Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG^@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

The rise of nanotechnology has opened new horizons for cancer immunotherapy. However, most nanovaccines fabricated with nanomaterials suffer from carrier-related concerns, including low drug loading capacity, unpredictable metabolism, and potential systemic toxicity, which bring obstacles for their clinical translation. Herein, we developed an antigen self-assembled nanovaccine, which was resulted from a simple acryloyl modification of the antigen to induce self-assembly. Furthermore, a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid (Zol) were integrated or absorbed onto the nanoparticles (denoted as MEAO-Z) to intensify the immune response. The synthesized nanovaccine with a diameter of around 70 nm showed successful lymph node transportation, high dendritic cell internalization, promoted costimulatory molecule expression, and preferable antigen cross-presentation. In virtue of the above superiorities, MEAO-Z induced remarkably higher titers of serum antibody, stronger cytotoxic T lymphocyte immune responses and IFN-γ secretion than free antigen and adjuvants. In vivo, MEAO-Z significantly suppressed EG7-OVA tumor growth and prolonged the survival time of tumor-bearing mice. These results indicated the translation promise of our self-assembled nanovaccine for immune potentiation and cancer immunotherapy.

Due to the insufficient long-term protection and significant efficacy reduction to new variants of current COVID-19 vaccines, the epidemic prevention and control are still challenging. Here, we employ a capsid and antigen structure engineering (CASE) strategy to manufacture an adeno-associated viral serotype 6-based vaccine (S663V-RBD), which expresses trimeric receptor binding domain (RBD) of spike protein fused with a biological adjuvant RS09. Impressively, the engineered S663V-RBD could rapidly induce a satisfactory RBD-specific IgG titer within 2 weeks and maintain the titer for more than 4 months. Compared to the licensed BBIBP-CorV (Sinopharm, China), a single-dose S663V-RBD induced more endurable and robust immune responses in mice and elicited superior neutralizing antibodies against three typical SARS-CoV-2 pseudoviruses including wild type, C.37 (Lambda) and B.1.617.2 (Delta). More interestingly, the intramuscular injection of S663V-RBD could overcome pre-existing immunity against the capsid. Given its effectiveness, the CASE-based S663V-RBD may provide a new solution for the current and next pandemic.

Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.

Purpose: Ischemic brain injury results in high mortality and serious neurologic morbidity. Here, we explored the role of SNHG15 in modulating neuronal damage and microglial inflammation after ischemia stroke. Materials and Methods: The hypoxia/ischemia models were induced by middle cerebral artery occlusion in mice and oxygenglucose deprivation/reoxygenation (OGD/R) in vitro. Quantitative real-time PCR (qRT-PCR) and Western blot were conducted to determine the levels of SNHG15, miR-302a-3p, and STAT1/NF-κB. Moreover, gain- or loss-of functional assays of SNHG15 and miR-302a-3p were conducted. MTT assay was used to evaluate the viability of HT22 cells, and the apoptotic level was determined by flow cytometry. Furthermore, enzyme-linked immunosorbent assay was performed to detect oxidative stress and inflammatory mediators in the ischemia cortex and OGD/R-treated BV2 microglia. Results: The SNHG15 and STAT1/NF-κB pathways were both distinctly up-regulated, while miR-302a-3p was notably down-regulated in the ischemia cortex. Additionally, overexpressing SNHG15 dramatically enhanced OGD/R-mediated neuronal apoptosis as well as the expression of oxidative stress and inflammation factors from microglia. In contrast, knocking down SNHG15 or overexpressing miR-302a-3p relieved OGD/R-mediated neuronal apoptosis and microglial activation. Moreover, the rescue experiment testified that overexpressing miR-302a-3p also attenuated SNHG15 up-regulation-induced effects. In terms of the mechanisms, SNHG15 sponged miR-302a-3p and activated STAT1/NF-κB as a competitive endogenous RNA, while miR-302a-3p targeted STAT1 and negatively regulated the STAT1/NF-κB pathway. Conclusion SNHG15 was up-regulated in the hypoxia/ischemia mouse or cell model. The inhibition of SNHG15 ameliorates ischemia/hypoxia-induced neuronal damage and microglial inflammation by regulating the miR-302a-3p/STAT1/NF-κB pathway.

Objective:To investigate the effect of transurethral plasma enucleation of prostate with bladder neck and prostatic apex urethral mucosa preservation on the incidence of retrograde ejaculation after surgery.Methods:The clinical data of 77 patients with benign prostatic hyperplasia (BPH) admitted to Jinhua people's Hospital from January 2018 to June 2020 were retrospectively analyzed. The ages of the two groups [(62.06±2.01)years old and (62.36 ± 2.12)years old] were comparable. There were no significant differences between the groups( P>0.05) in term of the prostate volume (72.91±17.57) ml vs. (68.07±17.28)ml, Q max [(7.33±2.02)ml/s vs. (7.79±2.09)ml/s)], and IPSS (25.51±5.66) vs.(25.17±4.90). The conventional operation group was treated with " trefoil" enucleation of prostate. The modified operation group underwent the following three improved techniques. Firstly, the anterior mucosa of the verumontanum was cut 1.5 cm away from the medial surface of the verumontanum to prevent the external sphincter injury. Secondly, part of the prostate tissue was retained by exceeding the verumontanum when cutting off the bilateral lobes. Thirdly, the middle lobe of the prostate was bluntly stripped to the bladder neck with the sheath of the electroscope in order to protect the transverse muscle fibers as well as the integrity of the bladder neck. The outcome and the ejaculation function of the two groups were analyzed. Results:There was no significant difference in operation time [(66.74±9.29)min vs. (71.29±15.32) min], catheter indwelling duration [(5.31±0.76)d vs.(5.00±1.06)d], and hospital stay [(7.57±0.88) d vs. (7.17±1.45)d] between the two groups ( P>0.05) after more than 6 months of follow-up. According to IIEF score, mild erectile dysfunction occurred in both groups, with the incidence rate of 20.7%(6/29) and 13.5%(5/37) respectively, and there was no significant difference between the two groups ( P>0.05). The postoperative maximum urinary flow rate (Q max) [(23.51±4.25) ml/s vs.(24.05±3.81)ml/s] and IPSS score (6.46±2.72 vs. 6.55±2.99) was significantly different from that before the operation ( P<0.05). However, there was no significant difference between the two groups ( P>0.05). The incidence of retrograde ejaculation in conventional operation group and modified operation group was 23/35(65.7%) and 13/42(31.0%), and the difference was statistically significant ( P<0.05). Immediate urinary continence were 24/35(68.6%) and 36/42(85.7%) in the conventional operation group and the modified operation group respectively, and there was no significant difference between the two groups( P>0.05). After 6 months of follow-up, urinary continence in both groups was 100.0%. Conclusions:Transurethral plasmakinetic enucleation of the prostate with the preservation of bladder neck and urethral mucosa of prostate apex is the same effective as conventional operation in the treatment of benign prostatic hyperplasia, but the incidence of retrograde ejaculation after operation is significantly reduced, which is suitable for those patients who desire to retain their ejaculation function.

Coronaviruses (CoVs) are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has caused major public health crises. There have been more than 4,400,000 reported cases of COVID-2019 and more than 300,000 reported deaths to date (16/05/2020). SARS-CoV, MERS-CoV and SARS-CoV-2 have attracted widespread global attention due to their high infectivity and pathogenicity. To date, there is no specific treatment proven effective against these viral infectious diseases. Vaccination is considered one of the most effective strategies to prevent viral infections. Therefore, the development of effective vaccines against highly pathogenic coronaviruses is essential. In this review, we will briefly describe coronavirus vaccine design targets, summarize recent advances in the development of coronavirus vaccines, and highlight current adjuvants for improving the efficacy of coronavirus vaccines.

Objective To discuss the application of cybernetics in hemodialysis nursing. Methods Cybernetics was applied to the standardized nursing quality management in 35 hemodialysis patients, namely to establish hemodialysis standard, weight the executive condition, correct deviation.The feed-forward control was emphasized in combination with the feedback control forming the feed forward-feedback control sys-tern in order to tighten the effect of the control. The dialysis indices before and after the intervention was compared. Results The average hematocfit and urea reduction rate greatly increased after cybernetics was applied to the standardized nursing quality management in 35 hemodialysis patients, but no change was seen in urea elimination index after the intervention. Conclusions Nursing quality can be enhanced by the application of cybernetics in hemodialysis.