An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species.

Recombinant adeno-associated viruses (rAAVs) have emerged as promising gene therapy vectors due to their proven efficacy and safety in clinical applications. In non-human primates (NHPs), rAAVs are administered via suprachoroidal injection at a higher dose. However, high doses of rAAVs tend to increase additional safety risks. Here, we present a novel AAV capsid (AAVv128), which exhibits significantly enhanced transduction efficiency for photoreceptors and retinal pigment epithelial (RPE) cells, along with a broader distribution across the layers of retinal tissues in different animal models (mice, rabbits, and NHPs) following intraocular injection. Notably, the suprachoroidal delivery of AAVv128-anti-VEGF vector completely suppresses the Grade IV lesions in a laser-induced choroidal neovascularization (CNV) NHP model for neovascular age-related macular degeneration (nAMD). Furthermore, cryo-EM analysis at 2.1 Å resolution reveals that the critical residues of AAVv128 exhibit a more robust advantage in AAV binding, the nuclear uptake and endosome escaping. Collectively, our findings highlight the potential of AAVv128 as a next generation ocular gene therapy vector, particularly using the suprachoroidal delivery route.

Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer.

Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and their overlap with autoimmune disease. Using lifelong records covering diagnoses, procedures, and clinic identity from 473,580 individuals in the FinnGen study, genome-wide association analyses were conducted on carefully constructed subcategories of OLP (n = 3,323) and non-oral LP (n = 4,356) and on the combined group. We identified 15 genome-wide significant associations in FinnGen and an additional 12 when meta-analyzed with UKBB (27 independent associations at 25 distinct genomic locations), most of which are shared between oral and non-oral LP. Many associations coincide with known autoimmune disease loci, consistent with the epidemiologic enrichment of LP with hypothyroidism and other autoimmune diseases. Notably, a third of the FinnGen associations demonstrate significant differences between OLP and non-OLP. We also observed a 13.6-fold risk for tongue cancer and an elevated risk for other oral cancers in OLP, in agreement with earlier reports that connect LP with higher cancer incidence. In addition to a large-scale dissection of LP genetics and comorbidities, our study demonstrates the use of comprehensive, multidimensional health registry data to address outstanding clinical questions and reveal underlying biological mechanisms in common but understudied diseases.

Malignant Extrarenal Rhabdoid tumor derived from the greater omentum: A case report and literature review.

BACKGROUND: Malignant extrarenal rhabdoid tumor (MERT) is a rare and highly metastatic tumor, which is more than 75% of patients dying within 6 months of initial diagnosis, and it often leads to misdiagnosis and delayed treatment. CASE: This paper reports a 16-year-old girl who presented with the chief complaint of acute abdominal pain. She underwent laparoscopic exploration and excisional biopsy, then pathological examination and immunohistochemistry revealed "extrarenal malignant rhabdomyoma." One month after operation, she died of intra-abdominal hemorrhage and multiple organ dysfunction. CONCLUSION: MERT were often misdiagnosed and had a poor prognosis. The surgery and chemotherapy are usually beneficial to prolong the survival time of patients with MERT.

Mechanism of microplastics effects on the purification of heavy metals in piggery effluents by microalgae.

Microalgae is an effective bioremediation technique employed for treating piggery effluent. However, there is insufficient study on how the presence of microplastics (MPs) in wastewater affects the ability of microalgae to remove heavy metals from piggery effluent. This study aims to investigate the influence of two prevalent heavy metals found in piggery wastewater, Cu2+ (2 mg/L) and Zn2+ (2 mg/L), on their removal by microalgae (Desmodesmus sp. CHX1) in the presence of four types of MPs: polyethylene (PE), polyvinyl chloride (PVC), polypropylene (PP), and polyethylene terephthalate (PET). The results revealed that smaller particle size MPs promoted chlorophyll accumulation, while larger particles inhibits it. Additionally, higher concentrations of MPs promoted chlorophyll accumulation, while lower concentrations inhibited it. As for heavy metals, the presence of microplastics reduced the removal efficiency of Cu2+ and Zn2+ by Desmodesmus sp. CHX1. The highest inhibition of Cu2+ was 30%, 10%, 19%, and 16% of the control (CK), and the inhibition of Zn2+ was 7%, 4%, 4%, and 13%, respectively, under the treatments of PE, PVC, PP and PET MPs. Furthermore, Desmodesmus sp. CHX1 can secrete more extracellular polymeric substances (EPS) and form heterogeneous aggregates with MPs to counteract their pressure. These findings elucidate the impact of MPs on microalgae in bioremediation settings and offer useful insights into the complex relationships between microalgae, MPs, and heavy metals in the environment.

Genome-wide analysis of ATP-binding cassette (ABC) transporter in Penaeus vannamei and identification of two ABC genes involved in immune defense against Vibrio parahaemolyticus by affecting NF-κB signaling pathway.

The ATP-binding cassette (ABC) transporters have crucial roles in various biological processes such as growth, development and immune defense in eukaryotes. However, the roles of ABC transporters in the immune system of crustaceans remain elusive. In this study, 38 ABC genes were systematically identified and characterized in Penaeus vannamei. Bioinformation analysis revealed that PvABC genes were categorized into ABC A-H eight subfamilies with 17 full-transporters, 11 half transporters and 10 soluble proteins, and multiple immunity-related cis-elements were found in gene promoter regions. Expression analysis showed that most PvABC genes were widely and highly expressed in immune-related tissues and responded to the stimulation of Vibrio parahaemolyticus. To investigate whether PvABC genes mediated innate immunity, PvABCC5, PvABCF1 and PvABCB4 were selected for dsRNA interference experiment. Knockdown of PvABCF1 and PvABCC5 not PvABCB4 increased the cumulative mortality of P. vannamei and bacterial loads in hepatopancreas after infection with V. parahaemolyticus. Further analysis showed that the PvABCF1 and PvABCC5 knockdown decreased expression levels of NF-κB pathway genes and antimicrobial peptides (AMPs). Collectively, these findings indicated that PvABCF1 and PvABCC5 might restrict V. parahaemolyticus challenge by positively regulating NF-κB pathway and then promoting the expression of AMPs, which would contribute to overall understand the function of ABC genes in innate immunity of invertebrates.

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity.

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 protective effects of icariin against testicular dysfunction in type 1 diabetic mice Via AMPK-mediated Nrf2 activation and NF-κB p65 inhibition.

BACKGROUND: Owing to the early suffering age and the rising incidence of type 1 diabetes (T1D), the resulting male reproductive dysfunction and fertility decline have become a disturbing reality worldwide, with no effective strategy being available. Icariin (ICA), a flavonoid extracted from Herba Epimedium, has been proved its promising application in improving diabetes-related complications including diabetic nephropathy, endothelial dysfunction and erectile dysfunction. Ensuring the future reproductive health of children and adolescents with T1D is crucial to improve global fertility. However, its roles in the treatment of T1D-induced testicular dysfunction and the potential mechanisms remain elusive. PURPOSE: The purpose of this present study was to investigate whether ICA ameliorates T1D-induced testicular dysfunction as well as its potential mechanisms. METHODS: T1D murine model was established by intraperitoneal injection of STZ with or without treated with ICA for eleven weeks. Morphological, pathological and serological experiments were used to determine the efficacy of ICA on male reproductive function of T1D mice. Western blotting, Immunohistochemistry analysis, qRT-PCR and kit determination were performed to investigated the underlying mechanisms. RESULTS: We found that replenishment of ICA alleviated testicular damage, promoted testosterone production and spermatogenesis, ameliorated apoptosis and blood testis barrier impairment in streptozotocin-induced T1D mice. Functionally, ICA treatment triggered adenosine monophosphate protein kinase (AMPK) activation, which in turn inhibited the nuclear translocation of nuclear factor kappa B p65 (NF-κB p65) to reduce inflammatory responses in the testis and activated nuclear factor erythroid 2-related factor 2(Nrf2), thereby enhancing testicular antioxidant capacity. Further studies revealed that supplementation with the AMPK antagonist Compound C or depletion of Nrf2 weakened the beneficial effects of ICA on testicular dysfunction of T1D mice. CONCLUSION: Collectively, these results demonstrate the feasibility of ICA in the treatment of T1D-induced testicular dysfunction, and reveal the important role of AMPK-mediated Nrf2 activation and NF-κB p65 inhibition in ICA-associated testicular protection during T1D.

Tissue and serum miR-149-3p/5p in hospitalized patients with inflammatory bowel disease: Correlation with disease severity and inflammatory markers.

This study aimed to investigate the expression levels of tissue and serum miR-149-3p and miR-149-5p in hospitalized patients with inflammatory bowel disease (IBD). A total of 35 ulcerative colitis (UC) patients, 12 Crohn's disease (CD) patients, and 25 healthy controls were included in the study. The miRNAs expressions were measured in tissue and serum samples using quantitative real-time polymerase chain reaction (qRT-PCR). Inflammatory biomarkers were measured, including serum albumin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), and fecal calprotectin. MiR-149-3p and miR-149-5p were significantly decreased in the inflamed areas of both CD and UC patients compared to tissue controls, which was consistent with decreased serum levels in IBD patients compared to healthy controls. When distinguishing UC patients from healthy controls, serum miR-149-3p showed 74% sensitivity and 96% specificity, while serum miR-149-5p exhibited 63% sensitivity and 96% specificity. In the CD versus healthy control comparison, miR-149-3p achieved 100% sensitivity and 96% specificity, while miR-149-5p demonstrated 92% sensitivity and 96% specificity. In the UC versus CD comparison, miR-149-5p showed 75% sensitivity and 77% specificity, while miR-149-3p displayed 67% sensitivity and 80% specificity. Significant correlations were identified between the tissue and serum expression of miR-149-3p/5p and disease activity scores, as well as inflammatory biomarkers in both CD and UC patients. Decreased expression of miR-149-3p and miR-149-5p is associated with disease activity in IBD patients. These miRNAs demonstrate diagnostic potential and may serve as biomarkers for monitoring disease activity in IBD.

Factors associated with thermal injury of abdominal skin in focused ultrasound ablation of uterine fibroids.

OBJECTIVE: To investigate the factors which may cause thermal injury of abdominal skin in patients with uterine fibroids (UFs) who underwent ultrasound-guided focused ultrasound ablation surgery (FUAS). METHOD: A total of 123 patients were enrolled in the injury group. In contrast, 246 patients without thermal injury were assigned to the non-injury group. The relationship between patient and treatment parameters and injury were explored using univariate analysis and multiple logistic regression analyses. In addition, the factors influencing the degree of thermal injury were analyzed using Kruskal-Wallis H. RESULTS: (1) Abdominal scars (p = .007, OR = 2.187, 95% CI: 1.242-3.849), abdominal wall thickness (p < .001, OR = 1.042, 95% CI: 1.019-1.067), fundus fibroids (p = .038, OR = 1.790, 95% CI: 1.033-3.100), UFs with hyperintense/mixed T2-weighted imaging (T2WI) signals (p = .022, OR = 1.843, 95% CI: 1.091-3.115), average sonication power (AP) (p = .025, OR = 1.021, 95% CI: 1.003-1.039), and treatment time (TT) (p < .001, OR = 1.017, 95% CI: 1.011-1.023) were independent risk factors for thermal injury, while treatment volume (TV) (p = .002, OR = 0.775, 95% CI: 0.661-0.909) was a protective factor for injury. (2) Four groups were subdivided according to the degree of thermal injury(Group A: without skin injury. Group B: with changed T2WI signal in the abdominal wall, Group C: mild skin injury, Group D: severe skin injury), comparison of each with every other showed that the abdominal wall in Groups A and D was thinner than Groups B and C, with statistically significant differences (PAB<0.05, PAC<0.01, PDC<0.05, PDB<0.05); Group A was slightly thicker than D, however, without statistical difference. The ratio of sonication time (ST) to TV in Group A was the lowest of all (PAB, PAC, PAD all < 0.05). And as the level of thermal injury rose, the ratio gradually increased, however, without statistical difference. CONCLUSIONS: Based on our limited results, the following conclusion was made. (1) Abdominal scars, abdominal wall thickness, fundus fibroids, UFs with T2WI hyperintense/mixed signals, AP and TT were independent risk factor. (2) Neither too thick nor too thin abdominal walls would be recommended, as both might increase the risk of skin injury. (3) Noticeably, the risk of skin injury might increase considerably when the ST was longer and the sonication area was more fixed.

Coptisine, the Characteristic Constituent from Coptis chinensis, Exhibits Significant Therapeutic Potential in Treating Cancers, Metabolic and Inflammatory Diseases.

Naturally derived alkaloids belong to a class of quite significant organic compounds. Coptisine, a benzyl tetrahydroisoquinoline alkaloid, is one of the major bioactive constituents in Coptis chinensis Franch., which is a famous traditional Chinese medicine. C. chinensis possesses many kinds of functions, including the ability to eliminate heat, expel dampness, purge fire, and remove noxious substances. In Asian countries, C. chinensis is traditionally employed to treat carbuncle and furuncle, diabetes, jaundice, stomach and intestinal disorders, red eyes, toothache, and skin disorders. Up to now, there has been plenty of research of coptisine with respect to its pharmacology. Nevertheless, a comprehensive review of coptisine-associated research is urgently needed. This paper was designed to summarize in detail the progress in the research of the pharmacology, pharmacokinetics, safety, and formulation of coptisine. The related studies included in this paper were retrieved from the following academic databases: The Web of Science, PubMed, Google scholar, Elsevier, and CNKI. The cutoff date was January 2023. Coptisine manifests various pharmacological actions, including anticancer, antimetabolic disease, anti-inflammatory disease, and antigastrointestinal disease effects, among others. Based on its pharmacokinetics, the primary metabolic site of coptisine is the liver. Coptisine is poorly absorbed in the gastrointestinal system, and most of it is expelled in the form of its prototype through feces. Regarding safety, coptisine displayed potential hepatotoxicity. Some novel formulations, including the [Formula: see text]-cyclodextrin-based inclusion complex and nanocarriers, could effectively enhance the bioavailability of coptisine. The traditional use of C. chinensis is closely connected with the pharmacological actions of coptisine. Although there are some disadvantages, including poor solubility, low bioavailability, and possible hepatotoxicity, coptisine is still a prospective naturally derived drug candidate, especially in the treatment of tumors as well as metabolic and inflammatory diseases. Further investigation of coptisine is necessary to facilitate the application of coptisine-based drugs in clinical practice.

Preclinical evaluation of KH631, a novel rAAV8 gene therapy product for neovascular age-related macular degeneration.

The upregulation of vascular endothelial growth factor (VEGF) is strongly associated with the development of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD). Currently, the standard treatment for nAMD involves frequent intravitreal injections of anti-VEGF agents, which inhibit the growth of new blood vessels and prevent leakage. However, this treatment regimen places a significant burden on patients, their families, and healthcare providers due to the need for repeated visits to the clinic for injections. Gene therapy, which enables the sustained expression of anti-VEGF proteins after a single injection, can dramatically reduce the treatment burden. KH631 is a recombinant adeno-associated virus 8 vector that encodes a human VEGF receptor fusion protein, and it is being developed as a long-term treatment for nAMD. In preclinical studies using non-human primates, subretinal administration of KH631 at a low dose of 3 × 108 vg/eye resulted in remarkable retention of the transgene product in the retina and prevented the formation and progression of grade IV CNV lesions. Furthermore, sustained transgene expression was observed for more than 96 weeks. These findings suggest that a single subretinal injection of KH631 has the potential to offer a one-time, low-dose treatment for nAMD patients.

Genome-Wide Association Study Identifies 4 Novel Risk Loci for Small Intestinal Neuroendocrine Tumors Including a Missense Mutation in LGR5.

BACKGROUND & AIMS: Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported. METHODS: Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls). RESULTS: We identified 6 genome-wide significant (P < 5 × 10-8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10-19) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling. CONCLUSIONS: Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.

Cleaner outdoor air diminishes the overall risk of intracerebral hemorrhage but brings differential benefits to subpopulations: a time-stratified case-crossover study.

BACKGROUND: Short-term air pollution exposure and intracerebral hemorrhage (ICH) risk are related. However, the impact of the pollutant levels decline on this relationship, which attributes to clean air policy implementation and the COVID-19 pandemic lockdown, is unclear. In the present research, we explored the influence of different pollutant levels on ICH risk during eight years in a southwestern China megacity. METHODS: Our research used a time-stratified case-crossover design. We retrospectively analyzed ICH patients in a teaching hospital from January 1, 2014, to December 31, 2021, and divided 1571 eligible cases into two groups (1st group: 2014-2017; 2nd group: 2018-2021). We observed the trend of every pollutant in the entire study period and compared the pollution levels in each group, using air pollutants data (PM2.5, PM10, SO2, NO2, CO, and O3) documented by the local government. We further established a single pollutant model via conditional logistic regression to analyze the association between short-term air pollutants exposure and ICH risk. We also discussed the association of pollution levels and ICH risk in subpopulations according to individual factors and monthly mean temperature. RESULTS: We found that five air pollutants (PM2.5, PM10, SO2, NO2, CO) exhibited a continuous downward trend for the whole duration, and the daily concentration of all six pollutants decreased significantly in 2018-2021 compared with 2014-2017. Overall, the elevation of daily PM2.5, SO2, and CO was associated with increased ICH risk in the first group and was not positively associated with risk escalation in the second group. For patients in subgroups, the changes in the influence of lower pollutant levels on ICH risk were diverse. In the second group, for instance, PM2.5 and PM10 were associated with lower ICH risk in non-hypertension, smoking, and alcohol-drinking participants; however, SO2 had associations with increased ICH risk for smokers, and O3 had associations with raised risk in men, non-drinking, warm month population. CONCLUSIONS: Our study suggests that decreased pollution levels diminish the adverse effects of short-term air pollutants exposure and ICH risk in general. Nevertheless, the influence of lower air pollutants on ICH risk in subgroups is heterogeneous, indicating unequal benefits among subpopulations.

Effects of clean intermittent catheterization and transurethral indwelling catheterization on the management of urinary retention after gynecological surgery: a systematic review and meta-analysis.

Background: Urinary retention is a common complication after gynecological surgery. Clean intermittent catheterization has been reported to have a lower incidence of urinary tract infections compared to transurethral indwelling catheterization. This study conducted a systematic review of randomized controlled trials (RCTs) to compare the effects of these two catheterization techniques after gynecological surgery. Methods: We searched PubMed, EMBASE, Web of Science, Cochrane, China National Knowledge Infrastructure (CNKI), Wanfang Data, and Chinese Scientific Journal Database (VIP) for 227 articles comparing the effects of the above two catheterization methods on urinary tract infections and urethral function after gynecological surgery up to November 2022. Subsequently, the Cochrane tool for assessing the risk of bias was employed to assess the quality of the included literature. Meta-analysis was performed using Stata software, and the appropriate models were adopted to pool the effect sizes. Results: A total of 19 articles involving 1,823 patients were included. The results showed that clean intermittent catheterization could greatly minimize the risk of urinary tract infections [relative risk (RR) =0.24, 95% confidence interval (CI): 0.20 to 0.28], improve the recovery of bladder function (RR =1.51, 95% CI: 1.32 to 1.72), reduce residual urine volume (mL) [weighted mean difference (WMD) = -82.64, 95% CI: -108.32 to -56.96], and shorten the duration of catheter maintenance (days) (WMD =-3.14, 95% CI: -4.98 to -1.30) compared with indwelling catheterization. Subgroup and regression analyses revealed that clean intermittent catheterization could achieve a more favorable therapeutic effect in patients receiving cervical cancer surgeries than those receiving other conventional gynecological procedures. Conclusions: Clean intermittent catheterization can lower the incidence of urinary tract infections, reduce residual urine volume, shorten the duration of catheter maintenance, and improve bladder function recovery. Thus, it may be more effective in patients undergoing radical cervical cancer resection.

High Intensity Focused Ultrasound Ablation for Juvenile Cystic Adenomyosis: Two Case Reports and Literature Review.

Cystic adenomyosis is a rare type of uterine adenomyosis, mainly seen in young women, which is often characterized by severe dysmenorrhea. The quality of life and reproductive function of young women could be affected by misdiagnosis and delayed treatment. At present, there are no universal guidelines and consensus. We report two cases of patients with cystic adenomyosis in juveniles treated with high-intensity focused ultrasound (HIFU) ablation. In the first case, magnetic resonance imaging (MRI) indicated a cystic mass of 2.0 cm × 3.1 cm × 2.4 cm in the uterus. After she underwent HIFU treatment, her pelvic MRI showed a mass of 1.1 × 2.4 cm in size, and her dysmenorrhea symptoms gradually disappeared. In the second case, a pelvic MRI indicated a 5.1 cm × 3.3 cm × 4.7 cm cystic mass in the uterus. After she underwent HIFU and combined four consecutive cycles of GnRH-a treatment, the lesion shrunk 1.2 cm ×1.4 cm × 1.6 cm, without dysmenorrhea. Simultaneously, the report reviewed 14 cases of juvenile cystic adenomyosis over the last ten years. HIFU or HIFU-combined drugs were safe and effective in treating juvenile cystic adenomyosis, but multicenter and prospective studies may be necessary to validate this in the future.

High intensity focused ultrasound treatment for adenomyosis: comparison of efficacy based on MRI features.

OBJECTIVE: To compare the clinical efficacy of High intensity-focused ultrasound(HIFU) for different types of adenomyosis classified by magnetic resonance imaging (MRI). METHODS: A total of 227 patients with adenomyosis who underwent HIFU treatment in Suining Central Hospital from January 2014 to December 2019 were included. Based on the preoperative pelvic MRI examination and Kishi isometric classification method, the patients were divided into 4 types according to the location of lesions. There were 82 cases of type I (endogenous type), 75 cases of type II (exogenous type), 34 cases of type III (nodular type), and 36 cases of type IV (heterogeneous type). The results of HIFU treatment for four types of adenomyosis and intraoperative adverse effects were analyzed. The changes of lesion size, dysmenorrhea, and menstrual volume were analyzed at 3 and 6 months after the operation. RESULT: (1) adverse effects: All patients successfully accepted HIFU treatment under sedation and analgesia. Grade A adverse effects occurred in 51 cases (22.47%) and grade B adverse effects in 3 cases (1.32%). The incidence of adverse effects in type I-IV patients was 21.95%, 22.66%, 23.53%, and 30.56%, respectively. There was no significant difference in the incidence of grade A and B adverse effects in all types, and no grade C-F adverse effects occurred. (2) Ablation effect: The ablation rate of type III(nodular type)patients was (74.7 ± 20.3) %, which was significantly higher than that of the other three types (p < .05). (3) Changes in lesion size: the lesion size of all patients decreased after treatment and the reduction rate gradually increased with time. At 6 months after the operation, the lesion reduction rate of type III patients was (70.8 ± 14.8) %, higher than that of the other three types patients (p < .05). There was no significant difference in the reduction rate of type I, type II and type IV. (4) Remission of menorrhagia: At 6 months after the operation, the total remission rate of type III patients was 100%, while the total remission rate of type IV patients (65.4%, 17/26) that was lower than that of type I, II and III patients(p < .05). (5) Dysmenorrhea relief: At 6 months after the operation, the total dysmenorrhea relief rate of type III patients was 100% and the complete relief rate (28.1%, 18/31) was higher than that of the other three types, which was significant differences (p < .05). CONCLUSIONS: HIFU is safe and effective in the treatment of different types of adenomyosis, the therapeutic effect of HIFU in patients with type III adenomyosis is better than that of the other three types.

The Role of Signaling Pathways in Pancreatic Cancer Targeted Therapy.

Signaling pathways play significant roles in the occurrence, development, and treatment of pancreatic cancer (PC). The main treatment options are surgery, chemotherapy, radiotherapy, arterial infusion chemotherapy in interventional therapy, and immunotherapy. Many studies have shown that signaling pathways perform a function in the occurrence and development of PC, for instance, phosphoinositide 3-kinase (PI3K)/AKT, nuclear factor-κB, Ras, interleukin (IL)-17B/IL-17RB, Wnt, and hepatocyte growth factor/c-MET, which play roles in the proliferation, metastasis, invasion, inhibition of apoptosis, promotion of angiogenesis, and drug resistance of PC. Interaction of signaling pathways has an impact on the biological behavior of PC; for example, activation of the neurotensin/NTSR1 pathway, which can activate mitogen-activated protein kinase, nuclear factor-κB, and other pathways related to PC stem cells, play an important role in PC, and an increase in their number is associated with the Wnt/ß-catenin and PI3K pathways. Chemotherapy is the main method for the treatment of PC, but drug resistance limits its use. In addition, abnormal activation of IL-17B/IL-17RB signaling pathway is associated with drug resistance. This article discusses the signaling pathways that play different roles in the occurrence and development of PC, as well as current research on signaling pathways in PC treatment.

Triple functional mild photothermal improves gene editing of PD-L1 for enhanced antitumor immunity.

Traditional photothermal therapy ablates tumor cells by a high temperature (> 50 °C). Although it has shown good anti-tumor effect in animal models, the potential damages to healthy tissues and the unnecessary inflammatory reactions caused by the high temperature have hindered the clinical transitions of traditional photothermal therapy. In this study, we used polydopamine (PDA) as a mild photothermal material and control the maximum temperature below 45 °C, which not only avoided the side effects caused by a high temperature, but also ablated a fraction of tumor cells and produced tumor antigens. Meanwhile, the near-infrared (NIR) light also served as a "switch" to trigger the release of CRISPR/Cas9 RNP from Fe3O4 nanoparticles (Fe3O4 NPs) after their accumulation to tumor sites via magnetic targeting. The triple functional mild photothermal therapy achieved significant PD-L1 gene knockout efficiency in the tumor-bearing mice, reversed the condition of immunosuppression in the tumor microenvironment, led to a higher level of anti-tumor immune responses and effectively inhibited the growth of melanoma. We anticipate that this triple functional mild photothermal therapy would provide a potential new approach for the treatment of malignant tumors.

Single-shot AAV-vectored vaccine against SARS-CoV-2 with fast and long-lasting immunity.

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.

Targeting hypoxia-inducible factors for breast cancer therapy: A narrative review.

Hypoxia-inducible factors (HIFs), central regulators for cells to adapt to low cellular oxygen levels, are often overexpressed and activated in breast cancer. HIFs modulate the primary transcriptional response of downstream pathways and target genes in response to hypoxia, including glycolysis, angiogenesis and metastasis. They can promote the development of breast cancer and are associated with poor prognosis of breast cancer patients by regulating cancer processes closely related to tumor invasion, metastasis and drug resistance. Thus, specific targeting of HIFs may improve the efficiency of cancer therapy. In this review, we summarize the advances in HIF-related molecular mechanisms and clinical and preclinical studies of drugs targeting HIFs in breast cancer. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for HIF targeting are increasingly being developed. Therefore, we highlight the HIF related DDS, including liposomes, polymers, metal-based or carbon-based nanoparticles.