Inhibition of human adenovirus replication by TRIM35-mediated degradation of E1A.

Human adenovirus (HAdV) is ubiquitous in the human population, constituting a significant burden of global respiratory diseases. Children and individuals with low immunity are at risk of developing severe infections without approved antiviral treatment for HAdV. Our study demonstrated that TRIM35 inhibited HAdV-C5 early gene transcription, early protein expression, genome replication, and infectious virus progeny production. Furthermore, TRIM35 was found to inhibit HAdV replication by attenuating E1A expression. Mechanistically, TRIM35 interacts with and degrades E1A by promoting its K48-linked ubiquitination. Additionally, K253 and K285 are the key sites necessary for TRIM35 degradation. Moreover, an oncolytic adenovirus carrying shTRIM35 was constructed and observed to exhibit improved oncolysis in vivo, providing new ideas for clinical tumor treatment. Our results expand the broad antiviral activity of TRIM35 and mechanically support its application as a HAdV replication inhibitor. IMPORTANCE E1A is an essential human adenovirus (HAdV) protein responsible for the early replication of adenovirus while interacting with multiple host proteins. Understanding the interaction between HAdV E1A and TRIM35 helps identify effective antiviral therapeutic targets. The viral E1A protein is a crucial activator and regulator of viral transcription during the early infection stages. We first reported that TRIM35 interacts with E1A to resist adenovirus infection. Our study demonstrated that TRIM35 targets E1A to resist adenovirus, indicating the applicability of targeting virus-dependent host factors as a suitable antiviral strategy.

The effect of ovarian response parameters and the synergistic effect of assisted reproduction of poor ovarian response treated with platelet rich plasma: systematic review and meta-analysis.

BACKGROUND: Poor ovarian response (POR) patients often encounter cycle cancellation and egg retrieval obstacles in assisted reproductive technology. Platelet rich plasma (PRP) ovarian injection is a potential treatment method, but the treatment methods are different, and the treatment results are controversial. OBJECTIVE: This study adopts a systematic review and meta-analysis method based on clinical research to explore the efficacy and safety of PRP injection on POR. METHOD: The following databases were searched for research published before March 2023; Medline (via PubMed), Web of Science, Scopus, Cochrane Library, Embase, Cochrane Library, and China National Knowledge Infrastructure Database (CNKI). The literature was then screened by two independent researchers, who extracted the data and evaluated its quality. Research was selected according to the inclusion criteria, and its quality was evaluated according to the NOS standard Cohort study. The bias risk of the included study was assessed with STATE 14.0. RevMan 5.3 software was used for meta-analysis. MAIN RESULTS: Ten studies were included in the analysis, including 7 prospective cohort studies and 3 retrospective studies involving 836 patients. The results showed that after PRP treatment, follicle stimulating hormone (FSH) significantly decreased and anti-Mueller hormone (AMH) and luteinizing hormone (LH) significantly increased in POR patients, but estradiol did not change significantly; The number of antral follicles increased, and the number of obtaining eggs and mature oocytes significantly increased; The number of Metaphase type II oocytes, 2PN and high-quality embryos, and cleavage stage embryos significantly increased. In addition, the patient cycle cancellation rates significantly decreased. The rate of natural pregnancy assisted reproductive pregnancy and live birth increased significantly. Four reports made it clear that no adverse reactions were observed. CONCLUSION: PRP may have the potential to improve pre-assisted reproductive indicators in POR patients, increase the success rate of in vitro fertilization-embryo transfer (IVF-ET) in POR patients, and improve embryo quality, and may be beneficial to the pregnancy outcome. There is no obvious potential risk in this study, but further clinical support is still needed.

Interleukin-35 expression promotes hepatocellular carcinogenesis by inducing γδ T-cell exhaustion.

Interleukin (IL)-35, a new member of the IL-12 family, exerts immunosuppressive effects in the hepatic microenvironment. Innate immune cells, such as γδ T cells, have vital roles in hepatic diseases, including acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). In the current study, we focused on the effects and mechanisms of IL-35 on the local immune status of γδ T cells, especially in liver tumors. Based on CCK8 assay and immunofluorescence results, we showed that exogenous IL-35 stimulation of γδ T cells attenuated proliferative ability and killing functions against Hepa1-6 or H22 cells. Flow cytometry results showed that exogenous IL-35 stimulated the expression of programmed cell death 1 (PDCD1) and lymphocyte activation gene 3 (LAG3) in γδ T cells. The exogenous IL-35 stimulated group also showed impairment of cytotoxic cytokine secretion. In addition, stat5a revealed a significant increase after IL-35 stimulation of γδ T cells screened via transcription factor based on PCR array analysis. Furthermore, bioinformatics analysis revealed that stat5a-related tumor-specific genes were mainly involved in immune regulatory pathways. Correlation analysis indicated that stat5a expression was significantly and positively correlated with tumor immune cell infiltration, and pdcd1 and lag3 expression. Finally, bioinformatics analysis using the TCGA and GSE36376 HCC datasets corroborated the significant positive correlation between IL-35 and stat5a. Taken together, overexpressed IL-35 promoted exhaustion and impaired the anti-tumor function of γδ T cells in HCC. Targeting IL-35 might be a promising means to enhance the antitumor therapy of γδ T cells, which would significantly improve prognosis.

Incidence and mortality trends in gastric cancer in the United States, 1992-2019.

Our study aimed to estimate the epidemiological trends of gastric cancer in the United States from 1992 to 2019. This population-based study used the US Surveillance, Epidemiology and End Results-12 database as a fundamental cohort to analyze gastric cancer incidence, incidence-based mortality (IBM), overall survival (OS) and cancer-specific survival (CSS) probabilities from 1992 to 2019. The Global Burden of Disease study (1990-2018) was used as a likely validation cohort. Age-period-cohort analyses were performed to explore the underlying causes of trend changes. We found that the incidence rate of gastric cancer decreased from 1992 to 2019. IBM also decreased significantly from 1997 to 2019. The 3-year OS and CSS of gastric cancer increased from 22.3% to 28.7% and 25.7% to 33.5%, respectively. However, the proportion of distant gastric cancer cases had unexpectedly increased rapidly from 33.1% in 1992 to 44.7% in 2019. Age-period-cohort modeling found that the incidence and IBM rates remained stable in the groups aged below 50 years, while that in all age groups older than 50 years showed a significant downward trend. High incidence and mortality risks were observed in the younger birth cohorts (birth year after 1990). To conclude, we observed a decline in incidence and mortality rates of gastric cancer in the United States in the past decades. We determined that progression of primary and tertiary preventive measures is the main reason for the reduction in the disease burden of gastric cancer. However, secondary preventive measures for gastric cancer still need to be strengthened.

Tyrosine phosphorylation of band 3 impairs the storage quality of suspended red blood cells in the Tibetan high-altitude polycythemia population.

Due to environmental hypoxia on the Tibetan Plateau, local residents often exhibit a compensative increase in hemoglobin concentration to maintain the body's oxygen supply. However, increases in hemoglobin and hematocrit (Hct) pose a serious challenge to the quality of stored suspended red blood cells (SRBCs) prepared from the blood of high-hemoglobin populations, especially populations at high altitude with polycythemia in Tibet. To explore the difference in storage quality of SRBCs prepared from plateau residents with a high hemoglobin concentration, blood donors were recruited from Tibet (> 3600 m) and Chengdu (≈ 500 m) and divided into a high-altitude control (HAC) group, high-altitude polycythemia (HAPC) group and lowland control (LLC) group according to their hemoglobin concentration and altitude of residence. The extracellular acidification rate (ECAR), pyruvate kinase (PK) activity and band 3 tyrosine phosphorylation were analyzed on the day of blood collection. Then, whole-blood samples were processed into SRBCs, and storage quality parameters were analyzed aseptically on days 1, 14, 21 and 35 of storage. Overall, we found that tyrosine 21 phosphorylation activated glycolysis by releasing glycolytic enzymes from the cytosolic domain of band 3, thus increasing glucose consumption and lactate accumulation during storage, in the HAPC group. In addition, band 3 tyrosine phosphorylation impaired erythrocyte deformability, accompanied by the highest hemolysis rate in the HAPC group, during storage. We believe that these results will stimulate new ideas to further optimize current additive solutions for the high-hemoglobin population in Tibet and reveal new therapeutic targets for the treatment of HAPC populations.

Rice FERONIA-LIKE RECEPTOR 3 and 14 affect grain quality by regulating redox homeostasis during endosperm development.

Chalky endosperm negatively affects the appearance, milling, and eating qualities of rice (Oryza sativa L.) grains. Here, we report the role of two receptor-like kinases, FERONIA-LIKE RECEPTOR 3 (FLR3) and FERONIA-LIKE RECEPTOR 14 (FLR14), in grain chalkiness and quality. Knockouts of FLR3 and/or FLR14 increased the number of white-core grains caused by aberrant accumulation of storage substances, resulting in poor grain quality. Conversely, the overexpression of FLR3 or FLR14 reduced grain chalkiness and improved grain quality. Transcriptome and metabolome analyses showed that genes and metabolites involved in the oxidative stress response were significantly up-regulated in flr3 and flr14 grains. The content of reactive oxygen species was significantly increased in flr3 and flr14 mutant endosperm but decreased in overexpression lines. This strong oxidative stress response induced the expression of programmed cell death (PCD)-related genes and caspase activity in endosperm, which further accelerated PCD, resulting in grain chalkiness. We also demonstrated that FLR3 and FLR14 reduced grain chalkiness by alleviating heat-induced oxidative stress in rice endosperm. Therefore, we report two positive regulators of grain quality that maintain redox homeostasis in the endosperm, with potential applications in breeding rice for optimal grain quality.

Oncolytic adenovirus-mediated expression of CCL5 and IL12 facilitates CA9-targeting CAR-T therapy against renal cell carcinoma.

Chimeric antigen receptor T-cell (CAR-T) is particularly prominent in hematological but not in solid tumors, mainly based on the complex tumor immune microenvironment. Oncolytic virus (OVs) is an emerging adjuvant therapy method. OVs may prime tumor lesions to induce anti-tumor immune response, thereby enhancing CAR-T cells functionality and possibly increasing response rates. Here, we combined CAR-T cells targeting carbonic anhydrase 9 (CA9) and an oncolytic adenovirus (OAV) carrying chemokine (C-C motif) ligand 5 (CCL5), cytokine interleukin-12 (IL12) to explore the anti-tumor effects of this combination strategy. The data showed that Ad5-ZD55-hCCL5-hIL12 could infect and replicate in renal cancer cell lines and induced a moderate inhibition of xenografted tumor in nude mice. IL12 mediated by Ad5-ZD55-hCCL5-hIL12 promoted the phosphorylation of Stat4 in CAR-T cells, induced CAR-T cells to secrete more IFN-γ. We also found that Ad5-ZD55-hCCL5-hIL-12 combined with CA9-CAR-T cells significantly increased the infiltration of CAR-T cells in tumor mass, prolonged the survival of the mice and restrained tumor growth in immunodeficient mice. Ad5-ZD55-mCCL5-mIL-12 could also increase CD45+CD3+T cell infiltration and prolong mice survival in immunocompetent mice. These results provided feasibility for the combination of oncolytic adenovirus and CAR-T cells, which demonstrated the sufficient potential and prospects of CAR-T for the treatment of solid tumors.

Challenges of hesitancy in human papillomavirus vaccination: Bibliometric and visual analysis.

BACKGROUND: Human papillomavirus (HPV) vaccine has immense research value in the prevention of related tumours. A huge body of work has been published in this field, which may pose difficulties for researchers aiming to investigate all the available information. However, bibliometrics can provide deep insights into this research field. OBJECTIVE: We aimed to study HPV vaccine development, visually analyse the development status, trends, research hotspots, and frontiers of this field, and provide a reference for research on it. METHODS: Articles were acquired from the Web of Science Core Collection. VOS viewer and CiteSpace software were used to analyse publication growth, country/region, institution, journal distribution, author, reference, and keywords, and collected burst keyword words to display research hotspots. RESULTS: A total of 4831 references were obtained, and the annual number of publications increased fluctuating over the past decade. The United States of America ranked at the top in terms of percentage of articles. The institution with the highest number of research publications in this field was the Centers for Disease Control and Prevention. The most productive and frequently cited authors was Lauri E Markowitz. The journal with the most publications in this field was Vaccine, and the most influential journal was Paediatrics. The most frequently cited reference was 'A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women'. Burst detection analysis of top keywords showed that 'national immunisation survey', 'social media', and 'hesitancy' are the current research frontiers in this field. CONCLUSION: This study provides useful information for acquiring knowledge on HPV vaccine. Research on solving the hesitation of HPV vaccination will become an academic trend in this field, which can offer guidance for more extensive and in-depth studies in the future.

Transcription factor OsSGL is a regulator of starch synthesis and grain quality in rice.

Starch biosynthesis during rice endosperm development is important for grain quality, as it influences grain size and physico-chemical properties, which together determine rice eating quality. Cereal starch biosynthetic pathways have been comprehensively investigated; however, their regulation, especially by transcriptional repressors remains largely unknown. Here, we identified a DUF1645 domain-containing protein, STRESS_tolerance and GRAIN_LENGTH (OsSGL), that participates in regulating rice starch biosynthesis. Overexpression of OsSGL reduced total starch and amylose content in the endosperm compared with the wild type. Chromatin immunoprecipitation sequencing and RNA-seq analyses indicated that OsSGL targets the transcriptional activity of several starch and sucrose metabolism genes. In addition, ChIP-qPCR, yeast one-hybrid, EMSA and dual-luciferase assays demonstrated that OsSGL directly inhibits the expression of SUCROSE SYNTHASE 1 (OsSUS1) in the endosperm. Furthermore, OsSUS1 interacts with OsSGL to release its transcriptional repression ability. Unexpectedly, our results also show that knock down and mutation of OsSGL disrupts the starch biosynthetic pathway, causing lower starch and amylose content. Therefore, our findings demonstrate that accurate control of OsSGL homeostasis is essential for starch synthesis and grain quality. In addition, we revealed the molecular mechanism of OsSGL in regulating starch biosynthesis-related genes, which are required for grain quality.

An Evaluation of Morphological Changes and Deformability of Suspended Red Blood Cells Prepared Using Whole Blood with Different Hemoglobin Levels of Tibetans.

BACKGROUND: The hypoxic environment stimulates the human body to increase the levels of hemoglobin (HGB) and hematocrit and the number of red blood cells. Such enhancements have individual differences, leading to a wide range of HGB in Tibetans' whole blood (WB). STUDY DESIGN: WB of male Tibetans was divided into 3 groups according to different HGB (i.e., A: >120 but ≤185 g/L, B: >185 but ≤210 g/L, and C: >210 g/L). Suspended red blood cells (SRBC) processed by collected WB and stored in standard conditions were examined aseptically on days 1, 14, 21, and 35 after storage. The routine biochemical indexes, deformability, cell morphology, and membrane proteins were tested. RESULTS: Mean corpuscular volume, adenosine triphosphate, pH, and deformability were not different in group A vs. those in storage (p > 0.05). The increased rate of irreversible morphology of red blood cells was different among the 3 groups, but there was no difference in the percentage of red blood cells with an irreversible morphology after 35 days of storage. Group C performed better in terms of osmotic fragility and showed a lower rigid index than group A. Furthermore, SDS-PAGE revealed similar cross-linking degrees of cell membrane protein but the band 3 protein of group C seemed to experience weaker clustering than that of group A as detected by Western Blot analysis after 35 days of storage. CONCLUSIONS: There was no difference in deformability or morphological changes in the 3 groups over the 35 days of storage. High HGB levels of plateau SRBC did not accelerate the RBC change from a biconcave disc into a spherical shape and it did not cause a reduction in deformability during 35 days of preservation in bank conditions.

Phloroglucinol averts isoprenaline hydrochloride induced myocardial infarction in rats.

Myocardial infarction (MI) is indicated by the symptoms like sharp chest pain, sweating, palpitations, and nervousness finally leading to heart attack. MI occurs mainly due to the risk factors like smoking, elevated blood pressure, diabetes, hypercholesterolemia, obesity, decreased HDL level, elevated LDL level, hyperlipoproteinemia and aging consequently leads to demandable coronary blood supply, oxidative stress, and acute necrosis of the myocardium. Cardioprotective potential of the phloroglucinol (PG) was assessed by treating isoprenaline hydrochloride (ISO; 85 mg/kg b.w., s.c.) induced MI model in rats. Pretreatment with PG in a dose of 30 mg/kg was done for 28 days and followed by ISO (for MI induction) on 29th and 30th days, exhibited decline in the abnormalities in the ECG patterns, cardiac marker enzymes, enzymic and nonenzymic antioxidants, lipid peroxidation, lipid profiles, and histopathological investigations compared to isoprenaline alone treated group. On the whole, the present investigations elucidate the significance of PG in alleviating the pathological process and appreciably prevent the induction of MI in experimental rats.

Radially realigning nematic liquid crystal for efficient tuning of microring resonators.

The efficient tuning of microring resonator with the radially realigning nematic liquid crystal (NLC) cladding is presented. By applying the voltage on the in-plane annular electrodes, the produced electric field realigns the homeotropically-aligned NLC in the radial direction. Under the voltage sufficient for 90° NLC reorientation, the guided mode senses the consistent cladding index distribution along the microring waveguide with the maximal index change equal to the optical anisotropy of NLC. The resultant tuning of the resonant wavelength has a blue shift of 23.1nm for the TM mode and a red shift of 10.1nm for the TE mode. The tuning rates for the TM and TE modes are -1.95nm/V and 0.90nm/V. The proposed microring resonator owns the excellent features of wide tuning ranges and high tuning rates for the TM and TE modes.

Clinical Pathological Characteristics and Prognosis of Multigene Co-Mutations in Elderly Patients With Non-Small Cell Lung Cancer: A Retrospective Analysis.

Background: With the development and wide application of next-generation sequencing (NGS), multiple-gene mutations related to lung cancer are detected using this technology. Notably, even multigene concomitant mutations (co-mutations), which occur at a relatively low incidence, can be detected more effectively using NGS. It is well-known that the percentages of non-small cell lung cancer (NSCLC) in the elderly lung cancer population are also gradually increasing, while its prognosis is hard and the quality of long-term survival is poor. This study aimed at investigating the common clinicopathologic features of multigene co-mutations for better evaluating the prognosis of elderly NSCLC patients. Methods: A total of 464 NSCLC patients were divided into 3 groups according to the types of gene mutation, whose clinical data were retrospectively analyzed. Results: In total, 38.36% (178/464) of NSCLC patients were in the nonmutation group, 50% in the single-gene mutation group, and 11.64% in the multigene co-mutation group. Nonmutation, single-gene mutation, and co-mutation groups were all prone to occur in male adenocarcinoma patients (P < .05). EGFR gene mutation rates were the highest in the single-gene mutation and co-mutation groups (54.31% and 24.35%). In the co-mutation group, the incidence of EGFR/PIK3CA, LK/KRAS, and EGFR/MET co-mutations was the highest (16.67%, 11.11%, and 7.41%). ALK/HER2/MET, EGFR/HER2/MET, and EGFR/HER2/MET/ROS1 multiple-gene co-mutations were, respectively, found in 1 case, and the multigene co-mutation patients commonly had a worse median progression-free survival (PFS) than that of single-gene mutation (7.13 vs 12.34 months, P = .013). Conclusion: With the application of NGS, the detectable rates of gene co-mutation are increasingly high in elderly patients with NSCLC, which mainly occurs in male adenocarcinoma patients commonly with poor PFS. It will be critically necessary to conduct multigene detections by NGS for directing targeted therapy of elderly NSCLC patients.

A functional lignin for heavy metal ions adsorption and wound care dressing.

Recently, the application of lignin activation by demethylation to improve reactivity and enrich multiple functions has intensively attracted attention. However, it is still challenge up to now due to the low reactivity and complexity of lignin structure. Here, an effective demethylation way was explored by microwave-assisted method for substantially enhancing the hydroxyl (-OH) content and retaining the structure of lignin. Then, the optimum demethylated lignin was used to removal heavy metal ions and promote wound healing, respectively. In detail, for microwave-assisted demethylated poplar lignin (M-DPOL), the contents of phenolic (Ar-OH) and total hydroxyl (Tot-OH) groups reached the maximum for 60 min at 90 °C in DMF with 7.38 and 9.13 mmol/g, respectively. After demethylation, with this M-DPOL as lignin-based adsorbent, the maximum adsorption capacity (Qmax) for Pb2+ ions reached 104.16 mg/g. Based on the isotherm, kinetic and thermodynamic models analyses, the chemisorption occurred in monolayer on the surface of M-DPOL, and all adsorption processes were endothermic and spontaneous. Meanwhile, M-DPOL as a wound dressing had excellent antioxidant property, outstanding bactericidal activity and remarkable biocompatibility, suggesting that it did not interfere with cell proliferation. Besides, the wounded rats treated with M-DPOL significantly promoted its formation of re-epithelialization and wound healing of full-thickness skin defects. Overall, microwave-assisted method of demethylated lignin can offer great advantages for heavy metal ions removal and wound care dressing, which facilitates high value application of lignin.

Inhibition of Cell Apoptosis by Apicomplexan Protozoa-Host Interaction in the Early Stage of Infection.

Apicomplexan protozoa, which are a group of specialized intracellular parasitic protozoa, infect humans and other animals and cause a variety of diseases. The lack of research on the interaction mechanism between Apicomplexan protozoa and their hosts is a key factor restricting the development of new drugs and vaccines. In the early stages of infection, cell apoptosis is inhibited by Apicomplexan protozoa through their interaction with the host cells; thereby, the survival and reproduction of Apicomplexan protozoa in host cells is promoted. In this review, the key virulence proteins and pathways are introduced regarding the inhibition of cell apoptosis by the interaction between the protozoa and their host during the early stage of Apicomplexan protozoa infection. It provides a theoretical basis for the development of drugs or vaccines for protozoal diseases.

Analysis of sheep peripheral blood mononuclear cells in response to Echinococcus granulosus microRNA-71 overexpression.

Cyst echinococcosis, caused by Echinococcus granulosus, remains a zoonotic disease posing a great threat to public health and meat production industry. Sheep infected with E. granulosus show relatively high abundance of egr-miR-71 in the sera, but its role is unknown. Using bioinformatics and cell migration and Transwell assays, we comparatively analyzed the proteomes and cell invasion of sheep PBMCs in response to egr-miR-71 overexpression. The results showed that the egr-miR-71 induced a total of 157 proteins being differentially expressed and mainly involved in immune responses. In sheep PBMCs, egr-miRNA-71 overexpression induced significant downregulation of macrophage migration inhibitory factor (MIF) and accordingly promoted cell migration and invasion compared with the control. The results will provide a clue for further investigation of a role of circulating egr-miR-71 in immune responses during E. granulosus infection.

Heat shock protein 60 in parasitic helminths: A role in immune responses and therapeutic applications.

Heat shock protein 60 (HSP60) is an unique member of the heat shock protein family, being involved in parasite infections. To cope with harsh environments where parasites live, HSP60s are indispensable and involved in a variety of biological processes. HSP60s have relative low similarity among parasites, but their ATPase /Mg2+ active sites are highly conserved. The interactions of HSP60s with signaling pathway regulators in immune cells suggest a crucial role in immune responses, rendering them a potential therapeutic target. This paper reviews the current understandings of HSP60s in parasitic helminths in aspects of molecular characteristics, immunoregulatory responses and HSP60-based therapeutics.

Hybrid liposome-erythrocyte drug delivery system for tumor therapy with enhanced targeting and blood circulation.

Liposome, a widely used drug delivery system (DDS), still shows several disadvantages such as dominant clearance by liver and poor target organ deposition. To overcome the drawbacks of liposomes, we developed a novel red blood cell (RBC)-liposome combined DDS to modulate the tumor accumulation and extend the blood circulation life of the existing liposomal DDS. Here, RBCs, an ideal natural carrier DDS, were utilized to carry liposomes and avoid them undergo the fast clearance in the blood. In this study, liposomes could either absorbed onto RBCs' surface or fuse with RBCs' membrane by merely altering the interaction time at 37°C, while the interaction between liposome and RBCs would not affect RBCs' characteristics. In the in vivo antitumor therapeutic efficacy study, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes attached onto RBCs' surfaces exhibited lung targeting effect (via RBC-hitchhiking approach) and reduced clearance in the liver, while DPPC liposomes fused with RBCs had prolong blood circulation up to 48 h and no enrichment in any organ. Furthermore, 20 mol% of DPPC liposomes were replaced with pH-sensitive phospholipid 1,2-dioleoyl-Sn-glycero-3-phosphoethanolamine (DOPE) as it could respond to the low pH tumor microenvironment and then accumulate in the tumor. The DOPE attached/fusion RBCs showed partial enrichment in lung and about 5-8% tumor accumulation, which were significantly higher than (about 0.7%) the conventional liposomal DDS. Thus, RBC-liposome composite DDS is able to improve the liposomal tumor accumulation and blood circulation and shows the clinical application promises of using autologous RBCs for antitumor therapy.

Recombinant oncolytic adenovirus armed with CCL5, IL-12, and IFN-γ promotes CAR-T infiltration and proliferation in vivo to eradicate local and distal tumors.

The efficacy of chimeric antigen receptor T (CAR-T) cells for solid tumors remains unsatisfactory due to the limited tumor infiltration and immunosuppressive microenvironment. To overcome these limitations, the genetically engineered recombinant oncolytic adenoviruses (OAVs) that conditionally replicate in tumor cells were developed to modify the tumor microenvironment (TME) to facilitate CAR-T-mediated tumor eradication. Here in the present study, a novel recombinant OAV carrying CCL5, IL12, and IFN-γ controlled by Ki67 promoter was constructed (named AdKi67-C3). The antitumor activity of AdKi67-C3 was tested in vitro and in vivo by using mono administration or combing with CAR-T cells targeting B7H3. It proved that CCL5 expressed by AdKi67-C3 indeed induced more CAR-T migration in vitro and CAR-T infiltration in tumor mass in vivo. Meanwhile, cytokines of IFN-γ and IL12 secreted by AdKi67-C3-infected tumor cells significantly promoted proliferation and persistence of CAR-T cells in vitro and in vivo. In tumor-bearing xenograft mouse models of kidney, prostate or pancreatic cancer, local pretreatment with AdKi67-C3 dramatically enhanced CAR-T cell efficacy and eliminated local and distant tumors. More importantly, mice achieving complete tumor regression resisted to re-challenge with the same tumor cells, suggesting establishment of long-term antitumor immune response. Therefore, OAVs armored with cytokines could be developed as a bioenhancer to defeat the immunosuppressive microenvironment and improve therapeutic efficacy of CAR-T in solid tumors.

γδ T cells: The potential role in liver disease and implications for cancer immunotherapy.

The γδ T cell subset was discovered over 30 years ago, yet continues to be an exciting and challenging component of the adaptive immune response. While γδ T cells represent a very small fraction of all T cells in humans, γδ T cells have a vital effect on human immunity, serving as a bridge between the innate and adaptive immune systems. The characteristics of γδ T cells include recognition of non-MHC restrictive antigens, as well as the ability to secrete an abundance of cytokines, suggesting that γδ T cells have high antitumor activity. As such, they have gained ample attention with respect to tumor immunotherapy in the last decade. The γδ T cell subset comprises up to ∼15-20% of the T-lymphocyte population in the liver, although the liver is recognized as an immune organ with primary immune functions, the role of γδ T cells in liver disease has not been established. Herein, we present a comprehensive overview of molecular mechanisms underlying immune γδ T cell activity in liver disease, including immune liver injury, viral hepatitis, cirrhosis, and hepatocellular carcinoma, and review γδ T cell-based clinical immunotherapeutic approaches.