tbuckley/cabot-search huggingface dataset:
Abstract 383: Metabolomic analysis of uterine serous carcinoma with acquired resistance to paclitaxel
Authors: Manabu Seino, Tsuyoshi Ohta, Hirotsugu Sakaki, Takeshi Sudo, Satoru Nagase
Journal: Cancer Research (2018)

Abstract Introduction: Uterine serous carcinoma (USC) is more aggressive than other subtypes of endometrial carcinoma and is associated with a poor prognosis. We analyzed the metabolomic profile of USC with acquired resistance to paclitaxel. Method: We compared metabolic profiles and reactions to paclitaxel in both a wild-type USC cell line (USPC-1) and PTX-1, a cell line derived from USPC-1 that acquired paclitaxel resistance, using a capillary electrophoresis CE-MS/MS system. Results: Glutathione (GSH) concentration in PTX-1 cells was higher than in USPC-1 cells. In addition, GSH concentration in the USPC-1 cells increased after treatment with paclitaxel but was unchanged in PTX-1 cells. Glucose-6-phosphate (G6P) and ribose-5-phosphate (R5P) concentrations in PTX-1 cells were higher than those in USPC-1 cells. G6P concentration in the USPC-1 cells was unchanged after treatment with paclitaxel, while it decreased in PTX-1 cells. Conclusion: Our results indicate that increased GSH and glucose metabolism may be related to acquiring resistance to paclitaxel in USC and thus may be targets for anti-USC therapy. Citation Format: Manabu Seino, Tsuyoshi Ohta, Hirotsugu Sakaki, Takeshi Sudo, Satoru Nagase. Metabolomic analysis of uterine serous carcinoma with acquired resistance to paclitaxel [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 383.
Exercise-Induced Pulmonary Edema in Heart Failure
Authors: PiergiuseppeAgostoni, GaiaCattadori, MicheleBianchi, KarlmanWasserman
Journal: Circulation (2003)

Background— In heart failure (HF) patients, exercise may increase pulmonary capillary hydrostatic pressure and thereby generate pulmonary edema. If pulmonary edema developed, alveolar-capillary membrane conductance (Dm), measured immediately after exercise, would decrease. To test this hypothesis, we measured Dm before and at 2 and 60 minutes after exercise. Methods and Results— We studied 10 HF patients with exercise-induced periodic breathing, 10 with peak Vo2 ≤15 mL · min−1 · kg−1 (severe HF), 10 with Vo2=15 to 20 mL · min−1 · kg−1 (moderate HF), and 10 normal subjects (control). Using the Roughton-Forster technique, we measured carbon monoxide diffusion capacity (DLco) and its components, capillary blood volume (Vc) and Dm, at rest and 2 and 60 minutes after exercise. At rest, DLco and Dm were lowest in periodic breathing and highest in control subjects. Dm decreased in periodic breathing, severe HF, and moderate HF (−7.83±3.98, −5.57±2.03, and −3.85±3.53 mL · min−1 · mm Hg−1, respectively; P<0.01) ...
Abstract 16525: Macrophage Insulin-Like Growth Factor I (IGF1) Reduces Matrix Metalloproteinases (MMPs), Upregulates Atherosclerotic Plaque Collagen and Suppresses Atherosclerosis
Authors: Patricia Snarski, Svitlana Danchuk, Sergiy Sukhanov, Shaw Yung Shai, Yusuke Higashi, Bysani Chandrasekar, Patrice Delafontaine
Journal: Circulation (2017)

We have shown that IGF1 decreased atherosclerotic burden in high fat diet fed Apoe-null mice and we also demonstrated that decline in macrophage (MF) IGF1 signaling promoted murine atherogenesis. T...
Anatomic Variations of the Auditory Canal Pertaining to the Fit of Stethoscope Earpieces
Authors: Dalegroom, Waddychapman
Journal: Circulation (1959)

Leaks in the enclosed acoustical system of the stethoscope reduce its efficiency and can greatly impair the physician's ability to detect the faint murmurs of early valvular heart disease. The results of this study demonstrate a high degree of variability in size and configuration of the external auditory meatus among different individuals. It appears probable that both excessive leaks and also partial or complete occlusion of the acoustical pathways commonly result with the use of standard stethoscope earpieces.
Mitochondrial Ca2+-Activated K+ Channels in Cardiac Myocytes
Authors: ToshiakiSato, TomoakiSaito, NorikoSaegusa, HaruakiNakaya
Journal: Circulation (2005)

Background— The large-conductance Ca2+-activated K+ (BKCa) channel in the cardiac inner mitochondrial membrane (mitoKCa channel) has been shown to protect the heart against ischemic injury. However, questions about the cardioprotective mechanism and the kinase-mediated regulation of mitoKCa channels remain to be answered. Methods and Results— Flavoprotein fluorescence in guinea pig ventricular myocytes was measured to assay mitoKCa channel activity. The mitochondrial Ca2+ concentration ([Ca2+]m) and membrane potential (ΔΨm) were measured by loading cells with rhod-2 and JC-1, respectively. Cell death was assessed by trypan blue permeability. The BKCa channel opener NS1619 reversibly increased the flavoprotein oxidation in a concentration-dependent manner. NS1619 (30 μmol/L) attenuated the ouabain (1 mmol/L)-induced elevation of [Ca2+]m with accompanying depolarization of ΔΨm. These effects of NS1619 were completely antagonized by the BKCa channel blocker paxilline (2 μmol/L) but not by the mitochondrial A...
Fascial tissue research in sports medicine: from molecules to tissue adaptation, injury and diagnostics: consensus statement
Authors: Martina Zügel, Constantinos N Maganaris, Jan Wilke, Karin Jurkat-Rott, Werner Klingler, Scott C Wearing, Thomas Findley, Mary F Barbe, Jürgen Michael Steinacker, Andry Vleeming, Wilhelm Bloch, Robert Schleip, Paul William Hodges
Journal: British Journal of Sports Medicine (2018)

The fascial system builds a three-dimensional continuum of soft, collagen-containing, loose and dense fibrous connective tissue that permeates the body and enables all body systems to operate in an integrated manner. Injuries to the fascial system cause a significant loss of performance in recreational exercise as well as high-performance sports, and could have a potential role in the development and perpetuation of musculoskeletal disorders, including lower back pain. Fascial tissues deserve more detailed attention in the field of sports medicine. A better understanding of their adaptation dynamics to mechanical loading as well as to biochemical conditions promises valuable improvements in terms of injury prevention, athletic performance and sports-related rehabilitation. This consensus statement reflects the state of knowledge regarding the role of fascial tissues in the discipline of sports medicine. It aims to (1) provide an overview of the contemporary state of knowledge regarding the fascial system from the microlevel (molecular and cellular responses) to the macrolevel (mechanical properties), (2) summarise the responses of the fascial system to altered loading (physical exercise), to injury and other physiological challenges including ageing, (3) outline the methods available to study the fascial system, and (4) highlight the contemporary view of interventions that target fascial tissue in sport and exercise medicine. Advancing this field will require a coordinated effort of researchers and clinicians combining mechanobiology, exercise physiology and improved assessment technologies.
Abstract 4852: Induction of HRD by targeting G9a and MTDH in DNA repair proficient endometrial cancer cells
Authors: Xiangbing Meng, Shujie Yang, Jianling Bi, Yiyang Li, Yuping Zhang, Sudartip Areecheewaku, Mary Li, Zihan Wang, Aliasger K. Salem, Kimberly K. Leslie
Journal: Cancer Research (2018)

Abstract The homologous recombination repair (HRR) pathway is required for high-fidelity repair of double-strand DNA breaks. Cancer cells with HRR deficiency due to somatic BRCA1 or BRCA2 mutations are sensitive to platinum agents and targeted therapy with PARP inhibitors. Endometrial cancer is the most common cancer of the female reproductive system. DNA damage agents are commonly used in treatment but tumors often develop resistance. Metadherin (MTDH) has been shown to be amplified in a wide range of solid tumors as well as in leukemia and lymphoma. Overexpression of MTDH is correlated with angiogenesis, metastasis, and chemoresistance. Histone lysine N-methyl-transferase G9a catalyzes the demethylation of histone H3 at lysine residue 9 (H3K9) resulting in a repressive histone modification. The objective of this study is to validate the function of MTDH and G9a in HRR and test the potential to target MTDH or G9a to increase drug sensitivity. p21 expression was induced when G9a was depleted. DNA damage induced MTDH expression at 4 hours after 8Gy γ-irradiation in the well validated endometrial adenocarcinoma cell line Ishikawa H. However, induction of MTDH protein expression by the same radiation dosage was reduced when G9a was depleted. The G9a inhibitor UNC0642 itself can also induce the expression of MTDH after 24 hours treatment. Ishikawa parental cells and two Ishikawa sub-cell lines in which G9a was depleted by CRISPR were tested for the DNA damage biomarker γH2Ax and Rad51 foci formation at 4 hours following 8Gy irradiation. G9a depletion was shown to decrease Rad51 foci formation and to increase the formation of γH2Ax foci. Two natural products, Celastrol and Pristimerim were found to inhibit MTDH, FANCD2 and FANCI protein levels, which may be used to induce BRCA-ness in homologous recombination repair proficient cancer cells. G9a depletion results in the reduction of irradiation-induced Rad51 foci formation and an increase of irradiation-induced γH2Ax foci formation. We suggest that G9a depletion can increase cancer cell sensitivity to DNA damage agents. MTDH is induced by DNA damage and is a G9a inhibitor. MTDH depletion causes reduction of irradiation-induced Rad51 foci. This study is supported by the University of Iowa Department of Obstetrics and Gynecology Research Development Fund, NIH grant R01CA99908 and R01CA184101. Citation Format: Xiangbing Meng, Shujie Yang, Jianling Bi, Yiyang Li, Yuping Zhang, Sudartip Areecheewaku, Mary Li, Zihan Wang, Aliasger K. Salem, Kimberly K. Leslie. Induction of HRD by targeting G9a and MTDH in DNA repair proficient endometrial cancer cells [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 4852.
Abstract 5526: Mapping signaling networks in <i>Nf1</i> mutant tumors
Authors: Daniela Pucciarelli, Ganesh Krishnamurthi, Steve Braunstein, Jean L. Nakamura
Journal: Cancer Research (2018)

Abstract Introduction: The tumor suppressor gene Neurofibromatosis type 1 (NF1) encodes the Ras-GTPase activating protein neurofibromin, which negatively regulates Ras signaling. Loss of NF1 increases signaling through Raf/MEK/ERK and PI3K/AKT/mTOR. Inhibition of each of these pathways can produce variable responses, suggesting compensatory mechanisms and heterogeneity in signaling mechanisms in cancers. To study the biochemical sources of signaling we sought to functionally characterize Nf1-mutant tumors based on their variable drug sensitivities and development of drug resistance. Methods: We previously established Nf1 null tumor cell lines from malignancies arising in irradiated Nf1+/- mice. We functionally profiled this panel of tumor cell lines using a custom 94 compound drug library targeting core signaling pathways commonly activated in cancers. Phosphorylated and total ERK, AKT, and S6 were assessed by western blotting. Cell lines resistant to treatment with MAPK and mTOR inhibitors were generated from parental cell lines. Parental and resistant cell lines were compared using MTS, exome and transcriptome sequencing, western blotting and kinome analysis. Results: Nf1 mutant tumor cell lines demonstrated heterogeneous drug responses and, based on this observation, they could be organized into 3 functional sub-classes sharing similar drug sensitivities. All 12 Nf1 null cell lines demonstrated heterogeneous basal Ras pathway activation, as indicated by phosphorylated ERK, AKT, and S6. This variability was associated with variable sensitivity to treatment with MAPK and mTOR inhibitors. Acquired resistance to MAPK or mTOR inhibition (MEKi and mTORi) revealed differences in Ras activation that distinguished resistant from parental lines. For example, in contrast to parental lines, Ras-GTP levels in mTORi resistant cell lines demonstrated stability after serum stimulation compared to the parental counterpart, suggesting a reprogrammed role for Ras activation when mTORi resistance is acquired. These data highlight the plasticity of Ras-driven signaling in Nf1 tumors, which likely must be addressed to optimize therapy and counter the emergence of resistant clones. Conclusion: Our analysis indicates significant variability in Ras pathway signaling in the context of Nf1 loss, which has implications for the choice of specific kinase inhibitors to use therapeutically. Cancers, including Nf1 null tumors, develop resistance to therapy and our data points to specific reprogramming of signaling pathways that distinguish resistance mechanisms. Citation Format: Daniela Pucciarelli, Ganesh Krishnamurthi, Steve Braunstein, Jean L. Nakamura. Mapping signaling networks in Nf1 mutant tumors [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 5526.
A Quantitative Comparison of Unipolar and Augmented Unipolar Limb Leads
Authors: Ernstsimonson, Ancelkeys
Journal: Circulation (1950)

Goldberger has claimed that his augmented unipolar limb leads (aV) are identical—except for a 50 per cent larger amplitude—and interchangeable with Wilson's original V leads, but this claim was not supported by quantitative evidence. The advantage of larger amplitudes explains the increasing preference for the aV leads. A quantitative comparison between V and aV leads revealed such tremendous variability of the augmentation ratio, both interindividual and between leads in the same individual, that standards obtained with V leads are not applicable to aV leads and vice versa. V leads and aV leads are not interchangeable.
Age-Associated Defects in EphA2 Signaling Impair the Migration of Human Cardiac Progenitor Cells
Authors: PolinaGoichberg, RamaswamyKannappan, MariaCimini, YingnanBai, FumihiroSanada, AndreaSorrentino, SergioSignore, JanKajstura, MarcelloRota, PieroAnversa, AnnarosaLeri
Journal: Circulation (2013)

Background—Aging negatively impacts on the function of resident human cardiac progenitor cells (hCPCs). Effective regeneration of the injured heart requires mobilization of hCPCs to the sites of damage. In the young heart, signaling by the guidance receptor EphA2 in response to the ephrin A1 ligand promotes hCPC motility and improves cardiac recovery after infarction. Methods and Results—We report that old hCPCs are characterized by cell-autonomous inhibition of their migratory ability ex vivo and impaired translocation in vivo in the damaged heart. EphA2 expression was not decreased in old hCPCs; however, the elevated level of reactive oxygen species in aged cells induced post-translational modifications of the EphA2 protein. EphA2 oxidation interfered with ephrin A1-stimulated receptor auto-phosphorylation, activation of Src family kinases, and caveolin-1–mediated internalization of the receptor. Cellular aging altered the EphA2 endocytic route, affecting the maturation of EphA2-containing endosomes and...
Abstract 1845: <i>TP53</i> status determines the fate of cancer cells exposed to ionizing radiation and DNA-PK inhibitor, M3814
Authors: Qing Sun, Yige Guo, Xiaohong Liu, Frank Czauderna, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev
Journal: Cancer Research (2018)

Abstract Inhibition of DNA double strand break repair in cancer cells has been proposed as a new therapeutic approach for potentiation of radiotherapy. M3814 is a potent and selective inhibitor of DNA-PK, a key component of non-homologous end joining repair pathway and is currently under clinical investigation in radiation combination trials. We studied the mechanism of cancer cell response to combined treatment with ionizing radiation and M3814 using cancer cell lines with different p53 status. M3814 blocked the repair of radiation-induced DSBs and suppressed a negative regulatory loop between DNA-PK and ATM causing enhanced phosphorylation and activation of ATM. In the p53 wild-type cells, ATM and its targets, CHK2 and p53, were activated more strongly by the combination treatment than by radiation alone, leading to a complete p53/CHK2-dependent cell cycle block and premature cell senescence. The p53-null or mutant cancer cells were unable to fully arrest the cell cycle and a substantial fraction entered S phase with unrepaired DNA, leading to mutations, chromosomal aberrations, aneuploidy, micronucleation and ultimately cell death, primarily due to mitotic catastrophe. Two isogenic pairs of p53 null/wt cells (A549 and HT-1080) were generated and used to demonstrate the critical role of p53 in the choice of M3814-modified radiation response. Time-lapse imaging of cell death kinetics using a small panel of p53 wild-type and p53 null/mutant cancer lines revealed clear differences in outcome dependent on p53 status. However, standard growth/viability assays failed to show a role of p53 in the response type, due to inability to discriminate between cell cycle arrest and cell killing. Similarly, screening results obtained from large cancer cell panels (&amp;gt;100 lines) did not identify p53 as a marker of response. Our data revealed an important role of p53 in determining the mode of cancer cells' response to radiation in the presence of M3814 and suggest that p53 mutation status should be considered in the design of clinical trials. The failure of standard growth/viability screens with large cancer cell line panels to identify p53 status as a response indicator raises an alert for the utility of these screening platforms currently widely used in cancer drug discovery and development. Citation Format: Qing Sun, Yige Guo, Xiaohong Liu, Frank Czauderna, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev. TP53 status determines the fate of cancer cells exposed to ionizing radiation and DNA-PK inhibitor, M3814 [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 1845.
Abstract 610: Dynamic immune landscape of the peripheral blood mononuclear cells from recurrent hepatocellular carcinoma patients undergoing radiofrequency ablation treatment
Authors: Dexi Chen, Yang Zhao, Yabo Ouyang, Kai Liu, Wei Rao, Feili Wei, Xiaoni Liu, Ying Shi, Shanshan Wang, Lijun Pang, Luxin Qiao, Yunjin Zang, Xiaoming Yin
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third most lethal malignancy worldwide. Radiofrequency ablation (RFA) is the most commonly used curative treatment for the patients not suitable for surgical resection or liver transplantation. It can cause regional and global anti-tumor immune response, but is insufficient to prevent HCC recurrence in many patients. Peripheral blood mononuclear cells (PBMC) are considered to be the best target for the study of the global immune status after RFA. Previous studies on PBMC were mainly based on traditional flow cytometry, which could not differentiate the complicated immune cell subtypes. In this study, we used mass cytometry to comprehensively characterize the phenotypic and functional alterations of the PBMC in recurrent HCC patients who had received RFA treatment. Fifty-four (54) blood samples from 13 patients were analyzed. Manual gating, SPADE analysis and viSNE analysis were used to interpret the mass cytometry data. The percentage of monocytes showed a fast increase after RFA, and reduced to the normal level before the HCC recurrence (P=0.026). A long-lasting reduction of B cells count were also found after the first RFA (P=0.021), and the B cell count remained at a low level before and after the secondary RFA. The percentage of CD4+ T cells in CD45+ cells was significantly reduced after the first RFA, then restored to the pretreatment level at the time of recurrence, and reduced again after the second RFA(P=0.024). CD8+ T cells showed the same alteration trend as CD4+ cells (P=0.03). We also examined the expression of functional markers in T cells and Tregs. Alterations of CD28 expression were most frequently found in T cells. The Treg population showed a large heterogeneity among the patients with TIM3, LAG3 or CTLA4 positive Tregs being the largest populations. These results suggest a more specific treating modality should be used in combination with the RFA treatment. Citation Format: Dexi Chen, Yang Zhao, Yabo Ouyang, Kai Liu, Wei Rao, Feili Wei, Xiaoni Liu, Ying Shi, Shanshan Wang, Lijun Pang, Luxin Qiao, Yunjin Zang, Xiaoming Yin. Dynamic immune landscape of the peripheral blood mononuclear cells from recurrent hepatocellular carcinoma patients undergoing radiofrequency ablation treatment [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 610.
Population Versus Clinical View of Case Fatality From Acute Coronary Heart Disease
Authors: LloydChambless, UlrichKeil, AnnetteDobson, MarkkuMähönen, KariKuulasmaa, Anna-MaijaRajakangas, HanneloreLöwel, HughTunstall-Pedoe
Journal: Circulation (1997)

Background The clinical view of case fatality (CF) from acute myocardial infarction (AMI) in those reaching the hospital alive is different from the population view. Registration of both hospitalized AMI cases and out-of-hospital coronary heart disease (CHD) deaths in the WHO MONICA Project allows both views to be reconciled. The WHO MONICA Project provides the largest data set worldwide to explore the relationship between CHD CF and age, sex, coronary event rate, and first versus recurrent event. Methods and Results All 79 669 events of definite AMI or possible coronary death, occurring from 1985 to 90 among 5 725 762 people, 35 to 64 years of age, in 29 MONICA populations are the basis for CF calculations. Age-adjusted CF (percentage of CHD events that were fatal) was calculated across populations, stratified for different time periods, and related to age, sex, and CHD event rate. Median 28-day population CF was 49% (range, 35% to 60%) in men and 51% (range, 34% to 70%) in women and was particularly hig...