Surface Science and Engineering for Electrochemical Materials.

ConspectusIn electrochemical energy storage systems, the reversible storage capacity of battery materials often degrades due to parasitic reactions at the electrode-electrolyte interface, transitional metal dissolution, and metallic dendrite growth at the surface. Surface engineering techniques offer the opportunity to modify the composition and structure of a surface, thereby enabling control over chemical reactions occurring at the surface and manipulating chemical interactions at the solid-solid or solid-liquid interface. These modifications can help stabilize the surface of electrode materials and prevent unwanted reactions with electrolytes without changing the original properties of the bulk structure. This allows for achieving full theoretical capacity and maximizing battery material capacity retention with minimal overpotentials. In the past decade, our teams have been working on developing a variety of surface engineering techniques. These include applying atomic and molecular layer deposition (ALD and MLD), templating, doping, and coating via wet-chemical processes to stabilize the surfaces of electrode materials. The aim is to mitigate parasitic side-reactions without impeding charge transfer kinetics, suppress dendrite growth, and ultimately improve the electrode performance.This Account summarizes the research conducted in our research laboratory with an aim to improve battery cycling durability and efficiency by modifying electrode surfaces. We have employed techniques such as ALD, MLD, templating, and wet-chemical processes to illustrate how the stabilized surface improves the performance of lithium-ion (Li-ion), solid-state electrolytes and magnesium-metal (Mg-metal) batteries. For instance, by applying ultrathin layers of inorganic (e.g., Al2O3) or organic-inorganic coatings (e.g., alucone, lithicone, and polyamides) to the surface of LiNixMnyCozO2 (x + y + z = 1, NMC) and silicon (Si) electrodes─usually just a few angstroms or nanometers thick─we have observed notable improvements in cycling efficiency and durability. When using ultrathick electrodes, the traditional electrode fabrication has a problem with high tortuosity, which hinders both rate capability and long-term cycling. To solve this issue, three-dimensional templates have been employed to reduce electrode tortuosity, enabling high-rate performance and long-term cycling. In the case of Mg-metal batteries, the buildup of an insulating MgO layer due to side reactions with electrolytes blocks Mg2+ ion transport, which can ultimately cause the battery to fail. To address this issue, we have developed an artificial solid-electrolyte interface using cyclized polyacrylonitrile and magnesium trifluoromethanesulfonate. This interface prevents the reduction of the carbonate electrolyte while allowing Mg2+ diffusion, ultimately boosting overall cell performance.This Account also discusses the significance of choosing suitable materials and effective surface engineering methods with the objective of enhancing surface properties while preserving the bulk properties of the electrodes. It is believed that surface modification and engineering can not only significantly improve the electrochemical performance of existing battery materials but also facilitate the development of new battery materials that were previously incompatible with current electrolytes. By highlighting these aspects, this Account underscores the transformative potential of surface modification and engineering in battery technology, paving the way for future innovations in energy storage solutions.

A model of pregnancy-associated malaria for inducing adverse pregnancy outcomes in ICR mouse.

BACKGROUND: Based on understanding of placental pathological features and safe medication in pregnancy-associated malaria (PAM), establishment of a stable pregnant mouse infection model with Plasmodium was urgently needed. METHODS: ICR mice with vaginal plugs detected were randomly divided into post-pregnancy infection (Malaria+) and uninfected pregnancy (Malaria-) cohorts. Age-matched mice that had not been mated were infected as pre-pregnancy infection group (Virgin control), which were subsequently mated with ICR males. All mice were inoculated with 1 × 106Plasmodium berghei ANKA-infected RBCs by intraperitoneal injection, and the same amount of saline was given to Malaria- group. We recorded the incidence of adverse pregnancy outcomes and the amounts of offspring in each group. RESULTS: The Virgin group mice were unable to conceive normally, and vaginal bleeding, abortion, or stillbirth appeared in the Malaria+ group. The incidence of adverse pregnancy outcomes was extremely high and statistically significant compared with the control (Malaria-) group (P < 0.05), of which placenta exhibited pathological features associated with human gestational malaria. CONCLUSIONS: The intraperitoneal injection of 1 × 106Plasmodium berghei ANKA-infected RBCs could establish a model of pregnancy-associated malaria in ICR mouse.

Case Report and Literature Review: Orthostatic Hypotension Due to Multiple System Atrophy.

Objective: Multiple system atrophy (MSA) is a rare and fatal adult-onset neurodegenerative disease with multiple clinical and pathological variants. The etiology of MSA remains uncertain. Orthostatic hypotension (OH) is the main characteristic of MSA. An upright position can trigger a syncope attack, making it impossible for the patient to stand and walk briefly. Case Study: We report the case of a 67-year-old man with initial symptoms of recurrent syncope and this patient was hospitalized several times, despite multiple therapeutic interventions, his symptoms persisted. Eventually, this patient died at the age of 68 with a diagnosis of MSA. Conclusion: For those patients with neurogenic OH, an underlying neurodegenerative disease should always be considered. Prompt diagnosis, early aggressive treatment, and prediction of complications may have a huge impact on the prognosis of MSA. This article also reviews relevant reported cases to enrich the experience of treating MSA in the clinic.

Chemokine Receptors CCR6 and PD1 Blocking scFv E27 Enhances Anti-EGFR CAR-T Therapeutic Efficacy in a Preclinical Model of Human Non-Small Cell Lung Carcinoma.

Chimeric antigen receptor (CAR)-T cells, a therapeutic agent for solid tumors, are not completely effective due to a lack of infiltration of T cells into the tumor site and immunity caused by Programmed Death Receptor 1(PD1). Here, an epidermal growth factor receptor (EGFR) CAR-T cell was engineered to express the chemokine receptor CCR6 and secrete PD1 blocking Single-chain antibody fragment (scFv) E27 to enhance their anti-tumor effects. The findings showed that CCR6 enhanced the migration of EGFR CAR-E27-CCR6 T cells in vitro by the Transwell migration assay. When incubated with tumor cells, EGFR CAR-E27-CCR6 T cells specifically exerted potent cytotoxicity and produced high levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), and interferon-γ (IFN-γ). A non-small cell lung carcinoma (NSCLC) cell line-derived xenograft model was constructed by implanting modified A549 cell lines into immunodeficient NOD.PrkdcscidIl2rgem1/Smoc (NSG) mice. In comparison with traditional EGFR CAR-T cells, live imaging indicated that EGFR CAR-E27-CCR6 T cells displayed superior anti-tumor function. In addition, the histopathological examination of mouse organs showed no obvious organic damage. Our findings confirmed that PD1 blocking and CCR6 can enhance the anti-tumor function of EGFR CAR-T cells in an NSCLC xenograft model, providing an effective treatment strategy to improve the efficacy of CAR-T in NSCLC.

n-type charge transport in heavily p-doped polymers.

It is commonly assumed that charge-carrier transport in doped π-conjugated polymers is dominated by one type of charge carrier, either holes or electrons, as determined by the chemistry of the dopant. Here, through Seebeck coefficient and Hall effect measurements, we show that mobile electrons contribute substantially to charge-carrier transport in π-conjugated polymers that are heavily p-doped with strong electron acceptors. Specifically, the Seebeck coefficient of several p-doped polymers changes sign from positive to negative as the concentration of the oxidizing agents FeCl3 or NOBF4 increase, and Hall effect measurements for the same p-doped polymers reveal that electrons become the dominant delocalized charge carriers. Ultraviolet and inverse photoelectron spectroscopy measurements show that doping with oxidizing agents results in elimination of the transport gap at high doping concentrations. This approach of heavy p-type doping is demonstrated to provide a promising route to high-performance n-type organic thermoelectric materials.

PEBP1 suppresses HIV transcription and induces latency by inactivating MAPK/NF-κB signaling.

The latent HIV-1 reservoir is a major barrier to viral eradication. However, our understanding of how HIV-1 establishes latency is incomplete. Here, by performing a genome-wide CRISPR-Cas9 knockout library screen, we identify phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitor protein (RKIP), as a novel gene inducing HIV latency. Depletion of PEBP1 leads to the reactivation of HIV-1 in multiple models of latency. Mechanistically, PEBP1 de-phosphorylates Raf1/ERK/IκB and IKK/IκB signaling pathways to sequestrate NF-κB in the cytoplasm, which transcriptionally inactivates HIV-1 to induce latency. Importantly, the induction of PEBP1 expression by the green tea compound epigallocatechin-3-gallate (EGCG) prevents latency reversal by inhibiting nuclear translocation of NF-κB, thereby suppressing HIV-1 transcription in primary CD4+ T cells isolated from patients receiving antiretroviral therapy (ART). These results suggest a critical role for PEBP1 in the regulation of upstream NF-κB signaling pathways governing HIV transcription. Targeting of this pathway could be an option to control HIV reservoirs in patients in the future.

Strategies to Enable Reversible Magnesium Electrochemistry: From Electrolytes to Artificial Solid-Electrolyte Interphases.

The first prototype of a rechargeable magnesium (Mg) battery demonstrated two decades ago sparked tremendous interest in the electrochemical community due to their potential low cost, high volumetric energy density. However, the development of rechargeable Mg batteries has been hampered by the incompatibility between the Mg-metal anode and conventional carbonate electrolytes. Research has focused on electrolytes that are thermodynamically stable against reduction at the expense of low oxidation potential at the cathode side. Alternatively, the use of an artificial solid-electrolyte interphase (SEI) via surface coating presents promising results to address the Mg/electrolyte incompatibility and significantly broaden the selection of electrolytes. This minireview discusses the limitations of electrolyte development and strategies for the design of artificial interphases in magnesium-ion batteries. Future perspectives in the development of artificial interphases for rechargeable magnesium batteries are also discussed.

Enhanced Near-Infrared-to-Visible Upconversion by Synthetic Control of PbS Nanocrystal Triplet Photosensitizers.

Photon upconversion employing semiconductor nanocrystals (NCs) makes use of their large and tunable absorption to harvest light in the near-infrared (NIR) wavelengths as well as their small gap between singlet and triplet excited states to reduce energy losses. Here, we report the highest QY (11.8%) thus far for the conversion of NIR to yellow photons by improving the quality of the PbS NC. This high QY was achieved by using highly purified lead and thiourea precursors. This QY is 2.6 times higher than from NCs prepared with commercially available lead and sulfide precursors. Transient absorption spectroscopy reveals two reasons for the enhanced QY: longer intrinsic exciton lifetimes of PbS NCs and the ability to support a longer triplet lifetime for the surface-bound transmitter molecule. Overall, this results in a higher efficiency of triplet exciton transfer from the PbS NC light absorber to the emitter and thus a higher photon upconversion QY.

Correction: Effects of graphene oxide size on curing kinetics of epoxy resin.

[This corrects the article DOI: 10.1039/D1RA05234A.].

Application of multiple occupational health risk assessment models in occupation health risk prediction of trichloroethylene in the electroplating and electronics industries.

Objectives. This study assessed the occupational health risks of work group exposure to trichloroethylene (TCE) in the electroplating and electronics industries in China. Methods. The UK Control of Substances Hazardous to Health (COSHH) Essential, the US Environmental Protection Agency (EPA) and the Singapore and the Chinese semiquantitative risk assessment models were used to assess the risks of TCE. Twenty degreasing groups and 14 cleaning groups were recruited in the companies selected. Results. The concentrations of TCE in 66.7% of the cleaning groups and 35.0% of the degreasing groups exceeded the permissible concentration time-weighted average (PC-TWA) in China, and the concentrations of TCE in 100.0% of the cleaning groups and 70.0% of the degreasing groups exceeded the permissible concentration short-term exposure limit (PC-STEL) in China. Over 60.0% of the work groups were evaluated at high risk and over half of the work groups were evaluated at high cancer risk by the risk assessment models. Conclusion. Most work groups exposed to TCE in the electroplating and electronics industries in China are at high risk. The cleaning groups may have a higher risk for TCE exposure. The Chinese exposure index method and the synthesis index method are more practical than the other methods.

Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells invivo.

HIV-specific chimeric antigen receptor (CAR) T-cells have been developed to target HIV-1 infected CD4+ T-cells that express HIV Env proteins. However, T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27 (3BE) CAR construct that enabled the expression of programmed cell death protein (PD-1) -blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env. Compared with T cells expressing 3BNC117-CAR alone, 3BE CAR-T cells showed greater cytotoxic activity against HIV Env+ cells with stronger proliferation capability, higher killing efficiency, and enhanced cytokine secretion in the presence of HIV Env-expressing cells. Furthermore, we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env â€‹+ â€‹cells in vivo without the occurrence of severe graft-versus-host disease (GvHD) in NSG mice. These data suggest that we have provided a feasible approach to the generation of "off-the-shelf" anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy, which can be a powerful therapeutic candidate for the functional cure of HIV.

Selenomethionine Alleviates Intestinal Ischemia-Reperfusion Injury in Mice Through the Bax-Caspase Pathway.

Selenomethionine (SeMet) is known to alleviate ischemia-reperfusion (I/R) injury. However, its details of action have not been thoroughly elucidated in mice with intestinal I/R injury. In this study, intestinal I/R injury mice models were established, and ELISAs were performed to determine the levels of redox factors, including glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA), in mice intestinal tissues. Furthermore, several apoptosis-related markers, such as cytochrome c (Cyt-c), Bcl-2, and Bax, were detected using qPCR and Western blotting, while caspase-3 was detected using Western blotting alone. The results showed that SeMet alleviated I/R damage by increasing GSH-Px, CAT, and SOD levels and reducing MDA levels. Our data demonstrated that SeMet reduced I/R injury and inhibited the expression of Cyt-c, Bax, and caspase-3. SeMet also increased the expression of Bcl-2 in the intestinal tissues of mice. In addition, the TUNEL assay results showed that SeMet mitigated apoptosis in the villi cells of the intestinal mucosa. The findings also revealed that I/R could lead to increased apoptosis levels and that SeMet alleviated I/R-induced apoptosis by mediating the Bax/cytochrome C/caspase-3 apoptotic signaling pathways in the intestinal I/R injury mice models. Thus, SeMet inhibited apoptosis and resulted in an increase of Bcl-2 levels; downregulated the expression of Bax, Cyt-c, and caspase-3; and alleviated the intestinal ischemia injury in mice. The I/R injury increased the cytosolic Bax, Cyt-c, and caspase-3 levels and significantly decreased Bcl-2 expression levels in the I/R group, compared to the Sham group. However, the levels of all markers were reversed post-SeMet pre-treatment.

Teaching Reform to the Biology Major During the COVID-19 Pandemic: A Study of the Method of Teaching Industrial Innovation and Entrepreneurial Talents.

The biology major has developed rapidly in recent years. Biology is a science that penetrates every aspect of human life and is one of the core majors in most agricultural colleges and universities. However, many teachers lack practical experience in the subject. To overcome this problem, in recent years, we have been trying to introduce new reforms into our teaching. This article provides some insight into the way that biology majors have been reformed, which will help educators in agricultural colleges and universities. At present, teachers implement the "Industrial Innovation and Entrepreneurship Talent Cultivation" (IIETC) model, but it is not clear whether this helps biology majors to master the course and improve their practical skills. In this study, the IIETC model is outlined, and the academic achievement and satisfaction of students taught under the IIETC model are assessed. A T-test is used to examine potential differences between IIETC and traditional teaching models. In-depth interviews and questionnaires were given to two groups of students who followed different teaching models as part of an exploratory study. The aim was to explore how effective IIETC is at helping biology majors master the course and improve students' wellbeing. Our results show that compared with traditional teaching methods, the IIETC model has a significant positive impact on the academic performance and happiness of biology students. Students trained under the IIETC model were more active and scored more highly in their final exams. They were more likely to feel that they had achieved success and happiness through the course (P = 0.03). The outcomes of this research reveal a novel teaching reform that improved students' enthusiasm for innovation and entrepreneurship during the ongoing COVID-19 pandemic. The effects are very encouraging and deserve further exploration and expansion in future work.

EK-16A liposomes enhance HIV replication in ACH2 or J-Lat 10.6 cell engrafted NSG mice.

Background: Numbers of HIV latency reversal agents (LRAs) have been tested in clinical trials, but with limited effect. EK-16A is an ingenol derivative that isolated from Euphorbia kansui. Our prior studies have suggested that it could reactivate latent HIV and meanwhile inhibit HIV infection in vitro. Here, we further advanced the research in vivo. Methods:In vitro, the activity of EK-16A liposomes was measured in HIV latently infected cells. In serum pharmacology test, BALB/c mice were orally administered with EK-16A liposomes, serum was separated and co-cultured with cells, HIV reactivation was measured. In vivo, NSG mice were transplanted with human cells for 3 weeks and then administered with EK-16A liposomes for 3 days. In ACH2 cell engrafted NSG mice, P24 in plasma and cell-associated HIV RNA in tissues was measured. In J-Lat 10.6 cell engrafted NSG mice, GFP expression of J-Lat 10.6 cells in diverse tissues was measured. Hematoxylin and eosin (HE) staining was carried out for histopathological examination in both mice. Results: EK-16A liposomes can reactivate latent HIV in ACH2 and J-Lat 10.6 cells. Serum pharmacological test showed that EK-16A retained activity after oral administration. Importantly, in ACH2 cell engrafted NSG mice, EK-16A liposomes increased the secretion of P24 in plasma and the expression of cell-associated HIV RNA in tissues. In J-Lat 10.6 cell engrafted NSG mice, EK-16A liposomes increased the GFP expression of J-Lat 10.6 cells in diverse tissues, including the bone marrow, spleen, liver, lung and peripheral blood. Furthermore, there was no obvious histopathological change associated with the use of EK-16A liposomes in both mice. Conclusions: Our results confirmed the enhancing HIV replication activity and preliminary security of EK-16A in human cell engrafted NSG mice, laying the foundation for research in clinical trials.

Reduction of Pre-Existing Adaptive Immune Responses Against SaCas9 in Humans Using Epitope Mapping and Identification.

The CRISPR-Cas9 system is increasingly being used as a gene editing therapeutic technique in complex diseases but concerns remain regarding the clinical risks of Cas9 immunogenicity. In this study, we detected antibodies against Staphylococcus aureus Cas9 (SaCas9) and anti-SaCas9 T cells in 4.8% and 70% of Chinese donors, respectively. We predicted 135 SaCas9-derived B cell epitopes and 50 SaCas9-derived CD8+ T cell epitopes for HLA-A*24:02, HLA-A*11:01, and HLA-A*02:01. We identified R338 as an immunodominant SaCas9 B cell epitope and SaCas9_200-208 as an immunodominant CD8+ T cell epitope for the three human leukocyte antigen allotypes through immunological assays using sera positive for SaCas9-specific antibodies and peripheral blood mononuclear cells positive for SaCas9-reactive T cells, respectively. We also demonstrated that an SaCas9 variant bearing an R338G substitution reduces B cell immunogenicity and retains its gene-editing function. Our study highlights the immunological risks of the CRISPR-Cas9 system and provides a solution to mitigate pre-existing adaptive immune responses against Cas9 in humans.

The neutralization of B.1.617.1 and B.1.1.529 sera from convalescent patients and BBIBP-CorV vaccines.

The SARS-CoV-2 variants B.1.617.1 (Kappa) contain multiple mutations in the spike protein. However, the effect of B.1.617.1 lineage-related mutants on viral infectivity and inactivated-virus vaccine efficacy remains to be defined. We therefore constructed 12 B.1.617.1-related pseudoviruses and systematically studied the effects of mutations on virus infectivity and neutralization resistance to convalescent and inactivated virus vaccine sera. Our results show that the B.1.617.1 variant exhibited both higher infectivity and neutralization resistance in sera at 1 or 3 months after vaccination of 28 individuals and at 14 and 200 days after discharge of 15 convalescents. Notably, 89% of vaccines and 100% of the convalescent serum samples showed more than 2.5-fold reduction in neutralization against one single mutation: E484Q. Besides, we found a significant decrease in neutralizing activity in convalescent patients and BBIBP-CorV vaccines for B.1.1.529. These findings demonstrate that inactivated-virus vaccination or convalescent sera showed reduced, but still significant, neutralization against the B.1.617.1 variant.

Neutralization of five SARS-CoV-2 variants of concern by convalescent and BBIBP-CorV vaccinee serum.

The prevalence of SARS-CoV-2 variants of concern (VOCs) is still escalating throughout the world. However, the level of neutralization of the inactivated viral vaccine recipients' sera and convalescent sera against all VOCs, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron) remains to be lack of comparative analysis. Therefore, we constructed pseudoviruses of five VOCs using a lentiviral-based system and analyzed their viral infectivity and neutralization resistance to convalescent and BBIBP-CorV vaccinee serum at different times. Our results show that, compared with the wild-type strain (WT), five VOC pseudoviruses showed higher infection, of which B.1.617.2 and B.1.1.529 variant pseudoviruses exhibited higher infection rates than wild-type or other VOC strains, respectively. Sera from 10 vaccinated individuals at the 1, 3 and 5-month post second dose or from 10 convalescent at 14 and 200 days after discharge retained neutralizing activity against all strains but exhibited decreased neutralization activity significantly against the five VOC variant pseudoviruses over time compared to WT. Notably, 100% (30/30) of the vaccinee serum samples showed more than a 2.5-fold reduction in neutralizing activity against B.1.1.529, and 90% (18/20) of the convalescent serum samples showed more than 2.5-fold reduction in neutralization against B.1.1.529. These findings demonstrate the reduced protection against the VOCs in vaccinated and convalescent individuals over time, indicating that it is necessary to have a booster shot and develop new vaccines capable of eliciting broad neutralization antibodies.

Effects of graphene oxide size on curing kinetics of epoxy resin.

To study the effects of graphene oxide (GO) size on the curing kinetics of epoxy resin (EP), two kinds of GO were selected and characterized by Fourier transform infrared spectrometry (FT-IR), FT-Raman spectrometry (FTIR-Raman), thermo gravimetric analysis (TGA), dynamic light scattering (DLS), transmission electron microscopy (TEM), X-ray diffractometry (XRD) and X-ray photoelectron spectroscopy (XPS). The results showed that the two kinds of GO had similar chemical structures but different sizes-the average particle size of GO-A was 190.1 nm and that of GO-B was 1510 nm, and GO-A has more oxidizing groups on its surface. The two kinds of GO were separately added to EP, and the curing kinetics of GO/EP composites and neat EP were investigated through differential scanning calorimetry (DSC). It can be seen that the addition of GO promoted the curing process of the EP system, and GO-A had a more significant catalytic effect. Furthermore, the curing activation energy (E a) was calculated by Kissinger model, and the change of E a in the whole curing reaction process was studied by Ozawa method to further understand the curing mechanism. It showed that the apparent E a of EP system increases with the increase of the conversion rate, and E a of EP-A is obviously lower in the early curing stage. However, as the curing reaction proceeds, E a of EP-B is a little lower than that of EP-A in the later curing stage. But EP-A has the lowest E a combined with the whole process from Kissinger method. To sum up, it can be concluded that the curing process of EP can be promoted by adding GO and the smaller size (190.1 nm) of GO had a greater effect and lower E a than the GO with particle size of 1510 nm. And the related mechanisms were discussed and analyzed.

Chemokine Receptor CCR2b Enhanced Anti-tumor Function of Chimeric Antigen Receptor T Cells Targeting Mesothelin in a Non-small-cell Lung Carcinoma Model.

Chimeric antigen receptor (CAR) T cell therapy faces a number of challenges for the treatment of non-small-cell lung carcinoma (NSCLC), and efficient migration of circulating CAR T cells plays an important role in anti-tumor activity. In this study, a CAR specific for tumor antigen mesothelin (Msln-CAR) was co-expressed with cell chemokine receptors CCR2b or CCR4. Findings showed that CCR2b and CCR4 enhanced the migration of Msln-CAR T cell in vitro by transwell assay. When incubated with mesothelin-positive tumor cells, Msln-CCR2b-CAR and Msln-CCR4-CAR T cell specifically exerted potent cytotoxicity and produced high levels of proinflammatory cytokines, including IL-2, IFN-γ, and TNF-α. Furthermore, NSCLC cell line-derived xenograft (CDX) model was constructed by implanting subcutaneously modified A549 into NSG mice. Compared to conventional Msln-CAR T cells, living imaging indicated that Msln-CCR2b-CAR T cells displayed superior anti-tumor function due to enhanced migration and infiltration into tumor tissue shown by immunohistochemistry (IHC) analysis. In addition, histopathological examinations of mice organs showed that no obvious organic damages were observed. This is the first time that CAR T cell therapy combined with chemokine receptor is applied to NSCLC treatment.

HIV-1-Specific CAR-T Cells With Cell-Intrinsic PD-1 Checkpoint Blockade Enhance Anti-HIV Efficacy in vivo.

Adoptive cellular immunotherapy therapy using broadly neutralizing antibody-based chimeric antigen receptor-T cells (bNAb-based CAR-T) has shown great potency and safety for the functional cure of HIV. The efficacy of bNAb-based CAR-T cells could be compromised by adaptive resistance during HIV chronic infection according to the phenomenon that cellular exhaustion was observed in endogenous cytotoxic T-lymphocytes (CTLs) along with upregulated expression of PD-1. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells (PBMCs) and a 3BNC117-DNR CAR (3BD CAR) construct that enables the expression of PD-1 dominant negative receptor (DNR) and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV envelope glycoprotein (Env). Compared with HIV CAR expression alone, 3BD CAR-T cells displayed potent lytic and functional responses to Env-expressing cell lines and HIV-infected CD4+ T cells. Moreover, 3BD CAR-T cells can kill HIV-latently-infected cell lines, which are reactivated by the secretory cytokines of effector cells followed by contact with initial HIV-expressing fraction. Furthermore, bioluminescence imaging indicated that 3BD CAR-T cells displayed superior anti-HIV function in an HIV NCG mouse model of transplanting Env+/PD-L1+ cells (LEL6). These studies suggested that our proposed combinational strategy of HIV CAR-T therapy with PD-1 blockade therapy is feasible and potent, making it a promising therapeutic candidate for HIV functional cure.