Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the ...growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-β (TGF-β) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.
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An immunotherapeutic molecule, HCW9218, demonstrated anti-tumor efficacy by eliminating chemotherapy-induced senescent cells and reducing the off-target effects mediated by chemotherapy. HCW9218 represents a potent anti-cancer immunotherapeutic for use in combination with approved therapies to improve the health span and life span of treated patients.
The host employs both cell-autonomous and system-level responses to limit pathogen replication in the initial stages of infection. Previously, we reported that the eukaryotic initiation factor 2α ...(eIF2α) kinases heme-regulated inhibitor (HRI) and protein kinase R (PKR) control distinct cellular and immune-related activities in response to diverse bacterial pathogens. Specifically for
, there was reduced translocation of the pathogen to the cytosolic compartment in HRI-deficient cells and consequently reduced loading of pathogen-derived antigens on major histocompatibility complex class I (MHC-I) complexes. Here we show that
mice, as well as wild-type mice treated with an HRI inhibitor, are more susceptible to listeriosis. In the first few hours of
infection, there was much greater pathogen proliferation in the liver of
mice than in the liver of
mice. Further, there was a rapid increase of serum interleukin-6 (IL-6) levels in
mice in the first few hours of infection whereas the increase in IL-6 levels in
mice was notably delayed. Consistent with these
findings, the rate of listeriolysin O (LLO)-dependent pathogen efflux from infected
macrophages and fibroblasts was significantly higher than the rate seen with infected
cells. Treatment of cells with an eIF2α kinase activator enhanced both the HRI-dependent and PKR-dependent infection phenotypes, further indicating the pharmacologically malleability of this signaling pathway. Collectively, these results suggest that HRI mediates the cellular confinement and killing of virulent
in addition to promoting a system-level cytokine response and that both are required to limit pathogen replication during the first few hours of infection.
Indium gallium nitride (InGaN) samples were grown on sapphire substrate with low temperature GaN buffer by metalorganic chemical vapor deposition (MOCVD) under varying growth conditions, such as ...temperature, pressure and ammonia flow. Although high indium composition is considered as indispensable parameter for sheet carrier concentration (ns) and low sheet resistance (Rs), our outcomes disclose that higher indium composition in InGaN film doesn't always have high ns and low Rs. Acceptor nature of carbon related defects, a major trapping sites for electrons, plays a crucial role to limit the carrier concentrations in the InGaN specially grown at low pressure, low temperature and low ammonia flow. Furthermore, study of metal contacts deposited on the grown samples by transmission line method (TLM) shows that carrier concentration is the most important factor to obtain low contact resistance. The measured contact resistance for the sample with 4.5× 1016 cm2 carrier concentration is 0.13 Ωmm which is among the lowest contact resistance for GaN based materials grown by MOCVD. This proves that the use of InGaN in source and drain contact region can surpassingly reduce contact resistance and significantly improve device performance of AlGaN/GaN device.
●InGaN samples were grown on sapphire substrate with low temperature GaN buffer by MOCVD.●Higher indium composition in InGaN film doesn’t always have high carrier concentration and low sheet resistance.●Acceptor nature of carbon related defects, a major trapping sites for electrons, play a crucial role to limit the carrier concentrations in the InGaN.●The measured contact resistance for the sample with 4.5×1016 cm2 carrier concentration is 0.13 Ωmm which is among the lowest contact resistance.
Abstract
We have constructed two heterodimeric multi-cytokine fusions, HCW9201 and HCW9206, to support a “Kick and Expand” approach to activate and induce proliferation of purified NK cells for ...adoptive cell therapy (ACT). HCW9201 is a heterodimeric fusion protein complex comprising human IL-15 (complexed with an IL-15Rα-sushi domain), IL-18 and IL-12. HCW9206 is heterodimeric fusion protein comprising human IL-15 (complexed with an IL-15Rα-sushi domain), IL-7, and IL-21. When purified human NK cells from peripheral blood were activated with HCW9201 for three hours and then incubated with HCW9206 in combination with a capture antibody, the HCW9201-activated NK cells expanded approximately 100–300 folds within 14 days. The expanded NK cells exhibit a cytokine-induced memory-like (CIML) phenotype with a high metabolic rate and respiratory capacity, remarkable anti-tumor activity, and persistence when they were adoptively transferred into NSG mice. They also retained their heightened responsiveness when re-stimulated with tumor targets. Cytokine dependent epigenetic demethylation imprints of the Ifng promoter region were also observed for at least 10 days after the NK cells were adoptively transferred to NSG mice. In conclusion, a simple, scalable, non-feeder-cell-based “Kick and Expand” process was developed to support the generation of large numbers of CIML NK cells for multiple rounds of ACT using peripheral blood NK cell. We also provide data to show that these CIML NK cells are an excellent source for generation of CAR-NK cells.
Organic p‐type semiconductors with tunable structures offer great opportunities for hybrid perovskite solar cells (PVSCs). We report herein two dithieno3,2‐b:2′,3′‐dpyrrole (DTP) cored molecular ...semiconductors prepared through π‐conjugation extension and an N‐alkylation strategy. The as‐prepared conjugated molecules exhibit a highest occupied molecular orbital (HOMO) level of −4.82 eV and a hole mobility up to 2.16×10−4 cm2 V−1 s−1. Together with excellent film‐forming and over 99 % photoluminescence quenching efficiency on perovskite, the DTP based semiconductors work efficiently as hole‐transporting materials (HTMs) for n‐i‐p structured PVSCs. Their dopant‐free MA0.7FA0.3PbI2.85Br0.15 devices exhibit a power conversion efficiency over 20 %, representing one of the highest values for un‐doped molecular HTMs based PVSCs. This work demonstrates the great potential of using a DTP core in designing efficient semiconductors for dopant‐free PVSCs.
Dopant‐free hole transport materials (HTMs) are essential for commercialization of perovskite solar cells (PSCs). However, power conversion efficiencies (PCEs) of the state‐of‐the‐art PSCs with small ...molecule dopant‐free HTMs are below 20%. Herein, a simple dithieno3,2‐b:2′,3′‐dpyrrol‐cored small molecule, DTP‐C6Th, is reported as a promising dopant‐free HTM. Compared with commonly used spiro‐OMeTAD, DTP‐C6Th exhibits a similar energy level, a better hole mobility of 4.18 × 10−4 cm2 V−1 s−1, and more efficient hole extraction, enabling efficient and stable PSCs with a dopant‐free HTM. With the addition of an ultrathin poly(methyl methacrylate) passivation layer and properly tuning the composition of the perovskite absorber layer, a champion PCE of 21.04% is achieved, which is the highest value for small molecule dopant‐free HTM based PSCs to date. Additionally, PSCs using the DTP‐C6Th HTM exhibit significantly improved long‐term stability compared with the conventional cells with the metal additive doped spiro‐OMeTAD HTM. Therefore, this work provides a new candidate and effective device engineering strategy for achieving high PCEs with dopant‐free HTMs.
An ecological time-series study is conducted to quantify health-effect coefficients associated with climate-sensitive variables namely temperature, rainfall, relative humidity, and wind speed and ...estimate environmental burden of diseases attributed to temperature as the main climatic variable together with climate change in Nepal. The study is based upon daily data of climate-sensitive variables and hospitalizations collected for 5 years between 2009 and 2014. Generalized linear model is used to estimate health-effect coefficients accounting distributed lag effects. Results show 3.08%, 10.14%, and 3.27% rise in water-borne, vector-borne, and renal disease hospitalizations, respectively, and 3.67% rise in water- and vector-borne disease deaths per 1 °C rise in average temperature. Similarly, 2.45% and 1.44% rise in heart disease hospitalization and all-cause mortality, respectively per 1 °C rise in absolute difference of average temperature with its overall average (20 °C). The computed attributable fractions are 0.3759, 0.6696, 0.2909, and 0.1024 for water-borne, vector-borne, renal, and heart disease hospitalizations, respectively, and 0.0607 and 0.4335 for all-cause mortality and disease-specific mortality of water- and vector-borne diseases, respectively. The percent change in attributable burdens due to climate change are found to be 4.32%, 4.64%, 7.20%, and −2.29% for water-borne, vector-borne, renal, and heart disease hospitalizations, respectively, and −1.39% and 6.55% for all-cause deaths and water-borne and vector-borne disease deaths, respectively. In conclusion, climate-sensitive variables have significant effects on many major health burdens in Nepal. In the context of changing climatic scenarios around the world including that of Nepal, such changes are bound to affect the health burden of Nepalese people.
Abstract
Adoptive cell therapy (ACT) using NK cells is a promising armament in the fight against cancer. Cytokine induced memory like (CIML) NK cells have been shown in clinical studies to have ...potent antitumor activity with superior in vivo persistence. Currently, the expansion of NK cells for clinical development is mainly based on feeder cells, which imposes significant regulatory hurdles and increases the costs for manufacturing. We have developed fusion proteins, HCW9201 and HCW9206 comprising of IL-15/IL-18/IL-12 and IL15/IL-7/IL-21, respectively, capable of priming memory-like differentiation and expanding CIML NK cell products without using feeder cells. This “Kick and Expand” strategy allows greater than 100x expansion of CIML NK cells from donor PBMCs in as little as 14 days without the use of exogenous feeder cells. Continued expansion can yield sufficient CIML NK cells for cryopreservation and multiple ACT infusions. The NK cells generated have bona fide memory-like properties: enhanced antitumor activity across multiple cancer cell lines, higher metabolic capacity, stable epigenetic demethylation of the IFN-γ promoter and increased persistence in NSG mice, when compared to conventional NK cells. In conclusion, this “Kick and Expand” process supports generation of abundant CIML NK cells for multiple ACT infusions and provides simpler, more regulatory friendly, off-the-shelf platform for generating NK cell products, including those with chimeric antigen receptor (CAR) constructs.
Organic–inorganic metal halide perovskite solar cells (PSCs) exhibit excellent photovoltaic performance but have the drawbacks of instabilities against moisture and heat due to the inherent ...hydroscopic nature and volatility of their organic components. Herein, it is reported that using the block copolymer F127 as the passivation reagent in conjunction with the solvent annealing process can efficiently improve the performance and stability of corresponding organic–inorganic PSCs. It is anticipated that the hydrophilic poly(ethylene oxide) tails of F127 polymers connect with contiguous perovskite crystals and passivate defects at perovskite grain boundaries, whereas the dangling hydrophobic poly(phenyl oxide) centers suppress perovskite decomposition caused by moisture and heat. After the optimization of the F127 additive, planar PSCs with champion power conversion efficiencies of 21.01% and 18.71% are achieved on rigid and flexible substrates, respectively. The F127 passivation strategy provides an effective approach for fabricating high‐efficiency and stable PSCs.
A block copolymer F127 passivation strategy in conjunction with the solvent annealing process significantly enhances the performance and stability of planar perovskite solar cells. Hydrophilic tails of F127 passivate defects at grain boundaries through hydrogen bonding, whereas the dangling hydrophobic groups suppress perovskite decomposition against moisture and heat.
In this work, a new AlGaN/GaN vertical high electron mobility transistor (HEMT) with silicon oxide (SiO2) current blocking layer (CBL) is designed and studied numerically for high-power devices. To ...overcome the excessive vertical leakage through CBL layer in conventional p-GaN CBL vertical HEMT, large band-gap material, SiO2 is, for the first time, introduced as a CBL material. The band-gap of SiO2 leads to a large barrier which can effectively suppress the vertical leakage even at high drain bias and enhance the breakdown voltage to 1270 V (154% enhancement compared with the conventional p-GaN CBL vertical HEMT). In addition, a device with four parallel apertures is proposed to reduce the aperture resistance, where the total aperture thickness is equal to the aperture thickness of the conventional one. Therefore, the drain current is increased. We not only focus on the vertical leakage control, but also, on the drain current boost (7% improvement).
•Silicon oxide material for current blocking layer in vertical HEMTs.•Regrowth by pendeo epitaxial method.•Vertical leakage is effectively decreased.•Breakdown voltage is sufficiently high.•Multiple apertures can reduce on-state resistance and increase drain current.
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