tbuckley/cabot-search huggingface dataset:
Abstract 2328: ADCs that induce necrosis and thwart apoptotic resistance
Authors: James R. Prudent, David Marshall
Journal: Cancer Research (2018)

Abstract Purpose: We have previously shown that targeting the Na,K-ATPase (NKA) with antibody drug conjugates is a powerful method for reducing tumors at levels found to be safe in cynomolgus monkeys. Currently no approved cancer drugs induce a potent necrotic type cell death even though experimental evidence shows that necrotic cell death has many notable and untapped benefits. Therefore, we wanted to better understand the driving mechanism by which ADCs targeting NKA inhibition induce necrosis. Experimental Design: Various cancer cell types were subjected to increasing and decreasing concentrations of Na+, K+ and Ca++, as well as various ADCs using bufalin as the warhead/payload/toxin. The cells were also subjected to siRNAs specific to the NKA and bufalin alone. The cells were then analyzed for the appearance and/or presence of necrosis, apoptosis, and markers indicating various stress pathways. Results: Conditions found to induce necrosis included: ADCs targeting specific NKA-protein complexes, cells subjected to media containing increased concentrations of K+, the specific Na,K-ATPase siRNAs, and bufalin alone. Conditions not found to induce necrosis included: media containing increased Na+, decreased Na+ or K+, control siRNAs, or ADCs that targeted proteins not complexed to the NKA or expressed on the cell surface. All cells undergoing necrosis lost their actin filaments, rounded up, and adherent cells detached from the surface and lost their motility. Markers indicated initial activation of the integrated stress responses (ISR). Minimal to no annexin staining indicated that apoptosis was not the dominate pathway in any experiment. Conclusion: Proper ion flux is important for maintaining cellular homeostasis. Cell swelling is a key process that is used to correct for changes in ion flux, induce inflammation and kill unwanted cells. The NKA is a key regulatory protein in this process and when blocked, leads to uncontrolled cells swelling and necrotic death. Precise inhibition of ion flux focused on cancer cells should be further investigated as a potential method for treating patients. Citation Format: James R. Prudent, David Marshall. ADCs that induce necrosis and thwart apoptotic 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 2328.
Abstract 4010: Identification of signaling pathways involved in colorectal adenoma-to-carcinoma progression using phosphoproteomics
Authors: Sanne Martens-de Kemp, Alex Henneman, Richard de Goeij-de Haas, Sander Piersma, Thang Pham, Gerrit Meijer, Beatriz Carvalho, Connie Jimenez
Journal: Cancer Research (2018)

Abstract Background Colorectal cancer (CRC) develops in a multi-step-process from normal epithelium, through a pre-malignant lesion (adenoma), into a malignant lesion (adenocarcinoma). A minority of about 5% of adenomas will ultimately progress into cancer. To improve clinical practice it is important to identify the subgroup of colorectal adenomas that is at risk of progressing to cancer. By extensive genomic analysis we have shown that specific copy number alterations are associated with risk of progression. An example of such an alteration is the gain of chromosome arm 20q and we identified AURKA and TPX2 as major drivers of this amplicon. Yet, the activation status of these and other genes during colorectal carcinogenesis and the downstream signaling pathways affected with gene (in)activation are not fully known. In order to better understand the biology of adenoma to carcinoma transition, we performed a comprehensive analysis of phosphoproteomes at different stages of colorectal carcinogenesis. Methods Phosphotyrosine containing peptides were immunoprecipitated from 5 mg of colorectal adenoma (n=81) and colorectal carcinoma tissues (n=50) using agarose bead-coupled phosphotyrosine antibody P-Tyr-1000. A Q Exactive HF mass spectrometer was used to perform NanoLC-MS/MS. Spectral counts of phosphoproteins and ion intensities of phosphopeptides were defined by MaxQuant for relative quantitation of protein phosphorylation. Results Phosphotyrosine-based phosphoproteomics of the 131 colorectal tissue samples yielded 6056 phosphopeptides, corresponding to 2745 unique phosphoproteins including 183 phosphokinases. Data analysis to identify regulated phosphorylation states and inference of kinase activity is ongoing. Conclusions and future plans This is the first large phosphoproteomics dataset of colorectal adenomas and carcinomas. Preliminary data analysis shows promising differences in kinase activities between adenomas and carcinomas. After further analysis, we will manipulate the activity of the driver kinases in adenoma-derived organoids and monitor tumor outgrowth in mice. Citation Format: Sanne Martens-de Kemp, Alex Henneman, Richard de Goeij-de Haas, Sander Piersma, Thang Pham, Gerrit Meijer, Beatriz Carvalho, Connie Jimenez. Identification of signaling pathways involved in colorectal adenoma-to-carcinoma progression using phosphoproteomics [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 4010.
Effects of Alfuzosin, an α1-Adrenergic Antagonist, on Anal Pressures and Bowel Habits in Women With and Without Defecatory Disorders
Authors: Subhankar Chakraborty, Kelly Feuerhak, Anjani Muthyala, William S. Harmsen, Kent R. Bailey, Adil E. Bharucha
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract 14921: Right Ventricular Extracellular Volume Fraction by Magnetic Resonance T1 Mapping in Pulmonary Hypertension and Heart Failure
Authors: Kenneth C Bilchick, Bhairav B Mehta, Virginia Workman, Daniel Auger, Xiao Chen, Jamie Kennedy, Elizabeth Gay, Frederick H Epstein
Journal: Circulation (2015)

Introduction: Current cardiac magnetic resonance (CMR) T1 mapping techniques such as Modified Look-Locker inversion recovery (MOLLI) imaging have limited resolution, but the Accelerated and Navigator-Gated Look-Locker Imaging for Cardiac T1 Estimation (ANGIE) is a novel CMR sequence with spatial resolution suitable for T1 mapping of the thin-walled RV. Hypothesis: In pulmonary hypertension (PH) and heart failure (HF), RV extracellular volume (ECV) fraction (as a surrogate measure for RV fibrosis) is a unique parameter describing RV structure that tends to increase with increasing RV size and declining RV function. Methods: Patients with either World Health Organization group 1 or group 4 pulmonary hypertension (PH) or heart failure with reduced ejection fraction (HFrEF) were recruited to undergo contrast-enhanced CMR. RV and LV ECV fractions were determined using pre-contrast and post-contrast T1 mapping using ANGIE (RV and LV) and MOLLI (LV). Results: 22 patients (41% female, median age 61 years old, IQR 51-70 years old) were enrolled, including n=12 with PH and n=10 with HFrEF. ANGIE ECV imaging was of high quality (Figure). A multivariable linear model with RVEF and RVEDVI as independent variables and RVECV as the outcome variable showed independent associations for RVEF and RVEDVI with RVECV (R 2 =0.553) (Table), consistent with a complex relationship involving RV function, dilation, and fibrosis. Conclusions: Pre- and post-contrast ANGIE imaging provides high-resolution ECV determination for the thin-walled RV. RV fibrosis increases with increasing RV size and decreasing overall RV function. Further studies of RVECV in PH and HFrEF are indicated.
Abstract 5767: Vascular endothelial growth factor receptor 2 targeted photoimmunotherapy
Authors: Makoto Mitsunaga, Takashi Nishimura, Kimihiro Ito
Journal: Cancer Research (2018)

Abstract Background Photoimmunotherapy (PIT) is a new class of molecular targeted cancer theranostics, which employs monoclonal antibody (mAb) conjugated to a photosensitizer, IR700, that is activated by focal near-infrared (NIR) light irradiation leading to necrotic cell death by cell membrane rapture where mAb-IR700 conjugates binds to target membrane proteins specifically. We have previously demonstrated HER2-targeted PIT employing trastuzumab-IR700 conjugates for HER2 expressing cancers. However, some cancer cells were survived partly because of tumor heterogeneity and inhomogeneous micro-distribution of mAb-IR700 conjugates. In this study, we developed a new type of PIT agents targeting VEGFR-2 expressed on vascular endothelium in a tumor and evaluated the feasibility by comparing conventional PIT in vitro and in vivo. Methods HER2-positive human gastric cancer cells, NCI-N87, were used for the experiments. HER2-targeting trastuzumab and VEGFR-2-targeting ramucirumab were conjugated to IR700. Cells were treated with mAb-IR700 conjugates followed by NIR light irradiation after washing the cells. LIVE/DEAD assay was performed to assess short-term phototoxicity and trypan blue dye exclusion assay to assess long-term phototoxicity. Next, mouse tumor xenograft models were created for in vivo PIT. Tumor-bearing mice were randomized and treated with mAb-IR700 conjugates followed by NIR light irradiation under anesthesia. Antitumor effects were monitored by measuring tumor diameters with a caliper. Results PIT utilizing ramucirumab-IR700 conjugates did not induce phototoxic effect in vitro because of the absence of membranous expression of VEGFR-2 in NCI-N87 cells, while PIT utilizing trastuzumab-IR700 conjugates induced rapid phototoxic effect because of the strong membranous expression of HER2 in NCI-N87 cells. By contrast, antitumor effects were observed in NCI-N87 xenograft tumors in vivo utilizing both ramucirumab- and trastuzumab-IR700 conjugates followed by NIR light irradiation. Microscopic analysis of the harvested tumors showed decreasing tumor micro-vessel densities only when tumors were treated with PIT utilizing ramucirumab-IR700 conjugates but not trastuzumab-IR700, which represents a different mechanism than that of conventional PIT targeting antigens expressed on the tumor cell membrane. Conclusion We demonstrated a new mechanism of PIT utilizing ramucirumab-IR700 conjugates. As VEGFR-2 is upregulated in many types of solid cancers, this method may be considered as being applicable to various types of cancers in future clinical settings. Citation Format: Makoto Mitsunaga, Takashi Nishimura, Kimihiro Ito. Vascular endothelial growth factor receptor 2 targeted photoimmunotherapy [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 5767.
αB-Crystallin Modulates Protein Aggregation of Abnormal Desmin
Authors: XuejunWang, RaisaKlevitsky, WeiHuang, JosephGlasford, FaqianLi, JeffreyRobbins
Journal: Circulation Research (2003)

αB-crystallin (CryAB) is the most abundant small heat shock protein in the heart. Upregulation of CryAB in desmin-related myopathy and its downregulation in end-stage congestive heart failure have both been reported. We previously demonstrated via cardiac-specific transgenesis that modest increases in normal CryAB are not detrimental to the heart, whereas expression of the R120G mutation of CryAB caused a desminopathy. It is generally believed that CryAB plays an important role in protecting the intermediate filaments, but the underlying mechanism is unclear. We hypothesized that CryAB protects the desmin filaments via preventing abnormal desmin protein from aggregating adversely. To test this hypothesis in vivo, mice expressing a desmin mutation that causes a desmin-related cardiomyopathy (D7) were bred into the R120G-CryAB transgenic (TG) background to examine the accumulation and aberrant aggregation of desmin protein. Despite lower mRNA expression of D7-des than in the D7-des TG hearts, the double-TG ...
Energy Metabolism of the Completely Isolated Mammalian Heart in Failure
Authors: Victorlorbek
Journal: Circulation Research (1953)

Experimental cardiac failure was reinvestigated in the completely isolated mammalian heart using a simplified system in which only the left ventricle performs work and exhibits volume changes. An effort was made to assess the importance of such experimental artefacts as acapnia, altered or depleted substrate, and controlled (constant) diastolic volume. None of these factors appeared to play a determining role in the mechanism of experimental failure, which was characterized by a decline in mechanical efficiency, with little or no impairment of total energy liberation.
Infliximab is associated with an increased risk of serious infection in patients with psoriasis in the U.K. and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register ( <scp>BADBIR</scp> )
Authors: Z.Z.N. Yiu, D.M. Ashcroft, I. Evans, K. McElhone, M. Lunt, C.H. Smith, S. Walton, R. Murphy, N.J. Reynolds, A.D. Ormerod, C.E.M. Griffiths, R.B. Warren
Journal: British Journal of Dermatology (2018)

Patients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections. To compare the risk of serious infections associated with infliximab in patients with chronic plaque psoriasis against a cohort on nonbiologic systemic therapies. A prospective cohort study was performed using data from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Infliximab was compared with nonbiologic systemic therapies, inclusive of any exposure to methotrexate, ciclosporin, acitretin, fumaric acid esters, psoralen‐ultraviolet A or hydroxycarbamide. Serious infections were those associated with hospitalization, the use of intravenous antimicrobial therapy and/or those that led to death. Propensity score inverse probability treatment weights were used to adjust for potential confounding from a priori identified covariates. Cox proportional hazards models were calculated to obtain hazard ratios (HRs). In total, 3843 participants were included for analysis up to October 2016. The incidence rates were significantly higher in the infliximab cohort (47·8 per 1000 person‐years) [95% confidence interval (CI) 35·7–64·0], compared with 14·2 per 1000 person‐years (95% CI 11·5–17·4) in the nonbiologic systemic cohort. Infliximab was associated with an overall increase in the risk of serious infection compared with nonbiologics [adjusted HR (adjHR) 1·95, 95% CI 1·01–3·75] and methotrexate only (adjHR 2·96, 95% CI 1·58–5·57) and a higher risk of serious infection in the first 6 months of therapy (adjHR 3·49, 95% CI 1·14–10·70). Infliximab is associated with an increased risk of serious infections compared with nonbiologic systemic therapies in patients with psoriasis in the U.K. and the Republic of Ireland.
Rate, Timing, Correlates, and Outcomes of Hemodynamic Valve Deterioration After Bioprosthetic Surgical Aortic Valve Replacement
Authors: Erwan Salaun, Haïfa Mahjoub, Nicolas Girerd, François Dagenais, Pierre Voisine, Siamak Mohammadi, Bobby Yanagawa, Dimitri Kalavrouziotis, Peter Juni, Subodh Verma, Rishi Puri, Nancy Coté, Josep Rodés-Cabau, Patrick Mathieu, Marie-Annick Clavel, Philippe Pibarot
Journal: Circulation (2018)

The incidence of structural valve deterioration after bioprosthesis (BP) aortic valve replacement (AVR) established on the basis of reoperation may substantially underestimate the true incidence. The objective is to determine the rate, timing, correlates, and association between hemodynamic valve deterioration (HVD) and outcomes assessed by Doppler echocardiography after surgical BP AVR.A total of 1387 patients (62.2% male, 70.5±7.8 years of age) who underwent BP AVR were included in this retrospective study. Baseline echocardiography was performed at a median time of 4.1 (1.3-6.5) months after AVR. All patients had an echocardiographic follow-up ≥2 years after AVR (926 at least 5 years and 385 at least 10 years). HVD was defined by Doppler assessment as a ≥10 mm Hg increase in mean gradient or worsening of transprosthetic regurgitation ≥1/3 class. HVD was classified according to the timing after AVR: "very early," during the first 2-years; "early," between 2 and 5 years; "midterm," between 5 and 10 years; and "long-term," >10 years.A total of 428 patients (30.9%) developed HVD. Among these patients, 52 (12.0%) were classified as "very early," 129 (30.1%) as "early," 158 (36.9%) as "midterm," and 89 (20.8%) as "long-term" HVD. Factors independently associated with HVD occurring within the first 5 years after AVR were diabetes mellitus ( P=0.01), active smoking ( P=0.01), renal insufficiency ( P=0.01), baseline postoperative mean gradient ≥15 mm Hg ( P=0.04) or transprosthetic regurgitation ≥mild ( P=0.04), and type of BP (stented versus stentless, P=0.003). Factors associated with HVD occurring after the fifth year after AVR were female sex ( P=0.03), warfarin use ( P=0.007), and BP type ( P<0.001). HVD was independently associated with mortality (hazard ratio, 2.18; 95% CI, 1.86-2.57; P<0.001).HVD as identified by Doppler echocardiography occurred in one third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes mellitus and renal insufficiency were associated with early HVD, whereas female sex, warfarin use, and stented BPs (versus stentless) were associated with late HVD.
Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor–Knockout Mice After Myocardial Infarction
Authors: JunKatada, TomomiMeguro, HitomiSaito, AkiraOhashi, ToshihisaAnzai, SatoshiOgawa, TsutomuYoshikawa
Journal: Circulation (2005)

Background— The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)–dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II–independent remodeling is unclear. Methods and Results— Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor–knockout (AT1A-KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT1A-KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT1A-KO mice. In AT1A-KO mice treated with spironolactone (20...
Increased Protein Kinase C Activity in Myotrophin-Induced Myocyte Growth
Authors: ParamesSil, VijayaKandaswamy, SubhaSen
Journal: Circulation Research (1998)

Abstract—Myotrophin, a novel protein that has been shown to stimulate myocyte growth, has been isolated, purified, and sequenced from the hearts of spontaneously hypertensive rats and dilated cardiomyopathic human tissue. Recently, the cDNA clones encoding myotrophin have been isolated and expressed in Escherichia coli, and the recombinant myotrophin was found to be as biologically and immunologically active as natural myotrophin. The mechanism by which myotrophin stimulates protein synthesis and initiates myocardial hypertrophy is not known. To evaluate the involvement of protein kinase C (PKC) in myotrophin-induced hypertrophy, PKC activity and its distribution in the subcellular fraction were determined in cultured neonatal and adult myocytes. PKC activity was determined by measuring the incorporation of 32P into histone type III-S and PKCe substrate peptide (epep) from [γ-32P]ATP in neonatal myocytes. Myotrophin significantly stimulated PKC activity in neonatal myocytes and was associated with a signi...
Comparison of the Double Two-Step Test and the Maximal Exercise Treadmill Test
Authors: Samuelbellet, Laurianroman
Journal: Circulation (1967)

A comparison of the double two-step test and a more strenuous type of exercise test was made to assess the value of the latter procedure in increasing the sensitivity of the electrocardiographic exercise test. In young, normal women, 17 to 20 years of age, who represent a group with minimal chances for significant silent coronary heart disease, both the double two-step test and graded maximal exercise tests were always normal. This is consistent with the view that ischemic electrocardiographic changes are not usually elicited in subjects with normal coronary circulation, even after strenuous exercise. In middle-aged men and women, 40 to 65 years of age, in whom the possible existence of clinically silent coronary heart disease was suggested by age and other parameters (atypical chest pain, hypertension, or diabetes, or all three), the maximal exercise test on the treadmill, as compared to the double two-step test, increased the yield of positive electrocardiographic results by 12%. These findings suggest ...
A Physician's Grammar
Authors: Gaetan Sgro
Journal: Annals of Internal Medicine (2018)

Ad Libitum7 August 2018A Physician's GrammarGaetan Sgro, MDGaetan Sgro, MDVA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (G.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-0355 Audio Reading - “A Physician's Grammar” Audio. Virginia L. Hood, MD, reads "A Physician's Grammar," by G. Sgro. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The young woman in the brilliant redwrap who clings to her daughterin the glow of the star lamphas not failed her treatmentThe young man who's traded hisbright eyes his best suit all the damned foolswho love him fora fistful of Oxys is not abusing themIt's not thatthe whiskered gentleman who stares past the curtain in 127having lost allinterest in taking your medicine is a difficult patientIt is pain once againupsetting syntax, confusing agents sharpening our owndisappointment, after allno one blames the surf for the tide's retreator chides the wind-whippedoak for letting go its leaves Author, Article, and Disclosure InformationAffiliations: VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (G.S.)Current Author Address: Gaetan Sgro, MD; e-mail, gaetan.[email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “A Physician's Grammar” Audio. Virginia L. Hood, MD, reads "A Physician's Grammar," by G. Sgro. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 7 August 2018Volume 169, Issue 3Page: 196 ePublished: 7 August 2018 Issue Published: 7 August 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...