Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer

Importance: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration–approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC. Objective: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC. Design, Settings, and Participants: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies. Interventions: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects. Main Outcomes and Measures: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity. Results: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit. Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02912572</p

High density and super ultra-microporous-activated carbon macrospheres with high volumetric capacity for CO2 capture

Activated carbon (AC) spheres with a diameter of 1.0–2.0 mm are synthesized from coal tar pitch for postcombustion carbon capture. The as-prepared AC macrospheres after KOH activation are found to possess extraordinarily developed microporosity of which 87% is ultra-microporosity with pore diameters less than 0.8 nm. Despite the relatively low surface area of just 714 m2 g−1 with a pore volume of 0.285 cm3 g−1, the macrospherical carbon adsorbents achieve exceedingly high CO2 uptake capacities of 3.15 and 1.86 mmol g−1 at 0 and 25 °C, respectively, with a CO2 partial pressure of 0.15 bar. Cyclic lifetime performance testing demonstrates that the CO2 uptake is fully reversible with fast adsorption and desorption kinetics. More importantly, due to their high bulk density of ≈1.0 g cm−3, the AC macrospheres exhibit extremely high volumetric CO2 uptakes of up to 81.8 g L−1 at 25 °C at 0.15 bar CO2, which represents the highest value ever reported for ACs. The high ultra-microporosity coupled with the potassium-modified physiochemical surface properties is found to be responsible for the outstanding CO2 adsorption performance of the pitch-based AC macrospheres

QCR7 affects the virulence of Candida albicans and the uptake of multiple carbon sources present in different host niches

BackgroundCandida albicans is a commensal yeast that may cause life-threatening infections. Studies have shown that the cytochrome b-c1 complex subunit 7 gene (QCR7) of C. albicans encodes a protein that forms a component of the mitochondrial electron transport chain complex III, making it an important target for studying the virulence of this yeast. However, to the best of our knowledge, the functions of QCR7 have not yet been characterized.MethodsA QCR7 knockout strain was constructed using SN152, and BALb/c mice were used as model animals to determine the role of QCR7 in the virulence of C. albicans. Subsequently, the effects of QCR7 on mitochondrial functions and use of carbon sources were investigated. Next, its mutant biofilm formation and hyphal growth maintenance were compared with those of the wild type. Furthermore, the transcriptome of the qcr7Δ/Δ mutant was compared with that of the WT strain to explore pathogenic mechanisms.ResultsDefective QCR7 reduced recruitment of inflammatory cells and attenuated the virulence of C. albicans infection in vivo. Furthermore, the mutant influenced the use of multiple alternative carbon sources that exist in several host niches (GlcNAc, lactic acid, and amino acid, etc.). Moreover, it led to mitochondrial dysfunction. Furthermore, the QCR7 knockout strain showed defects in biofilm formation or the maintenance of filamentous growth. The overexpression of cell-surface-associated genes (HWP1, YWP1, XOG1, and SAP6) can restore defective virulence phenotypes and the carbon-source utilization of qcr7Δ/Δ.ConclusionThis study provides new insights into the mitochondria-based metabolism of C. albicans, accounting for its virulence and the use of variable carbon sources that promote C. albicans to colonize host niches

Gas storage

International audienceThe continuous increase of energy demands based on fossil fuels in the last years have lead to an increase of greenhouse gases (GHG) emission which strongly contribute to global warming. The main strategies to limit this phenomenon are related to the efficient capture of these gases and to the development of renewable energies sources with limited environmental impact. Particularly, carbon dioxide (CO2) and methane (CH4) are the main constituents of greenhouse gases while hydrogen (H2) is considered an alternative clean energy source to fossil fuels. Therefore, tremendous research to store these gases has been reported by several approaches and among them the physisorption on activated carbons (AC) have received significant attention. Their abundance, low cost and tunable porous structure and chemical functionalities with an existing wide range of precursors that includes bio-wastes make them ideal candidates for gas applications. This chapter presents the recent developments on CH4, CO2 and H2 storage by activated carbons with focus on biomass as precursor materials. An analysis of the main carbon properties affecting the AC's adsorption capacity (i.e. specific surface area, pore size and surface chemistry) is discussed in detail herein

Supercapacitors (electrochemical capacitors)

International audienceRapid development of the technologies based on electric energy in the last decades have stimulated intensive research on efficient power sources. Electrochemical energy conversion and storage systems are based on Faradaic reactions (charge transfer) and electrostatic attraction of ions at the electrode/electrolyte interface. The latter might be an interesting solution for applications requiring moderate energy density, high power rates, and long cycle life. Electrochemical capacitors (ECs) store the charge in a physical manner, hence, their energy density is moderate. At the same time, the lack of electrochemical reactions ensures very high power and long cycle life compared to batteries. Activated carbons with their versatile properties (like specific surface area, well-developed and suitable porosity, heteroatoms in the graphene matrix) are the most popular materials in EC application. This chapter provides a comprehensive overview of the carbon-based materials recently developed, with special attention devoted to those obtained by biomass carbonization and activation. Electrochemical properties demonstrated by such carbons are discussed in respect to their physicochemical characteristic

The Effects of Cytokines in Adipose Stem Cell-Conditioned Medium on the Migration and Proliferation of Skin Fibroblasts In Vitro

Although adipose stem cell-conditioned medium (ASC-CM) has demonstrated the effect of promoting the cutaneous wound healing, the mechanism for this response on the effector cells (e.g., dermal fibroblasts) during the process remains to be determined. In this study, we aim to investigate the types and contents of cytokines in ASC-CM and the effects of some kinds of common cytokines in ASC-CM, such as EGF, PDGF-AA, VEGF, and bFGF, on dermal fibroblasts proliferation and migration in wound healing process. Results showed that these four cytokines had high concentrations in ASC-CM. The migration of skin fibroblasts could be significantly stimulated by VEGF, bFGF, and PDGF-AA, and the proliferation could be significantly stimulated by bFGF and EGF in ASC-CM. Additionally, ASC-CM had more obvious promoting effect on fibroblasts proliferation and migration than single cytokine. These observations suggested that ASC-CM played an important role in the cutaneous injury partly by the synergistic actions of several cytokines in promoting dermal fibroblasts proliferation and migration, and ASC-CM was more adaptive than each single cytokine to be applied in promoting the wound healing