tbuckley/cabot-search huggingface dataset:
Abstract 3820: Novel PD-1/GITRL bispecific fusion protein delivering concurrent T cell co-stimulation and checkpoint pathway inhibition
Authors: Simon J. Dovedi, Jonathan Seaman, Ines Osma-Garcia, Katharina Deschler, Edmund Poon, Ronald Herbst, Robert Wilkinson
Journal: Cancer Research (2018)

Abstract Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is a co-stimulatory receptor, and programmed cell death protein 1 (PD-1) is an important co-inhibitory receptor involved in controlling T-cell activation and function. Preclinical studies using murine cross-reactive molecules demonstrate that the combination of an αPD-1 monoclonal antibody (mAb) with a GITR-ligand (GITRL) fusion protein can elicit synergistic antitumor activity and long-term survival benefit in syngeneic mouse tumor models. Here we describe the activity of two bispecific fusion proteins, each comprising two GITR ligand trimers fused to the Fc region of an αPD1 mAb, in an IgG1 (MEDI5771) or IgG4P (MEDI3387) format. We show that these bispecific molecules are able to concurrently engage both targets and are effective in cell-based PD-1 and GITR reporter assays, and in a range of human primary T-cell assays. Furthermore, the PD-1/GITRL FP bispecific constructs elicit T-cell responses in vitro that are at least equivalent to a combination of a) the parental molecules and b) MEDI1873 (a GITR agonist currently undergoing clinical evaluation) and an αPD-1 mAb. Moreover, using surrogate molecules we demonstrate that IV administration leads to dose-dependent pharmacodynamic responses on CD4+ and CD8+ T cells for both isotypes of the bispecific molecule. These data demonstrate that the antitumor activity for these novel molecules is equivalent to the combination of GITRL-FP and PD-1 mAb in the B16 model. In summary, the simultaneous dual targeting of PD-1 and GITR pathways mediated by these two novel bispecific molecules induces robust T-cell activity that is at least equivalent to a combination of molecules targeting these pathways, thereby demonstrating strong potential as a novel anticancer therapy. Citation Format: Simon J. Dovedi, Jonathan Seaman, Ines Osma-Garcia, Katharina Deschler, Edmund Poon, Ronald Herbst, Robert Wilkinson. Novel PD-1/GITRL bispecific fusion protein delivering concurrent T cell co-stimulation and checkpoint pathway inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3820.
Patch tests should include chemicals used in false nail products, say dermatologists
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

A growing number of people are allergic to chemicals used in false nails and gel polishes, dermatologists have warned. They have recommended that patch test series should include (meth)acrylate chemicals to detect those with allergic responses.

In an audit of 4931 patients carried out in 13 UK and Irish dermatology units during 2017, 2.4% tested positive to at least one type of (meth)acrylate—either 2-hydroxyethyl methacrylate (2-HEMA) (1.5%), 2-hydroxypropyl methacrylate (1%,) or ethyl acrylate (0.9%), which can be found in medical and other …
Abstract 4139: SNAI2 inhibition promotes myogenic differentiation and prevents tumorigenic features of embryonal rhabdomyosarcoma
Authors: Silvia Pomella, Elena Carcarino, Cristina Cossetti, Franco Locatelli, Rossella Rota
Journal: Cancer Research (2018)

Abstract Pediatric Rhabdomyosarcoma (RMS) is a soft tissue sarcoma of childhood that in its high risk form has a dismal prognosis. RMS includes two histological subtypes, embryonal and alveolar, which differ clinically and molecularly. Both are characterized by the expression of Myogenic Regulatory Factors (MRFs) such as MYOD and MYOG but tumor cells are unable to differentiate in skeletal muscle cells and proliferate indefinitely. For this reason, differentiation therapies have anticancer potential in this tumor. Interestingly, one of the cause of the inability of MRFs in inducing myogenic-like differentiation is related to the loss of transcriptional activity of these factors partly due to the lack of availability of DNA binding sites and/or of capability to form transcriptional complexes. We demonstrate here that the repressor SNAI2 is upregulated in embryonal RMS (ERMS) patients and cells lines compared to their normal counterparts. Silencing of SNAI2 in 2 ERMS patient-derived cell lines using a puromycin pLKO lentiviral vector expressing a SNAI2 shRNA results in a slowdown of cell proliferation associated to p21Cip1 and Myogenin upregulation starting 3 days post-selection, as compared to control vector. These molecular changes are followed by the induction of Myosin-Heavy Chain and the formation of myogenic-like multinucleated structures reminiscent of myogenic fibers. Moreover, colony formation and anchorage independent growth are both strongly impaired. Finally, SNAI2 depleted cells form smaller spheres when cultured in cancer stem cells conditions. Therefore, SNAI2 down-regulation could have therapeutic value in ERMS. Studies are ongoing to verify the restoring of MYOD transcriptional activity and to identify genes regulated by SNAI2 in our system. The work is supported by Associazione Italiana Ricerca sul Cancro project IG15312 to RR. Citation Format: Silvia Pomella, Elena Carcarino, Cristina Cossetti, Franco Locatelli, Rossella Rota. SNAI2 inhibition promotes myogenic differentiation and prevents tumorigenic features of embryonal rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4139.
Role of Angiotensin II in Activation of the JAK/STAT Pathway Induced by Acute Pressure Overload in the Rat Heart
Authors: JingPan, KeiichiFukuda, HiroakiKodama, ShinjiMakino, ToshiyukiTakahashi, MotoakiSano, ShingoHori, SatoshiOgawa
Journal: Circulation Research (1997)

Abstract This study was designed to determine whether the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway is activated in cardiac hypertrophy induced in vivo by pressure overload in rats and to demonstrate whether angiotensin II is involved in the activation of the JAK/STAT pathway. Acute pressure overload was produced by constricting the abdominal aorta of Wistar rats. Immunoprecipitation–Western blot analysis revealed that pressure overload activated JAK1, JAK2, and Tyk2 as early as 5 minutes and that STAT1, STAT2, and STAT3 were tyrosine-phosphorylated rapidly after exposure to the pressure overload. Phosphorylation of STAT1 and STAT2 peaked in the early stage at 5 to 15 minutes, whereas that of STAT3 peaked in the late stage at 60 minutes. Gel mobility shift of the interferon gamma activation site/interferon alpha–stimulating response element was observed immediately after the aortic banding, whereas the band of sis-inducing element was shifted in the...
Drug Eluting Stents: Arsenic Trioxide–Coated Stent Is an Endothelium‐Friendly Drug Eluting Stent (Adv. Healthcare Mater. 15/2018)
Authors: Yinping Zhao, Ruolin Du, Tian Zhou, Dongchuan Yang, Yuhua Huang, Yi Wang, Junli Huang, Xiaoyi Ma, Fugui He, Juhui Qiu, Guixue Wang
Journal: Advanced Healthcare Materials (2018)

Traditional drug-eluting stents often delay endothelialization whilst inhibiting intimal hyperplasia. In article 1800207 by Juhui Qiu, Guixue Wang, and co-workers, an arsenic trioxide-eluting stent effectively facilitates rapid re-endothelialization whilst preventing in-stent restenosis. Cover image designed and produced by Jin Yang.
Abstract B44: Early loss of monoubiquitylation of H2B alters key metabolic and immune signaling pathways promoting the progression of high-grade serous ovarian cancer
Authors: Jagmohan Hooda, Marian Novak, Emily MacDuffie, Melissa Song, Jenny Lester, Vinita Parkash, Gordon B. Mills, Beth Y. Karlan, Moshe Oren, Ronny Drapkin
Journal: Clinical Cancer Research (2018)

Abstract High-grade serous ovarian carcinoma (HGSOC) is the most common form of ovarian cancer, accounting for over 70% of all cases. HGSOC is frequently complicated by the inevitable development of therapeutic resistance, and thus remains an incurable disease. Recent insights supporting the fallopian tube epithelium (FTE) as a point of origin for HGSOC and the serous tubal intraepithelial carcinoma (STIC) as the precursor lesion for a majority of HGSOCs provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Understanding these key molecular processes is essential to inform the development of next-generation therapies. In this study we investigated the role of the ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis. H2Bub1, catalyzed largely by RNF20, is an epigenetic mark with tumor-suppressor properties. The loss of RNF20/H2Bub1 has been linked with cancer progression. We used immunohistochemistry to characterize the expression of H2Bub1 in HGSOC and FTE precursors. We found that H2Bub1 is lost or downregulated in a large proportion of STICs and HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in serous tumorigenesis. Consistent with our findings, analysis of TCGA data shows that the majority of HGSOCs exhibit heterozygous loss of RNF20. Functionally, we demonstrated that shRNA-mediated knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to increase cell migration and clonogenic growth of immortalized FTE cells. To understand the mechanisms underlying these effects, we performed RNA-seq and proteomics profiling (RPPA) in RNF20 knockdown cells. Major changes were observed in a number of structural, metabolic (e.g., glutamine pathway), and cytokines and inflammatory signaling pathways, providing early mechanistic insights for the observed oncogenic phenotypes. In summary, our study identifies that loss of H2Bub1 is an early epigenetic event in HGSOC that rewires glutamine metabolism and certain inflammatory pathways, which may represent unique therapeutic opportunities. Citation Format: Jagmohan Hooda, Marian Novak, Emily MacDuffie, Melissa Song, Jenny Lester, Vinita Parkash, Gordon B. Mills, Beth Y. Karlan, Moshe Oren, Ronny Drapkin. Early loss of monoubiquitylation of H2B alters key metabolic and immune signaling pathways promoting the progression of high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B44.
Increasing Long-Term Major Vascular Events and Resource Consumption in Patients Receiving Off-Pump Coronary Artery Bypass
Authors: ShengshouHu, ZheZheng, XinYuan, WeiWang, YunhuSong, HansongSun, JianpingXu
Journal: Circulation (2010)

Background— Despite its widespread use and short-term efficacy, substantial uncertainty remains about the long-term outcomes and cost-effectiveness of off-pump coronary artery bypass (OPCAB). Methods and Results— A retrospective review of prospectively collected data was conducted of 6665 consecutive patients undergoing isolated coronary artery bypass graft (CABG) at our institution during 1999 to 2006. All patients were followed up until September 30, 2008. Short- and long-term outcomes were compared between OPCAB and conventional CABG. The 2 main long-term outcome measures were repeat revascularization and the composite outcome of major vascular events. Cost comparison at 2 years in a propensity-matched sample during follow-up was also a study interest. The overall mean baseline age was 60.3±8.6 years, and 17.0% were women. Compared with conventional CABG, patients who underwent OPCAB had lower rates of atrial fibrillation (P=0.003) and requirements for blood transfusion (P=0.03) and ventilation time >2...
Abstract 19152: Lamin A/C-Deficient Bone Marrow-Derived Mesenchymal Stem Cells Exhibit Spontaneous Pre-Adipogenic Conversion
Authors: Diana E Jaalouk, Chin Yee Ho, Francesco S Loffredo, Philipp Isermann, Jan Lammerding
Journal: Circulation (2013)

Laminopathies are disorders that affect multiple tissues including skeletal muscle as in Emery-Dreifuss muscular dystrophy (EDMD) and cardiac as in dilated cardiomyopathy (DCM). They arise from mutations in the LMNA gene that encodes the nuclear envelope proteins lamins A/C. To date, the underlying mechanisms are poorly understood. Recently, several studies established a link between lamin A and dysfunction of adult stem cells. Considering that muscular laminopathies adversely affect tissues of mesenchymal origin, we rationalized that this may be in part attributed to altered differentiation of MSCs. Our aim is to characterize the differentiation of MSCs isolated from an EDMD ( Lmna -/- ) mouse model which also develops DCM. Marrow aspirates from age- and gender- matched Lmna +/- and Lmna +/+ littermates were used as controls. After limited passages in tissue culture, we noted that a large proportion of the Lmna -/- MSCs readily differentiated into fat-containing cells without pre-stimulation with adipogenic supplements. Grown under similar conditions, we did not observe any changes in the control groups. Absorbance measurements of Oil Red O stain alcohol extracts showed significantly higher quantities of fat-containing droplets in Lmna -/- MSCs (2.209 ± 0.039) compared to wild-type (0.095 ± 0.019) and heterozygous controls (0.062 ± 0.001); (mean OD 520 ± SEM); p&lt;0.01 . Likewise, we observed similar PPAR-gamma -dependent pre-adipogenic conversion in Lmna -/- mouse embryo fibroblasts (MEFs) grown to over-confluence in monolayers in vitro. Real-Time PCR quantification showed no significant induction in the expression of the transcriptional regulators SREBP-1 and FAS post adipogenic stimulation in MEFs, but both had higher baseline expression in Lmna -/- compared to controls. IHC staining of paraffin-embedded tissue sections of de-calcified bone marrow showed elevated expression of FABP-4 in Lmna -/- mice compared to controls, suggesting an in vivo predisposition of Lamin A/C - deficient marrow - derived MSCs to spontaneous adipogenic conversion. Research is underway to characterize the expression of other transcriptional regulators in MSCs and in bone marrow sections from Lamin A/C - deficient mice.
Abstract 773: A heterochromatin gene signature unveils HP1α mediating neuroendocrine prostate cancer development and aggressiveness
Authors: Xinpei Ci, Jun Hao, Xin Dong, Stephen Y. Choi, Hui Xue, Sifeng Qu, Ladan Fazli, Francesco Crea, Christopher Ong, Amina Zoubeidi, Housheng H. He, Martin E. Gleave, Colin C. Collins, Dong Lin, Yuzhuo Wang
Journal: Cancer Research (2018)

Abstract Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. However, mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei is a distinguishing histopathological feature of NEPC, we identified 36 heterochromatin-related genes that are significantly enriched in NEPC by transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression is increased early and steadily during NEPC development and remain elevated in the developed NEPC tumor. Its elevated expression is further confirmed in multiple PDX and clinical NEPC samples. Functional studies showed that HP1α knockdown in the NCI-H660 NEPC cell line dramatically inhibits proliferation, completely ablates colony formation, and induces apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promotes NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduces expression of androgen receptor (AR) and RE1 silencing transcription factor (REST), two crucial transcription factors silenced in NEPC, and enriches the repressive histone mark trimethylation of histone H3 at Lys9 (H3K9me3) on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and/or management. Citation Format: Xinpei Ci, Jun Hao, Xin Dong, Stephen Y. Choi, Hui Xue, Sifeng Qu, Ladan Fazli, Francesco Crea, Christopher Ong, Amina Zoubeidi, Housheng H. He, Martin E. Gleave, Colin C. Collins, Dong Lin, Yuzhuo Wang. A heterochromatin gene signature unveils HP1α mediating neuroendocrine prostate cancer development and aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 773.
Abstract 3246: Association between colorectal cancer and red or processed meat among Korean diet: A molecular approach
Authors: Mihi Yang, Jeongseon Kim, Jong Y. Park
Journal: Cancer Research (2018)

Abstract To study whether red or processed meat cause colorectal cancer in non- western population, we performed a pilot study in Korean people (N=30, case, 15 vs. control 15, mean of age=59.7 yrs) with biological monitoring of exposure and response biomarkers, i.e. metabolites of polycyclic aromatic hydrocarbons and heterocyclic amine (1-OHP, PhIP, and MeIQx), their DNA-adducts (dG-C8-MeIQx), and homocysteine, malondialdehyde (MDA), C-reactive protein and epigenetic alteration (5mC). The subjects also filled out daily consumption of food before diagnoses. As results, they averagely consumed 59.89 g/day and 2.47 g/day of red and processed meat, respectively. There were positive associations among consumption of Kimch(g), folate (ug) and fruits(g). The consumption of red meat was not associated with the cancer and the control even showed higher processed meat (g). From biomonitoring, the average levels of urinary 1-OHP, PhIP, and MeIQx, blood-dG-C8-MeIQx and 5mC were 0.13 ppb, 9.9 ppt, 14.63 ppt, 5.23 ppt/1.8 ug of DNA, and 5.3%, respectively. We found younger people more consumed processed meat or beverage and showed higher urinary levels of MeIQx than elderly people. The urinary levels of PhIP were negatively associated with folate consumption. The cases showed higher levels of LDL-cholesterol, homocysteine, urinary 1-OHP and dG-C8-MeIQx than controls. There were positive associations among levels of MeIQx, MDA, and 1-OHP. In addition, levels of dG-C8-MeIQx were positively associated with those of 1-OHP and total cholesterol. The levels of global methylation of 5mC (%) were higher in well done meat consumers than others. In conclusion, the Korean subjects might consume less volume of red or processed meat than western people. From questionnaire (FFQ), we could not find association between red or processed meat and colorectal cancer. However, biological monitoring showed the Korean colorectal cancer could be affected by red or processed meat, due to association with exposure or response biomarkers, particularly long term exposure biomarkers, such as dG-C8-MeIQx. This molecular epidemiological approach provides more reliable evidences to overcome limitation of case-control studies. Citation Format: Mihi Yang, Jeongseon Kim, Jong Y. Park. Association between colorectal cancer and red or processed meat among Korean diet: A molecular approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3246.
MicroRNA-30c-5p modulates neuropathic pain in rodents
Authors: Mónica Tramullas, Raquel Francés, Roberto de la Fuente, Sara Velategui, María Carcelén, Raquel García, Javier Llorca, María A. Hurlé
Journal: Science Translational Medicine (2018)

miR-30c-5p expression modulates pain in rodent models of nerve injury and is overexpressed in patients with neuropathic pain due to leg ischemia.
Abstract 18986: Unopposed TNF/TNFR1 Signaling Prevents Therapeutic Benefit From Cardiac Stem Cell Therapy After Reperfused Myocardial Infarction in Mice
Authors: Tariq Hamid, Yuanyuan Xu, Mohammad A Ismahil, Mehak Goel, Bindiya Patel, Amy M Michaud, Qianghong Li, Aruni Bhatnagar, Roberto Bolli, Sumanth D Prabhu
Journal: Circulation (2015)

Despite expansion of resident cardiac stem cells (CSCs) after myocardial infarction (MI), the heart is unable to regenerate, suggesting that local factors inhibit CSC function. Tumor necrosis factor-α (TNF), increased in infarcted and failing hearts, is one candidate inhibitory factor; its effects are specific to its two receptors (TNFRs). We hypothesized that TNF/TNFR signaling in CSCs modulates the efficacy of CSC therapy after reperfused MI in mice. Magnetically sorted, c-kit enriched, Lin– CSCs were isolated from wild-type (WT), TNFR1-/-, and TNFR2-/- mice, expanded, and 1 x 105 CSCs were administered via intramyocardial injection in the border zone 48 h after 60 min ischemia in WT C57BL/6 mice (n = 13-18/group). Five weeks after CSC therapy, as compared with PBS-injected MI mice, WT CSC transplantation significantly (p&lt;0.05) improved LV systolic function (ESV 50 ± 14 vs 63 ± 23 μL; EF 31 ± 11 vs 24 ± 9%). Analogous to WT CSCs, TNFR1-/- CSCs also significantly improved LV systolic function (ESV 44 ± 5 uL; EF 35 ± 3%). In contrast, TNFR2-/- CSC transplanted MI hearts exhibited greater LV systolic dysfunction (ESV 62 ± 5 uL; EF 29 ± 4%) as compared with both WT and TNFR1-/- CSC injected hearts, and were comparable to PBS-injected MI hearts. There was signficantly reduced border zone (BZ) fibrosis in both WT (7.6 ± 3.2%) and TNFR1-/- CSC (7.2 ± 1.9%) injected hearts as compared with either PBS-injected MI hearts (11.6 ± 2.8%), or TNFR2-/- CSC injected MI hearts (15.7 ± 4.0%). Analogous to fibrotic change, cardiomyocyte hypertrophy in post-MI hearts was significantly decreased after cell transplantation with either WT CSCs (322 ± 56 μm2) or TNFR1-/- CSCs (244 ± 29 μm2), as compared with PBS-injected MI hearts (423 ± 56 μm2), with more robust improvements in hypertrophy in the TNFR1-/- CSC MI hearts. In contrast, cardiomyocyte size after TNFR2-/- CSC transplantation (389 ± 58 μm2) was comparable to PBS injected hearts, and significantly greater than either WT or TNFR1-/- CSC injected MI hearts. We conclude that myocardial TNF diminishes the efficacy of CSC therapy via TNFR1 signaling, especially when unopposed by concomitant TNFR2 signaling. Selective TNFR1 blockade, or TNFR2 agonism, at the time of cell transplantation may improve the functional outcomes of CSC therapy after MI.