Talazoparib,a Poly(ADP-ribose) Polymerase Inhibitor,for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses

BackgroundThe phase II TALAPRO-1 study ({"type":"clinical-trial","attrs":{"text":"NCT03148795","term_id":"NCT03148795"}}NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib.Patients and MethodsMen received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs.ResultsIn the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127]).ConclusionCommon TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC.ClinicalTrials.gov identifier{"type":"clinical-trial","attrs":{"text":"NCT03148795","term_id":"NCT03148795"}}NCT03148795     

Worldwide Web: High Venom Potency and Ability to Optimize Venom Usage Make the Globally Invasive Noble False Widow Spider Steatoda nobilis (Thorell, 1875) (Theridiidae) Highly Competitive against Native European Spiders Sharing the Same Habitats

Venom compositions include complex mixtures of toxic proteins that evolved to immobilize/dissuade organisms by disrupting biological functions. Venom production is metabolically expensive, and parsimonious use is expected, as suggested by the venom optimisation hypothesis. The decision-making capacity to regulate venom usage has never been demonstrated for the globally invasive Noble false widow Steatoda nobilis (Thorell, 1875) (Theridiidae). Here, we investigated variations of venom quantities available in a wild population of S. nobilis and prey choice depending on venom availability. To partially determine their competitiveness, we compared their attack rate success, median effective dose (ED₅₀) and lethal dose (LD₅₀), with four sympatric synanthropic species: the lace webbed spider Amaurobius similis, the giant house spider Eratigena atrica, the missing sector orb-weaver Zygiella x-notata, and the cellar spider Pholcus phalangioides. We show that S. nobilis regulates its venom usage based on availability, and its venom is up to 230-fold (0.56 mg/kg) more potent than native spiders. The high potency of S. nobilis venom and its ability to optimize its usage make this species highly competitive against native European spiders sharing the same habitats.     

Nylon-fiber-induced neutrophil fragmentation

We have investigated the effects of mechanical elution of neutrophils from nylon-wool fiber (NWF) using the scanning electron microscope and biochemical analysis of elution fractions. We have determined that mechanical removal of neutrophils from nylon-wool fiber disrupts neutrophils adherent to nylon-wool fiber and augments release of granules, release of peripheral cytoplasmic fragments, and release of lactic dehydrogenase, a soluble cytoplasmic enzyme. Mechanical shearing of the adherent cell, and not adherence per se, causes the fragmentation. The extent of fragmentation is proportional to the NWF surface area available to neutrophils and is maximal at the temperature for optimal adherence and spreading. Agents that decrease cell spreading (n-ethylmaleimide and cold) diminish fragmentation. Cytochalasin B, an agent that destabilizes the neutrophil cortex, increases fragmentation. Fragmentation may be an important contributing cause of the abnormal morphology, function, and in vivo survival of nylon-wool-fiber procured human neutrophils. The prevention of fragmentation would appear to be necessary to insure the procurement of optimally functioning cells. Elution of NWF-adherent neutrophils in the cold might be a practical way to diminish neutrophil damage during clinical filtration leukapheresis.