RIP) were employed to determine the effects of KHSRP SUMO1 modification on the miRNA biogenesis. The soft-agar colony formation, migration, vasculogenic mimicry (VM) and three-dimensional (3D) cell culture assays were performed to detect the phenotypes of tumor cells in vitro, and the xenograft tumor model in mice was conducted to verify that SUMO1 modification of KHSRP regulated tumorigenesis in vivo. KHSRP is modified by SUMO1 at the major site K87, and this modification can be increased upon the microenvironmental hypoxia while reduced by the treatment with growth factors. SUMO1 modification of KHSRP inhibits its interaction with the pri-miRNA/Drosha-DGCR8 complex and probably increases its translocation from the nucleus to the cytoplasm. Consequently, SUMO1 modification of KHSRP impairs the processing step of pre-miRNAs from pri-miRNAs which especially harbor short G-rich stretches in their terminal loops (TL), resulting in the downregulation of a subset of TL-G-Rich miRNAs such as let-7 family and consequential tumorigenesis. Our data demonstrate how the miRNA biogenesis pathway is connected to tumorigenesis and cancer progression through the reversible SUMO1 modification of KHSRP.
Wnt/β-Catenin–Promoted Macrophage Alternative Activation Contributes to Kidney Fibrosis
Authors: Ye Feng, Jiafa Ren, Yuan Gui, Wei Wei, Bingyan Shu, Qingmiao Lu, Xian Xue, Xiaoli Sun, Weichun He, Junwei Yang, Chunsun Dai
Journal: Journal of the American Society of Nephrology (2017)

The Wnt/ β -catenin pathway is crucial in normal development and throughout life, but aberrant activation of this pathway has been linked to kidney fibrosis, although the mechanisms involved remain incompletely determined. Here, we investigated the role of Wnt/ β -catenin in regulating macrophage activation and the contribution thereof to kidney fibrosis. Treatment of macrophages with Wnt3a exacerbated IL-4– or TGF β 1-induced macrophage alternative (M2) polarization and the phosphorylation and nuclear translocation of STAT3 in vitro . Conversely, inhibition of Wnt/ β -catenin signaling prevented these IL-4– or TGF β 1-induced processes. In a mouse model, induced deletion of β -catenin in macrophages attenuated the fibrosis, macrophage accumulation, and M2 polarization observed in the kidneys of wild-type littermates after unilateral ureter obstruction. This study shows that activation of Wnt/ β -catenin signaling promotes kidney fibrosis by stimulating macrophage M2 polarization.
Uterine Metastasis From Gastric Adenocarcinoma Masquerading as Physiologic Endometrial Uptake in FDG PET/CT
Authors: Yutang Yao, Minggang Su, Xiaohong Ou, Yangmei Shen
Journal: Clinical Nuclear Medicine (2017)

Abstract A 44-year-old woman with newly diagnosed gastric adenocarcinoma by gastroscopy underwent 18 F-FDG PET/CT to evaluate possible metastasis. The images demonstrated intense activity in the region of uterine corpus, as well as greater gastric curvature. Physiologic uptake of endometrium was initially suspected, given the rarity with which extragenital cancers metastasize to the uterus. Ultimately, the endometrium proved to be mucinous adenocarcinoma of gastric origin based on its shared histological features and compatible immunostaining profile.
Botulismo na Noruega
Authors: M Kuusi, V Hasseltvedt, P Aavitsland
Journal: Eurosurveillance (1999)

O botulismo e uma doenca neuroparalisante grave, provocada pela toxina produzida pelo Clostridium botulinum, um bacilo anaerobio formador de esporos. Na Noruega, os medicos sao obrigados a notificar o Instituto Nacional de Saude Publica (INSP) dos casos de botulismo, de imediato atraves do telefone, e pelo correio num impresso de notificacao especial. Devem ser referidos o nome, a idade, a data de nascimento, o numero de identificacao e o endereco do doente, assim como a suspeita da fonte da infeccao. O INSP possui uma base de dados de todos os dados de vigilância desde 1975. O botulismo de origem alimentar e raro na Noruega e o botulismo infantil e com origem em feridas foram descritos pela primeira vez em 1997 (1). Um aumento recente no numero de casos de botulismo na Noruega (figura 1) veio realcar a necessidade da manutencao da vigilância para melhorar o reconhecimento dos casos e para apoiar as medidas de prevencao.
Metabolic Acidosis and Subclinical Metabolic Acidosis in CKD
Authors: Kalani L. Raphael
Journal: Journal of the American Society of Nephrology (2017)

Metabolic acidosis is not uncommon in CKD and is linked with bone demineralization, muscle catabolism, and higher risks of CKD progression and mortality. Clinical practice guidelines recommend maintaining serum total CO2 at ≥22 mEq/L to help prevent these complications. Although a definitive trial testing whether correcting metabolic acidosis improves clinical outcomes has not been conducted, results from small, single-center studies support this notion. Furthermore, biologic plausibility supports the notion that a subset of patients with CKD have acid-mediated organ injury despite having a normal serum total CO2 and might benefit from oral alkali before overt acidosis develops. Identifying these individuals with subclinical metabolic acidosis is challenging, but recent results suggest that urinary acid excretion measurements may be helpful. The dose of alkali to provide in this setting is unknown as well. The review discusses these topics and the prevalence and risk factors of metabolic acidosis, mechanisms of acid-mediated organ injury, results from interventional studies, and potential harms of alkali therapy in CKD.
970P MEDINDUCTION: Phase I trial evaluating the safety of durvalumab in combination with docetaxel, cisplatin and 5-FU (DCF) as induction therapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: C. Even, M. Texier, C. Le Tourneau, R. Bahleda, E. Borcoman, M. Vinches, P. Toussaint, A. Marabelle, I. Breuskin, D. Cupissol, J. Fayette
Journal: Annals of Oncology (2020)
Activity of afatinib in heavily pretreated patients (pts) with HER2 mutation-positive (HER2m+) advanced non-small cell lung cancer (NSCLC): findings from a global named patient use (NPU) program
Authors: S. Peters, A. Curioni-Fontecedro, H. Nechushtan, J.-Y. Shih, W.-Y. Liao, O. Gautschi, V. Spataro, M. Unk, J.C.-H. Yang, R. Lorence, P. Carrière, A. Cseh, G.-C. Chang
Journal: Annals of Oncology (2017)
Phase 3 study of platinum-based chemotherapy with or without pembrolizumab for first-line metastatic, nonsquamous non-small cell lung carcinoma (NSCLC): KEYNOTE-189.
Authors: Richard Delmar Hall, Shirish M. Gadgeel, Edward B. Garon, Emilio Bria, Martin Reck, John Vida, Honghong Zhou, Harry Raftopoulos, Leena Gandhi
Journal: Journal of Clinical Oncology (2016)

TPS9104 Background: Platinum-based chemotherapy is the standard of care for treatment-naive NSCLC patients without an activating EGFR mutation or ALK gene rearrangement. Preliminary data from the phase 1/2 KEYNOTE-021 (NCT02039674) study suggest manageable toxicity and encouraging efficacy of platinum-doublet chemotherapy plus pembrolizumab, an anti–PD-1 monoclonal antibody, in treatment-naive NSCLC. KEYNOTE-189 (NCT02578680) is a randomized, double-blind, phase 3 study to compare the efficacy and safety of platinum-doublet chemotherapy with/without pembrolizumab as first-line treatment in nonsquamous NSCLC. Methods: Patients ≥ 18 years with advanced nonsquamous NSCLC in whom EGFR- or ALK-directed therapy is not indicated, ECOG PS 0-1, and no prior systemic chemotherapy are eligible. Approximately 570 patients will be randomly assigned (2:1) to pembrolizumab 200 mg plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5 Q3W for 4 cycles followed by pembrolizumab 200 mg plus pemetrexed 500 mg/m2 Q3W or to placebo plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5 Q3W for 4 cycles followed by placebo plus pemetrexed 500 mg/m2 Q3W. Patients are to be stratified by smoking status (never vs former/current), cisplatin vs carboplatin, and PD-L1 status (tumor proportion score [TPS] ≥ 1% vs < 1%). TPS < 1% group includes PD-L1–inevaluable patients. Pembrolizumab will continue for 35 cycles or until disease progression, intolerable toxicity, or investigator or patient decision to withdraw. Eligible patients may continue pembrolizumab monotherapy after initial disease progression. Treatment may be discontinued in patients with a complete response by immune-related RECIST. Adverse events (AEs) will be monitored throughout the study and for 30 days (90 days for serious AEs) after treatment end and graded per NCI CTCAE v4.0. Response will be assessed by RECIST v1.1 (central imaging vendor review) at weeks 6 and 12, then every 9 weeks until week 48 and every 12 weeks thereafter. The primary end point is PFS; secondary end points are ORR, DOR, OS, PFS in patients with PD-L1 TPS ≥ 1%, and safety. Clinical trial information: NCT02578680.
Exercise and the Prevention of Depression: Results of the HUNT Cohort Study
Authors: Samuel B. Harvey, Simon Øverland, Stephani L. Hatch, Simon Wessely, Arnstein Mykletun, Matthew Hotopf
Journal: American Journal of Psychiatry (2017)

Objective: The purpose of the present study was to address 1) whether exercise provides protection against new-onset depression and anxiety and 2) if so, the intensity and amount of exercise required to gain protection and, lastly, 3) the mechanisms that underlie any association. Method: A “healthy” cohort of 33,908 adults, selected on the basis of having no symptoms of common mental disorder or limiting physical health conditions, was prospectively followed for 11 years. Validated measures of exercise, depression, anxiety, and a range of potential confounding and mediating factors were collected. Results: Undertaking regular leisure-time exercise was associated with reduced incidence of future depression but not anxiety. The majority of this protective effect occurred at low levels of exercise and was observed regardless of intensity. After adjustment for confounders, the population attributable fraction suggests that, assuming the relationship is causal, 12% of future cases of depression could have been prevented if all participants had engaged in at least 1 hour of physical activity each week. The social and physical health benefits of exercise explained a small proportion of the protective effect. Previously proposed biological mechanisms, such as alterations in parasympathetic vagal tone, did not appear to have a role in explaining the protection against depression. Conclusions: Regular leisure-time exercise of any intensity provides protection against future depression but not anxiety. Relatively modest changes in population levels of exercise may have important public mental health benefits and prevent a substantial number of new cases of depression.
The impact of TSG101 in triple-negative breast cancers.
Authors: Shiva D.J. Sharma, Luke Gubbins, Karolina Weiner-Gorzel, Jeremy Simpson, Amanda McCann, Malcolm R. Kell
Journal: Journal of Clinical Oncology (2014)

1114 Background: TSG101 is an essential protein and constituent of cellular function involved in the sorting and trafficking of cell components destined for processing or degradation and is also integral to exosome production and release. Limited information is known about TSG101 and exosomes in the field of breast cancer and even less in the difficult to treat subset of triple-negative breast cancer (TNBC). We propose that TNBC tumours demonstrating high levels of TSG101 are more likely to recur locally and at distant sites due to enhanced exosome mediated communication in the tumour microenvironment through the propagation of chemoresistance. Methods: Cellular viability of our TNBC cell lines (BT-549 and MDA-MB-231) after incremental Paclitaxel treatments were assessed by MTT viability assay. Using an siRNA knockdown we were able to selectively target and reduce the intracellular levels of TSG101 protein. TNBC cell lines were treated with Paclitaxel at 24 and 48 hours. Immunohistochemical staining for TSG101 was performed to evaluate the expression of TSG101 in breast cancer clinical cases. Results: Using an MTT viability assay, BT-549 TNBC cells were found to be more sensitive to the chemotherapeutic drug Paclitaxel compared to the MDA-MB-231 TNBC cells which were shown to be more chemoresistant. Following 24 and 48hours of treatment with Paclitaxel the levels of TSG101 in the MDA-MB-231 cells remained level, while the levels of TSG101 were lower in the more Paclitaxel sensitive BT-549 cells. Subsequent exosome profiling of media collected from TSG101 protein knockdown cells showed differential size and number of exosomes released from BT-549 and MDA-MB-231 cells after Paclitaxel treatment. Immunohistochemical analysis of 85 breast cancer cases on TissueMicroArray established strong cytoplasmic staining of TSG101 in 20% of cases, while 53% of tumours demonstrated none/weak staining of TSG101. Conclusions: We conclude that TSG101 is differentially expressed in the TNBC in vitro and that expression levels are influenced by Paclitaxel treatment. We also conclude that siRNA knockdown of TSG101 impedes the release of exosomes. We suggest that TNBC tumours that clinically express high levels of TSG101 may express a more aggressive phenotype.
Detection of driver and resistance mutations in leptomeningeal metastases of NSCLC by next-generation sequencing of cerebrospinal fluid circulating tumor cells
Authors: Y.-S. Li, B.-Y. Jiang, W.-B. Guo, X.-C. Zhang, J.-J. Yang, Y. Shao, B. Huang, Y.-H. Liu, Y.-L. Wu
Journal: Annals of Oncology (2017)
Impact of co-occurring genomic alterations on overall survival of BRAF V600E and non-V600E mutated NSCLC patients: Results of the Network Genomic Medicine
Authors: A. Kron, R. Riedel, S. Michels, J. Fassunke, S. Merkelbach-Bruse, M. Scheffler, L. Nogova, R. Fischer, F. Ueckeroth, D. Abdulla, F. Kron, B. Pauli, B. Kaminsky, J. Braess, U. Graeven, C. Grohe, S. Krueger, R. Büttner, J. Wolf
Journal: Annals of Oncology (2017)
Letter to the editor: Sampling bias should be minimised when analysing influenza transmission zones involving very large countries
Authors: Gee Yen Shin, Rohini Manuel
Journal: Eurosurveillance (2017)

Preview this article: Letter to the editor: Sampling bias should be minimised when analysing influenza transmission zones involving very large countries, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/22/40/eurosurv-22-40-3-1.gif
Death by Gun Violence—A Public Health Crisis
Authors: Howard Bauchner, Frederick P. Rivara, Robert O. Bonow, Neil M. Bressler, Mary L. (Nora) Disis, Stephan Heckers, S. Andrew Josephson, Melina R. Kibbe, Jay F. Piccirillo, Rita F. Redberg, John S. Rhee, June K. Robinson
Journal: JAMA (2017)