Systemic delivery of glycosylated-PEG-masked oncolytic virus enhances targeting of antitumor immuno-virotherapy and modulates T and NK cell infiltration.

Rationale: Immuno-virotherapy has emerged as a promising approach for cancer treatment, as it directly and cytotoxically eliminates tumors with systemic immune stimulation. However, the clinical efficacy of this approach remains limited by inappropriate delivery routes, robust antiviral responses, and the tumor immunosuppressive microenvironment. Methods: To address these challenges, we propose a surface engineering strategy that masks oncolytic herpes simplex virus (oHSV) with a galactose-polyethylene-glycol (PEG) polymer chain to minimize host antiviral responses and selectively targets tumors by limiting exposure to circulation upon systemic administration. We evaluated the antitumor efficacy of glycosylated-PEG-oHSV by examining tumor growth in animal models and analyzing tumor-infiltrating CD8+T cells and NK cells in the tumor microenvironment (TME). To assess the neutralizing antibody levels after systemic administration of glycosylated-PEG-oHSV, we utilized a mouse model and measured oHSV-specific IgG. Results: We demonstrate that the glycosylated-PEG modified oHSV does not affect the replication of oHSV yet exhibits high specificity to the asialoglycoprotein receptor (ASGPR) overexpressed in hepatocellular carcinoma cells. This results in selectively targeting cancer cells and deep penetration into tumors while avoiding spreading into the brain. Our approach also effectively reduces oHSV-specific neutralizing antibody levels to mitigate host antiviral immune response. Notably, our glycosylated-PEG-oHSV alleviates the immunosuppressive microenvironment within tumors by reducing regulatory T cells, augmenting the infiltration of activated CD8+T cells and NK cells with increasing release of anti-tumor cytokines, to impede tumor progression. Conclusion: Our findings offer a widely applicable and universal strategy to enhance cancer immuno-virotherapy through systemic administration of non-genetically engineered oncolytic viruses. This approach has the potential to overcome the limitations of current immune-virotherapy strategies and may improve clinical outcomes for cancer patients.

Prevalence and associated factors of vitamin D deficiency after Roux-en-Y gastric bypass: a systematic review and meta-analysis.

OBJECTS: To estimate the prevalence and associated factors of vitamin D deficiency (VDD) after Roux-en-Y gastric bypass (RYGB). METHODS: PubMed, EMBASE, and CENTRAL were searched for relevant records from inception to 17 March 2023, using search terms: vitamin D, vitamin D3, vitamin D deficiency, hypovitaminosis D, gastric bypass, and RYGB. Studies were eligible for inclusion if they provided related data on VDD prevalence after RYGB. RESULTS: Of the 1119 screened studies, 72 studies involving 7688 individuals were enrolled in the final analysis. The prevalence estimates of VDD after RYGB were 42%. Subgroup analyses suggested the pooled prevalence of postoperative VDD was 35% for follow-up duration less than or equal to 1 year, 43% for greater than 1 and less than or equal to 5 years, and 54% for greater than 5 years. Meta-regression showed that VDD prevalence was positively correlated with follow-up time. Also, the prevalence was higher in studies with inadequate vitamin D supplementation than in those with adequate supplementation and in Asia population than in those from South America, Europe, and North America. Other factors associated with high VDD prevalence after RYGB included high presurgical VDD prevalence, noncompliant patients, and black populations. No significant association existed between VDD and alimentary length. CONCLUSION: VDD presented a high prevalence in patients following RYGB. It occurred more frequently with longer postoperative follow-up time. Population-specific vitamin D supplementation measures, targeted treatment for presurgical VDD, improved patient compliance, and periodical follow-ups were necessary to reduce VDD and other adverse outcomes.

Caveolin-mediated cytosolic delivery of spike nanoparticle enhances antitumor immunity of neoantigen vaccine for hepatocellular carcinoma.

Rationale: Although neoantigen-based cancer vaccines have shown promise in various solid tumors, limited immune responses and clinical outcomes have been reported in patients with advanced disease. Cytosolic transport of neoantigen and adjuvant is required for the activation of intracellular Toll-like receptors (TLRs) and cross-presentation to prime neoantigen-specific CD8+T cells but remains a significant challenge. Methods: In this study, we aimed to develop a virus-like silicon vaccine (V-scVLPs) with a unique spike topological structure, capable of efficiently co-delivering a hepatocellular carcinoma (HCC)-specific neoantigen and a TLR9 agonist to dendritic cells (DCs) to induce a robust CD8+T cell response to prevent orthotopic tumor growth. We evaluated the antitumor efficacy of V-scVLPs by examining tumor growth and survival time in animal models, as well as analyzing tumor-infiltrating CD8+T cells and cytokine responses in the tumor microenvironment (TME). To evaluate the synergistic efficacy of V-scVLPs in combination with α-TIM-3 in HCC, we used an orthotopic HCC mouse model, a lung metastasis model, and a tumor rechallenge model after hepatectomy. Results: We found that V-scVLPs can efficiently co-deliver the hepatocellular carcinoma (HCC)-specific neoantigen and the TLR9 agonist to DCs via caveolin-mediated endocytosis. This advanced delivery strategy results in efficient lymph node draining of V-scVLPs to activate lymphoid DC maturation for promoting robust CD8+T cells and central memory T cells responses, which effectively prevents orthotopic HCC tumor growth. However, in the established orthotopic liver tumor models, the inhibitory receptor of TIM-3 was significantly upregulated in tumor-infiltrating CD8+T cells after immunization with V-scVLPs. Blocking the TIM-3 signaling further restored the antitumor activity of V-scVLPs-induced CD8+T cells, reduced the proportion of regulatory T cells, and increased the levels of cytokines to alter the tumor microenvironment to efficiently suppress established orthotopic HCC tumor growth, and inhibit lung metastasis as well as recurrence after hepatectomy. Conclusion: Overall, the developed novel spike nanoparticles with efficient neoantigen and adjuvant intracellular delivery capability holds great promise for future clinical translation to improve HCC immunotherapy.

Navoximod modulates local HSV-1 replication to reshape tumor immune microenvironment for enhanced immunotherapy via an injectable hydrogel.

Oncolytic virotherapy can lead to tumor lysis and systemic anti-tumor immunity, but the therapeutic potential in humans is limited due to the impaired virus replication and the insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). To solve the above problems, we identified that Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor Navoximod promoted herpes simplex virus type 1 (HSV-1) replication and HSV-1-mediated oncolysis in tumor cells, making it a promising combination modality with HSV-1-based virotherapy. Thus, we loaded HSV-1 and Navoximod together in an injectable and biocompatible hydrogel (V-Navo@gel) for hepatocellular carcinoma (HCC) virotherapy. The hydrogel formed a local delivery reservoir to maximize the viral replication and distribution at the tumor site with a single-dose injection. Notably, V-Navo@gel improved the disease-free survival time of HCC- bearing mice and protects the mice against tumor recurrence. What's more, V-Navo@gel also showed an effective therapeutic efficacy in the rabbit orthotopic liver cancer model. Mechanistically, we further discovered that our combination strategy entirely reprogramed the TME through single-cell RNA sequencing. All these results collectively indicated that the combination of Navoximod with HSV-1 could boost the viral replication and reshape TME for tumor eradication through the hydrogel reservoir.

Normalization of Tumor Vessels by Lenvatinib-Based Metallo-Nanodrugs Alleviates Hypoxia and Enhances Calreticulin-Mediated Immune Responses in Orthotopic HCC and Organoids.

Immunocheckpoint inhibitors combined with Lenvatinib is the first line treatment for hepatocellular carcinoma (HCC), but their potency is hampered by the low response rate and adverse events. Herein, a targeted therapeutic strategy through the coassembly of Lenvatinib, Adriamycin, Fe3+ ion, and a natural polyphenol (metallo-nanodrugs) is presented by coordination effect for potentiating tumor vascular normalization and systematic chemo-immunotherapy to effectively inhibit the progression of HCC in both orthotopic model and patients-derived organoids. In mice with orthotopic HCC, the obtained metallo-nanodrugs efficiently increase the drug accumulation in orthotopic tumors and can respond to acidic tumor environment. The promotion of tumor vascular normalization by metallo-nanodrugs is observed, which enhances the infiltrating T lymphocytes in tumor, and reinforces the calreticulin-mediated antitumor immunity through alleviating hypoxia, reducing regulatory T cells, and down-regulating PDL1 expression of tumors. The excellent therapeutic efficiency with complete remission of orthotopic tumors (3/6) and long-term survival of mice (4/6, 42 days) are also achieved. Furthermore, the excellent therapeutic effect of metallo-nanodrugs is also validated in 5 patient-derived organoids, and hence can provide a marvelous systemic chemo-immunotherapy strategy for enhancing HCC treatment.

Prevalence of Rhabdomyolysis Following Bariatric Surgery and its Associated Risk Factors: a Meta-Analysis.

PURPOSE: This study aimed to evaluate the prevalence of rhabdomyolysis (RML) following bariatric surgery and potential associated factors. MATERIALS AND METHODS: We systematically searched PubMed, Embase, and CENTRAL for relevant trials from database inception through August 2022. Articles were eligible for inclusion if they reported the prevalence of RML after bariatric surgery and provided at least one of the following outcome indicators: preoperative mean BMI/mean operative time for the included population. RESULTS: Sixteen studies with a total of 1540 patients were analyzed. The mean preoperative age distribution of the included patients was centered between 32.9 and 47.0 years, and the mean preoperative BMI ranged from 42.3 to 60.0 kg/m2. The operative time varied between 126.7 and 403.3 min. The overall pooled crude prevalence of post-bariatric surgery RML was 19.4%. Subgroup analyses showed the pooled prevalence of RML was 8.1% for operative duration > 120 and ≤ 180 min, 32.8% for > 180 and ≤ 240 min, and 47.4% for > 240 min. Meta-regression revealed that operation time was an independent risk factor for developing RML. Besides, BMI > 50 kg/m2 and open Roux-en-Y gastric bypass (RYGB) indicated a higher risk of RML. CONCLUSION: Post-bariatric surgery RML prevalence occurred more frequently with the extension of the operation time. For bariatric subjects with surgery time > 180 min, open RYGB, or BMI > 50 kg/m2, CKP could be routinely measured early to verify the presence of RML and to actively prevent its fatal complications.

Automatic Mesh and Shader Level of Detail.

The level of detail (LOD) technique has been widely exploited as a key rendering optimization in many graphics applications. Numerous approaches have been proposed to automatically generate different kinds of LODs, such as geometric LOD or shader LOD. However, none of them have considered simplifying the geometry and shader at the same time. In this paper, we explore the observation that simplifications of geometric and shading details can be combined to provide a greater variety of tradeoffs between performance and quality. We present a new discrete multiresolution representation of objects, which consists of mesh and shader LODs. Each level of the representation could contain both simplified representations of shader and mesh. To create such LODs, we propose two automatic algorithms that pursue the best simplifications of meshes and shaders at adaptively selected distances. The results show that our mesh and shader LOD achieves better performance-quality tradeoffs than prior LOD representations, such as those that only consider simplified meshes or shaders.

Prevalence and associated factors of secondary hyperparathyroidism after Roux-en-Y gastric bypass: A meta-analysis.

This study aimed to investigate the prevalence and factors associated with secondary hyperparathyroidism (SHPT) after Roux-en-Y gastric bypass (RYGB). We searched PubMed, EMBASE, and CENTRAL for relevant studies using search terms gastric bypass, RYGB and hyperparathyroidism. Thirty-four cohort studies with 4331 patients were incorporated into the final meta-analysis. Overall estimates of the prevalence of SHPT following RYGB were 39%. Subgroup analyses indicated the pooled prevalences of SHPT were 25%, 42%, 48%, and 54% for ≤1 year, >1 and ≤5 years, >5 and ≤10 years, and >10 years, respectively, after RYGB. Meta-regression showed that SHPT occurred was positively related to follow-up durations (p = 0.001). Additionally, SHPT prevalence was higher in studies in which calcium and vitamin D supplementation were considered inadequate than in those which were adequate (p = 0.002). SHPT is highly prevalent in individuals with obesity after RYGB. It seems to progress with time after surgery. Routine calcium and vitamin D supplementation post-RYGB together with targeted treatment of vitamin D deficiency, reasonable adjustment of the doses of supplementation with regular follow-up, and improved patient compliance, as well as long-term screening, are necessary to prevent the development of SHPT.

Changes in Gastric Inhibitory Polypeptide (GIP) After Roux-en-Y Gastric Bypass in Obese Patients: a Meta-analysis.

This meta-analysis aimed to evaluate changes in GIP after RYGB in obese patients. We searched PubMed, EMBASE, and CENTRAL for relevant studies from database inception through July 2021. Articles were eligible for inclusion if they reported pre-operative and post-operative fasting GIP levels. We found fasting GIP levels had a decreasing tendency. The decrease in fasting glucose and postprandial GIP levels was also observed. Subgroup analysis indicated diabetic subjects tended to have a more obvious fasting GIP reduction compared to non-diabetic individuals. Meta-regression showed that the amount of weight loss (% total body weight), gastric pouch volume, alimentary limb length, and biliopancreatic limb length were not related to fasting GIP decrease. Fasting GIP levels decreased significantly after RYGB in obese people, especially in diabetic patients.

Biosynthetic cell membrane vesicles to enhance TRAIL-mediated apoptosis driven by photo-triggered oxidative stress.

Due to its tumor-specificity and limited side effects, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown great potential in cancer treatments. However, the short half-life of TRAIL protein and the poor death receptor (DR) expression of cancer cells severely compromise the therapeutic outcomes of TRAIL in clinical studies. Herein, a novel ROS-dependent TRAIL-sensitizing nanoplatform, CPT MV, with a Ce6-PLGA core and a TRAIL-modified cell membrane shell was explored to improve the in vivo circulation stability of TRAIL and to amplify TRAIL-induced apoptosis. CPT MV could produce ROS in the targeted cells upon laser irradiation to improve death receptor (DR)-5 expression and trigger Cyt c release from mitochondria. When engaged with TRAIL, the up-regulated DR5 could recruit more Fas-associated death domain (FADD) to transport the extrinsic apoptotic signal to the initiator caspase (caspase 8) and then the executioner caspase (caspase 3), while leaked Cyt c could trigger the intrinsic apoptotic pathway to further strengthen TRAIL-induced apoptosis. Therefore, the designed CPT MV could enhance TRAIL-mediated apoptosis driven by photo-triggered oxidative stress, which provides a very promising approach to clinically overcome tumor resistance to TRAIL therapy.

Bariatric Surgery Does Not Improve Semen Quality: Evidence from a Meta-analysis.

The meta-analysis aimed to explore the possible relationship between bariatric surgery and semen quality. PubMed, EMBASE, and CENTRAL were searched from database inception through October 28, 2021. Articles were eligible for inclusion if they evaluated the impact pre- and post-bariatric surgery on semen parameters. A total of 9 studies with 218 patients were found. The mean preoperative age distribution of the patients included centralized from 18 to 50 years, and the mean pre-op BMI ranged from 36.7 to 70.5 kg/m2. The follow-up period ranged from 6 to 24 months. The results revealed that bariatric surgery had no significant effect on sperm volume, concentration, total count, morphology, total motility, progressive motility, viability, semen pH, and semen leukocytes. Bariatric surgery does not improve semen quality in obese males.

Complicated appendicitis are common during the epidemic period of 2019 novel coronavirus (2019-nCoV).

OBJECTIVES: To assess the prevalence of complicated appendicitis (including gangrene, abscess and perforation) after the outbreak of the 2019-nCoV epidemic and to identify the risk factors associated with complicated appendicitis. METHODS: Two groups were established in the study consisting of: one group for cases of acute appendicitis before the 2019-nCoV epidemic (before January 1, 2020; pre-epidemic group) and another group for those after the epidemic outbreak (after January 1, 2020; epidemic group). These two groups were compared in terms of demographic and clinical characteristics, prevalence of complicated appendicitis, and treatment intention. A multivariate analysis model using binary logistic regression was constructed. RESULTS: A total of 163 patients were included in this study, with 105 in the pre-epidemic group and 58 in the epidemic group. In the epidemic group, the interval from the onset of symptoms to admission was 65.0 h, which is significantly longer than the 17.3 h interval noted in the pre-epidemic group (P < 0.001). The prevalence of complicated appendicitis after the epidemic outbreak was significantly higher than before the outbreak (51.7% vs. 12.4%, P < 0.001). In addition, the epidemic group had a lower score of patient's intention to seek treatment than the pre-epidemic group (9.5 ± 2.7 vs. 3.4 ± 2.6, P < 0.001). Based on the multivariate analysis, the risk factors for complicated appendicitis included the time from symptoms onset to admission (OR = 1.075) and the patients' intention to receive treatment (OR = 0.541). CONCLUSION: Complicated appendicitis was more common in patients with acute appendicitis after the outbreak of the 2019-nCoV epidemic.

Impact of Bariatric Surgery on Female Sexual Function in Obese Patients: a Meta-Analysis.

We aimed to make a meta-analysis regarding the effect of bariatric surgery on female sexual function. PubMed, EMBASE, and CENTRAL were searched from database inception through August 2019. Articles were eligible for inclusion if they examined the effect of bariatric surgery on obese women's sexual function assessed by the Female Sexual Functioning Index (FSFI) or/and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). Twenty articles were included into meta-analysis. Bariatric surgery was associated with significant increase in the total FSFI score. When parameters included in the FSFI scoring system were separately evaluated, significant improvements were observed in sexual desire, sexual arousal, lubrication, orgasm, sexual satisfaction, and sexual pain. However, the PISQ-12 and FSFI scores in women with pelvic floor disorders (PFDs) were not significantly changed postoperatively. Bariatric surgery improves female sexual function in obese patients, but not in women with PFD.

Expression and significance of angiostatin, vascular endothelial growth factor and matrix metalloproteinase-9 in brain tissue of diabetic rats with ischemia reperfusion.

OBJECTIVE: To discuss the expression and significance of angiostatin, vascular endothelial growth factor and matrix metalloproteinase-9 in the brain tissue of diabetic rats with ischemia reperfusion. METHODS: A total of 60 male Wistar rats were randomly divided into the normal group, sham group, diabetic cerebral infarction group and single cerebral infarction group according to the random number table, with 15 rats in each group. The high sucrose diet and intraperitoneal injection of streptozotocin were performed for the modeling of diabetic rats, while the thread-occlusion method was employed to build the model of cerebral ischemia reperfusion. The immunohistochemical staining was performed to detect the expression of angiostatin, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in the brain tissue. RESULTS: The expression of angiostatin after the reperfusion in the brain tissue of rats in the single cerebral infarction group and diabetic cerebral infarction group was increased 6 h after the reperfusion, reached to the peak on 1 d and then decreased gradually. The expression of angiostatin in the diabetic cerebral infarction group 6 h, 1 d, 3 d and 7 d after the reperfusion was significantly higher than that in the single cerebral infarction group (P < 0.05). VEGF began to be increased 1 h after the reperfusion in the single cerebral infarction group and diabetic cerebral infarction group, reached to the peak at 6 h and then decreased gradually. The expression of VEGF in the diabetic cerebral infarction group at each time point after the reperfusion was significantly lower than that in the single cerebral infarction group (P < 0.05). MMP-9 began to be increased 1 h after the reperfusion in the single cerebral infarction group and diabetic cerebral infarction group, reached to the peak on 1 d and then decreased gradually. The expression of MMP-9 in the diabetic cerebral infarction group at each time point after the reperfusion was significantly higher than that in the single cerebral infarction group (P < 0.05). CONCLUSIONS: The high glucose environment in which the diabetic cerebral infarction is occurred is to induce the formation of MMP-9 at first and then activate and increase the expression of angiostatin. Afterwards, the expression of VEGF is inhibited, resulting in the poor angiogenesis after cerebral infarction, which thus makes the injury of brain tissue after cerebral infarction even worse than the non-diabetes mellitus.