tbuckley/cabot-search huggingface dataset:
Abstract B26: Immune-active microenvironment in SCCOHT: Rationale for therapy with immune checkpoint blockade
Authors: Elke Van Oudenhove, Petar Jelinic, Jacob Ricca, Narciso Olvera, Taha Merghoub, Douglas A. Levine, Zamarin Dmitriy
Journal: Clinical Cancer Research (2018)

Abstract Introduction: Small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT) is a rare and very aggressive malignancy with limited treatment options. SCCOHT is described as an epigenetically altered SMARCA4-mutated monogenic disease, but the exact mechanism of SCCOHT tumorigenesis is not clear. Immune checkpoint-targeting antibodies have not been considered as a suitable treatment option for SCCOHT, because this cancer is characterized by a small number of mutations. Anecdotal reports of patients with SCCOHT responding to PD-1 blockade have challenged this view. We aimed to characterize the immune microenvironment of SCCOHT in order to evaluate a rationale for therapy with PD-1/PD-L1 targeting antibodies. Methods: To test whether SCCOHT tumors were identified by the immune system, we examined PD-L1 expression and T cell populations within tumor samples. The immune landscape was profiled using quantitative immunofluorescence and gene expression profiling. Results: Most tumors showed PD-L1 expression and prominent T cell infiltration, with PD-L1 being primarily limited to tumor-infiltrating immune cells. Gene expression analyses revealed upregulation of genes related to T-cell infiltration and cytolytic function in the PD-L1-high tumors. We hypothesize that PD-L1 upregulation in SCCOHT is an adaptive immune response to T-cell infiltration, as has been previously reported for several other cancer types. Conclusions: Our findings provide an impetus for further investigation of PD-1/PD-L1 as a potential therapy for patients with SCCOHT. More generally, these results challenge the prevailing view that tumor immunogenicity is primarily driven by mutational burden, calling for identification of additional immune pathways involved in tumor recognition. Citation Format: Elke Van Oudenhove, Petar Jelinic, Jacob Ricca, Narciso Olvera, Taha Merghoub, Douglas A. Levine, Zamarin Dmitriy. Immune-active microenvironment in SCCOHT: Rationale for therapy with immune checkpoint blockade. [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 B26.
Cholangiocarcinoma therapy with nanoparticles that combine downregulation of MicroRNA-210 with inhibition of cancer cell invasiveness
Authors: Ying Xie, Yazhe Wang, Jing Li, Yu Hang, Lee Jaramillo, Cody J. Wehrkamp, Mary Anne Phillippi, Ashley M. Mohr, Yi Chen, Geoffrey A. Talmon, Justin L. Mott, David Oupický
Journal: Theranostics (2018)

Cholangiocarcinoma (CCA) is the second most common primary liver malignancy with extremely poor therapeutic outcome due to high drug resistance, widespread metastasis and lack of effective treatment options. CCA progression and metastasis are regulated by multiple biological factors including multiple miRNAs and chemokine receptor CXCR4. The goal of this study was to test if nanotherapeutic blockade of CXCR4 by polymeric CXCR4 antagonist (PCX) combined with inhibition of hypoxia-inducible miR-210 cooperatively enhances therapeutic efficacy in CCA through reducing invasiveness, inducing cell killing, and reversing drug resistance. Methods: We first tested the activity of PCX to inhibit migration of CCA cells. We then prepared PCX/anti-miRNA nanoparticles and analyzed their miRNA delivery efficacy and anticancer activity in vitro. Finally, in vivo biodistribution assay and anticancer activity study were performed in CCA tumor-bearing mice. Results: Our results show that PCX had a broad inhibitory effect on cell migration, effectively delivered anti-miR-210, and downregulated miR-210 expression in CCA cells. Combination PCX/anti-miR-210 nanoparticles showed cytotoxic activity towards CCA cells and reduced the number of cancer stem-like cells. The nanoparticles reversed hypoxia-induced drug resistance and sensitized CCA cells to standard gemcitabine and cisplatin combination treatment. Systemic intravenous treatment with the nanoparticles in a CCA xenograft model resulted in prominent combined antitumor activity. Conclusion: Our findings support PCX-based nanoparticles as a promising delivery platform of therapeutic miRNA in combination CCA therapies.
Trajectory of Disability in Older Adults With Newly Diagnosed Diabetes: Role of Elevated Depressive Symptoms
Authors: Chao-Yi Wu, Lauren Terhorst, Jordan F. Karp, Elizabeth R. Skidmore, Juleen Rodakowski
Journal: Diabetes Care (2018)

OBJECTIVE We examined whether the trajectory of disability differed between older adults with and without elevated depressive symptoms before and after the onset of diabetes mellitus (DM) over 10 years (2004–2014) and explored difficulties in basic and instrumental activities of daily living between the two groups. RESEARCH DESIGN AND METHODS A generalized linear mixed-model analysis was conducted using five waves (8th–12th) of Health and Retirement Study (HRS) data. We included 419 older adults who self-reported new DM diagnosis within the previous 2 years and used the Center of Epidemiologic Studies Depression Scale to measure elevated depressive symptoms. Disability was measured by 10 items defined in the HRS data set. RESULTS The trajectory of disability differed between older adults with and without elevated depressive symptoms after newly diagnosed DM over time. Significant and clinically meaningful between-group differences were found in disability after the onset of DM (waves 10 and 11) but not before the onset of DM (waves 8 and 9). Among older adults with elevated depressive symptoms, disability at pre-DM waves (8 and 9) was significantly less than post-DM waves (10–12). Difficulties with shopping, walking, and dressing were mostly reported by older adults with elevated depressive symptoms. CONCLUSIONS Older adults with newly diagnosed DM and elevated depressive symptoms have a clinically meaningful and faster disablement trajectory than those without elevated depressive symptoms. Future interventions may take an indicated approach to disability prevention in older adults with newly diagnosed DM, especially in those with a change in depression severity.
The Role of Wnt Signaling in Physiological and Pathological Angiogenesis
Authors: ElisabettaDejana
Journal: Circulation Research (2010)

Early stages of vascular development include endothelial cell differentiation in a network of arteries, veins, and lymphatics. Subsequently, to respond to the specific needs of the organs, endothelial cells acquire specialized properties such as permeability control, expression of specific transcellular transport systems, membrane adhesive molecules, and others. Endothelial cell differentiation depends on communication between the surrounding tissues, which is mediated by growth and differentiation factors able to activate specific gene expression programs. Recent reports underline the important role of the Wnt system in vascular morphogenesis in the embryo and in organ-specific endothelial differentiation. Wnt signaling regulates fundamental aspects of development, including cell fate specification, proliferation, and survival, and may use different receptors and signaling pathways. Both loss- and gain-of-function experiments of members of the Wnt signaling pathway were found to cause marked alterations ...
Abstract 14943: Significance of Improvement of Advanced Heart Block in Response to Corticosteroid Therapy in Patients With Cardiac Sarcoidosis
Authors: Masato Segawa, Koji Fukuda, Makoto Nakano, Masateru Kondo, Michinori Hirano, Hiroaki Shimokawa
Journal: Circulation (2015)

Introduction: Advanced heart block (AHB) is one of the major manifestations in patients with cardiac sarcoidosis (CS) and is regarded as a prognostic factor of poor prognosis. Although it has been reported that AHB is improved in response to corticosteroid therapy in some cases, the significance of the improvement remains to be examined. Methods and Result: We examined 68 consecutive patients with CS who admitted to Tohoku University Hospital from October 1998 to September 2014 (57±11 years-old, M/F 18/50, mean follow-up 5.5-year). CS was diagnosed based on the original guidelines for diagnosis of CS from the Japanese Ministry of Health and Welfare. Corticosteroid therapy was performed in all CS patients. Among the 68 patients, 29 (43%) had AHB at admission (AHB group). The AHB group tended to have higher BNP level as compared with those without AHB (no-AHB group) (358±92 vs 200±35 pg/ml, P=0.086), whereas there was no difference in left ventricular ejection fraction between the two groups (50.0±18.9 vs 51.0±14.6%, P=0.801). Kaplan-Meier estimate of freedom from heart failure hospitalization, but not that from all-cause death or VT/VF, showed that the AHB group had more events than the no-AHB group (log-rank P=0.032) (Figure A). Importantly, among the 20 AHB patients after excluding 9 patients with CRT therapy at admission, AHB was improved in 6 in response to corticosteroid therapy but was sustained in the remaining 14, where event-free survival was significantly better in the former than in the latter (log-rank P=0.014) (Figure B). Although BNP levels were comparable between the two groups at admission (242±52 vs. 213±74 pg/ml, P=0.761), there was a significantly greater improvement in the BNP levels in patients with improvement of AHB (125±26 vs 22±7 pg/ml, P=0.022). Conclusions: These results indicate that improvement of AHB in response to corticosteroid therapy may be an important prognostic factor of better prognosis associated with improved cardiac function.
Abstract 3345: MAZ is a downstream target of CCN1 and promotes aggressive behavior of pancreatic cancer cells via CRAF-ERK signaling pathway
Authors: Gargi Maity, Inamul Haque, Arnab Ghosh, Gopal Dhar, Vijayalaxmi Gupta, Sandipto Sarkar, Imaan Azeem, Douglas McGregor, Abhishek Choudhary, Donald R Campbell, Sushanta K. Banerjee, Snigdha Banerjee
Journal: Cancer Research (2018)

Abstract MAZ (Myc-associated zinc-finger protein) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression has been shown to associate with the progression of pancreatic ductal adenocarcinoma cancer (PDAC). However, underlying mechanisms of action of MAZ in PDAC progression are largely unknown. Here we present evidence that MAZ mRNA expression and protein level were increased in human PDAC cell lines, tissue samples, subcutaneous tumor xenograft model in a nude mouse, and spontaneous cancer in the genetically engineered PDAC mouse model. We found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis demonstrates that the depletion of MAZ in PDAC cells results in inhibition of invasive phenotypes such as phenotypic shift, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we found no direct effect of MAZ on the expression of K-Ras mutants, but evidently MAZ increases the activity of CRAF-ERK-signaling, which is a downstream signaling target of K-Ras. Activation of CRAF-ERK-signaling by MAZ is mediated via p21-activated protein kinases (PAK) and protein kinase B (AKT/PKB) signaling cascades and promotes invasive phenotypes of PDAC cells. Moreover, a matricellular oncoprotein CCN1 regulates MAZ expression in PDAC cells. Thereby, we proposed that CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells is not through direct K-Ras activation as presently thought but instead through the activation of CRAF-ERK signals. Collectively, these studies highlight key players that could help in clinical management, prognosis, and therapeutic strategies. This project is funded by VA Merit Award grants (SB &amp; SKB). Citation Format: Gargi Maity, Inamul Haque, Arnab Ghosh, Gopal Dhar, Vijayalaxmi Gupta, Sandipto Sarkar, Imaan Azeem, Douglas McGregor, Abhishek Choudhary, Donald R Campbell, Sushanta K. Banerjee, Snigdha Banerjee. MAZ is a downstream target of CCN1 and promotes aggressive behavior of pancreatic cancer cells via CRAF-ERK signaling pathway [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 3345.
Outcome of Watchful Waiting in Asymptomatic Severe Mitral Regurgitation
Authors: RaphaelRosenhek, FlorianRader, UrsulaKlaar, HaraldGabriel, MarcelKrejc, DanielKalbeck, MichaelSchemper, GeraldMaurer, HelmutBaumgartner
Journal: Circulation (2006)

Background— The management of asymptomatic severe mitral regurgitation remains controversial. The aim of this study was to evaluate the outcome of a watchful waiting strategy in which patients are referred to surgery when symptoms occur or when asymptomatic patients develop left ventricular (LV) enlargement, LV dysfunction, pulmonary hypertension, or recurrent atrial fibrillation. Methods and Results— A total of 132 consecutive asymptomatic patients (age 55±15 years, 49 female) with severe degenerative mitral regurgitation (flail leaflet or valve prolapse) were prospectively followed up for 62±26 months. Patients underwent serial clinical and echocardiographic examinations and were referred for surgery when the criteria mentioned above were fulfilled. Overall survival was not statistically different from expected survival either in the total group or in the subgroup of patients with flail leaflet. Eight deaths were observed. Thirty-eight patients developed criteria for surgery (symptoms, 24; LV criteria, ...
Upregulation of Nitric Oxide Production in Vascular Endothelial Cells by All-trans Retinoic Acid Through the Phosphoinositide 3-Kinase/Akt Pathway
Authors: AkiraUruno, AkiraSugawara, HiroshiKanatsuka, HiroyukiKagechika, AkikoSaito, KazunoriSato, MasatakaKudo, KazuhisaTakeuchi, SadayoshiIto
Journal: Circulation (2005)

Background— A natural retinoid all-trans retinoic acid (ATRA) contains various beneficial effects on vasculature, including suppression of neointima formation after balloon injury. However, little is known about the effects of ATRA on vascular endothelial function. We therefore studied its role in nitric oxide (NO) production of vascular endothelial cells (ECs). Methods and Results— Human dermal microvascular ECs, human umbilical vein ECs, and SV40-transformed rat lung vascular ECs were incubated with or without ATRA (1 μmol/L) for 48 hours. Their NO production was determined with the use of a fluorescent NO indicator, diaminofluorescein-2 diacetate. ATRA significantly increased their basal as well as acetylcholine-induced NO production. Treatment with Nω-nitro-l-arginine methyl ester or carboxy-PTIO suppressed their fluorescence. Increase of NO production was also observed by incubation with retinoic acid receptor (RAR) agonist Am580. ATRA-induced NO increase was abolished by coincubation with RAR antago...
TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization
Authors: MontserratCliment, ManuelaQuintavalle, MicheleMiragoli, JuChen, GianluigiCondorelli, LeonardoElia
Journal: Circulation Research (2015)

Rationale:The miR-143/145 cluster is highly expressed in smooth muscle cells (SMCs), where it regulates phenotypic switch and vascular homeostasis. Whether it plays a role in neighboring endothelial cells (ECs) is still unknown. Objective:To determine whether SMCs control EC functions through passage of miR-143 and miR-145. Methods and Results:We used cocultures of SMCs and ECs under different conditions, as well as intact vessels to assess the transfer of miR-143 and miR-145 from one cell type to another. Imaging of cocultured cells transduced with fluorescent miRNAs suggested that miRNA transfer involves membrane protrusions known as tunneling nanotubes. Furthermore, we show that miRNA passage is modulated by the transforming growth factor (TGF) β pathway because both a specific transforming growth factor-β (TGFβ) inhibitor (SB431542) and an shRNA against TGFβRII suppressed the passage of miR-143/145 from SMCs to ECs. Moreover, miR-143 and miR-145 modulated angiogenesis by reducing the proliferation ind...
Abstract 12136: Decreased Mortality With Direct Oral Anticoagulants in Patients With Heart Failure and Atrial Fibrillation
Authors: Yu Sato, Akiomi Yoshihisa, Yusuke Kimishima, Takatoyo Kiko, Shunsuke Watanabe, Yuki Kanno, Satoshi Abe, Makiko Tatsumi, Takamasa Sato, Satoshi Suzuki, Masayoshi Oikawa, Atsushi Kobayashi, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Shu-ichi Saitoh, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2017)

Background: Atrial fibrillation (AF) is common in patients with heart failure (HF) and is associated with higher mortality. Although previous studies have reported that direct oral anticoagulants (...
Abstract 3349: TEAD4 expression in human hepatocellular carcinoma correlates with poor prognosis and promotes tumor growth and migration
Authors: Nadia Tosti, Manuela Lanzafame, Viola Paradiso, Charlotte K. Ng, Salvatore Piscuoglio, Cristina Quintavalle, Luigi Maria Terracciano
Journal: Cancer Research (2018)

Abstract Background: TEAD family is a group of four transcription factor members, including TEAD1, TEAD2, TEAD3 and TEAD4. These genes are known to be involved in the regulation of different genes associated with cell proliferation, differentiation and apoptosis. TEAD proteins represent the major downstream effectors of the conserved Hippo signalling pathway, known to be deregulated in different cancer entities. In the present study, we sought to explore the expression of TEAD4 in hepatocellular carcinoma (HCC) and its effect in in vitro models. Methods: We evaluated TEAD4 expression at mRNA level using data from The Cancer Genome Atlas (liver dataset) and at protein level using a tissue microarray containing 192 HCCs, 108 cirrhotic tissues and 79 normal liver samples. For in vitro experiments, two liver cancer cell lines were stably overexpressed and downregulated for TEAD4 to characterize its role in in vitro models, in terms of proliferation, migration and anchorage-independent growth. Results: TEAD4 was found overexpressed in a subset of HCCs in the TCGA dataset and its overexpression correlated with worst overall survival (p=0.03). The tissue microarray analysis showed a similar trend not only in the HCCs but also in cirrhotic tissues. The in vitro assays demonstrated that the overexpression of TEAD4 promoted tumour growth and migration as well as increased foci formation capacity. On the other hand, TEAD4 knockdown was able to revert the phenotype, suggesting a putative oncogenic role of TEAD4 in hepatocarcinogenesis. Conclusions: Finally, TEAD4 is frequently overexpressed in HCCs and in cirrhotic tissues and its expression is associated with poor prognosis. Furthermore, in vitro evidence suggests that TEAD4 may act as oncogene and may have a pivotal role in hepatocarcinogenesis. Citation Format: Nadia Tosti, Manuela Lanzafame, Viola Paradiso, Charlotte K. Ng, Salvatore Piscuoglio, Cristina Quintavalle, Luigi Maria Terracciano. TEAD4 expression in human hepatocellular carcinoma correlates with poor prognosis and promotes tumor growth and migration [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 3349.
Abstract 15563: Prognostic Impact of Postprocedual TIMI Flow Grade in STEMI Patients With Cardiogenic Shock Undergoing Primary Percutaneous Coronary Intervention - Analysis From JCS Shock Registry
Authors: Tetsuya Matoba, Kazuo Sakamoto, Masahiro Mohri, Nobuhiro Tanaka, Yohei Hokama, Motoki Fukutomi, Katsutaka Hashiba, Rei Fukuhara, Yasushi Ueki, Satoru Suwa, Hirohide Matsuura, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao
Journal: Circulation (2015)

Background: ST-segment elevation myocardial infarction (STEMI) complicated with cardiogenic shock, Killip class 4, is a severe condition with high mortality, for which primary percutaneous coronary intervention (PPCI) is recommended. Cardiogenic shock is a predictor for slow flow/no reflow (TIMI ≤2) during PPCI. Methods and Results: The Japanese Circulation Society Cardiovascular Shock registry (JCS Shock registry) was a prospective, observational, multi-center, cohort study. Between May, 2012 and June, 2014, a total of 980 patients with cardiovascular shock were enrolled from 82 centers in Japan. We assessed the prognostic impact of postprocedual TIMI flow grade in 341 patients who underwent primary PCI (PPCI) among 408 STEMI patients. Ninety percent of PPCI were performed within 120 min of arrival, in which thrombus aspiration (TA), stenting, and distal protection (DP) were applied in 228 (67%), 303 (89%), and 29 (9%) patients, respectively. Postprocedual TIMI grade 3 flow was achieved in 283 (83%) patients, whereas TIMI ≤2 in 58 (17%) patients. Thirty-day mortality in subgroups with TIMI 3, TIMI ≤2, and No PPCI (n=66) was 24.0%, 48.3% and 48.5%, respectively (P&lt;0.01 by Chi-square, Fig. A), which suggest the importance of TIMI 3 achievement in PPCI. We compared the rate of postprocedual TIMI 3 in different PCI strategies; (1) TA and stenting without DP (TIMI 3 achievement 84%, n=179), (2) stenting without TA or DP (83%, n=96), (3) TA and stenting with DP (93%, n=27), (4) TA alone (71%, n=21), and (5) None of 3 devices (67%, n=16), suggesting the therapeutic effects of the devices (Fig. B). Conclusions: In the JCS Shock registry that observed contemporary emergency cardiovascular care in Japan, 30-day mortality of STEMI complicated with cardiogenic shock was 24% in patients underwent PPCI and resulted in TIMI grade 3 flow in the culprit arteries. The use of TA, stent, and DP in PPCI are associated with the better chances of postprocedual TIMI grade 3 flow.