Dual-loss of PBRM1 and RAD51 identifies hyper-sensitive subset patients to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Homologous recombination deficiency (HRD), though largely uncharacterized in clear cell renal cell carcinoma (ccRCC), was found associated with RAD51 loss of expression. PBRM1 is the second most common mutated genes in ccRCC. Here, we introduce a HRD function-based PBRM1-RAD51 ccRCC classification endowed with diverse immune checkpoint blockade (ICB) responses. METHODS: Totally 1542 patients from four independent cohorts were enrolled, including our localized Zhongshan hospital (ZSHS) cohort and Zhongshan hospital metastatic RCC (ZSHS-mRCC) cohort, The Cancer Genome Atlas (TCGA) cohort and CheckMate cohort. The genomic profile and immune microenvironment were depicted by genomic, transcriptome data and immunohistochemistry. RESULTS: We observed that PBRM1-loss ccRCC harbored enriched HRD-associated mutational signature 3 and loss of RAD51. Dual-loss of PBRM1 and RAD51 identified patients hyper-sensitive to immunotherapy. This dual-loss subtype was featured by M1 macrophage infiltration. Dual-loss was, albeit homologous recombination defective, with high chromosomal stability. CONCLUSIONS: PBRM1 and RAD51 dual-loss ccRCC indicates superior responses to immunotherapy. Dual-loss ccRCC harbors an immune-desert microenvironment but enriched with M1 macrophages. Dual-loss ccRCC is susceptible to defective homologous recombination but possesses high chromosomal stability.

A novel mini-retractor for retroperitoneal laparoscopic partial nephrectomy.

BACKGROUND: Retroperitoneal partial nephrectomy (RLPN) is the premier treatment for localized renal tumors despite narrow operation space. Many efforts have been taken to facilitate the operation of RLPN, but the optimal resolution remains debatable. OBJECTIVE: To explore the feasibility of using Mini-lap to improve workspace and surgical vision in RLPN. DESIGN, SETTING, AND PARTICIPANTS: A multicenter retrospective review of 51 patients who underwent RLPN with Mini-lap from January 2018 to December 2020 was conducted. SURGICAL PROCEDURE: Standard RLPN under three poles was performed in all cases. We highlighted the usage of Mini-lap (Teleflex Minilap percutaneous Surgical System) as a novel retractor in RLPN. OUTCOME AND MEASUREMENTS AND STATICAL ANALYSIS: Demographics, preoperative, intraoperative, and postoperative outcomes were assessed. RESULTS AND LIMITATIONS: All 51 cases completed RLPN with three ports successfully and no conversion to open surgery. The mean diameter of tumors was (3.53 ± 1.05) cm, in which 62.7% (32/51) were located anteriorly. The operation time and warm ischemic time (WIT) were (86.7 ± 15.9) min and (25.6 ± 5) min respectively. Minor complications (Clavien grade 1-2) occurred in 6 cases. The limitations were small sample size, retrospective design, and absence of control. CONCLUSIONS: Mini-lap could be used as a mini-retractor in RLPN, sparing extra assistant ports, expanding workspace, and optimizing vision. PATIENT SUMMARY: With highlights of larger workspace and less instrument interference, mini-lap could be applied in retroperitoneal laparoscopic partial nephrectomy.

In vivo evaluation of safety and performance of a tapered nitinol venous stent with inclined proximal end in an ovine iliac venous model.

A tapered stent with inclined proximal end is designed for fitting the iliac anatomically. The aim of the present study was to evaluate the safety and performance of the new stent in ovine left iliac veins. The experiment was performed in 30 adult sheep, and one nitinol-based VENA-BT® iliac venous stent (KYD stent) was implanted into each animal's left common iliac vein. Follow-up in all sheep consisted of angiographic, macroscopic, and microscopic examinations at Day 0 (< 24 h), Day 30, Day 90, Day 180 and Day 360 post-stenting (six animals per each time-point). 30 healthy ~ 50 kg sheep were included in this study and randomly divided into five groups according to the follow-up timepoint. All stents were implanted successfully into the left ovine common iliac vein. No significant migration occurred at follow-up. There is no statistically significant difference between the groups (p > 0.05), indicating no serious lumen loss occurred during the follow-up period. Common iliac venous pressure was further measured and the results further indicated the lumen patency at follow-up. Histological examinations indicated that no vessel injury and wall rupture, stent damage, and luminal thrombus occurred. There was moderate inflammatory cell infiltration around the stent in Day-0 and Day-30 groups with the average inflammation score of 2.278 and 2.167, respectively. The inflammatory reaction was significantly reduced in Day-90, Day-180 and Day-360 groups and the average inflammation scores were 0.9444 (p < 0.001, Day-90 vs Day-0), 1.167 (p < 0.001, Day-180 vs Day-0) and 0.667 (p < 0.001, Day-90 vs Day-0), respectively. The microscopic examinations found that the stents were well covered by endothelial cells in all follow-up time points. The results suggested that the KYD stent is feasible and safe in animal model. Future clinical studies may be required to further evaluate its safety and efficacy.

Renal anatomical classification systems cannot predict the occurrence of vascular complications after partial nephrectomy.

OBJECTIVES: To determine the relationship between renal tumor complexity and vascular complications after partial nephrectomy using PADUA, RENAL, and ZS scores. METHODS: Between January 2007 and December 2018, a total of 1917 patients with available cross-sectional imaging were enrolled in the study. Logistic regressions were used to identify independent predictors of vascular complications. RESULTS: Of 1917 patients, 31 (1.6%) developed vascular complications, including 10 females and 21 males. The high-complexity category was significantly associated with a decreased risk of vascular complication in PADUA (OR = 0.256; 95%CI = 0.086-0.762; P = 0.014) and ZS score (OR = 0.279; 95%CI = 0.083-0.946; P = 0.040). Laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy were independent risk factors for vascular complications. Meanwhile, the incidence was significantly reduced in the recent 4 years in the high score tumor group alone in PADUA (0.2% [1/474] vs. 2.2% [3/139], P = 0.038) and ZS score (0.2% [1/469] vs. 2.7% [3/112], P = 0.024). In the first 8 years, laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy were the only two independent risk factors for vascular complications. In the recent 4 years, only the high-complexity category was significantly associated with a decreased risk of vascular complication in the PADUA score (OR = 0.110; 95%CI = 0.013-0.938; P = 0.044). CONCLUSION: The renal anatomic classification system cannot predict the occurrence of vascular complications after partial nephrectomy.

Effect of galectin-1 on prognosis and responsiveness of immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma.

BACKGROUND: In renal cell carcinoma (RCC), no clinically available biomarker has been utilized for checkpoint inhibitor immunotherapy (IO) + tyrosine kinase inhibitor (TKI) combinations. Galectin-1 overexpression is found in tumors, with potential immune-regulating roles. METHODS: RNA-sequencing was performed in two cohorts of RCC treated with IO/TKI combination therapy (ZS-MRCC, JAVELIN-101). Immunohistochemistry and flow cytometry were performed to investigate immune cell infiltration and function in the tumor microenvironment of RCC. The RECIST criteria were used to define response and progression-free survival (PFS). RESULTS: Galectin-1 expression was elevated in RCC with higher stage (p < 0.001) and grade (p < 0.001). Galectin-1 expression was also elevated in non-responders of IO/TKI therapy (p = 0.047). High galectin-1 was related with shorter PFS in both ZS-MRCC cohort (p = 0.036) and JAVELIN-101 cohort (p = 0.005). Multivariate Cox analysis defined galectin-1 as an independent factor for PFS (HR 2.505; 95% CI 1.116-5.622; p = 0.026). In the tumor microenvironment, high galectin-1 was related with decreased GZMB+CD8+ T cells (Speraman's ρ = -0.31, p = 0.05), and increased PD1 + CD8+ T cells (Speraman's ρ = 0.40, p = 0.01). Besides, elevated number of regulatory T cells (p = 0.039) and fibroblasts (p = 0.011) was also found in high galectin-1 tumors. Finally, a random-forest score (RFscore) was built for predicting IO/TKI benefit. IO/TKI therapy showed benefit only in low-RFscore patients (HR 0.489, 95% CI 0.358-0.669, p < 0.001), rather than high-RFscore patients (HR 0.875, 95% CI 0.658-1.163, p = 0.357). CONCLUSIONS: High galectin-1 indicated therapeutic resistance and shorter PFS of IO/TKI therapy. High galectin-1 also indicated CD8+ T cell dysfunction. High galectin-1 could be applied for patient selection of IO/TKI therapy in RCC.

Astragalus membranaceus Polysaccharide Regulates Small Intestinal Microbes and Activates IL-22 Signal Pathway to Promote Intestinal Stem Cell Regeneration in Aging Mice.

Aging can cause degenerative changes in multiple tissues and organs. Gastrointestinal diseases and dysfunctions are common in the elderly population. In this study, we investigated the effects of Astragalus membranaceus polysaccharide (APS) and Astragalus membranaceus ethanol extract (AEE) on age-related intestinal dysfunction and gut microbiota dysbiosis in naturally aging mice. The energy expenditure and physical activity of 23-month-old C57BL6/J mice were recorded using a metabolic cage system. Pathological changes in the intestine were evaluated using Alcian blue staining. The protein levels of leucine-rich repeats containing G protein-coupled receptor 5 (Lgr5) and Stat3 in the small intestine were determined using immunohistochemistry. The intestinal cell migration distance was assessed using bromodeoxyuridine (BrdU) immunofluorescence staining. The gene transcription levels of intestinal stem cell (ISC) markers and ISC-related signaling pathways were detected using quantitative real-time PCR (qRT-PCR). Microbiota analysis based on 16S rDNA was performed to evaluate the composition of the gut microbiota. APS and AEE improved a series of aging phenotypes in female but not in male aging mice. APS and AEE ameliorate intestinal dysfunction and histopathological changes in aging mice. APS had a more significant anti-aging effect than AEE, particularly on intestinal dysfunction. APS promotes ISC regeneration by activating the IL-22 signaling pathway. Cohousing (CH) experiments further confirmed that APS induced the IL-22 signaling pathway by increasing the abundance of Lactobacillus, thereby promoting the regeneration of ISCs. Our results show that APS may serve as a promising agent for improving age-related intestinal dysfunction.

Effect of Annexin A2 on prognosis and sensitivity to immune checkpoint plus tyrosine kinase inhibition in metastatic renal cell carcinoma.

BACKGROUND: Immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) therapy is the first-line recommendation for advanced renal cell carcinoma (RCC), but no biomarker has been approved for it. Annexin A2 (ANXA2) can induce immune escape in tumors. METHODS: Two independent cohorts of advanced RCC treated by IO + TKI were utilized for survival analysis (ZS-MRCC, n = 45; Javelin-101, n = 726). ANXA2 expression was determined by RNA-sequencing. The impact of ANXA2 on the tumor microenvironment was assessed by RNA-sequencing, flow cytometry and immunohistochemistry in two localized RCC datasets (ZS-HRRCC, n = 40; TCGA-KIRC, n = 530). RESULTS: ANXA2 was upregulated in non-responders of IO + TKI therapy (p = 0.027). High-ANXA2 group showed poor progression-free survival (PFS) in both the ZS-MRCC cohort (HR, 2.348; 95% CI 1.084-5.085; P = 0.025) and the Javelin-101 cohort (HR, 1.472; 95% CI 1.043-2.077; P = 0.027). Multivariate Cox regression determined ANXA2 as an independent prognostic factor (HR, 2.619; 95% CI 1.194-5.746; P = 0.016). High-ANXA2 was correlated with decreased proportion of granzyme B+ CD8+ T cells (Spearman's ρ = - 0.40, P = 0.01), and increased TIM-3+ (Spearman's ρ = 0.43, P < 0.001) and CTLA4+ (Spearman's ρ = 0.49, P < 0.001) tumor-infiltrating lymphocytes. A random forest (RF) score was further build by integrating ANXA2 and immune genes, which stratified patients who would benefit from IO + TKI therapy (low-RF score, IO + TKI vs TKI, HR = 0.453, 95% CI 0.328-0.626; high-RF score, IO + TKI vs TKI, HR = 0.877, 95% CI 0.661-1.165; interaction P = 0.003). CONCLUSIONS: Upregulated ANXA2 was associated with poor PFS and therapeutic resistance in RCC treated by IO + TKI therapy, and related with T cell exhaustion. The integrated RF score could stratify patients who would benefit from IO + TKI therapy.

Advances in the study of mitophagy in osteoarthritis. / çº¿ç²’ä½“è‡ªå™¬è°ƒæŽ§éª¨å ³èŠ‚ç‚Žçš„æœ€æ–°è¿›å±•.

Osteoarthritis (OA), characterized by cartilage degeneration, synovial inflammation, and subchondral bone remodeling, is among the most common musculoskeletal disorders globally in people over 60 years of age. The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process. Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism. Therefore, maintaining mitochondrial homeostasis is an important strategy to mitigate OA. Mitophagy is a vital process for autophagosomes to target, engulf, and remove damaged and dysfunctional mitochondria, thereby maintaining mitochondrial homeostasis. Cumulative studies have revealed a strong association between mitophagy and OA, suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA. By reviewing the literature on mitophagy and OA published in recent years, this paper elaborates the potential mechanism of mitophagy regulating OA, thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.

Advances in the study of protein folding and endoplasmic reticulum-associated degradation in mammal cells. / å“ºä¹³åŠ¨ç‰©ç»†èƒžè›‹ç™½è´¨æŠ˜å å’Œå† è´¨ç½‘ç›¸å ³é™è§£çš„ç ”ç©¶è¿›å±•.

The endoplasmic reticulum is a key site for protein production and quality control. More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulum. However, during protein folding, unfolded and/or misfolded proteins are prone to occur, which may lead to endoplasmic reticulum stress. Organisms can monitor the quality of the proteins produced by endoplasmic reticulum quality control (ERQC) and endoplasmic reticulum-associated degradation (ERAD), which maintain endoplasmic reticulum protein homeostasis by degrading abnormally folded proteins. The underlying mechanisms of protein folding and ERAD in mammals have not yet been fully explored. Therefore, this paper reviews the process and function of protein folding and ERAD in mammalian cells, in order to help clinicians better understand the mechanism of ERAD and to provide a scientific reference for the treatment of diseases caused by abnormal ERAD.

Association of prognostic nutritional index with peripheral artery disease in US adults: a cross-sectional study.

BACKGROUND: The objective of this study was to investigate the relationship between the prognostic nutritional index (PNI) and peripheral artery disease (PAD). METHODS: The present study is a cross-sectional study based on the National Health and Nutrition Survey (1999-2004). The laboratory-calculated PNI was divided into four groups based on quartiles(Q1:PNI ≤ 50.00; Q2: 50.01-53.00; Q3:53.01-56.00; Q4: > 56.00). PAD was defined as an ankle brachial pressure index (ABPI) ≤ 0.9 on the left or right. The relationship between PNI and PAD was examined using multifactor weighted logistic regression analysis, as well as subgroup analysis. Subgroup analyses were conducted based on demographic and clinical variables. RESULTS: A total of 5,447 individuals were included in our final analysis. The age of the participants was 59.56 ± 13.10 years, and males accounted for 52.8% (n = 2820). The prevalence of PAD was 6.7% (n = 363). After adjusting for all factors, participants with Q1 still had an increased risk of PAD, with an OR value of 1.593 and a 95% CI of 1.232-1.991. Subgroup analysis showed no significant interaction among multiple factors. CONCLUSIONS: In summary, we report that lower PNI are associated with a higher risk of PAD in US adults. It is hoped that this discovery can provide a reference for the prevention of PAD.

Comparison of Different Endovascular Treatments of Femoropopliteal Artery In-Stent Restenosis: A Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND: This Bayesian network meta-analysis (NMA) sought to evaluate the efficacy of different endovascular treatments for femoropopliteal artery in-stent restenosis (FP-ISR). METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of science for clinical trials from database inception to March 31, 2023, with no language restrictions to retrieve randomized controlled trials or cohort studies evaluating the impact of any kind of endovascular treatments for FP-ISR. Pair-wise meta-analysis and Bayesian NMA were performed to pool the outcome estimates different endovascular treatments. The primary end points under consideration were primary patency rates at both 6-month and 12-month follow-up. RESULTS: A total of 15 studies with 1,424 patients were ultimately enrolled to be analyzed, 7 types of endovascular treatment were identified for comparison. In terms of primary patency and freedom from target lesion revascularization (TLR) at 6-month and12-month follow-up, the direct meta-analysis findings showed that drug-coated balloons (DCB) and covered stent (CS) are considerably superior to plain old balloon angioplasty (POBA), Excimer laser atherectomy (ELA) + DCB is significantly better than DCB. According to the meta-analysis based on Bayesian theory, during the 6-month and 12-months follow-up, we could not find significant difference between the different treatments in terms of the primary patency and the freedom from TLR, based on the surface values under the cumulative ranking curve (SUCRA), CS was considered the best treatment in terms of primary patency (6 months SUCRA = 85.2; 12 months SUCRA = 78.9) and freedom from TLR (6 months SUCRA = 84.9; 12 months SUCRA = 70.9); directional atherectomy + POBA may lead to higher survival rate at 12 months (SUCRA = 89.1) than others treatments; in addition, both ELA + POBA and ELA + DCB have higher limb salvage than POBA. CONCLUSIONS: The findings of this NMA suggest that CS showed positive encouraging results in primary patency and TLR in FP-ISR at 6 and 12 months. However, due to the potential influence of certain confounding factors, the long-term results necessitate validation through numerous randomized controlled trials.

Association of serum 25-hydroxyvitamin D concentration with all-cause and cause-specific mortality in hypertensive patients.

BACKGROUND AND AIMS: To examine the association of serum 25-hydroxyvitamin D [25(OH)D] with all-cause mortality and disease-specific mortality in patients with hypertension. METHODS AND RESULTS: This cohort study included US adults in the National Health and Nutrition Examination Survey from 2007 to 2018. All-cause mortality and cause-specific mortality outcomes were determined by association with National Death Index records. Cox proportional risk models were used to estimate hazard ratios (HRs) for all-cause mortality and cause-specific mortality and 95% confidence intervals (CIs) for serum 25(OH)D concentrations. The cohort included 10,325 adult participants. The mean serum 25(OH)D level was 65.87 nmol/L, and 32.2% of patients were vitamin D deficient (<50 nmol/L). During a mean follow-up of 77 months, 1290 deaths were recorded, including 345 cardiovascular deaths and 237 cancer deaths. Patients with higher serum 25(OH)D were more likely to have lower all-cause mortality and cardiovascular mortality than those with serum 25(OH)D < 25.00 nmol/L. For cancer mortality in hypertensive patients, vitamin D may not have a predictive role in this. CONCLUSIONS: This study shows that higher 25(OH)D levels are significantly associated with lower all-cause mortality and cardiovascular disease (CVD) mortality. These findings suggest that maintaining adequate vitamin D status may reduce the risk of death in patients with hypertension.

NKG2A+CD8+ T cells infiltration determines immunosuppressive contexture and inferior response to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Immunotherapy is gaining momentum, but current treatments have limitations in terms of beneficiaries. Clear cell renal cell carcinoma (ccRCC) harbors the highest expression of human leukocyte antigen E (HLA-E), ligand of NKG2A, among all solid tumors. In this study, we aim to investigate the role of NKG2A+CD8+ T cells in tumor microenvironment and its potential as a novel target in ccRCC. METHODS: This study included four independent cohorts, including 234 patients from Zhongshan cohort (ZSHC) who underwent partial or radical nephrectomy at Zhongshan Hospital, and 117 metastatic patients from metastatic Zhongshan cohort (ZSHC-metastatic renal cell carcinoma) who were treated with immune checkpoint inhibitor or tyrosine kinase inhibitor alone. We also incorporated a cohort of 530 patients diagnosed with ccRCC from The Cancer Genome Atlas (referred to as TCGA-kidney renal clear cell carcinoma) and 311 patients from CheckMate cohort for bioinformatics exploration and hypothesis validation. Fresh surgical specimens from 15 patients who underwent ccRCC surgery at Zhongshan Hospital were collected for flow cytometry analysis. Another 10 fresh surgical specimens were used to investigate the therapeutic potential of NKG2A blockade after in vitro intervention. The infiltration of NKG2A+CD8+ T cells was assessed using immunohistochemical staining, flow cytometry, and immunofluorescence staining in ZSHC cohort. RESULTS: Patients with higher infiltration of NKG2A+CD8+ T cells in ccRCC exhibited shorter overall survival and resistance to immunotherapy. NKG2A+CD8+ T cells expressed upregulated checkpoint molecules and displayed impaired effector functions, along with tissue-residency characteristics. Combination of programmed cell death protein-1 (PD-1) blockade and NKG2A blockade demonstrated an enhanced capability in reactivating CD8+ T cells effector functions. CONCLUSION: Intense infiltration of NKG2A+CD8+ T cells were associated with poorer prognosis and response to immunotherapy. NKG2A blockade combined with current immunotherapy exhibited a robust ability to reactivate CD8+ T cells effector functions.

Unveiling the Hidden Burden: Estimating All-Cause Mortality Risk in Older Individuals with Type 2 Diabetes.

Background: The mortality rate among older persons with diabetes has been steadily increasing, resulting in significant health and economic burdens on both society and individuals. The objective of this study is to develop and validate a predictive nomogram for estimating the 5-year all-cause mortality risk in older persons with T2D (T2D). Methods: We obtained data from the National Health and Nutrition Survey (NHANES). A random 7 : 3 split was made between the training and validation sets. By linking the national mortality index up until December 31, 2019, we ensured a minimum of 5 years of follow-up to assess all-cause mortality. A nomogram was developed in the training cohort using a logistic regression model as well as a least absolute shrinkage and selection operator (LASSO) regression model for predicting the 5-year risk of all-cause mortality. Finally, the prediction performance of the nomogram is evaluated using several validation methods. Results: We constructed a comprehensive prediction model based on the results of multivariate analysis and LASSO binomial regression. These models were then validated using data from the validation cohort. The final model includes four independent predictors: age, gender, estimated glomerular filtration rate, and white blood cell count. The C-index values for the training and validation cohorts were 0.748 and 0.762, respectively. The calibration curve demonstrates satisfactory consistency between the two cohorts. Conclusions: The newly developed nomogram proves to be a valuable tool in accurately predicting the 5-year all-cause mortality risk among older persons with diabetes, providing crucial information for tailored interventions.

RUNX3 pathway signature predicts clinical benefits of immune checkpoint inhibition plus tyrosine kinase inhibition in advanced renal cell carcinoma.

BACKGROUND: Checkpoint inhibitor immunotherapy plus tyrosine kinase inhibitor (IO/TKI) have been recently recommended as standard first-line therapy for advanced renal cell carcinoma, while no clinical-available biomarker has been applied. This study aimed to investigate the associations between RUNX3 pathway signature and IO/TKI benefits in renal cell carcinoma (RCC). METHODS: Two IO/TKI cohorts (ZS-MRCC, JAVELIN-101) and one high-risk localized RCC cohort (ZS-HRRCC) were included. All samples were evaluated by RNA-sequencing, and RUNX Family Transcription Factor 3 (RUNX3) pathway were determined by single sample gene set enrichment analysis. Flow cytometry were applied for immune cell infiltration and function. RESULTS: RUNX3 signature was elevated in RCC samples, compared non-tumor tissues (P < 0.001). High-RUNX3 signature was associated with shorter progression-free survival (PFS) in both IO/TKI cohorts (ZS-MRCC cohort, P = 0.025; JAVELIN-101 cohort, P = 0.019). RUNX3 signature also predicted IO/TKI benefit in advanced RCC, compared with TKI monotherapy (interaction p = 0.027). RUNX3 signature was associated with decreased number of GZMB + CD8 + T cells (Spearman's ρ=-0.42, P = 0.006), and increased number of PD1 + CD8 + T cells (Spearman's ρ = 0.29, P = 0.072). Moreover, the integration of RUNX3 signature and GZMB expression showed predictive potential for TKI/IO (log-rank P < 0.001). In addition, the predictive value of RUNX3 signature for IO/TKI benefit was restricted in SETD2-wild type patients (log-rank P < 0.001). Finally, a risk score was established by random forest for IO/TKI benefit, showing remarkable predictive potency (Log-rank P < 0.001). CONCLUSIONS: RUNX3 pathway signature could be a potential predictive biomarker for IO/TKI treatment in advanced RCC, for both prognosis and treatment selection between IO/TKI and TKI monotherapy.

Safety and Efficacy of Excimer Laser Atherectomy Combined with a Drug-Coated Balloon in De Novo Femoral Popliteal Artery Disease: A Retrospective Study.

BACKGROUND: The effectiveness of excimer laser atherectomy (ELA) combined with drug-coated balloon (DCB) for de novo femoropopliteal artery disease (FPAD) is currently unknown. This case series evaluated the clinical outcomes of ELA combined with DCB in de novo FPAD from a real-world clinical perspective. METHODS: We conducted a retrospective study of patients treated with ELA + DCB for de novo FPAD between November 2016 and January 2020. The primary efficacy endpoint was the initial patency rate; secondary endpoints included target lesion revascularization without clinically driven target lesion revascularization (CD-TLR) and technical success. Primary safety endpoints included all-cause death, unplanned major amputation, and postoperative complications. RESULTS: The mean follow-up was 37.8 ± 25.3 months and included 56 consecutive patients (68.23 ± 8.01 years, 41 men). Forty-three patients had lifestyle-restricted claudication, and 13 patients had critical limb-threatening ischemia. The mean length of the lesion was 178.41 mm in all patients. The total lesion occlusion rate was 48.2 (n = 27), and the overall technical success rate was 100%. The 12-month, 24-month, 36-month, and 48-month primary patency rates of the ELA + DCB group were 75%, 66.1%, 58.9%, and 42.8%, respectively. Freedom from CD-TLR at 12, 24, 36, and 48 months was 83.9%, 80.3%, 76.8%, and 57.1%, respectively. CONCLUSIONS: In real-world clinical practice, ELA + DCB appears to be a safe and effective endovascular treatment for de novo FPAD, with a low rate of freedom from CD-TLR and a good patency rate.

Immunogenicity of mucosal COVID-19 vaccine candidates based on the highly attenuated vesicular stomatitis virus vector (VSVMT) in golden syrian hamster.

COVID-19 is caused by coronavirus SARS-CoV-2. Current systemic vaccines generally provide limited protection against viral replication and shedding within the airway. Recombinant VSV (rVSV) is an effective vector which inducing potent and comprehensive immunities. Currently, there are two clinical trials investigating COVID-19 vaccines based on VSV vectors. These vaccines were developed with spike protein of WA1 which administrated intramuscularly. Although intranasal route is ideal for activating mucosal immunity with VSV vector, safety is of concern. Thus, a highly attenuated rVSV with three amino acids mutations in matrix protein (VSVMT) was developed to construct safe mucosal vaccines against multiple SARS-CoV-2 variants of concern. It demonstrated that spike protein mutant lacking 21 amino acids in its cytoplasmic domain could rescue rVSV efficiently. VSVMT indicated improved safeness compared with wild-type VSV as the vector encoding SARS-CoV-2 spike protein. With a single-dosed intranasal inoculation of rVSVΔGMT-SΔ21, potent SARS-CoV-2 specific neutralization antibodies could be stimulated in animals, particularly in term of mucosal and cellular immunity. Strikingly, the chimeric VSV encoding SΔ21 of Delta-variant can induce more potent immune responses compared with those encoding SΔ21 of Omicron- or WA1-strain. VSVMT is a promising platform to develop a mucosal vaccine for countering COVID-19.

Heterogeneous MXene Hybrid-Oriented Exosome Isolation and Metabolic Profiling for Early Screening, Subtyping and Follow-up Evaluation of Bladder Cancer.

Exosome metabolite-based noninvasive liquid biopsy is an emerging research hotspot that tends to substitute current means in clinics. Nanostructure-based mass spectrometry enables continuous exosome isolation and metabolic profiling with superior analysis speed and high efficiency. Herein, we construct a heterogeneous MXene hybrid that possesses ternary binding sites for exosome capture and outstanding matrix performance for metabolite analysis. Upon optimizing experimental conditions, the average extraction of exosomes and their metabolic patterns from a 60 mL urine sample is completed within 45 s (40 samples per batch for 30 min). According to the exosomal metabolic patterns and the subsequently established biomarker panel, we distinguish early bladder cancer (BCa) from healthy controls with an area under the curve (AUC) value greater than 0.995 in model training and validation sets. As well, we realize subtype classification of BCa in the blind test on metabolic patterns, with an AUC value of 0.867. We also explore the significant biomarkers that are sensitive to follow-up patients, which indeed present reverse change levels compared with pathological progression. This study has the potential to guide the development of the liquid biopsy approach.

Efficacy and Safety of Atherectomy Combined With Balloon Angioplasty vs Balloon Angioplasty Alone in Patients With Femoro-Popliteal Lesions: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Balloon angioplasty (BA), including drug-coated balloons (DCBs) and percutaneous transluminal angioplasty (PTA), has traditionally been used to treat femoral-popliteal lesions. However, in recent years, atherectomy (ATH) has been proposed as a complementary approach. To assess the effectiveness of ATH compared with BA alone in patients with femoral-popliteal artery lesions, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: We included RCTs that focused on patients with femoral-popliteal artery lesions and reported data on the use of ATH and BA therapy. Two reviewers conducted a literature search, refined the data, and assessed the risk of bias. RESULTS: We included a total of 6 RCTs involving 399 patients with femoral-popliteal artery lesions. The use of ATH in combination with BA appeared to improve the patency rate at 12 months (odds ratio [OR]=2.04, 95% confidence interval [CI]=1.14-3.62). In addition, ATH with BA was associated with lower major amputation rates (MD=2.01, 95% CI=0.06-0.77, p=0.02) and a decreased likelihood of bailout stenting (OR=0.07, 95% CI=0.02-0.25, p=0.001). However, there were no statistically significant differences between the groups in terms of target lesion revascularization (TLR) at 12 months, major adverse cardiovascular events (MACEs), and distal embolization events. In addition, we performed subgroup analysis for different ATH devices and BA types. CONCLUSIONS: Based on this meta-analysis, it can be concluded that the use of ATH in combination with BA is a safe and effective method for treating femoral-popliteal artery lesions. In addition, the patency rate at 1 year is superior to treatment with BA alone. Atherectomy also reduces the likelihood of amputation and bailout stenting. Clinicians should consider these findings when designing future RCTs and developing clinical practice guidelines. CLINICAL IMPACT: This meta-analysis summarises a number of existing studies to advance understanding of the atherectomy devices and to reveal its potential. This new technique, when compared with drug coated balloon, shows the possibility of obtaining better clinical outcomes in femoro-popliteal lesions than drug-coated balloon alone, such as higher 12-month primary patency rates as shown in some studies. Currently, it is important to consider the appropriate technology applicable for individualised treatment. atherectomy devices seem to provide clinicians with additional options in clinical practice and to benefit patients in the future. This requires more high quality studies to explore the role and benefits of atherectomy devices in femoro-popliteal lesions.

Drug-Coated Balloon Angioplasty of Infrapopliteal Lesions in Chronic Limb-Threatening Ischemia: Six-month Outcomes of PRIME-WIFI.

PURPOSE: To evaluate 6-month outcomes of drug-coated balloon (DCB) angioplasty of infrapopliteal lesions in patients with chronic limb-threatening ischemia (CLTI). METHODS: We analyzed 6-month follow-up data from the 10-center PRIME-WIFI prospective registry on 300 consecutive patients (33.000% female) with CLTI who underwent DCB angioplasty for infrapopliteal arterial lesions. The primary outcome was freedom from major adverse event (MAE), a composite of major amputation, all-cause death, and clinically-driven target limb reintervention (CD-TLR). Secondary outcomes included amputation-free survival (AFS), freedom from each primary outcome component, primary sustained clinical improvement, and quality of life (QOL) score. Independent risk factors of MAE were determined using Cox proportional hazards regression analysis. RESULTS: A total of 409 infrapopliteal lesions in 312 limbs were treated with DCB, with 54.167% of the limbs being treated for isolated infrapopliteal lesions. By Kaplan-Meier analysis, at 6 months post- procedure (follow-up rate, 85.000%), freedom from MAE was 86.353%; AFS was 90.318%; and freedom from major amputation, all-cause death, and CD-TLR were 96.429%, 93.480%, and 95.079%, respectively. At 6-month follow-up, 83.590% of patients showed primary sustained clinical improvement, and QOL score (4.902±1.388) improved compared with that before procedure (2.327±1.109; p<0.001). Chronic renal insufficiency, chronic obstructive pulmonary disease, Rutherford grade, and postoperative infrapopliteal runoff score were independent risk factors for MAE within 6 months. CONCLUSION: In CLTI, DCB angioplasty of infrapopliteal lesions yields acceptable early efficacy and safety. CLINICAL IMPACT: This study evaluated the 6-month outcomes of DCB angioplasty in infrapopliteal lesions in CLTI patients by analyzing multicenter prospective data, showing that infrapopliteal DCB angioplasty can be performed with acceptable freedom from MAE rate, amputation-free survival rate, freedom from major amputation rate, survival rate, and freedom from CD-TLR rate. No patient experienced DCB-related intraoperative distal embolism. Chronic renal insufficiency, chronic obstructive pulmonary disease, Rutherford grade and postoperative infrapopliteal runoff score were independent risk factors for MAE within 6 months. Comparative real-world studies are needed.