Background: Activation of two receptors for adenosine diphosphate (ADP), P2Y1 and P2Y12, is necessary for ADP‐induced platelet aggregation (PA). It is generally believed that the antithrombotic ...effects of drugs inhibiting P2Y12, such as clopidogrel, are uniquely mediated by inhibition of P2Y12‐dependent PA. However, as P2Y12 is negatively coupled to adenylyl cyclase (AC), its inhibition may also exert antithrombotic effects through the potentiation of prostacyclin (PGI2), which inhibit PA by stimulating AC. Objectives: To test whether inhibition of P2Y12 potentiates the antiplatelet effects of PGI2. Methods: We measured the effects of PGI2 (0.01–10 μm) on PA of washed human platelets induced by thrombin (0.5 U mL−1) in the presence or absence of ARC69931MX (anti‐P2Y12) or MRS2500 (anti‐P2Y1). Results: PGI2 inhibited PA in the presence of anti‐P2Y12, but not in the presence of anti‐P2Y1 or in the absence of inhibitors. In contrast, dibutyryl‐cyclicAMP inhibited PA both in the presence and absence of anti‐P2Y1 or anti‐P2Y12. PGI2 increased platelet cyclicAMP levels only in the absence of thrombin or in the presence of thrombin plus anti‐P2Y12. Conclusions: PGI2 did not inhibit PA induced by thrombin, because its effect on AC was prevented by released ADP interacting with P2Y12. Anti‐P2Y12 drugs, by rescuing AC activity, potentiate the antiplatelet effect of PGI2, which may contribute to their antithrombotic effect.
New P2Y12 blockers CATTANEO, M.
Journal of thrombosis and haemostasis,
July 2009, Letnik:
7
Journal Article
Recenzirano
A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome (ACS). This article reviews the ...pharmacology and clinical development of three of these agents: prasugrel, cangrelor, and ticagrelor. Prasugrel, a third‐generation, oral thienopyridine, has been shown to be superior to clopidogrel, the current gold standard, in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention (PCI), although the bleeding rate was higher. Cangrelor, a chemical analog of adenosine triphosphate, is a potent direct platelet P2Y12 antagonist. In development as an intravenous agent, cangrelor is currently being evaluated in two phase III studies in patients requiring PCI. Ticagrelor is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by P2Y12; it is currently being studied in a phase III trial in patients with ACS.
Cancer neoantigens that arise from tumor mutations are drivers of tumor-specific T cell responses, but identification of T cell-recognized neoantigens in individual patients is challenging. Previous ...methods have restricted antigen discovery to selected HLA alleles, thereby limiting the breadth of neoantigen repertoires that can be uncovered. Here, we develop a genetic neoantigen screening system that allows sensitive identification of CD4
and CD8
T cell-recognized neoantigens across patients' complete HLA genotypes.
Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical ...effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR colorectal cancer preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies. SIGNIFICANCE: We found that a large, diverse set of dMMR/MSI-H colorectal cancer preclinical models, including models of treatment-refractory disease, are WRN-dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy.
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Background The purpose of this study was to determine if the utilization of video-assisted thoracic surgery (VATS) for lobectomy for clinical stage I non-small cell lung cancer in elderly patients ...results in decreased complications compared with lobectomy by thoracotomy (THOR). Methods A retrospective, matched case-control study was performed evaluating the perioperative outcomes after lobectomy by VATS versus THOR performed in elderly patients (age ≥70 years) at a single institution. All complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 ( http://ctep.cancer.gov/reporting/ctc.html ). Results Between May 1, 2002 and December 31, 2005 333 patients (245 THOR, 88 VATS) 70 years old or greater underwent lobectomy for clinical stage I non-small cell lung cancer. After matching based on age, gender, presence of comorbid conditions, and preoperative clinical stage, there were 82 patients in each group. Patients had similar preoperative characteristics. A VATS approach resulted in a significantly lower rate of complications compared with THOR (28% vs 45%, p = 0.04) and a shorter median length of stay (5 days, range 2 to 20 vs 6 days, range 2 to 27, p < 0.001). No patients undergoing VATS lobectomy had higher than grade 2 complications, whereas 7% of complications in the THOR group were grade 3 or higher. There were no perioperative deaths in the VATS patients compared with an in-hospital mortality rate of 3.6% (3 of 82) for THOR patients. Conclusions A VATS approach to lobectomy for clinical stage I non-small cell lung cancer in the elderly was associated with fewer and overall reduced severity of complications as well as a shorter hospital stay compared with thoracotomy.
Background: Closure time (CT), measured by platelet function analyzer (PFA‐100®) device, is now available to the clinical laboratory as a possible alternative or supplement to the bleeding time test. ...Aim: On behalf of the Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH‐SSC), a working Group was formed to review and make recommendations on the use of the PFA‐100 CT in the evaluation of platelet function within the clinical laboratory. Methods: The Medline database was searched to review the published information on the PFA‐100 CT in the evaluation of platelet disorders and platelet function. This information, and expert opinion, was used to prepare a report and generate consensus recommendations. Results: Although the PFA‐100 CT is abnormal in some forms of platelet disorders, the test does not have sufficient sensitivity or specificity to be used as a screening tool for platelet disorders. A role of the PFA‐100 CT in therapeutic monitoring of platelet function remains to be established. Conclusions: The PFA‐100 closure time should be considered optional in the evaluation of platelet disorders and function, and its use in therapeutic monitoring of platelet function is currently best restricted to research studies and prospective clinical trials.
SUMMARY
The 2016–2017 central Italy earthquake sequence began with the first main shock near the town of Amatrice on August 24 (Mw 6.0), and was followed by two subsequent large events near Visso on ...October 26 (Mw 5.9) and Norcia on October 30 (Mw 6.5), plus a cluster of four events with Mw > 5.0 within few hours on 18 January 2017. The affected area had been monitored before the sequence started by the permanent Italian National Seismic Network (RSNC), and was enhanced during the sequence by temporary stations deployed by the National Institute of Geophysics and Volcanology and the British Geological Survey. By the middle of September, there was a dense network of 155 stations, with a mean separation in the epicentral area of 6–10 km, comparable to the most likely earthquake depth range in the region. This network configuration was kept stable for an entire year, producing 2.5 TB of continuous waveform recordings.
Here we describe how this data was used to develop a large and comprehensive earthquake catalogue using the Complete Automatic Seismic Processor (CASP) procedure. This procedure detected more than 450 000 events in the year following the first main shock, and determined their phase arrival times through an advanced picker engine (RSNI-Picker2), producing a set of about 7 million P- and 10 million S-wave arrival times. These were then used to locate the events using a non-linear location (NLL) algorithm, a 1-D velocity model calibrated for the area, and station corrections and then to compute their local magnitudes (ML). The procedure was validated by comparison of the derived data for phase picks and earthquake parameters with a handpicked reference catalogue (hereinafter referred to as ‘RefCat’). The automated procedure takes less than 12 hr on an Intel Core-i7 workstation to analyse the primary waveform data and to detect and locate 3000 events on the most seismically active day of the sequence. This proves the concept that the CASP algorithm can provide effectively real-time data for input into daily operational earthquake forecasts,
The results show that there have been significant improvements compared to RefCat obtained in the same period using manual phase picks. The number of detected and located events is higher (from 84 401 to 450 000), the magnitude of completeness is lower (from ML 1.4 to 0.6), and also the number of phase picks is greater with an average number of 72 picked arrival for a ML = 1.4 compared with 30 phases for RefCat using manual phase picking. These propagate into formal uncertainties of ±0.9 km in epicentral location and ±1.5 km in depth for the enhanced catalogue for the vast majority of the events. Together, these provide a significant improvement in the resolution of fine structures such as local planar structures and clusters, in particular the identification of shallow events occurring in parts of the crust previously thought to be inactive. The lower completeness magnitude provides a rich data set for development and testing of analysis techniques of seismic sequences evolution, including real-time, operational monitoring of b-value, time-dependent hazard evaluation and aftershock forecasting.
Glucocorticoids (GCs) act through their receptor (GR) as regulators in different biological processes such as reproduction. In the absence of GCs, the GR remains inactive in the cytoplasm by ...associating with heat shock proteins (HSPs), which act as molecular chaperones, among which the most relevant are HSP90 and HSP70. Cytoplasmic GC-activated GR mediates non-genomic effects, interacting with members of signaling pathways such as PI3K/Akt, which participates in several metabolic processes, including the insulin signaling pathway. The aim of the present study was to evaluate possible associations between the cytoplasmic GR and the main intermediates of the insulin signaling pathway and HSP90 and HSP70 in ovaries of dairy cows. To this end, the protein expression of cytoplasmic GR, key members of the insulin signaling pathway, and HSPs was evaluated in ovarian preovulatory follicles of non-lactating Holstein cows in proestrus. Positive associations were observed between protein expression of GR and HSP90, IRS1, pIRS1, PI3K and pAkt (p < 0.05; β > 0) in granulosa cells of dominant follicles of dairy cows. Instead, in theca cells, no associations were observed between protein expression of GR and members of the insulin signaling pathway or HSPs. These data provide evidence of the possible association between the non-genomic mechanisms of action of the GR and the insulin signaling pathway in the bovine ovary.
•Cytoplasmic GC-activated GR mediates non-genomic effects.•GR expression shown associations with HSP90 expression in bovine ovary.•GR expression shown associations with members of the insulin signaling pathway.
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