tbuckley/cabot-search huggingface dataset:
A Novel Dual Class III/Src Family Tyrosine Kinase Inhibitor Is Highly Active Against FLT3-ITD Leukemia Cells In Vivo
Authors: Tereza Radosova Muchova, Eva Reznickova, Zuzana Somikova, Tomas Gucky, Miroslav Strnad, Vladimir Krystof, Vladimir Divoky
Journal: Blood (2016)
Gastroenteropancreatic neuroendocrine neoplasia G3 according to 2019 WHO classification: a comprehensive clinicopathological characterization including mismatch repair proteins and PDL1 expression in a large cohort of patients
Authors: J. Grasselli, M. Rizzolo, G. Ruiz, R. Salanova, J. Mariani, J. O’Connor, R. Luca, A. Cabanne, G. Mendez, E. Roca
Journal: Annals of Oncology (2019)
Abstract 875: Targeting Nrf2 driven glutathione <i>de novo</i> synthesis as a novel strategy to suppresses IDH1-mutated glioma
Authors: Yang Liu, Di Yu, Sabrina Cai, Chunzhang Yang
Journal: Cancer Research (2019)

Abstract Background: Isocitrate dehydrogenase (IDH) mutation frequently occurs in low grade glioma and secondary glioblastoma, characterizing by the abnormally catalyzation of alpha-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D-2-HG), which induces CpG island methylator phenotype, as well as metabolic reprogramming and high reactive oxygen species (ROS) generation. Our previous data showed that nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a crucial role in maintaining redox homeostasis of IDH1-mutated glioma cells, while the detail mechanism remains elusive. Our recent data showed that glutathione de novo synthesis is governed by Nrf2, which makes great contribution to ROS scavenging in IDH1-mutated tumors and could serve as a potential therapeutic target. Methods: In this study, we explored the important role of glutathione de novo synthetic pathway in maintaining ROS homeostasis by small RNA interference of key enzymes GCLC, GCLM and SLC7A11. We also investigated the correlation between Nrf2 and glutathione de novo synthetic pathway by Chromatin Immunoprecipitation. We further investigated the therapeutic value of Nrf2 inhibitor, Brusatol, in IDH1-mutated cancer both in vitro and in vivo. Results: Our data showed that IDH1 mutation cells exhibit high level steady-state of ROS generation and detoxification. Prolonged Nrf2 activity enhanced transcriptional activity of key enzymes in glutathione de novo synthesis, such as GCLC, GCLM and SLC7A11. Targeting Nrf2 using Brusatol suppressed glutathione synthesis in IDH1-mutated cells, resulted in cytotoxic effect and suppressed xenograft growth in vivo. Conclusions: IDH1-mutated glioma highly depends on Nrf2 activity to maintain ROS homeostasis. Enhanced glutathione de novo synthesis is an important mechanism that governed by Nrf2 and plays critical role in ROS scavenging. Targeting ROS scavenging might be a novel approach to treat gliomas with IDH1 mutation. Citation Format: Yang Liu, Di Yu, Sabrina Cai, Chunzhang Yang. Targeting Nrf2 driven glutathione de novo synthesis as a novel strategy to suppresses IDH1-mutated glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 875.
Abstract 987: Glycoengineered MSCs for targeting platinum resistant ovarian tumors
Authors: Buddhadev Layek, Drishti Sehgal, Jayanth Panyam, Swayam Prabha
Journal: Cancer Research (2019)

Abstract Tumor-targeted delivery of chemotherapeutics can improve efficacy while mitigating their debilitating side effects. However, current drug delivery approaches rely on inefficient passive accumulation of delivery systems in the tumor and suffer from significant non-specific distribution. Here, we propose a novel two-step tumor targeting strategy that can improve delivery of cytotoxic agents to both primary tumor as well as metastatic lesions, resulting in effective tumor inhibition. This strategy involves introduction of non-natural targets in the tumor tissue via glycoengineered mesenchymal stem cells (MSCs expressing targetable synthetic azide groups) followed by the delivery of drug-loaded polymeric nanoparticles (surface functionalized with dibenzyl cyclooctyne; DBCO) that have high affinity for these synthetic targets. DBCO surface functionalized, paclitaxel (PTX)-loaded nanoparticles (DBCO-PTX NP; 17.6% w/w PTX; diameter 313.7 ± 13 nm; and zeta potential -12.5 ± 1.9 mV) were formulated using poly (DL-lactide-co-glycolide) (PLGA) polymer by emulsion-solvent evaporation method. Glycoengineered MSCs (MSC-Az) were generated by culturing MSCs in N-azidoacetylmannosamine-tetraacylated supplemented media without affecting their viability or tumor homing properties. Binding of MSC-Az to DBCO-PTX NP was confirmed with confocal microscopy and flow cytometry analysis. Anticancer efficacy of two-step targeting strategy was evaluated in murine model of platinum-resistant orthotopic ovarian C200-luc tumors. Treatment with MSC-Az + DBCO-PTX nanoparticles resulted in significant inhibition of the tumor growth (p &amp;lt; 0.05) and improved survival (p &amp;lt; 0.05) compared to that with other controls. In summary, our results demonstrate the potential of two-step tumor targeting strategy to enhance the anticancer efficacy of conventional chemotherapeutic drugs. Citation Format: Buddhadev Layek, Drishti Sehgal, Jayanth Panyam, Swayam Prabha. Glycoengineered MSCs for targeting platinum resistant ovarian tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 987.
Small animal models of heart failure
Authors: Christian Riehle, Johann Bauersachs
Journal: Cardiovascular Research (2019)

Heart disease is a major cause of death worldwide with increasing prevalence, which urges the development of new therapeutic strategies. Over the last few decades, numerous small animal models have been generated to mimic various pathomechanisms contributing to heart failure (HF). Despite some limitations, these animal models have greatly advanced our understanding of the pathogenesis of the different aetiologies of HF and paved the way to understanding the underlying mechanisms and development of successful treatments. These models utilize surgical techniques, genetic modifications, and pharmacological approaches. The present review discusses the strengths and limitations of commonly used small animal HF models, which continue to provide crucial insight and facilitate the development of new treatment strategies for patients with HF.
Doctors have cut extra work and avoided promotion because of pension changes, poll finds
Authors: Gareth Iacobucci
Journal: BMJ (2019)

A poll of senior NHS employees including over 1800 consultants has found that one in five has avoided promotion at work because of the impact of pension tax charges, and more than four in 10 have reduced their additional work.

A small proportion (3%) of the 2521 staff surveyed at 30 NHS organisations said that they had already taken early retirement because of changes to the NHS pension scheme, and a third (33%) were considering this option. Another 3% said that they had already retired and returned to work, …
Abstract 855: Analysis of a novel variant of HER2 detected by clinical sequencing in cancer of unknown primary
Authors: Yohei Harada, Tomomi Kashiwada, Akemi Sato, Tomonori Abe, Chiho nakashima, Eisaburo Sueoka, Shinya Kimura, Naoko Sueoka-Aragane
Journal: Cancer Research (2019)

Abstract A patient with cancer of unknown primary underwent an NGS-based multiplex gene assays (OncoPrime). As a result, a novel variant of HER2 (E401G) which is a missense alteration located in the extracellular domain of the HER2 protein was detected. This alteration has not been reported (COSMIC, Nov 2018) and its effect on protein function is unknown. Sanger sequencing using genomic DNA from peripheral blood sample showed that the variant was a somatic variant. HER2 E401G variant was confirmed by Sanger sequencing using genomic DNA extracted from the formalin-fixed paraffin-enbedded tumor tissues. In spite of somatic variant, the variant allele frequency was relatively high (55.8%). This result suggested the amplification of HER2 gene, FISH analysis confirmed the copy number gain of HER2 gene (21 copies). The prediction tools in silico (SIFT, PolyPhen-2 and PROVEAN) suggested pathogenicity of the variant, so we are now performing the functional analysis of the mutant HER2 protein. Many variants of unknown significance have been identified through clinical sequencing, establishing a database of integrated information of variant is essential to implement precision medicine of oncology. This study was approved by the Ethics Committee and the patient provided written informed consent for the use of genomic and clinical data for research purposes. Citation Format: Yohei Harada, Tomomi Kashiwada, Akemi Sato, Tomonori Abe, Chiho nakashima, Eisaburo Sueoka, Shinya Kimura, Naoko Sueoka-Aragane. Analysis of a novel variant of HER2 detected by clinical sequencing in cancer of unknown primary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 855.
Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia
Authors: Krzysztof Brzezinka, Ekaterina Nevedomskaya, Ralf Lesche, Michael Steckel, Ashley L. Eheim, Andrea Haegebarth, Carlo Stresemann
Journal: Journal of Hematology & Oncology (2019)

The chromosomal rearrangements of the mixed-lineage leukemia gene MLL (KMT2A) have been extensively characterized as a potent oncogenic driver in leukemia. For its oncogenic function, most MLL-fusion proteins exploit the multienzyme super elongation complex leading to elevated expression of MLL target genes. High expression of MLL target genes overwrites the normal hematopoietic differentiation program, resulting in undifferentiated blasts characterized by the capacity to self-renew. Although extensive resources devoted to increased understanding of therapeutic targets to overcome de-differentiation in ALL/AML, the inter-dependencies of targets are still not well described. The majority of inhibitors potentially interfering with MLL-fusion protein driven transformation have been characterized in individual studies, which so far hindered their direct cross-comparison.In our study, we characterized head-to-head clinical stage inhibitors for BET, DHODH, DOT1L as well as two novel inhibitors for CDK9 and the Menin-MLL interaction with a focus on differentiation induction. We profiled those inhibitors for global gene expression effects in a large cell line panel and examined cellular responses such as inhibition of proliferation, apoptosis induction, cell cycle arrest, surface marker expression, morphological phenotype changes, and phagocytosis as functional differentiation readout. We also verified the combination potential of those inhibitors on proliferation and differentiation level.Our analysis revealed significant differences in differentiation induction and in modulating MLL-fusion target gene expression. We observed Menin-MLL and DOT1L inhibitors act very specifically on MLL-fused leukemia cell lines, whereas inhibitors of BET, DHODH and P-TEFb have strong effects beyond MLL-fusions. Significant differentiation effects were detected for Menin-MLL, DOT1L, and DHODH inhibitors, whereas BET and CDK9 inhibitors primarily induced apoptosis in AML/ALL cancer models. For the first time, we explored combination potential of the abovementioned inhibitors with regards to overcoming the differentiation blockage.Our findings show substantial diversity in the molecular activities of those inhibitors and provide valuable insights into the further developmental potential as single agents or in combinations in MLL-fused leukemia.
Serum BCMA levels to predict outcomes for patients with MGUS and smoldering multiple myeloma (SMM).
Authors: Angela Dispenzieri, Camilia M Soof, S. Vincent Rajkumar, Morie A. Gertz, Shaji Kumar, Sean Bujarski, Robert A. Kyle, James R. Berenson
Journal: Journal of Clinical Oncology (2019)

8020 Background: BCMA (B-cell maturation antigen) is a TNF receptor family member found on normal and malignant B-cells, including multiple myeloma (MM). It plays a role in proliferation and antiapoptotic pathways. Levels of serum (s)BMCA are elevated in patients (pts) with plasma cell disorders (PCD) and increase with each stage of disease: healthy donor&lt; MGUS&lt;SMM&lt; active untreated MM. The purpose of this study was to test whether sBCMA levels predict progression of MGUS or SMM to MM. Methods: There were 3 cohorts in this retrospective study: MGUS progressing to MM (n=42); MGUS not progressing to MM (n=49); SMM progressing to MM (n=32). sBCMA levels were measured using an ELISA-based assay with a polyclonal anti-BCMA antibody from R&amp;D Systems (Minneapolis, MN). The Kruskal-Wallis analysis was used to assess differences. The relationships between sBCMA and both time to progression and overall survival were also assessed using Cox proportional hazard models. Results: The highest values of sBCMA were seen among pts with more advanced PCD (Table). The lowest baseline levels were seen in pts with MGUS who did not progress; the change of sBCMA over time was lowest in the MGUS non-progressors. ROC analysis identified a cutoff of 74.4 ng/mL to be predictive of progression at 5 years. This cut-point was associated with a risk ratio of progression of 5.8 (95%CI 3.2, 11.3) for all comers, a risk ratio of death for all comers of 2.5 (95%CI 1.5, 4.2), and a risk ratio of death for MGUS pts of 3.3 (95%CI 1.9, 5.7). Conclusions: Serum BCMA levels were predictive of diagnosis, progression and death among pts with MGUS or SMM. Limitations of the current study are that only a minority of pts had baseline bone marrow exams or serum FLCs to place sBCMA risk in the context of other previously described risk factors. Serum FLC is now being determined on all patients. [Table: see text]
Postholiday Heart Failure Triggered by Dietary Salt Excess
Authors: Franz H. Messerli, Thomas Suter, Marie-Theres Anwander
Journal: JAMA Internal Medicine (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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Internal Medicine journal
Abstract 3043: Examination of NMT1 and NMT2 as independent prognostic markers and novel drug targets in adult acute myeloid leukemia
Authors: John R. Mackey, Aishwarya Iyer, Megan C. Yap, Zoulika Zak, Krista Vincent, Erwan Beauchamp, Lynne M. Postovit, Joseph Brandwein, Luc G. Berthiaume
Journal: Cancer Research (2019)

Abstract Myristoylation is required for biological activity of &amp;gt;200 intracellular proteins. N-myristoyltransferases (NMTs) transfer the fatty acid myristate to N-terminal glycine residue; there are two isoforms, NMT1 and 2. In acute myeloid leukemia (AML), upregulation of Lyn and Src, important myristoylated proteins, contribute to cell survival and proliferation. The specific roles of NMT1 and NMT2 are unknown in this context. The relationships among NMT1/NMT2 expression and acute AML patient outcomes were studied using RNA-sequencing and microarray cohorts with over 350 patients. We found that high NMT1 and low NMT2 expression were associated with reduced overall and event-free survival in adult AML, which was independent of other prognostic markers on multivariate analysis. High NMT1, but not NMT2, expression was associated with proliferative gene sets in AML cell lines, indicating potential for distinct isozyme substrates. Given these results, we examined NMT1 and NMT2 levels in AML cell lines and AML patient blast cells using Western blotting and flow cytometry. We determined that NMT2 expression varied greatly among patients, but was markedly reduced in most cases, while NMT1 expression was relatively preserved. A potent small molecule NMT inhibitor, PCLX-001, preferentially induced apoptosis and reduced viability in NMT2-deficient AML cell lines cultured in vitro compared with normal lymphocytes and peripheral blood mononuclear cells. PCLX-001 also killed freshly isolated human AML blasts ex vivo with an IC50 of ~170nM regardless of their mutational background. In a murine AML xenograft model, subcutaneously delivered PCLX-001 monotherapy demonstrated dose-dependent anticancer activity and produced complete remissions after five daily 50 mg/kg doses. NMT expression provides independent prognostic information to refine existing clinical stratification, and NMT inhibition is a promising novel therapeutic strategy for AML. Citation Format: John R. Mackey, Aishwarya Iyer, Megan C. Yap, Zoulika Zak, Krista Vincent, Erwan Beauchamp, Lynne M. Postovit, Joseph Brandwein, Luc G. Berthiaume. Examination of NMT1 and NMT2 as independent prognostic markers and novel drug targets in adult acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3043.
Review of the Tokyo Guidelines 2018: Antimicrobial Therapy for Acute Cholangitis and Cholecystitis
Authors: Sara A. Buckman, John E. Mazuski
Journal: JAMA Surgery (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 Surgery HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Surgery journal
Abstract 17534: mitoNEET Regulates Mitochondrial Iron Homeostasis Interacting With Transferrin Receptor
Authors: Takaaki Furihata, Shingo Takada, Wataru Mizushima, Satoshi Maekawa, Arata Fukushima, Masaya Tsuda, Junichi Matsumoto, Naoya Kakutani, Takashi Yokota, Shintaro Kinugawa
Journal: Circulation (2017)

Introduction: Iron is an essential trace element for regulation of redox and mitochondrial function, and then mitochondrial iron content is tightly regulated in mammals. We focused on a novel prote...
Abstract 3304: CNS metastases in prostate cancer: an analysis of SEER database
Authors: Lin Mei, Taha Al-Juhaishi, Andrew Poklepovic, Asit Paul
Journal: Cancer Research (2019)

Abstract Metastases to central nervous system (CNS) from various solid tumors, such as lung cancer (40-50%), breast cancer (15-25%) and melanoma (5-20%), are relatively common and confer a poor prognosis. CNS metastases from prostate cancer are uncommon. Due to the rarity of this disease and lack of studies, little is known about the clinical and pathological characteristics as well as outcome of these patients. CNS metastases also have therapeutic implications in terms of targeting hypothalamic-pituitary axis for androgen deprivation as well as CNS penetration of systemic chemotherapy agents. The objective of this study is to analyze clinicopathologic features and outcome of prostate cancer patients with CNS metastases in Survival, Epidemiology, and End Result (SEER) database. Between 2010 and 2015, a total of 23,776 patients with metastatic prostate were identified. Among them, 23,468 cases were adenocarcinoma and 308 cases were prostate cancer with neuroendocrine differentiation. A number of variables, including age, race, prostate-specific antigen (PSA) level, Gleason score, and prior radiotherapy, site of metastases were extracted. Primary outcome were overall survival (OS) and disease specific survival (DSS). CNS metastases were identified in 208 (0.89%) and 11 (3.57%) patients with adenocarcinoma and neuroendocrine tumor, respectively. Majority of patients (56.2%) were 65 years or older. Median OS and DSS were 13 months and 14 months, respectively. In comparison to patients with lymph nodes metastases only (n=8,103), the median OS and DSS were 40 months and 58 months, respectively. In patients with bone dominant metastasis (n=14,407), the median OS and DSS were 27 months and 34 months, respectively. Multivariate analysis identified age was an adverse predictive factor in patients with CNS metastasis. Race, high Gleason score (≥9), high PSA level (≥98ng/ml) and prior radiotherapy were not associated with OS and DSS. In conclusion, CNS metastases are more common in neuroendocrine tumor than in adenocarcinoma of prostate, and it confers poor survival outcome irrespective of histological subtypes. OS and DSS were worse in patients with prostate cancer and CNS metastases compared to those with lymph node metastases only or bone-dominant metastases. Note: This abstract was not presented at the meeting. Citation Format: Lin Mei, Taha Al-Juhaishi, Andrew Poklepovic, Asit Paul. CNS metastases in prostate cancer: an analysis of SEER database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3304.