Emerging roles of lactate in acute and chronic inflammation.

Traditionally, lactate has been considered a 'waste product' of cellular metabolism. Recent findings have shown that lactate is a substance that plays an indispensable role in various physiological cellular functions and contributes to energy metabolism and signal transduction during immune and inflammatory responses. The discovery of lactylation further revealed the role of lactate in regulating inflammatory processes. In this review, we comprehensively summarize the paradoxical characteristics of lactate metabolism in the inflammatory microenvironment and highlight the pivotal roles of lactate homeostasis, the lactate shuttle, and lactylation ('lactate clock') in acute and chronic inflammatory responses from a molecular perspective. We especially focused on lactate and lactate receptors with either proinflammatory or anti-inflammatory effects on complex molecular biological signalling pathways and investigated the dynamic changes in inflammatory immune cells in the lactate-related inflammatory microenvironment. Moreover, we reviewed progress on the use of lactate as a therapeutic target for regulating the inflammatory response, which may provide a new perspective for treating inflammation-related diseases.

Acidity-activatable upconversion afterglow luminescence cocktail nanoparticles for ultrasensitive in vivo imaging.

Activatable afterglow luminescence nanoprobes enabling switched "off-on" signals in response to biomarkers have recently emerged to achieve reduced unspecific signals and improved imaging fidelity. However, such nanoprobes always use a biomarker-interrupted energy transfer to obtain an activatable signal, which necessitates a strict distance requisition between a donor and an acceptor moiety (<10 nm) and hence induces low efficiency and non-feasibility. Herein, we report organic upconversion afterglow luminescence cocktail nanoparticles (ALCNs) that instead utilize acidity-manipulated singlet oxygen (1O2) transfer between a donor and an acceptor moiety with enlarged distance and thus possess more efficiency and flexibility to achieve an activatable afterglow signal. After in vitro validation of acidity-activated afterglow luminescence, ALCNs achieve in vivo imaging of 4T1-xenograft subcutaneous tumors in female mice and orthotopic liver tumors in male mice with a high signal-to-noise ratio (SNR). As a representative targeting trial, Bio-ALCNs with biotin modification prove the enhanced targeting ability, sensitivity, and specificity for pulmonary metastasis and subcutaneous tumor imaging via systemic administration of nanoparticles in female mice, which also implies the potential broad utility of ALCNs for tumor imaging with diverse design flexibility. Therefore, this study provides an innovative and general approach for activatable afterglow imaging with better imaging performance than fluorescence imaging.

Connections between body composition and dysregulation of islet α- and ß-cells in type 2 diabetes.

BACKGROUND: Accompanying islet α- and ß-cell dysregulation in type 2 diabetes (T2D) at the microscopic scale, alterations in body composition at the macroscopic scale may affect the pathogenesis of T2D. However, the connections between body composition and islet α-cell and ß-cell functions in T2D have not been thoroughly explored. METHODS: For this cross-sectional study, we recruited a total of 729 Chinese Han patients with T2D in a consecutive manner. Dual-energy X-ray absorptiometry (DXA) was used to measure body composition, which included total bone-free mass, total fat and lean mass, trunk fat and lean mass and limb fat and lean mass. Every patient underwent an oral glucose tolerance test to simultaneously detect glucose, C-peptide and glucagon. The indices of islet α-cell function included fasting glucagon levels and the area under the curve of glucagon after a challenge (AUCglucagon), while the indices of ß-cell function included the insulin sensitivity index derived from C-peptide (ISIC-peptide) and the area under the curve of C-peptide after a challenge (AUCC-peptide). RESULTS: Among all patients, fat mass, especially trunk fat mass, was significantly correlated with ISIC-peptide and AUCC-peptide levels (r = - 0.330 and 0.317, respectively, p < 0.001), while lean mass, especially limb lean mass, was significantly correlated with fasting glucagon and AUCglucagon levels (r = - 0.196 and - 0.214, respectively, p < 0.001). Moreover, after adjusting for other relevant variables via multivariate linear regression analysis, increased trunk fat mass was independently associated with decreased ISIC-peptide (ß = - 0.247, t = - 3.628, p < 0.001, partial R2 = 10.9%) and increased AUCC-peptide (ß = 0.229, t = 3.581, p < 0.001, partial R2 = 8.2%), while decreased limb lean mass was independently associated with increased fasting glucagon (ß = - 0.226, t = - 2.127, p = 0.034, partial R2 = 3.8%) and increased AUCglucagon (ß = - 0.218, t = - 2.050, p = 0.041, partial R2 = 2.3%). Additionally, when separate analyses were performed with the same concept for both sexes, we found that increased trunk fat mass was still independently associated with decreased ISIC-peptide and increased AUCC-peptide, while decreased limb lean mass was still independently associated with increased fasting glucagon and AUCglucagon. CONCLUSIONS: Increased trunk fat mass may partly account for decreased insulin sensitivity and increased insulin secretion, while decreased limb lean mass may be connected to increased fasting glucagon and postprandial glucagon secretion.

An Activatable Phototheranostic Probe for Anti-hypoxic Type I Photodynamic- and Immuno-Therapy of Cancer.

Photodynamic therapy (PDT), which utilizes type I photoreactions, has great potential as an effective cancer treatment because of its hypoxia-tolerant superiority over the commonly used type II pathway. A few type I photosensitizers are exploited; however, they majorly induce cytotoxicity and possess poor tumor specificity and low-efficient theranostics. To resolve this issue, herein an aminopeptidase N (APN)-activated type I phototheranostic probe (CyA) is reported for anti-hypoxic PDT in conjunction with immunotherapy for effective cancer treatment. CyA can specifically activate near-infrared fluorescence, photoacoustic signals, and phototoxicity following APN-induced substrate cleavage and the subsequent generation of active phototheranostic molecules (such as CyBr). CyA endows specific imaging capabilities and effective phototoxicity toward tumor cells overexpressing APN under both normoxia and hypoxia. In addition, the locally activatable PDT induces systemic antitumor immune responses. More importantly, the integration of localized activated PDT and systemic immunotherapy evokes enhanced therapeutic effects with improved tumor inhibition efficiency in live mice compared with individual treatments. This study aims to present an activatable phototheranostic probe for effective hypoxia-tolerant PDT and combination therapy.

Comparison of 1Beta- and 5Beta-hydroxylation of Deoxycholate and Glycodeoxycholate as In Vitro Index Reactions for Cytochrome P450 3A Activities.

Cytochrome P450 3A (CYP3A) participates in the metabolism of more than 30% of clinical drugs. The vast intra- and inter-individual variations in CYP3A activity pose great challenges to drug development and personalized medicine. It has been disclosed that human CYP3A4 and CYP3A7 are exclusively responsible for the tertiary oxidations of deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA) regioselectivity at C-1ß and C-5ß This work aimed to compare the 1ß- and 5ß-hydroxylation of DCA and GDCA as potential in vitro CYP3A index reactions in both human liver microsomes and recombinant P450 enzymes. The results demonstrated that the metabolic activity of DCA 1ß- and 5ß-hydroxylation was 5-10 times higher than that of GDCA, suggesting that 1ß-hydroxyglycodeoxycholic acid and 5ß-hydroxyglycodeoxycholic acid may originate from DCA oxidation followed by conjugation in humans. Metabolic phenotyping data revealed that DCA 1ß-hydroxylation, DCA 5ß-hydroxylation, and GDCA 5ß-hydroxylation were predominantly catalyzed by CYP3A4 (>80%), while GDCA 1ß-hydroxylation had approximately equal contributions from CYP3A4 (41%) and 3A7 (58%). Robust Pearson correlation was established for the intrinsic clearance of DCA 1ß- and 5ß-hydroxylation with midazolam (MDZ) 1'- and 4-hydroxylation in fourteen single donor microsomes. Although DCA 5ß-hydroxylation exhibited a stronger correlation with MDZ oxidation, DCA 1ß-hydroxylation exhibited higher reactivity than DCA 5ß-hydroxylation. It is therefore suggested that DCA 1ß- and 5ß-hydroxylations may serve as alternatives to T 6ß-hydroxylation as in vitro CYP3A index reactions. SIGNIFICANCE STATEMENT: The oxidation of DCA and GDCA is primarily catalyzed by CYP3A4 and CYP3A7. This work compared the 1ß- and 5ß-hydroxylation of DCA and GDCA as in vitro index reactions to assess CYP3A activities. It was disclosed that the metabolic activity of DCA 1ß- and 5ß-hydroxylation was 5-10 times higher than that of GDCA. Although DCA 1ß-hydroxylation exhibited higher metabolic activity than DCA 5ß-hydroxylation, DCA 5ß-hydroxylation demonstrated stronger correlation with MDZ oxidation than DCA 1ß-hydroxylation in individual liver microsomes.

A Self-Assembled Organic Probe with Activatable Near-Infrared Fluoro-Photoacoustic Signals for In Vivo Evaluation of the Radiotherapy Effect.

Early evaluation and prediction of the radiotherapy effect against tumors are crucial for effective radiotherapy management. The clinical approach generally relies on anatomical changes in tumor size, which is unable to promptly reflect clinical outcomes and guide a timely adjustment of therapy regimens. To resolve it, we herein develop a self-assembled organic probe (dCyFFs) with caspase-3 (Casp-3)-activatable near-infrared (NIR) fluoro-photoacoustic signals for early evaluation and prediction of radiotherapy efficacy. The probe contains an NIR dye that is caged with a Casp-3-cleavable substrate and linked to a self-assembly initiating moiety. In the presence of Casp-3, the self-assembled probe can undergo secondary assembly into larger nanoparticles and simultaneously activate NIR fluoro-photoacoustic signals. Such a design endows a superior real-time longitudinal imaging capability of Casp-3 generated by radiotherapy as it facilitates the passive accumulation of the probe into tumors, activated signal output with enhanced optical stability, and retention capacity relative to a nonassembling small molecular control probe (dCy). As a result, the probe enables precise prediction of the radiotherapy effect as early as 3 h posttherapy, which is further evidenced by the changes in tumor size after radiotherapy. Overall, the probe with Casp-3-mediated secondary assembly along with activatable NIR fluoro-photoacoustic signals holds great potential for evaluating and predicting the response of radiotherapy in a timely manner, which can also be explored for utilization in other therapeutic modalities.

Pharmacokinetics, Safety, and Tolerability of Vonoprazan- or Esomeprazole-Based Bismuth-Containing Quadruple Therapy: A Phase 1, Double-Blind, Parallel-Group Study in Adults with Helicobacter pylori Infection in China.

Quadruple therapy comprising 2 antibiotics, a proton pump inhibitor, and bismuth, is recommended for Helicobacter pylori eradication in China. This Phase 1, double-blind, parallel-group study aimed to evaluate the pharmacokinetics, safety, and tolerability of bismuth-containing vonoprazan- or esomeprazole-based quadruple therapy in H. pylori-positive healthy subjects at a single site in China. Quadruple therapy comprising vonoprazan 20 mg or esomeprazole 20 mg with bismuth potassium citrate 600 mg (equivalent to bismuth 220 mg), clarithromycin 500 mg, and amoxicillin 1000 mg was administered twice daily for 2 weeks. Forty-four subjects were enrolled, 22 each in the vonoprazan (mean age, 34.5 years; men, 63.6%) and esomeprazole (mean age, 31.6 years; men, 59.1%) groups. Day 14 bismuth plasma pharmacokinetic parameters area under the plasma concentration-time curve during a dosing interval (geometric mean ratio, 1.07 [90% confidence interval, 0.82-1.40]) and maximum observed plasma concentration (geometric mean ratio, 1.30 [90% confidence interval, 0.94-1.81]) were similar between the treatment groups. At Day 42 follow-up, 100% and 94.4% of subjects were H. pylori negative in the vonoprazan and esomeprazole groups, respectively. The incidence of treatment-emergent adverse events was similar between the groups, with no serious adverse events. No new safety concerns were identified. In conclusion, vonoprazan had no significant effect on plasma bismuth exposure compared with esomeprazole.

Cathepsin K-Activated Probe for Fluoro-Photoacoustic Imaging of Early Osteolytic Metastasis.

Precise detection of early osteolytic metastases is crucial for their treatment but remains challenging in the clinic because of the limited sensitivity and specificity of traditional imaging techniques. Although fluorescence imaging offers attractive features for the diagnosis of osteolytic metastases, it is hampered by limited penetration depth. To address this issue, a fluoro-photoacoustic dual-modality imaging probe comprising a near-infrared dye caged by a cathepsin K (CTSK)-cleavable peptide sequence on one side and functionalized with osteophilic alendronate through a polyethylene glycol linker on the other side is reported. Through systematic in vitro and in vivo experiments, it is demonstrated that in response to CTSK, the probe generated both near-infrared fluorescent and photoacoustic signals from bone metastatic regions, thus offering a potential strategy for detecting deep-seated early osteolytic metastases.

An activatable near-infrared molecular reporter for fluoro-photoacoustic imaging of liver fibrosis.

Noninvasive and accurate detection of liver fibrosis is extremely significant for well-timed intervention and treatment to prevent or reverse its progression. Fluorescence imaging probes hold great potential for imaging of liver fibrosis, but they always encounter the inherent limitation of shallow penetration depth, which compromises their ability of in vivo detection. To overcome this issue, an activatable fluoro-photoacoustic bimodal imaging probe (IP) is herein developed for specific visualization of liver fibrosis. The probe IP is constructed on a near-infrared thioxanthene-hemicyanine dye that is caged with gamma-glutamyl transpeptidase (GGT) responsive substrate and linked with integrin-targeted peptide (cRGD). Such molecular design permits IP to effectively accumulate in the liver fibrosis region through specific recognition of cRGD towards integrin and activate its fluoro-photoacoustic signal after interaction with overexpressed GGT to precisely monitor the liver fibrosis. Thus, our study presents a potential strategy to design dual-target fluoro-photoacoustic imaging probes for noninvasive detection of early-stage liver fibrosis.

Gene signature and prediction model of the mitophagy-associated immune microenvironment in renal ischemia-reperfusion injury.

Background: Renal ischemia-reperfusion injury (IRI) is an inevitable occurrence during kidney transplantation. Mitophagy, ferroptosis, and the associated immune microenvironment (IME) have been shown to play important roles in renal IRI. However, the role of mitophagy-associated IME genes in IRI remains unclear. In this study, we aimed to construct a prediction model of IRI prognosis based on mitophagy-associated IME genes. Method: The specific biological characteristics of the mitophagy-associated IME gene signature were comprehensively analyzed using public databases such as GEO, Pathway Unification, and FerrDb. Correlations between the expression of prognostic genes and immune-related genes and IRI prognosis were determined by Cox regression, LASSO analysis, and Pearson's correlation. Molecular validation was performed using human kidney 2 (HK2) cells and culture supernatant as well as the serum and kidney tissues of mice after renal IRI. Gene expression was measured by PCR, and inflammatory cell infiltration was examined by ELISA and mass cytometry. Renal tissue damage was characterized using renal tissue homogenate and tissue sections. Results: The expression of the mitophagy-associated IME gene signature was significantly correlated with IRI prognosis. Excessive mitophagy and extensive immune infiltration were the primary factors affecting IRI. In particular, FUNDC1, SQSTM1, UBB, UBC, KLF2, CDKN1A, and GDF15 were the key influencing factors. In addition, B cells, neutrophils, T cells, and M1 macrophages were the key immune cells present in the IME after IRI. A prediction model for IRI prognosis was constructed based on the key factors associated with the mitophagy IME. Validation experiments in cells and mice indicated that the prediction model was reliable and applicable. Conclusion: We clarified the relationship between the mitophagy-related IME and IRI. The IRI prognostic prediction model based on the mitophagy-associated IME gene signature provides novel insights on the prognosis and treatment of renal IRI.

Molecular mechanisms of the chemical constituents from anti-inflammatory and antioxidant active fractions of Ganoderma neo-japonicum Imazeki.

Ganoderma neo-japonicum Imazeki is a rare medicinal mushroom that has been reported to play a role in scavenging free radicals, protecting the liver, and inhibiting tumor cell activity. In this study, crude extracts were prepared, and 47 triterpenoids were identified by Ultra-high-performance liquid chromatography coupled with triple quadrupole time-of flight mass spectrometry (UHPLC-Triple TOF-MS/MS). Then, the crude extracts were subjected to column chromatography for the first time to obtain six fractions (Fr. (a), (b), (c), (d), (e) and (f)). Antioxidant and anti-inflammatory active tracking assays of all fractions found that Fr. (c) exhibited the strongest bioactivity. Subsequently, the chemical composition of Fr. (c) was clarified, and eight triterpenoids were determined in combination with the standard substances. In addition, this study demonstrated that Fr. (c) reduced the levels of inflammatory cytokines and reactive oxygen species (ROS) in LPS-stimulated RAW264.7 macrophages. Further studies showed that Fr. (c) could down-regulate the expression level of proteins associated of NF-κB signaling pathway, and upregulated Nrf2 and HO-1 protein level. In conclusion, our study showed that Fr. (c) inhibited LPS-mediated inflammatory response and oxidative stress by activating the Nrf2/HO-1 pathway and inactivating the NF-κB pathway. In the future, with the clearing of its composition and activity mechanism, Fr. (c) of G. neo-japonicum are expected to become a functional food for health and longevity.

Does the Internet Moderate the Neighborhood Effect? Internet Use, Neighborhoods, and Mental Health among Older Adults in Shanghai.

Internet use may reduce the impact of the neighborhood on residents' well-being by helping people utilize resources beyond their immediate neighborhoods or strengthen neighborhood influences by widening the digital divide across neighborhoods. This study investigates how internet use moderates neighborhood effects on mental health among older adults in Shanghai. Using data from the Shanghai Urban Neighborhood Survey (SUNS) and population census, hierarchical linear models reveal that older adults who more frequently use the internet report lower levels of mental distress. Internet use attenuates the negative effects of living in low-socioeconomic status (SES) neighborhoods. We also examine the roles of three types of internet use: social networking, leisure, and information seeking. The results show that only social networking and leisure internet use are significantly associated with improved mental health among older adults. The results suggest that social programs are needed to increase internet literacy among older adults to promote active aging, and priority should be given to relatively disadvantaged neighborhoods.

An Activatable NIR-II Fluorescent Reporter for In Vivo Imaging of Amyloid-ß Plaques.

Fluorescence imaging in the second near-infrared (NIR-II) window holds great promise for in vivo visualization of amyloid-ß (Aß) pathology, which can facilitate characterization and deep understanding of Alzheimer's disease (AD); however, it has been rarely exploited. Herein, we report the development of NIR-II fluorescent reporters with a donor-π-acceptor (D-π-A) architecture for specific detection of Aß plaques in AD-model mice. Among all the designed probes, DMP2 exhibits the highest affinity to Aß fibrils and can specifically activate its NIR-II fluorescence after binding to Aß fibrils via suppressed twisted intramolecular charge transfer (TICT) effect. With suitable lipophilicity for ideal blood-brain barrier (BBB) penetrability and deep-tissue penetration of NIR-II fluorescence, DMP2 possesses specific detection of Aß plaques in in vivo AD-model mice. Thus, this study presents a potential agent for non-invasive imaging of Aß plaques and deep deciphering of AD progression.

The role of symbiotic fungi in the life cycle of Gastrodia elata Blume (Orchidaceae): a comprehensive review.

Gastrodia elata Blume, a fully mycoheterotrophic perennial plant of the family Orchidaceae, is a traditional Chinese herb with medicinal and edible value. Interestingly, G. elata requires symbiotic relationships with Mycena and Armillaria strains for seed germination and plant growth, respectively. However, there is no comprehensive summary of the symbiotic mechanism between fungi and G. elata. Here, the colonization and digestion of hyphae, the bidirectional exchange of nutrients, the adaptation of fungi and G. elata to symbiosis, and the role of microorganisms and secondary metabolites in the symbiotic relationship between fungi and G. elata are summarized. We comprehensively and deeply analyzed the mechanism of symbiosis between G. elata and fungi from three perspectives: morphology, nutrition, and molecules. The aim of this review was to enrich the understanding of the mutualistic symbiosis mechanisms between plants and fungi and lay a theoretical foundation for the ecological cultivation of G. elata.

Aerobic nitrous oxide emission in anoxic/aerobic and intermittent aeration sequencing batch reactors.

This study characterized nitrogen removal and nitrous oxide (N2O) emissions from lab-scale anoxic/aerobic sequencing batch reactor (AOSBR) and intermittent aeration sequencing batch reactor (IASBR), respectively, for treating synthetic municipal wastewater. The N2O emission was evaluated in a simulated cycle, and batch conditions of aerobic nitrification, simultaneous nitrification and denitrification (SND), and aerobic denitrification. The results show that nitrogen removal was enhanced in IASBR compared to AOSBR, with 94.2% and 67.9% of total inorganic nitrogen removal efficiency in IASBR and AOSBR, respectively. In the simulated cycle, the emission factors (of oxidized ammonium) were 4.9% and 0.6% in AOSBR and IASBR, respectively. Under batch conditions, the N2O emission factors during SND were obviously higher than that during aerobic nitrification and denitrification. The N2O emission factors during SND ranging 0.68-11.68% in AOSBR and 1.25-5.13% in IASBR. Furthermore, N2O emission under batch conditions was affected by the aeration ratios. Moderate and high aeration ratios used in this study stimulated the N2O emission from SND. The N2O emission was enhanced with the nitrite accumulation during aerobic nitrification when the nitrite-oxidizing bacteria was inhibited by a chemical inhibitor. Aerobic denitrification via nitrite could be the main pathway of N2O generation from SND processes. The findings from our study can help further understand N2O emission mechanisms and guide the optimization of the current wastewater treatment process for minimizing N2O emission.

The predictors and surgical outcomes of different distant metastases patterns in upper tract urothelial carcinoma: A SEER-based study.

The purpose of this study was to investigate the predictors of metastatic patterns of upper tract urothelial carcinoma (UTUC) and to analyze the surgical outcomes of different metastatic patterns of UTUC. Data on patients with UTUC from 2010 to 2017 were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) database. Kaplan-Meier analysis was applied to compare the patients' survival distributions. Univariate and multivariate logistic regression was used to assess the specific predictors of site-specific metastases, while competitive risk regression was applied to estimate the predictors of cancer-specific mortality in patients with metastases. A total of 9,436 patients were enrolled from the SEER database, of which 1,255 patients had distant metastases. Lung metastasis (42.5%) was most common and patients with single distant lymph node metastasis had a better prognosis. Clinical N stage (N1, N2, N3) was the strongest predictors of the site specific metastatic sites. Renal pelvis carcinoma was more prone to develop lung metastases (OR = 1.67, P < 0.01). Resection of the primary tumor site is beneficial for the prognosis of patients with metastatic UTUC, whether local tumor resection (HR = 0.72, P < 0.01) or nephroureterectomy (HR = 0.64, P < 0.01). Patients with single distant lymph node metastasis have the greatest benefit in nephroureterectomy compared to other specific-site metastases (median survival 19 months vs. 8 months). An understanding of distant metastatic patterns and surgical outcomes in patients with UTUC is important in clinical settings and helpful in the design of personalized treatment protocols.

Students' online interaction, self-regulation, and learning engagement in higher education: The importance of social presence to online learning.

Online learning have played a very significant role for achieving professional and academic qualifications in higher education. There have been more and more researches that explore the issues of learning activities, satisfaction, engagement, and interactions between instructors and students. To promote learning engagement in online learning environments in higher education, this study collected data from 334 full-time undergraduate students in a large public Chinese university and explored the correlation of online interaction, self-regulation learning and social presence on learning engagement in online environments. The research findings indicated that online interaction affected social presence and indirectly affected learning engagement through social presence. In addition, social presence affected learning engagement, self-regulation affected social presence, and social presence also mediated the relationship between self-regulation and learning engagement. This study reported that self-regulation learning and social presence had positive correlation with on students' learning engagement in online environments. The findings of this study have significant practical implications for teaching practices.

Influence of Active Surveillance on Gleason Score Upgrade and Prognosis in Low- and Favorable Intermediate-Risk Prostate Cancer.

Few studies have focused on the link between active surveillance (AS) and Gleason score upgrade (GSU) and its impact on the prognosis of patients with prostate cancer (PCa). This study aimed to analyze the effect of AS duration on GSU and prognostic value based on risk stratification. All eligible patients were risk-stratified according to AUA guidelines into low-risk (LR), favorable intermediate-risk (FIR), and unfavorable intermediate-risk (UIR) PCa. Within the Surveillance, Epidemiology, and End Results Program (SEER) database, 28,368 LR, 27,243 FIR, and 12,210 UIR PCa patients were included. The relationship between AS duration and GSU was identified with univariate and multivariate logistic regression. Discrimination according to risk stratification of AS duration and GSU was tested by Kaplan-Meier analysis and competing risk regression models. The proportion of patients who chose AS was the highest among LR PCa (3434, 12.1%), while the proportion in UIR PCa was the lowest (887, 7.3%). The AS duration was only associated with GSU in LR PCa, with a high Gleason score (GS) at diagnosis being a strong predictor of GSU for FIR and UIR PCa. Kaplan-Meier analysis indicated that long-term surveillance only made a significant difference in prognosis in UIR PCa. The competing risk analysis indicated that once GS was upgraded to 8 or above, the prognosis in each group was significantly worse. AS is recommended for LR and FIR PCa until GS is upgraded to 8, but AS may not be suitable for some UIR PCa patients.

COVID-19 is associated with the risk of cardiovascular disease death: A two-sample Mendelian randomization study.

Objective: This study aimed to estimate the causal effects of Coronavirus disease 2019 susceptibility and hospitalization on cardiovascular disease death using two-sample Mendelian randomization analysis. Methods: We used statistics from a genome-wide association study. A total of 2,568,698 participants were assessed in this study, including 1,299,010 in Coronavirus disease 2019 susceptibility databases, 908,494 in Coronavirus disease 2019 hospitalization database, and 361,194 in a cardiovascular disease death database. We performed two-sample Mendelian randomization analysis using the inverse variance weighted method. As sensitivity analysis techniques, Mendelian randomization-Egger regression, heterogeneity analyses, and Leave-one-out analysis were employed. Reverse Mendelian randomization analysis was used to detect reverse causality. Statistical significance was defined as P < 0.05. Results: Coronavirus disease 2019 susceptibility may be a causal factor for cardiovascular disease death (ß = 2.188 × 10-3, P = 0.002), which involves five common single nucleotide polymorphisms. Similarly, Coronavirus disease 2019 hospitalization may also be a causal factor for cardiovascular disease death (ß = 8.626 × 10-4, P = 0.010), which involves nine common single nucleotide polymorphisms. Furthermore, sensitivity and reverse Mendelian randomization analysis suggested that no heterogeneity, horizontal pleiotropy or reverse causality was found between Coronavirus disease 2019 and cardiovascular disease death. Conclusion: Our bidirectional Mendelian randomization analysis showed a causal relationship between Coronavirus disease 2019 susceptibility and hospitalization associated with an increased risk of cardiovascular disease death.

Oncolytic viruses combined with immune checkpoint therapy for colorectal cancer is a promising treatment option.

Immunotherapy is one of the promising strategies in the treatment of oncology. Immune checkpoint inhibitors, as a type of immunotherapy, have no significant efficacy in the clinical treatment of patients with pMMR/MSS/MSI-L mCRC alone. Therefore, there is an urgent need to find combination therapies that can improve the response rate of immune checkpoint inhibitors. Oncolytic viruses are a new class of cancer drugs that, in addition to directly lysing tumor cells, can facilitate the action of immune checkpoint inhibitors by modulating the tumor microenvironment and transforming "cold" tumors into "hot" ones. The combination of oncolytic viruses and immune checkpoint inhibitors is currently being used in several primary and clinical studies to treat tumors with exciting results. The combination of genetically modified "armed" OV with ICIs is expected to be one of the treatment options for pMMR/MSS/MSI-L mCRC. In this paper, we will analyze the current status of oncolytic viruses and ICIs available for the treatment of CRC. The feasibility of OV in combination with ICI for CRC will be discussed in terms of the mechanism of action of OV in treating tumors.