tbuckley/cabot-search huggingface dataset:
Exercise in type 2 diabetes: genetic, metabolic and neuromuscular adaptations. A review of the evidence
Authors: Silvano Zanuso, Massimo Sacchetti, Carl Johan Sundberg, Giorgio Orlando, Paolo Benvenuti, Stefano Balducci
Journal: British Journal of Sports Medicine (2017)

The biological responses to exercise training are complex, as almost all organs and systems are involved in interactions that result in a plethora of adaptations at the genetic, metabolic and neuromuscular levels. To provide the general practitioner and the sports medicine professionals with a basic understanding of the genetic, metabolic and neuromuscular adaptations at a cellular level that occur with aerobic and resistance exercise in subjects with type 2 diabetes. For each of the three domains (genetic, metabolic and neuromuscular), the results of the major systematic reviews and original research published in relevant journals, indexed in PubMed, were selected. Owing to limitations of space, we focused primarily on the role of skeletal muscle, given its pivotal role in mediating adaptations at all levels. Generally, training-induced adaptations in skeletal muscle are seen as changes in contractile proteins, mitochondrial function, metabolic regulation, intracellular signalling, transcriptional responses and neuromuscular modifications. The main adaptation with clinical relevance would include an improved oxidative capacity derived from aerobic training, in addition to neuromuscular remodelling derived from resistance training. Both training modalities improve insulin sensitivity and reduce cardiovascular risk. Taken together, the modifications that occur at the genetic, metabolic and neuromuscular levels, work correlatively to optimise substrate delivery, mitochondrial respiratory capacity and contractile function during exercise.
REACTIONS OF RABBITS TO INTRACUTANEOUS INJECTIONS OF PNEUMOCOCCI AND THEIR PRODUCTS
Authors: Louis A. Julianelle
Journal: The Journal of Experimental Medicine (1930)

1. Injection of suspensions of heat-killed pneumococci into the skin of rabbits is followed by an active immunity which is effective against intravenous infection by homologous and heterologous types of Pneumococcus. 2. This form of active immunity may be induced by the injection of S or R strains of Pneumococcus. 3. Intracutaneous immunization with soluble derivatives of Pneumococcus does not induce active immunity to infection. 4. The sera of seventy-nine per cent of the rabbits immunized to Type I Pneumococcus by intracutaneous injections afforded no protection to mice against infection with pneumococci. 5. None of the sera of rabbits intracutaneously immunized to the type-specific Type III (S) pneumococci, to R cells, or to soluble derivatives of Pneumococcus protected white mice against infection. 6. The sera of rabbits immunized first intracutaneously and subsequently intravenously possess a high titre of protective antibodies. 7. It may be concluded that when type-specific pneumococci are injected into the skin they lose the property of stimulating an active immunity of a specific type and of stimulating the production of type-specific antibodies, but they act just as do the degraded or R forms, causing the animals to become resistant to infection with pneumococci of all types without the development of any type-specific antibodies in the serum.
IMpower110: Phase III trial of 1L atezolizumab in PD-L1–selected chemotherapy-naive NSCLC
Authors: J. Jassem, F. de Marinis, D.R. Spigel, S. Lam, S. Mocci, A. Sandler, A. Lopez-Chavez, Y. Deng, G. Giaccone, R.S. Herbst
Journal: Annals of Oncology (2017)
ING5 suppresses breast cancer progression and is regulated by miR-24
Authors: Shufang Cui, Xin Liao, Chao Ye, Xin Yin, Minghui Liu, Yeting Hong, Mengchao Yu, Yanqing Liu, Hongwei Liang, Chen-Yu Zhang, Xi Chen
Journal: Molecular Cancer (2017)

The inhibitor of growth (ING) gene family of tumor suppressors is involved in multiple cellular functions such as cell cycle regulation, apoptosis, and chromatin remodeling. ING5 is a new member of the ING family whose function and regulation remain largely unknown.Quantitative real-time PCR and western blot were used to examine the expression levels of ING5 in breast cancer tissues. The miRNAs that potentially targeted ING5 were determined by bioinformatics analysis and luciferase reporter assay. Cell viability assay, transwell invasion and apoptosis assay were used to characterize the changes induced by overexpressing or knocking down miR-24 or ING5. Hematoxylin and eosin (H&E) staining and immunohistochemical staining for ING5 and Ki-67 were used for xenograft assays in BALB/c nude mice.We showed that the ING5 protein rather than the mRNA, was significantly downregulated in breast cancer tissues. We also investigated the potential function of ING5 in breast tumorigenesis and found that ING5 suppressed the proliferation and invasion of breast cancer cells and promoted their apoptosis. Furthermore, we explored the molecular mechanisms accounting for the dysregulation of ING5 in breast cancer cells and identified an oncomiR, miR-24, as a direct upstream regulator of ING5. We revealed that miR-24 had the opposite effects to those of ING5 on breast cancer cells and could accelerate xenografted tumor growth in vivo.Our findings uncover the tumor-suppressive role of ING5 and the regulatory pathway of ING5 in breast cancer and may provide insights into the molecular mechanisms of breast carcinogenesis.
Disruption of tumour necrosis factor-alpha receptor 1 signalling pathway increases interleukin-1 beta levels, exacerbates liver insulin resistance and apoptosis during a high fat diet
Authors: F. Lambertucci, A.S. Arboatti, M.G. Sedlmeier, E. Roggero, A.D. Quiroga, C.E. Carnovale, D.E. Frances, M.T. Ronco
Journal: Journal of Hepatology (2017)
First-Line Dasatinib Treatment of CML-CP Leads to Earlier Achievement of MMR and MR4.5 with High Safety
Authors: Kazunori Murai, Kohei Yamaguchi, Shigeki Ito, Takuto Miyagishima, Motohiro Shindo, Kentaro Wakasa, Mitsue Inomata, Takahiro Nagashima, Takeshi Kondo, Nozomu Fujimoto, Satoshi Yamamoto, Masakatsu Yonezumi, Tatsuo Oyake, Shugo Kowata, Yasuhiko Tsukushi, Takahiro Mine, Kuniaki Meguro, Kazuhiko Ikeda, Reiko Watanabe, Souichi Saito, Shinji Sato, Takaaki Chou, Kohmei Kubo, Koji Oba, Junichi Sakamoto, Yoji Ishida
Journal: Blood (2016)
Abstract IA15: Novel approaches for targeting MYC
Authors: William Tansey
Journal: Clinical Cancer Research (2017)

Abstract The MYC family (c-, L-, and N-MYC) is one of the most important groups of proteins in human cancer. More than 50% of all malignancies overexpress at least one MYC family member, and estimates suggest that upwards of 100,000 Americans die from cancer every year as a result of inappropriate MYC expression or activity. Preclinical mouse models have demonstrated that perturbing MYC function in preexisting cancers promotes frank tumor regression, establishing MYC proteins as bonafide and high-value targets for discovery of broadly effective anti-cancer therapies. Despite the potential of MYC inhibitors to impact cancer therapy, efforts to discover MYC inhibitors are stymied by numerous factors, including an absence of MYC interaction partners with characteristics that make them amenable to drug discovery efforts. The best understood MYC interaction partner, MAX, is required for MYC to assemble a competent DNA-binding module and would theoretically be a superb target for anti-MYC therapies. The MYC–MAX interaction, however, encompasses more that 1800 Å2 of buried protein surface, making it difficult to effectively disrupt by a small molecule with drug-like properties. Breaking the stalemate in drugging MYC requires a fresh perspective on how MYC functions and where the vulnerabilities in its molecular mechanisms of action lie. Structure-function studies have delineated a potent activation domain at the amino-terminus of MYC and a DNA-binding domain at the carboxy-terminus, but the central portion between these domains has not been studied in detail. To rectify this deficit, we recently initiated screens to identify proteins that bind to the central portion of MYC, with the idea that these proteins would reveal new aspects of MYC regulation or function; some of which may expose new ways to target MYC activity. One novel MYC-interaction partner to emerge from this screen was WDR5. WDR5 is a chromatin-associated protein that co-binds with MYC at a majority of its target genes. MYC binds weakly to WDR5 by engaging a structured hydrophobic cleft on one side of the WDR5 protein. Mutations in MYC that disrupt interaction with WDR5 block the ability of MYC to bind chromatin and disable its tumorigenic properties in mice, demonstrating that WDR5 is a critical co-factor for MYC. These studies led to a revised model for target gene recognition by MYC in which WDR5 facilitates the recruitment of MYC/MAX complexes to chromatin, and revealed that the MYC–WDR5 interface is a tractable surface for small molecule inhibition. In collaboration with the laboratory of Dr. Stephen Fesik we seek to discover and validate drug-like molecules that disrupt the MYC–WDR5 interaction and explore their utility in cell and animal-based models of cancer. Citation Format: William Tansey. Novel approaches for targeting MYC. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA15.
Thrombosis in Myeloproliferative Neoplasms Is Linked to Increased Neutrophil Extracellular Trap (NET) Formation
Authors: Ofir Wolach, Rob S Sellar, Kimberly Martinod, Marie E. McConkey, Alexander J. Silver, Ryan Chappell, Richard M. Stone, Martha Wadleigh, David P Steensma, Daniel J. DeAngelo, Ilene Galinsky, Rebekka K. Schneider, Robert F. Padera, Ann Mullally, Denisa D. Wagner, Benjamin L. Ebert
Journal: Blood (2016)
Genome-wide DNA Methylation Analysis Reveals <i>GABBR2</i> as a Novel Epigenetic Target for <i>EGFR</i> 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment
Authors: Xiaomin Niu, Fatao Liu, Yi Zhou, Zhen Zhou, Daizhan Zhou, Ting Wang, Ziming Li, Xiangyun Ye, Yongfeng Yu, Xiaoling Weng, Hong Zhang, Junyi Ye, Meilin Liao, Yun Liu, Zhiwei Chen, Shun Lu
Journal: Clinical Cancer Research (2017)

Purpose: The past decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR)-mutated lung cancer.Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N = 2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response.Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild-type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6, and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway.Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma. Clin Cancer Res; 23(17); 5003-14. ©2017 AACR.
Abstract A09: The role of pre-mRNA splicing factor in Glioblastoma Multiforme by regulating EGFRvIII
Authors: Young Taek Oh, Jun Hee Hong, Jong Bae Park
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. Therefore, there is a critical unmet need to predict therapeutic responses for individual patients. There is 50% of GBM patient has EGFR over-expression and mutation. Because of this reason, there are various EGFRvIII target inhibitor for GBM patient. However, the efficacy of EGFRvIII specific drugs is not good because of autophosphorylation. We found Tra2β, which is pre-mRNA splicing factor, can bind in first intron and there are 9 consensus sequences. Because of EGFRvIII has deletion of second exon, Tra2β can regulate the expression of EGFRvIII. We validated low WTAP expression level in differentiated GBM stem cells, and confirmed the tumorigenic function of Tra2β in GBM cells. Furthermore, we are going to find the mechanism of Tra2β that can regulated by CDC-like kinase. As a result, we connected Tra2β function and EGFR specific drug resistance problem. This study could be helpful on personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs. Citation Format: Young Taek Oh, Jun Hee Hong, Jong Bae Park. The role of pre-mRNA splicing factor in Glioblastoma Multiforme by regulating EGFRvIII. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A09.
Abstract IA31: Phthalimide conjugation as a strategy for targeted protein degradation
Authors: Georg E. Winter, Dennis L. Buckley, James E. Bradner
Journal: Clinical Cancer Research (2017)

Abstract Ligand-induced target protein destabilization is an efficacious therapeutic strategy in cancer, but discovery in this field has historically been serendipitous given the lack of rational design principles. Building on the molecular logic of immunomodulatory drugs (“IMiDs”), we innovated a facile chemical solution for targeted protein degradation using bifunctional small molecules capable of recruiting the E3 ligase cereblon (CRBN). These bifunctional molecules induce immediate, and complete proteasomal degradation of their target proteins and thus represent a novel class of small molecule therapeutics with an entirely uncharted and unique molecular pharmacology. Focusing our initial efforts on degraders of the BET family of proteins, we observed that they exhibit superior efficacy than BET inhibitors through unknown mechanisms. In order to dissect and mechanistically explain that differential molecular pharmacology, we used optimized small-molecule degraders and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in global control of transcriptional pause-release. Targeted BET degradation nucleates a collapse in the transcriptional core regulatory circuitry and thus enabled us to exploit transcriptional addictions in T-Cell acute lymphoblastic leukemia (T-ALL) that were intractable using competitive BET bromodomain inhibitors. Citation Format: Georg E. Winter, Dennis L. Buckley, James E. Bradner. Phthalimide conjugation as a strategy for targeted protein degradation. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA31.
Abstract 301: Targeting Mixed Lineage Kinases in pathological cardiac fibroblast activation and intercellular communication
Authors: Emily M Schulz, Melissa L Martin, Val S Goodfellow, Stephen Dewhurst, Harris A Gelbard, Bruns C Blaxall
Journal: Circulation Research (2013)

Cardiovascular disease (CVD) and the final clinical iteration, heart failure (HF), affect more than 82 million Americans yearly, affects &gt;5.7 million). Although the cardiac myocyte has long been the focus of cardiac cellular research, our lab and others have demonstrated that pathological activation of cardiac fibroblasts (CF) after onset of disease or cardiac injury is also a key player in HF pathogenesis. Pathologic activation of CFs causes a release of various paracrine and autocrine factors that target cardiomyocytes (CM), local inflammatory cells and the CFs themselves. Elucidating the mechanisms involved in pathological ‘support cell (CF)’- ‘functional cell (CM)’ communication may hold therapeutic promise. Mixed lineage kinase 3 (MLK3) is a stress activated mitogen-activated protein kinase kinase kinase (MAPKKK) involved in pro-apoptotic pathways. Inhibition of MLK3 in HAND results in the attenuation of microglial cell activation, preservation of neuronal function and synaptic structures. The parity between microglia-neuron communication and CF-CM communication and the effects of pathological activation on the respective support cells for each tissue type suggested a role for MLK3 in aberrant CF-CM cross-talk associated with the development and progression of HF. Preliminary data in mice subjected to a pharmacological model of HF (chronic isoproterenol) that were treated with a small molecule inhibitor (URMC-099) of MLK3 demonstrated a reduction in the development of myocardial fibrosis compared to vehicle treated animals. Additionally, small molecule MLK3 inhibition attenuated the development of myocardial hypertrophy as measured by heart weight: body weight and heart weight: tibia length ratios. Studies in cultured neonatal rat ventricular fibroblasts (NRVF) demonstrated that small molecule MLK3 inhibition attenuated CF activation and transition to a myofibroblast phenotype, including reductions of pathologic CF markers such as α-SMA, IL-6, IL-1β, and others. Our data demonstrate that MLK3 plays an important role in pathologic CF-CM communication and myocardial hypertrophy, and suggest that small molecule inhibition of MLK3 holds therapeutic promise for HF.
Soluble CD163 and their expression on monocytes, constituent potential molecular signature associated with liver inflammation and HBV-specific immune responses
Authors: D. Huang, B. Sansass, J. Jiang, Q. Gong, M. Wan, L. Chen, W. Yang, G. Jin, D. Yu, M. Zhu, D. Wei, D. Zhang, G. Inchauspé, X. Zhang, R. Zhu
Journal: Journal of Hepatology (2017)
CCCS-SSAI WikiRecs clinical practice guideline: vasopressor blood pressure targets in critically ill adults with hypotension and vasopressor use in early traumatic shock
Authors: B. Rochwerg, M. Hylands, M. H. Møller, P. Asfar, D. Cohen, R. G. Khadaroo, J. H. Laake, A. Perner, T. Tanguay, S. Widder, P. Vandvik, A. Kristiansen, F. Lamontagne
Journal: Intensive Care Medicine (2017)
Taxane-based chemotherapy in senior adults with metastatic castration-resistant prostate cancer (mCRPC): A prospective international registry.
Authors: Jean-Pierre Droz, Eleni Efstathiou, Axel Heidenreich, Asif Yildirim, Paula Cabrera, Choung-Soo Kim, Ali Horchani, Jose A. Rinck, Haluk Ozen
Journal: Journal of Clinical Oncology (2012)

e15122 Background: Docetaxel every 3 weeks is the standard of care in mCRPC. Efficacy and toxicity of taxanes in older men (70+) is poorly documented. Their enrolment in randomized trials is limited by exclusion criteria. This prospective international registry evaluates taxane toxicity and efficacy in such men in real life. Methods: 333 men with mCRPC (median age 76) were evaluated. PS, grade 3-4 comorbidities (Cumulative Illness Scoring Rate-Geriatrics [CISR-G]), dependence (Activity Daily Living [ADL], Instrumental ADL [IADL]), nutritional status, primary therapy received and outcomes (overall survival (OS), progression-free survival (PFS), best clinical benefit [based on pain, analgesic consumption, PS], PSA response, toxicity) were collected. Follow-up under therapy was 6 months. Results: In all, 24.0% had PS ≥2, 13.5% grade 3-4 comorbidities, 21% were dependent in ≥1 IADL, 15.6% in ≥1 ADL and 12.8% had a weight loss ≥5% within the past 3 months. According to SIOG (International Society of Geriatric Oncology, BJU Int 2010; 106: 462-69) algorithm, 65.2% were fit, 13.5% vulnerable, 16.8% frail and 4.5% had terminal illness. Most patients (62.4%) had pain at enrolment. Primary therapy was a taxane in 58% (3-weekly, 84.4%; median, 5 months) and another therapy in 42%. Clinical characteristics of men treated by taxanes and other therapies were comparable. At 6 months, 91% were still alive with taxanes vs 81% with other therapies (HR [95% CI] 0.53 [0.30-0.93] p=0.027). Taxanes also significantly increased PFS (66% vs 50%, HR 0.55 [0.40-0.76], p&lt;0.001), best clinical benefit (60% vs 36%, HR 2.05 [1.47-2.85], p&lt;0.001) and PSA response ≥50% (52.5% vs 37.4%, p=0.018). Main grade 3-4 toxicities with taxanes were fatigue (17.1%), nausea/vomiting (14%), diarrhoea (8.8%), anaemia (7.8%), nail change (6.7%) and febrile neutropenia (2.6%). Conclusions: Taxanes appear the most effective first-line therapy in older men with mCRPC and show an acceptable and manageable toxicity. Further analyses will compare health status measured by SIOG algorithm to physician independent evaluation and identify the most pertinent geriatric predictors of health status.
Hepatic targeted RNA interference provides deep and prolonged knockdown of alpha-1 antitrypsin levels in ZZ patients
Authors: A. Turner, J. Stolk, R. Bals, J. Lickliter, J. Hamilton, D. Christianson, B. Given, J. Burdon, R. Loomba, J. Stoller, J. Teckman
Journal: Journal of Hepatology (2017)
PD-1 regulates KLRG1+ group 2 innate lymphoid cells
Authors: Samuel Taylor, Yuefeng Huang, Grace Mallett, Chaido Stathopoulou, Tania C. Felizardo, Ming-An Sun, Evelyn L. Martin, Nathaniel Zhu, Emma L. Woodward, Martina S. Elias, Jonathan Scott, Nick J. Reynolds, William E. Paul, Daniel H. Fowler, Shoba Amarnath
Journal: The Journal of Experimental Medicine (2017)

Group 2 innate lymphoid cells (ILC-2s) regulate immune responses to pathogens and maintain tissue homeostasis in response to cytokines. Positive regulation of ILC-2s through ICOS has been recently elucidated. We demonstrate here that PD-1 is an important negative regulator of KLRG1+ ILC-2 function in both mice and humans. Increase in KLRG1+ ILC-2 cell numbers was attributed to an intrinsic defect in PD-1 signaling, which resulted in enhanced STAT5 activation. During Nippostrongylus brasiliensis infection, a significant expansion of KLRG1+ ILC-2 subsets occurred in Pdcd1−/− mice and, upon adoptive transfer, Pdcd1−/− KLRG1+ ILC-2s significantly reduced worm burden. Furthermore, blocking PD-1 with an antibody increased KLRG1+ ILC-2 cell number and reduced disease burden. Therefore, PD-1 is required for maintaining the number, and hence function, of KLRG1+ ILC-2s.