Enzalutamide is a second-generation androgen receptor (AR) antagonist for the treatment of metastatic castration-resistant prostate cancer (mCRPC).Unfortunately, AR dysfunction means that resistance to enzalutamide will eventually develop.Thus, novel agents are urgently needed to treat this devastating disease.Triptolide (TPL), a key active compound extracted from the Chinese herb Thunder God Vine (Tripterygium wilfordii Hook F.), possesses anti-cancer activity in human prostate cancer cells.However, the effects of TPL against CRPC cells and the underlying mechanism of any such effect are unknown.In this study, we found that TPL at low dose inhibits the transactivation activity of both full-length and truncated AR without changing their protein levels.Interestingly, TPL inhibits phosphorylation of AR and its CRPC-associated variant AR-V7 at Ser515 through XPB/CDK7.As a result, TPL suppresses the binding of AR to promoter regions in AR target genes along with reduced TFIIH and RNA Pol II recruitment.Moreover, TPL at low dose reduces the viability of prostate cancer cells expressing AR or AR-Vs.Low-dose TPL also shows a synergistic effect with enzalutamide to inhibit CRPC cell survival in vitro, and enhances the anti-cancer effect of enzalutamide on CRPC xenografts with minimal side effects.Taken together, our data demonstrate that TPL targets the transactivation activity of both full-length and truncated ARs.Our results also suggest that TPL is a potential drug for CRPC, and can be used in combination with enzalutamide to treat CRPC.
Summary Intracellular Ca 2+ overload has been associated with established atrial arrhythmogenesis. The present experiments went on to correlate acute initiation of atrial arrhythmogenesis in Langendorff‐perfused mouse hearts with changes in Ca 2+ homeostasis in isolated atrial myocytes following pharmacological procedures that modified the storage or release of sarcoplasmic reticular (SR) Ca 2+ or inhibited entry of extracellular Ca 2+ . Caffeine (1 mmol/L) elicited diastolic Ca 2+ waves in regularly stimulated atrial myocytes immediately following addition. This was followed by a decline in the amplitude of the evoked transients and the disappearance of such diastolic events, suggesting partial SR Ca 2+ depletion. Cyclopiazonic acid (CPA; 0.15 µmol/L) produced more gradual reductions in evoked Ca 2+ transients and abolished diastolic Ca 2+ events produced by the further addition of caffeine. Nifedipine (0.5 µmol/L) produced immediate reductions in evoked Ca 2+ transients. Further addition of caffeine produced an immediate increase followed by a decline in the amplitude of the evoked Ca 2+ transients, without eliciting diastolic Ca 2+ events. These findings correlated with changes in spontaneous and provoked atrial arrhythmogenecity in mouse isolated Langendorf‐perfused hearts. Thus, caffeine was pro‐arrhythmogenic immediately following but not > 5 min after application and both CPA and nifedipine pretreatment inhibited such arrhythmogenesis. Together, these findings relate acute atrial arrhythmogenesis in intact hearts to diastolic Ca 2+ events in atrial myocytes that, in turn, depend upon a finite SR Ca 2+ store and diastolic Ca 2+ release following Ca 2+ ‐induced Ca 2+ release initiated by the entry of extracellular Ca 2+ .
3550 Background: NIVO + IPI demonstrated robust, durable clinical benefit, and was well tolerated as a 1L therapy in pts with MSI-H/dMMR mCRC in the phase 2 CheckMate 142 study (NCT02060188), leading to the inclusion of NIVO + IPI in the NCCN guidelines as an initial therapy option for these pts. At 52-mo median follow-up, 1L NIVO + IPI continued to demonstrate durable clinical benefit, and no new safety signals were identified. Here we report longer follow-up results. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV; overall survival (OS); and safety. Results: In total, 45 pts received 1L NIVO + IPI. With median follow-up of 64.2 mo (range, 59.4–68.9 mo), ORR by INV was 71% (95% CI, 56–84%). The proportion of pts with a best overall response of complete response (CR) was 20%, partial response (PR) was 51%, stable disease (SD) was 13%, and progressive disease was 16%. Median DOR (mDOR) was not reached, and the 60-mo DOR rate was 72%. Median PFS (mPFS) by INV and median OS (mOS) were not reached, with 60-mo PFS and OS rates of 55% and 67%, respectively (Table). Among pts alive at the data cutoff (n = 31), 30 remained treatment-free after initial study treatment without receiving any subsequent systemic therapy, with a median treatment-free interval of 34.7 mo (range, 1.6–61.4 mo). Exploratory analysis by tumor mutational burden status will be presented. Safety data are shown in the Table. Conclusions: At 64-mo follow-up, NIVO + IPI continued to demonstrate clinically meaningful survival and durable responses, with mPFS, mOS, and mDOR still not reached, suggesting the potential for long-term clinical benefit. Safety remained consistent with previous data. These findings further support current recommendations for NIVO + IPI as a 1L treatment for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188 . [Table: see text]
All data are provided in .mat format, and organised so that each folder contains an individual experiment (i.e. whole heart or isolated atrium). All PCLs are within single experimental files. .txt are also provided that contain suggested setting for use in ElectroMap, and regions of interest. Filenames include animal ID and intervention.
Functional roles of ionic currents in a membrane delimited sino-atrial node (SAN) cell model were investigated. Ionic currents were blocked and intracellular calcium ([Ca2+] i ) buffered to study their effects on action potential (AP) characteristics. The simulations revealed that blocking the hyperpolarization activated current and the T-type calcium current caused an increase of cycle length (CL) due to reduced diastolic depolarization rate (DDR). Blocking of sustained outward (I st ) and sodium currents (I Na,1.1 , I Na,1.5 ) had no effect. Blocking the L-type calcium current's Ca v 1.3 isoform (I CaL1.3 ) and rapidly activating delayed rectifier arrested pacemaking. Blocking sodium-calcium exchanger (I NaCa ) caused a CL reduction but did not affect DDR. Reducing [Ca2+] i increased CL marginally. A small increase of [Ca2+] i arrested pacemaking. I st , I Na1.1 , and I Na1.5 are not functional and I NaCa is a background current in the model.
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