Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune ...response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment was lost in Stinggt/gt mice, but not in Cgas−/− mice. Abolishing cGAMP production in Cgas−/− tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy.
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•Antibody blockade of MerTK prevents apoptotic cell clearance by macrophages•MerTK blockade induces tumor-cGAS- and host-STING-dependent type I IFN response•Extracellular ATP facilitates transfer of tumor-derived cGAMP to TAMs via P2X7R•MerTK blockade increases tumor immunogenicity and enhances anti-PD-1/PD-L1 therapy
Zhou et al. generate an antibody that selectively inhibits efferocytosis by the phagocytic receptor MerTK and show that MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity via the transfer of tumor-derived cGAMP into tumor-associated macrophages (TAMs) through the ATP-gated channel P2X7R and subsequent STING activation.
We are interested in identifying mechanisms of resistance to the current generation of antibody-drug conjugates (ADC) and developing ADCs that can overcome this resistance.
Pinatuzumab vedotin ...(anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin lymphoma (NHL); however, some patients do not respond or become resistant to the ADCs. Anthracyclines are very effective in NHL, but ADCs containing the anthracycline doxorubicin were not clinically efficacious probably due to the low drug potency and inadequate linker technology. The anthracycline analogue PNU-159682 is thousands of times more cytotoxic than doxorubicin, so we used it to develop a new class of ADCs. We used the same MC-vc-PAB linker and antibody in pinatuzumab vedotin but replaced the MMAE with a derivative of PNU-159682 to make anti-CD22-NMS249 and tested it for in vivo efficacy in xenograft tumors resistant to MMAE-based ADCs.
We derived cell lines from in vivo xenograft tumors that were made resistant to anti-CD22-vc-MMAE and anti-CD79b-vc-MMAE. We identified P-gp (ABCB1/MDR1) as the major driver of resistance to the vc-MMAE-based conjugates. Anti-CD22-NMS249 was at least as effective as anti-CD22-vc-MMAE in xenograft models of the parental cell lines and maintained its efficacy in the resistant cell lines.
These studies provide proof of concept for an anthracycline-based ADC that could be used to treat B-cell malignancies that are resistant to vc-MMAE conjugates.
ObjectivesTo find out and explore the knowledge and opinion of Chinese people on cardiovascular disease and awareness of cardiac rehabilitation.DesignA cross-sectional study using 14-item bilingual ...(Chinese and English) questionnaires that include information on demographics, health status, cardiovascular disease related knowledge and perception, and awareness and understanding of the cardiac rehabilitation programme.SettingChinese community groups in the Midlands, UK from January to April 2008.Participants436 questionnaires from Chinese adults over 18 were obtained.Main outcome measuresCurrent knowledge and attitude towards cardiovascular disease and awareness of cardiac rehabilitation.ResultsObesity was the most common risk factor identified by 80.7% of participants. Those originated from China had significantly less knowledge compared with subjects from other countries (p<0.001). People who have had exposure or experience of cardiac disease rated a higher risk of cardiac disease for Chinese living in the UK than people without experience. A majority (81.7%) used orthodox medicine and perceived it to be most effective against cardiac disease. Only 30% of participants were aware of cardiac rehabilitation.ConclusionThe coronary artery disease (CAD) risk factors of Chinese population have increased significantly in the last decade. Cardiac rehabilitation awareness was poor among the sample population of this study and language barrier is still a problem. More large studies on Chinese population assessing CAD risk should be done to provide more evidence on CAD prevention for this growing population in the Western world.
Antibody–drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ...ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine–citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.
Previous investigations on antibody-drug conjugate (ADC) stability have focused on drug release by linker-deconjugation due to the relatively stable payloads such as maytansines. Recent development ...of ADCs has been focused on exploring technologies to produce homogeneous ADCs and new classes of payloads to expand the mechanisms of action of the delivered drugs. Certain new ADC payloads could undergo metabolism in circulation while attached to antibodies and thus affect ADC stability, pharmacokinetics, and efficacy and toxicity profiles. Herein, we investigate payload stability specifically and seek general guidelines to address payload metabolism and therefore increase the overall ADC stability. Investigation was performed on various payloads with different functionalities (e.g., PNU-159682 analog, tubulysin, cryptophycin, and taxoid) using different conjugation sites (HC-A118C, LC-K149C, and HC-A140C) on THIOMAB antibodies. We were able to reduce metabolism and inactivation of a broad range of payloads of THIOMAB antibody-drug conjugates by employing optimal conjugation sites (LC-K149C and HC-A140C). Additionally, further payload stability was achieved by optimizing the linkers. Coupling relatively stable sites with optimized linkers provided optimal stability and reduction of payloads metabolism in circulation in vivo.
Organic pollutants such as polyaromatic hydrocarbons are harmful to wildlife and the environment. To clean up accidental releases of hydrocarbon pollutants so they do not negatively affect living ...organisms, remediation of the pollutant is necessary. Bioremediation is an alternative to physical and chemical methods of environmental decontamination such as incineration, catalytic hydrolysis, the use of adsorbents, and the physical removal of the polluted substrate. Bioremediation pathways can be studied in mesocosms that mimic environmental conditions and therefore can provide information about the effectiveness of a remediation technique at specific environmental sites. In this study, a series of mesocosms were created with increasing amounts of contaminant (diesel fuel) under controlled environmental conditions to replicate an environmental spill in deep soil. Each mesocosm was spiked with a culture of Pseudomonas putida mt-2, which is a known aromatic hydrocarbon degrader. Mesocosms constructed with soil from the Adelphi University campus showed the highest gene copy number of a gene encoding a hydrocarbon degrading 2, 3-catechol dioxygenase at 5 ml diesel per 100 g of soil (vol/wt). Mesocosms constructed with peat soil showed highest copy number of 2, 3-catechol dioxygenase genes with addition of 10 ml diesel per 100 g soil. Evidence shows that even at high concentrations of diesel (10%), the levels of 2, 3-catechol dioxygenase gene copy number is high. This observation was contrary to what was expected, and shows that even under diesel saturated conditions, P. putida mt-2 is able to persist and to contribute to an overall increase in prevalence of 2, 3-catecol dioxygenase genes in the environments examined in this study.
A Novel 4-to-1 Switched-Capacitor Converter Lau, Kin Keung Jeff; Choi, Jaesoon; Choi, Seokmum ...
2021 IEEE Applied Power Electronics Conference and Exposition (APEC),
2021-June-14
Conference Proceeding
This paper presents a novel patent pending 4-to-1 switched-capacitor converter (SCC) for fixed ratio step down conversion applications. Optimization method is introduced to get the maximum efficiency ...at target output current. This shows the optimized region of operation that set up a performance comparison framework. Analysis shows that the proposed topology has performance advantages over the other four popular topologies. The proposed work is designed in 130nm technology and achieves 96.7% efficiency at 8A output current. Two 16-to-4V SCC prototypes for smart phone application using discrete switches are built and tested. Doubler cascade (existing commercial solution) shows 95.1% peak efficiency (including gate driving loss) and 93.2% at 12A output current. The proposed topology achieves 95.8% peak efficiency (including gate driving loss) and 94.1% at 12A output current. The proposed topology can be generalized to any exponential ratio of conversion like doubler topology in multiple cascade stages.
A compact, accurate sub-1V low impedance, low dropout bandgap reference is presented in this paper. Firstly, a new 1V bandgap core (corel) is introduced by the simple addition of two resistors to the ...generic core. Using this concept, an improved version (core 2) is presented to generate a sub-1V(0.9V in the design example) bandgap reference that can be set from a bit above Vbe, up to the normal bandgap voltage. Both cores are in low dropout and low output impedance configurations. The circuit idea is realized in 90nm BiCMOS technology. Simulation results show that over a 200oC temperature range, core 1 can achieve 20ppm over line and load regulation. Core 2 can achieve 15ppm over line and load regulation. Both cores can be realized in a CMOS process using parasitic PNP devices.
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