tbuckley/cabot-search huggingface dataset:
Abstract 666: Gut microbiota SCFA modulates DCs antigen presentation and impacts tumor response to radiotherapy
Authors: Andrea Facciabene, Stavros Rafail, Luis Gil de Gomez, Stefano Pierini, Mireia Uribe-Herranz, Kyle Bittinger
Journal: Cancer Research (2018)

Abstract Alterations in gut microbiota modulate host physiologic functions, including immune responses, and they play a role in the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. Herein, we tested whether the gut microbiota modulates antitumor immune response following RT. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on tumor-associated antigen cross-presentation enanchement, cytolytic CD8+ T cells and on IFN-g. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, gram-positive bacteria depletion by vancomycin enhances the antitumor activity of RT, which has important clinical ramifications. Citation Format: Andrea Facciabene, Stavros Rafail, Luis Gil de Gomez, Stefano Pierini, Mireia Uribe-Herranz, Kyle Bittinger. Gut microbiota SCFA modulates DCs antigen presentation and impacts tumor response to radiotherapy [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 666.
Abstract 11973: Clinical Outcome and Predictors of Short-term Mortality in Cardiogenic Shock Treated With Venous-arterial Extracorporeal Membrane Oxygenation: Results From the Japanese Circulation Society Cardiovascular Shock Registry
Authors: Yasushi Ueki, Hiroshi Imamura, Takahiro Miyamoto, Tsukasa Yagi, Kazuo Sakamoto, Hiroshi Takahashi, Hiroyuki Hanada, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao
Journal: Circulation (2015)

Introduction: Venous-arterial extracorporeal membrane oxygenation (ECMO) should be considered as a means of rescuing patients with refractory cardiogenic shock and cardiac arrest. Few data are available regarding predicting the outcome of patients with cardiogenic shock treated with ECMO. The aim of this study was to investigate the outcomes of patients with cardiogenic shock assisted by ECMO and to identify the predictors of 30-day mortality. Methods: The Japanese Circulation Society Cardiovascular Shock registry is 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. Finally, 162 patients (mean age 60.2±14.7 years, 81.5% male) required ECMO and completing 30-day follow-up were analyzed. The primary endpoint was all-cause death at 30 days. Results: Of 162 patients, 80 (49.7%) were shock after return of spontaneous circulation (ROSC) and 102 (63%) had acute coronary syndrome (ACS). The 30-day mortality overall, the non-shock after ROSC group, and the ACS group were 69.1%, 59.3%, and 68.6%, respectively. The causes of death were heart failure in 30 patients (26.8%), multiple organ failure in 49 (43.8%), respiratory failure in 2 (1.8%), sepsis in 2 (1.8%), arrhythmia in 12 (10.7%), neurological death in 8 (7.1%), and others in 9 (7.6%). On multivariate analysis, neurological status on admission (odds ratio 2.188, 95% confidence interval 1.23-3.66, p=0.007) was an independent predictor of all cause death at 30-days. Conclusion: Patients with cardiovascular shock who required ECMO demonstrated high mortality. Neurological status was an independent predictor of 30-day mortality.
Abstract 15786: Ddit4L: A Novel Differential Regulator of mTor and Autophagy in Cardiomyocytes
Authors: BridgetSimonson, VinitaSubramanya, Chun-YangXiao, ManojMishra, TejvirKhurana, JonSeidman, ChristineSeidman, AnthonyRosenzweig, SaumyaDas
Journal: Circulation (2014)

DNA-Damage-Inducible Transcript 4-Like (DDiT4L) protein regulates mTOR signaling in skeletal muscle, however its role in the heart is unknown. Here we investigated the role of DDiT4L in regulating mTOR signaling in cardiomyocytes. We show that DDiT4L differentially regulates mTORC1 and mTORC2 signaling in cardiomyocytes and regulates autophagy in an mTOR dependent, TSC2 independent manner. We studied DDiT4L regulation in the heart using murine models of cardiomyopathy and isolated rat neonatal cardiomyocytes (NRVMs). The functional role of DDiT4L was assessed with loss and gain of function approaches in NRVMs, and an HA-DDiT4L cardiac specific conditional transgenic mouse using Western blotting, PCR, ECHO and confocal imaging. DDiT4L expression increased in mouse models of pathological (pressure overload hypertrophy and dilated cardiomyopathy (myosin heavy chain F764L knock in) n=3-5, p<0.001) but not physiological hypertrophy (swim model) compared to WT. In NRVMs, DDiT4L mRNA increased with the pathologi...
Heightened Tissue Factor Associated With Tissue Factor Pathway Inhibitor and Prognosis in Patients With Unstable Angina
Authors: HirofumiSoejima, HisaoOgawa, HirofumiYasue, KoichiKaikita, KoichiNishiyama, KenjiMisumi, KeijiTakazoe, YujiMiyao, MichihiroYoshimura, KiyotakaKugiyama, ShinNakamura, IchiroTsuji, KousukeKumeda
Journal: Circulation (1999)

Background—This study was designed to evaluate the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with unstable angina and investigate whether there is a relationship between these levels and unfavorable outcome. Methods and Results—The plasma TF and free TFPI antigen levels were determined in plasma samples taken from 51 patients with unstable angina, 56 with stable exertional angina, and 55 with chest pain syndrome. The plasma TF and free TFPI antigen levels were higher in the unstable angina group than in the stable exertional angina and chest pain syndrome group. There was a good correlation between TF and TFPI. We established borderline as maximum level in the patients with chest pain syndrome. Seven patients (of the 22 in the high TF group) required revascularization to control their unstable angina during in-hospital stay. On the other hand, only 1 of the 29 patients in the low TF group required myocardial revascularization. Four patients of the 14 patien...
Abstract 12766: Dissection of the Interventricular Septum: Echocardiographic Features
Authors: Xiaoyan Gu, Yihua He, Shurong Luan, Ying Zhao, J V (Ian) Nixon
Journal: Circulation (2015)

Objective: Dissection of the interventricular septum (IVS) is an extremely rare entity. An institutional data base review identified 13 pts with the diagnosis, confirmed by cardiac surgery. The purpose of the study was to determine the value of transthoracic echocardiography (TTE) in establishing the diagnosis and to summarize the TTE features of IVS dissection. Methods: The 13 pts with IVS dissection, 8 males and 5 females (age range: 36-75 yrs) were taken from 789,114 TTEs performed between 1985 and 2014. The etiology, anatomical location, echocardiographic morphology, and color Doppler findings of the IVS dissection were noted. Results: The incidence of IVS dissection in our center was 0.000016 %. Among 13 patients with IVS dissection, the right sinus of Valsalva (RSOV) was involved in 11 pts. In 5 pts, a single aneurysm of the RSOV dissected into the IVS. In 4 pts, aortic valve (AoV) endocarditis was associated with the IVS dissection, including one pt with a bicuspid AoV infection, 2 pts with absess formation adjacent to an AoV replacement, one pt. with a combination of a bicuspid AoV and RSOV dissecting into the IVS, and one pt with an AoV prosthetic paravalvular leak following absess formation dissecting into the IVS. In one patient, a bicuspid AoV valve combined with RSOV dissected into the IVS. Also, in one pt, mechanical AoV prosthetic replacement was complicated by annular detachment and a severe paravalvular leak. In all 11 pts with RSOV involvement, TTE showed a dissecting cystic-like mass in the IVS from the base to mid-septum or confined to the septal base. The path of the dissection in all these pts was traced to the RSOV. Also, communications between the dissection and the aortic root were seen in these 11 patients. In the other 2 pts, IVS dissection followed septal rupture due to a myocardial infarction. In these pts, communication between the dissection and the right ventricle was seen. Conclusions: The study showed that dissections of the IVS usually commenced in the RSOV, due to either congenital anomalies or infective endocarditis, or following AoV replacement. The other cause of IVS dissection is a myocardial infarction. The TTE characteristic of IVS dissection is a cystic-like mass in the IVS.
Abstract 1940: Thymine DNA glycosylase (TDG) as a novel target for melanoma
Authors: Rossella Tricarico, Pietro Mancuso, Vikram Bhattacharjee, Laura Cosentino, Emmanuelle Nicolas, Margret Einarson, Neil Beeharry, Karthik Devarajan, Rich Katz, Dorjbal G. Dorjsuren, Anton Simeonov, Yuwaraj Kadariya, Guillaume Davidson, Joseph R. Testa, Irwin Davidson, Lionel Larue, Robert W. Sobol, Timothy Yen, Alfonso Bellacosa
Journal: Cancer Research (2018)

Abstract Melanoma is an aggressive neoplasm with increasing incidence that bears the infamous distinction of being a recalcitrant cancer, i.e. a cancer with poor prognosis, lacking progress in diagnosis and treatment. In addition to conventional therapy, melanoma treatment is currently based on targeting the BRAF/MEK/ERK signal transduction pathway and immune checkpoints; however, advanced therapeutic approaches based on novel targets are urgently needed. We reasoned that the base excision repair enzyme Thymine DNA Glycosylase (TDG) could be such a target for its dual role in safeguarding genome stability and in effecting active DNA demethylation downstream the Ten-Eleven Translocation (TET) dioxygenases. TDG knockdown in melanoma cell lines causes cell cycle arrest, senescence and death by mitotic alterations, and impairs xenograft formation. Importantly, untransformed melanocytes are not affected by TDG knockdown, and adult mice with conditional knockout of TDG are viable. Candidate TDG inhibitors, identified through a high-throughput screen, reduced viability and clonogenic capacity of melanoma cell lines. Candidate TDG inhibitors increased cellular levels of 5-carboxylcytosine, the last intermediate in DNA demethylation, which is specifically removed by TDG, indicating successful targeting. These findings suggest that TDG may provide critical functions in cancer cells, but not in normal cells, that make it a highly suitable anti-melanoma drug target. By potentially disrupting both DNA repair and the epigenetic state, targeting TDG may represent a completely new approach to melanoma therapy. Citation Format: Rossella Tricarico, Pietro Mancuso, Vikram Bhattacharjee, Laura Cosentino, Emmanuelle Nicolas, Margret Einarson, Neil Beeharry, Karthik Devarajan, Rich Katz, Dorjbal G. Dorjsuren, Anton Simeonov, Yuwaraj Kadariya, Guillaume Davidson, Joseph R. Testa, Irwin Davidson, Lionel Larue, Robert W. Sobol, Timothy Yen, Alfonso Bellacosa. Thymine DNA glycosylase (TDG) as a novel target for melanoma [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 1940.
Abstract 479: <i>miR-372</i> enhances tumorigenesis and drug resistance in oral carcinoma by targeting ZBTB7A transcription factor
Authors: Li-Yin Yeh, Chung-Hsien Chou, Chung-Ji Liu, Shu-Chun Lin, Kuo-Wei Chang
Journal: Cancer Research (2018)

Abstract miRNA-mediated post-transcriptional regulation of targeted genes plays crucial roles in neoplastic process. miR-372 has been shown an oncogenic miRNA which is hypoxia-inducible and is conspicuously up-regulated in oral squamous cell carcinoma (OSCC). Zinc finger and BTB domain containing 7A (ZBTB7A) is a transcriptional repressor modulating a great diversities of physiological or oncogenic regulation. This study identified that ZBTB7A was a direct target of miR-372. ZBTB7A was down-regulated in 75% of OSCC tumors relative to adjacent oral mucosa. Reverse correlation across miR-372 expression and ZBTB7A expression was found in tumor samples. In OSCC cells with the stable knockdown of ZBTB7A, the oncogenic potential and drug resistance increased. Whereas, such increase was attenuated by ZBTB7A expression. High throughput screening and validation assay confirmed that ZBTB7A was able to repress multiple oncogenic factors and activate the expression of Trail-R1, Trail-R2 and Fas to increase the drug sensitivity in OSCC cells. miR-372 induction drastically repressed the expression of apoptosis genes by inhibiting ZBTB7A. This was accompany with the enrichment of oncogenicity and the increased tolerance to the toxicity of cisplatin and taxol. This study signifies the importance of miR-372-ZBTB7A-downstream effectors in mediating pathogenesis and drug resistance of OSCC. Interception of this pathogenic cascade would confer therapeutic benefits against oral carcinoma. Citation Format: Li-Yin Yeh, Chung-Hsien Chou, Chung-Ji Liu, Shu-Chun Lin, Kuo-Wei Chang. miR-372 enhances tumorigenesis and drug resistance in oral carcinoma by targeting ZBTB7A transcription factor [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 479.
Pulmonary Veno-Occlusive Disease
Authors: Donaldheath, Nathansegel, Johnbishop
Journal: Circulation (1966)

A woman, 45 years old at the time of her death, showed the clinical features of primary  hypertension and the results of cardiac catheterization and  function tests were consistent with this diagnosis. Histological examination of the lung showed that the  veins were severely involved by cellular fibrous tissue. These distinctive lesions appear to constitute a separate  entity for which the name pulmonary veno-occlusive disease is suggested.
Margaret McCartney: Reading makes us better doctors
Authors: Margaret McCartney
Journal: BMJ (2018)

You can do it alone, on an aeroplane, in the bathroom, or at the end of a shift. You can do it in the garden or in an office. You can squeeze it into bursts of a few minutes or spread it over a long, indulgent day of indolent lounging.

I dislike the call to arms of “all doctors should . . .” but really, all doctors should read. What other occupation is so enlightening, empowering, thought provoking, and yes, infuriating?

The book in the hand is a gift. We have the opportunity for new knowledge. We’re challenged and informed by new perspectives. Our imaginations are coached …
Effects of Adrenomedullin Inhalation on Hemodynamics and Exercise Capacity in Patients With Idiopathic Pulmonary Arterial Hypertension
Authors: NoritoshiNagaya, ShingoKyotani, MasaakiUematsu, KazuyukiUeno, HideoOya, NorifumiNakanishi, MikiyasuShirai, HidezoMori, KunioMiyatake, KenjiKangawa
Journal: Circulation (2004)

Background— Adrenomedullin (AM) is a potent pulmonary vasodilator peptide. However, whether intratracheal delivery of aerosolized AM has beneficial effects in patients with idiopathic pulmonary arterial hypertension remains unknown. Accordingly, we investigated the effects of AM inhalation on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Methods and Results— Acute hemodynamic responses to inhalation of aerosolized AM (10 μg/kg body wt) were examined in 11 patients with idiopathic pulmonary arterial hypertension during cardiac catheterization. Cardiopulmonary exercise testing was performed immediately after inhalation of aerosolized AM or placebo. The work rate was increased by 15 W/min until the symptom-limited maximum, with breath-by-breath gas analysis. Inhalation of AM produced a 13% decrease in mean pulmonary arterial pressure (54±3 to 47±3 mm Hg, P<0.05) and a 22% decrease in pulmonary vascular resistance (12.6±1.5 to 9.8±1.3 Wood units, P<0...
Evaluation of Prenatal Exposure to Bisphenol Analogues on Development and Long-Term Health of the Mammary Gland in Female Mice
Authors: Deirdre K. Tucker, Schantel Hayes Bouknight, Sukhdev S. Brar, Grace E. Kissling, Suzanne E. Fenton
Journal: Environmental Health Perspectives (2018)

BACKGROUND: Continued efforts to phase out bisphenol A (BPA) from consumer products have been met with the challenges of finding safer alternatives.OBJECTIVES: This study aimed to determine whether early-life exposure to BPA and its related analogues, bisphenol AF (BPAF) and bisphenol S (BPS), could affect female pubertal mammary gland development and long-term mammary health in mice.METHODS: Timed pregnant CD-1 mice were exposed to vehicle, BPA (0.5, 5, 50 mg=kg), BPAF (0.05, 0.5, 5 mg=kg), or BPS (0.05, 0.5, 5 mg=kg) via oral gavage between gestation days 10-17.Mammary glands were collected from resulting female offspring at postnatal day (PND) 20, 28, 35, and 56, and at 3, 8, and 14 months for whole mount, histopathological evaluation, and quantitative real-time polymerase chain reaction (qPCR); serum steroid concentrations were also measured at these time points.RESULTS: In the bisphenol-exposed mice, accelerated mammary gland development was evident during early puberty and persisted into adulthood.By late adulthood, mammary glands from bisphenol-exposed female offspring exhibited adverse morphology in comparison with controls; most prominent were undifferentiated duct ends, significantly more lobuloalveolar hyperplasia and perivascular inflammation, and various tumors, including adenocarcinomas.Effects were especially prominent in the BPAF 5 mg=kg and BPS 0:5 mg=kg groups.Serum steroid concentrations and mammary mRNA levels of Esr1, Pgr, Ar, and Gper1 were similar to controls.CONCLUSIONS: These data demonstrate that prenatal exposure of mice to BPAF or BPS induced precocious development of the mammary gland, and that siblings were significantly more susceptible to spontaneous preneoplastic epithelial lesions and inflammation, with an incidence greater than that observed in vehicle-and BPA-exposed animals.
Abstract 2836: Spatially resolved single-cell analysis of cellular plasticity and mechanisms of drug resistance
Authors: Sethuramasundaram Pitchiaya, Jeremy D'silva, Nicole Lee, Sathiyapandi Narayanan, Xia Jiang, Saravana M. Dhanasekaran, Arul M. Chinnaiyan
Journal: Cancer Research (2018)

Abstract Cellular heterogeneity adversely affects clinical stratification, treatment decisions, and development of therapeutic resistance in cancer. Heterogeneity manifests as variability in gene expression and scales with the number of unique cell types and/or the extent of phenotypic plasticity. Therefore, an incisive tool that effectively quantifies heterogeneity, robustly identifies rare cell populations, efficiently predicts cell state transitions, and preserves the associated phenotypic manifestations will provide key insights into the mechanisms of plasticity and development of drug resistance. To this end, we developed High-Throughput Single-cell analysis using single-molecule Fluorescence In Situ Hybridization (HITS-FISH) - a completely automated imaging-based tool that provides absolute quantification of gene expression (mature and immature transcripts that are coding or non-coding), while still preserving spatial and morphological information. Using a combination of HITS-FISH and single cell RNAseq, which provides a high-throughput readout of gene expression signatures, we find that multiple, potentially plastic cell states (genetic, epigenetic, and cell cycle) coexist within a seemingly homogeneous population of cancer cells from various tissues. HITS-FISH suggests that one of the major contributors of such heterogeneity is pervasive aneuploidy, which is accentuated during treatment of cancer cells with chemotherapeutic agents and subsequent development of resistance against such drugs. Currently, we are further characterizing these plastic cells via lineage tracing and single-cell analysis to identify pre-resistant cell states and drug-induced gene-expression reprogramming. Citation Format: Sethuramasundaram Pitchiaya, Jeremy D'silva, Nicole Lee, Sathiyapandi Narayanan, Xia Jiang, Saravana M. Dhanasekaran, Arul M. Chinnaiyan. Spatially resolved single-cell analysis of cellular plasticity and mechanisms of drug resistance [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 2836.
Abstract 18383: Circulating Exosomal miR-1a is Markedly Induced by Myocardial Infarction and Downregulates CXCR4 Expression in the Bone Marrow Mononuclear Cells
Authors: MinCheng, XiaoqiZhao, BangweiWu, XiaoboMao, GuiwenYi, QiutangZeng, GangjianQin
Journal: Circulation (2014)

Rationale: The level of miR-1a in the blood of patients with myocardial infarction (MI) is markedly elevated; however, whether the circulating miR-1 impacts on remote organs has not been studied. Because it is known that MI leads to mobilization of various bone marrow (BM) cells, and that microRNAs are often carried in exosomes, we hypothesize that the MI-induced miR-1 is associated with exosomes and mediates a functional crosstalk between the ischemic heart and the BM. Methods and Results: We isolated plasma exosomes 12 h after induction of MI in mice and analyzed the exosomal miR-1a by qRT-PCR. The level of circulating exosomal miR-1a was 68 fold higher (p<0.01) in MI group than in Sham-operated group. Additionally, we found a greater amount of miR-1a in the BM mononuclear cells (MNCs) isolated from the MI mice. After MI surgery, the level of miR-1a in the BM MNCs peaked at day 2 (5.7 fold vs. baseline, p<0.05), declined at day 3 (1.7 fold, p0.05). To test whether exosomes mediate transfer of miR-1a int...