tbuckley/cabot-search huggingface dataset:
Abstract 1563: Characterization of two new recombinant rabbit anti-PDL1 IHC staining in bladder cancer, NSCLC, and melanoma with immune cell markers
Authors: Rachel M. Gonzalez, Wei Fu, Evelin Logis, Emma Ding, Casey Chen, Xiaojie Li, Sonia Merritt, Mingjuan Liu, Amy Zhang, Yiran Wang, Guangli Wang, Donghui Ma
Journal: Cancer Research (2018)

Abstract Published studies show tumor cells overexpress PD-L1 to escape the host immune defense by binding to PD-1 on surveilling T-cells causing the T-cells to shut down. Immunotherapies disrupting PD-1/PD-L1 signaling interactions have great success in treating PD-L1 positive tumors. Immunohistochemistry (IHC) is an important diagnostic tool currently used to determine the expression level of PD-L1 in tumor and immune cells. The FDA approved PD-L1 clones (SP142 and 28-8) for IHC present different staining patterns when evaluated on the same tumor tissue. In this study, we assessed both the immune cells and tumor cells IHC positive stain of PD-L1. To do this we evaluated multiple immune cell markers with multiple PD-L1 antibodies. IHC screens were done with 5 PD-L1 antibodies, 2 recombinant rabbit monoclonal antibodies (clone OR-5E3 and OR-5H8), the mouse monoclonal antibody (clone UMAB229), and the FDA approved clones (SP142 and 28-8). The immune cell markers used were CD3, CD8A, CD20, CD68, and FOXP3. NSCLC, Bladder Cancer, and Melanoma immune cells, as indicated by the CD3, CD8A, CD20, CD68 and FOXP3 staining, generated different distribution pattern in the three tumor types. The five PD-L1 antibodies did show variation in detection of both the immune and tumor cells. For example, PD-L1 clones OR-5E3 and OR-5H8 stained tumor cells stronger and picked up weak expression of PD-L1 better than clone SP142, suggesting the two antibodies have higher affinity. The mouse monoclonal anti-PDL1 clone UMAB229 picked up strong and weak staining similar or better than clones OR-5H8 and picked up the immune cells similar to SP-142. The five PD-L1 antibodies were made from different antigens which may contribute to their sensitivity and specificity to detect PD-L1 in tumor cells. This study suggests the new generation of PD-L1 antibodies may make a better tool for diagnostic screens. Citation Format: Rachel M. Gonzalez, Wei Fu, Evelin Logis, Emma Ding, Casey Chen, Xiaojie Li, Sonia Merritt, Mingjuan Liu, Amy Zhang, Yiran Wang, Guangli Wang, Donghui Ma. Characterization of two new recombinant rabbit anti-PDL1 IHC staining in bladder cancer, NSCLC, and melanoma with immune cell markers [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 1563.
Interaction of α1-Adrenoceptor Subtypes With Different G Proteins Induces Opposite Effects on Cardiac L-type Ca2+ Channel
Authors: JinO-Uchi, HiroyukiSasaki, SatoshiMorimoto, YoichiroKusakari, HitomiShinji, ToruObata, KenichiHongo, KimiakiKomukai, SatoshiKurihara
Journal: Circulation Research (2008)

We examined the effect of α1-adrenoceptor subtype-specific stimulation on L-type Ca2+ current (ICa) and elucidated the subtype-specific intracellular mechanisms for the regulation of L-type Ca2+ channels in isolated rat ventricular myocytes. We confirmed the protein expression of α1A- and α1B-adrenoceptor subtypes at the transverse tubules (T-tubules) and found that simultaneous stimulation of these 2 receptor subtypes by nonsubtype selective agonist, phenylephrine, showed 2 opposite effects on ICa (transient decrease followed by sustained increase). However, selective α1A-adrenoceptor stimulation (≥0.1 μmol/L A61603) only potentiated ICa, and selective α1B-adrenoceptor stimulation (10 μmol/L phenylephrine with 2 μ mol/L WB4101) only decreased ICa. The positive effect by α1A-adrenoceptor stimulation was blocked by the inhibition of phospholipase C (PLC), protein kinase C (PKC), or Ca2+/calmodulin-dependent protein kinase II (CaMKII). The negative effect by α1B-adrenoceptor stimulation disappeared after th...
Relationship of Plasma Digitoxin and Digoxin to Cardiac Response Following Intravenous Digitalization in Man
Authors: Williamshapiro, Kennethnarahara, Kathryntaubert
Journal: Circulation (1970)

The value of plasma digitalis determinations will depend upon the accuracy with which they mirror the myocardial effects of digitalis. Ten volunteers received 0.8 mg of digitoxin intravenously, and after 2 hours the mean plasma digitoxin level was 45.6 ± 6 mµg/ml but declined over 4 to 6 hours during plasma-tissue equilibration. The cardiac response, as indicated by decreases in the left ventricular ejection time index (LVETI) and Q-S2 intervals (P < 0.01), was present at 2 hours and reached maximum at 4 to 6 hours. Subsequently, plasma level, LVETI, and Q-S2 changed in the same direction during slow excretion. Six subjects received 1.0 mg of digoxin intravenously. Mean plasma digoxin at 30 min was 6.8 ± 0.3 mµg/ml; it fell after 3 to 4 hours to levels usually seen during maintenance digoxin administration (<3 mµg/ml) and then declined more slowly. Correlation of individual digoxin levels with ΔLVETI values during the first 4 hours was significant (P < 0.01). The half-life (T½) for the dominant slope of t...
Transforming Growth Factor-β/Smads Signaling Induces Transcription of the Cell Type–Restricted Ankyrin Repeat Protein CARP Gene Through CAGA Motif in Vascular Smooth Muscle Cells
Authors: HiroyoshiKanai, ToruTanaka, YasushiAihara, Sin-ichiTakeda, MasahiroKawabata, KoheiMiyazono, RyozoNagai, MasahikoKurabayashi
Journal: Circulation Research (2001)

Abstract—Transforming growth factor (TGF)-β plays a major role in the development of vascular diseases. Despite the pleiotropic effects of TGF-β on vascular smooth muscle cells (VSMCs), only a few genes have been characterized as direct targets of TGF-β in VSMCs. Cardiac ankyrin repeat protein (CARP) has been thought to be expressed exclusively in the heart. In the present study, we showed that CARP is expressed in the vasculature after balloon injury and in cultured VSMCs in response to TGF-β. Analysis of a half-life of the cytoplasmic CARP mRNA levels and the transient transfection of the CARP promoter/luciferase gene indicates that the regulation of CARP expression is increased by TGF-β at the transcriptional level. Transfection of expression vectors encoding Smads significantly activated the CARP promoter/luciferase activity. Deletion analysis and site-specific mutagenesis of the CARP promoter indicate that TGF-β response element is localized to CAGA motif at −108 bp relative to the transcription star...
Senescence and senotherapeutics: a new field in cancer therapy
Authors: Vassilios Myrianthopoulos, Konstantinos Evangelou, Panagiotis V.S. Vasileiou, Tomer Cooks, Theodoros P. Vassilakopoulos, Gerassimos A. Pangalis, Myrsini Kouloukoussa, Christos Kittas, Alexandros G. Georgakilas, Vassilis G. Gorgoulis
Journal: Pharmacology & Therapeutics (2018)

Cellular senescence is a stress response mechanism ensuring homeostasis. Its temporal activation during embryonic development or normal adult life is linked with beneficial properties. In contrast, persistent (chronic) senescence seems to exert detrimental effects fostering aging and age-related disorders, such as cancer. Due to the lack of a reliable marker able to detect senescence in vivo, its precise impact in age-related diseases is to a large extent still undetermined. A novel reagent termed GL13 (SenTraGorTM) that we developed, allowing senescence recognition in any type of biological material, emerges as a powerful tool to study the phenomenon of senescence in vivo. Exploiting the advantages of this novel methodological approach, scientists will be able to detect and connect senescence with aggressive behavior in human malignancies, such as tolerance to chemotherapy in classical Hodgkin Lymphoma and Langerhans Cell Histiocytosis. The latter depicts the importance of developing the new and rapidly expanding field of senotherapeutic agents targeting and driving to cell death senescent cells. We discuss in detail the current progress of this exciting area of senotherapeutics and suggest its future perspectives and applications.
Blood Pressure Targets Recommended by Guidelines and Incidence of Cardiovascular and Renal Events in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)
Authors: GiuseppeMancia, HelmutSchumacher, JosepRedon, PaoloVerdecchia, RolandSchmieder, GarryJennings, KhalidYusoff, LarsRyden, G. LishengLiu, KoonTeo, PeterSleight, SalimYusuf
Journal: Circulation (2011)

Background—Hypertension treatment guidelines recommend that blood pressure (BP) be lowered to  75%) in which BP was reduced to <140/90 or <130/80 mm Hg. After adjustment for demographic and clinical variables, a progressive increase in the proportion of visits in which BP was reduced to <140/90 or <130/80 mm Hg was associated with a progressive reduction in the risk of stroke, new onset of microalbuminuria or macroalbuminuria, and return to normoalbuminuria in albuminuric patients. An increased frequency of BP control to either target did not have an...
Pharmacokinetic equivalence observed between an emulsion formulation of vinorelbine (ANX-530) and vinorelbine solution in a clinical study of patients with advanced cancer.
Authors: Hugo Requejo, Lino Arboit, Geraldo Arroyo, Cesar Blajman, Luis Fein, Pablo Quintana, Matias Chacon, Mark Cantwell, Daryl Smith, Jennifer Ellis, Bill Demers, Jeffrey Stewart, Joachim Schupp
Journal: Cancer Research (2008)

207  Background: An oil-in-water emulsion formulation of vinorelbine, ANX-530, was evaluated for bioequivalence with vinorelbine solution in a multi-center, open label, randomized, crossover study. Vinorelbine is a semisynthetic derivative of vinblastine and is approved for use in patients with non-small cell lung cancer. However, vinorelbine solution is a vesicant and venous irritant, and these adverse effects can limit its tolerability. Preclinical studies demonstrated less venous irritation, decreased hemolysis, equivalent antitumor activity, and similar pharmacokinetic profiles for ANX-530 and vinorelbine solution. Methods: A clinical trial was performed to determine the bioequivalence of ANX-530 and vinorelbine solution. The bioequivalence study enrolled cancer patients in a standard 2-period crossover design randomized for sequence. Patients were eligible with an advanced cancer potentially sensitive to vinorelbine after failure of standard treatments for the tumor. Patients requiring concomitant chemotherapeutic agents or having prior vinorelbine or mitomycin treatment were excluded. The patients were randomly assigned to receive a single intravenous dose of either ANX-530 or vinorelbine solution in the first study period, then one week later, crossover to the other vinorelbine formulation. All drug administrations were given as 10 minute infusions at a dose of 30 mg/m2. Blood samples for pharmacokinetic analysis were collected predose, 10, 20, and 40 min, and 1, 3, 6, 24, 48, 72, and 144 hr after the end of the infusion. Hematology, serum chemistry, and adverse event reporting were performed throughout the study period. The primary endpoint of pharmacokinetic equivalence was assessed by analysis of variance comparison of the log transformed values of vinorelbine area under the curve (AUC) and maximum plasma concentration (Cmax). Results: A total of 31 patients were enrolled. The median age was 60 years (range 31-83) and 26 patients (84%) were female. 20 patients (64%) had breast cancer, 3 patients (10%) had lung cancer, and 8 patients (26%) had other cancer types. All patients had been previously treated with chemotherapy. All 31 patients received both formulations and had adequate pharmacokinetic data. The geometric mean ratio percentage (90% confidence interval) of Cmax was 104% (87% - 123%), of AUClast was 106% (99% - 112%), and of AUCinfinity was 106% (100% - 112%). Complete safety results will be presented. Conclusion: The 90% confidence intervals of the ratio for Cmax and AUC parameters were within the 80-125% predefined interval for bioequivalence based on FDA guidelines. As such, pharmacokinetic equivalence was observed between ANX-530 and vinorelbine solution.
Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene in Rat Diabetic Hind Limb Ischemia Model
Authors: YoshiakiTaniyama, RyuichiMorishita, KazuyaHiraoka, MotokuniAoki, HironoriNakagami, KeitaYamasaki, KunioMatsumoto, ToshikazuNakamura, YasufumiKaneda, ToshioOgihara
Journal: Circulation (2001)

Background Because no study has documented the angiogenic properties of hepatocyte growth factor (HGF) in a diabetes model, we examined the feasibility of gene therapy using HGF to treat peripheral arterial disease in diabetes. Methods and Results Because intramuscular injection of luciferase plasmid by the hemagglutinating virus of Japan (HVJ)–liposome method had much higher efficiency than injection of naked plasmid, we used the HVJ-liposome method to transfect the human HGF gene into the rat diabetic hindlimb model. As expected, transfection of human HGF vector resulted in a significant increase in blood flow as assessed by laser Doppler imaging and capillary density, even in the diabetes model, accompanied by the detection of human HGF protein. Interestingly, the degree of natural recovery of blood flow was significantly greater in nondiabetic rats than in diabetic rats. Thus, in an in vitro culture system, we further studied the molecular mechanisms of how diabetes delayed angiogenesis. Importantly, ...
Abstract 5766: Multifunctional biologics for targeted T-cell therapy based onin vivomatured fully human VH domains
Authors: Brian Mcguinness, James Legg, Phil Bland-Ward, Peter Pack
Journal: Cancer Research (2018)

Abstract Crescendo Biologics has created a proprietary transgenic mouse devoid of any antibody light chains from which it generates highly diverse fully human VH domain (‘Humabody') building blocks. In vivo maturation optimizes Humabody potency and develops superior biophysical properties. Their small size (13kDa) and high stability permits Humabody assembly into an almost limitless array of multifunctional formats optimally configured for therapeutic efficacy. These small versatile single VH domain building blocks permit the rapid exploration of a vast range of 3D format space to identify optimal therapeutic solutions. This fully modular plug &amp; play approach lacks the constraints of traditional mAbs and enables a radical rethink of how a multifunctional molecule can be designed and assembled to deliver enhanced therapeutic benefit. Such molecules are capable of target engagement that is unachievable using regular mAbs. Using Humabody VH addressing key targets in the immune-oncology space, Crescendo has exemplified the potential for optimally configured molecules to deliver enhanced efficacy both in vitro and in vivo. Examples include: CB307, a unique T-cell engaging format with a novel mode of action. CB201, a biparatopic antagonist which ‘handcuffs' PD1: one domain binding and blocking PD1 from engaging with its ligands, the other binding a nonblocking epitope. With a binding affinity of 175pM and a unique ability to localise rapidly to PD-1 positive T-cells, CB201 demonstrates significantly enhanced in vivo efficacy over IgG-based PD-1 antagonists in a PDX tumour model in NSG mice. CB108, a half-life extended paratopic Humabody binding PSMA has demonstrated superior tumour targeting with enhanced internalisation and highly efficient accumulation in target-positive tumours with up to 18 percent ID per g recorded in a 24hr imaging study. These data support the progression of highly differentiated therapeutics into the clinic. Citation Format: Brian Mcguinness, James Legg, Phil Bland-Ward, Peter Pack. Multifunctional biologics for targeted T-cell therapy based on in vivo matured fully human VH domains [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 5766.
Abstract LB-387: In vivo study on the pathological role of microRNA 155 in liver malignancy
Authors: Tae Jin Lee, Ji Young Yoo, Balveen Kaur, Carlo Croce
Journal: Cancer Research (2018)

Abstract Growing body of evidence proposes that causative factor for liver damage, such as viral infection, inflammation, fatty liver and genotoxin, induces over-expression of microRNA-155 (miR-155), and increases the chance to develop hepatocellular carcinoma (HCC), where miR-155 is also found to be highly over-expressed. To understand the underlying mechanism how over-expression of miR-155 in liver induces pathologic changes linking early liver damage to malignant HCC development, we have generated conditional transgenic and knockout mice for hepatocyte-specific over-expression or deletion of miR-155 using Cre-LoxP technology. Although the miR-155 over-expressing Tg mice did not develop spontaneous HCC, they showed early inflammation in liver with elevated level of pro-inflammatory cytokines in both liver and serum through Caspase-I activation. Postnatal insulting by genotoxin, Diethylnitrosamine (DEN), has dramatically increased incidents of HCC in miR-155 Tg mice (82%) compared to wildtype mice (21%) by 9 months. Microarray analysis on whole mouse liver transcriptome has revealed that 294 genes were significantly up-regulated in the Tg mice while 147 genes were significantly down-regulated. Further pathway analysis showed that those affected genes mainly involve in acute-phase response, inflammatory response, fatty acid metabolic process, and cholesterol metabolic process, which coincides with our phenotypic observation. In addition, it was found that high incidence of HCC by DEN insult is consequence of impaired DNA damage repair and apoptosis pathways through downregulation of several genes including Foxo3a, Sirt1, C/EBP-beta and Smac by miR-155. Our in vivo study provides first insight of dysregulation of single microRNA can set forth liver damage to malignant HCC, which makes miR-155 a promising therapeutic target not only for HCC but also many type of liver damage-related liver diseases. Citation Format: Tae Jin Lee, Ji Young Yoo, Balveen Kaur, Carlo Croce. In vivo study on the pathological role of microRNA 155 in liver malignancy [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 LB-387.
Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Obesity-Induced Hypertension
Authors: AiNagae, MegumiFujita, HirooKawarazaki, HiromitsuMatsui, KatsuyukiAndo, ToshiroFujita
Journal: Circulation (2009)

Background— Obesity is one of the major risk factors for cardiovascular disease and is often associated with increased oxidative stress and sympathoexcitation. We have already suggested that increased oxidative stress in the brain modulates the sympathetic regulation of arterial pressure in salt-sensitive hypertension, which is often associated with obesity. The present study was performed to determine whether oxidative stress could mediate central sympathoexcitation in the initial stage of obesity-induced hypertension. Methods and Results— Four-week-old male Sprague-Dawley rats were fed a high-fat (45% kcal as fat) or low-fat (10% kcal as fat) diet for 6 weeks. Fat loading elicited hypertension and sympathoexcitation, along with visceral obesity. In urethane-anesthetized and artificially ventilated rats, arterial pressure and renal sympathetic nerve activity decreased in a dose-dependent fashion when 53 or 105 μmol/kg tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral...
Abstract 14539: Adverse Fibrin Clot Properties Are Associated With Worse Outcome Following Acute Coronary Syndrome: A PLATO Substudy
Authors: Wael Sumaya, Lars Wallentin, Stefan K James, Agneta Siegbahn, Katja Gabrysch, Maria Bertilsson, Anders Himmelmann, Ramzi Ajjan, Robert F Storey
Journal: Circulation (2017)

Introduction: Compact fibrin clots that resist lysis have been implicated in thrombotic conditions but large studies are lacking. We investigated fibrin clot properties and clinical outcomes in pat...
Asok Ranjan Das Gupta
Authors: John Temple
Journal: BMJ (2018)

Asok Ranjan Das Gupta was born into a highly educated Hindu family in Dualaptur, East Bengal. His father later became professor of mathematics at the University of Calcutta (now Kolkata). Before Asok could complete his primary education, he and his family were forced, in 1947, to migrate to Calcutta because of the partition of India, as East Bengal became a predominantly Muslim state, which eventually separated from Pakistan and became Bangladesh. Asok completed his early schooling in West Bengal, and entered the Nil Ratan Sircar Medical College …
Predictors of disease activity and structural progression after treatment with adalimumab plus methotrexate or continued methotrexate monotherapy in patients with early rheumatoid arthritis and suboptimal response to methotrexate
Authors: Josef S Smolen, Ronald F van Vollenhoven, Stefan Florentinus, Su Chen, Jessica L Suboticki, Arthur Kavanaugh
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Methotrexate is considered to be first-line therapy for rheumatoid arthritis (RA). However, a substantial proportion of treated patients do not achieve the desired goals of therapy. This analysis aimed to identify predictors of insufficient response to methotrexate in patients with early RA. Methods The Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PREMIER studies in patients with RA for &lt;1 and &lt;3 years, respectively, examined the efficacy of methotrexate and adalimumab in methotrexate-naive patients. This post hoc analysis included patients for whom initial methotrexate monotherapy was not successful after 6 months. Candidate predictors of insufficient response and clinically relevant radiographic progression (CRRP) included demographics, baseline disease characteristics and time-averaged disease variables over a 12-week interval. In OPTIMA, adalimumab was added to therapy after insufficient treatment response; in PREMIER, initial methotrexate therapy was continued; clinical, functional and radiologic outcomes were assessed after 1 year. Results Baseline 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)) and time-averaged DAS28(CRP) over 4, 8 and 12 weeks were the strongest predictors of insufficient response to methotrexate and CRRP. Addition of adalimumab to methotrexate therapy was associated with better clinical, functional and radiographic outcomes after 1 year compared with continuing on methotrexate monotherapy. Conclusions In patients with early RA, baseline disease characteristics and early disease activity can predict response to methotrexate treatment and radiographic progression at 6 months. The addition of adalimumab at 6 months after methotrexate failure is associated with improved outcomes. These results support treatment-to-target strategies and timely adaptation of therapy in patients with early RA. Trial registration number NCT00420927 , NCT00195663 ; Post-results.