PSCK9 inhibitors reduced early recurrent stroke in patients with symptomatic intracranial atherosclerotic stenosis.

BACKGROUND: Symptomatic intracranial atherosclerotic stenosis (ICAS) is prone to cause early recurrent stroke (ERS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels and prevent cardiovascular events. This multicentre, hospital-based prospective cohort study was designed to investigate whether PCSK9 inhibitors would prevent ERS in patients with symptomatic ICAS. METHODS: From 1 October 2020 to 30 September 2022, consecutive patients with acute ischaemic stroke attributed to ICAS admitted within 1 week after onset were enrolled and followed up for 1 month. Patients were divided into two groups, the PCSK9 inhibitors group receiving PCSK9 inhibitors add-on therapy, and the control group receiving statins and/or ezetimibe. The primary outcome was ERS. Cox proportional hazard models and Kaplan-Meier survival curve were used to estimate the association between PCSK9 inhibitors and ERS. RESULTS: At the end of follow-up, the LDL-C levels were further lowered by PCSK9 inhibitors add-on therapy (n=232, from 3.06±1.16 mmol/L to 2.12±1.19 mmol/L) than statins and/or ezetimibe treatment (n=429, from 2.91±1.05 mmol/L to 2.64±0.86 mmol/L, p<0.001). The Kaplan-Meier survival curves showed that PCSK9 inhibitors add-on therapy significantly reduced ERS (5.59%, 24/429, vs 2.16%, 5/232; log-rank test, p=0.044). The multivariate Cox regression analysis revealed that, after adjusting for confounders with a p value less than 0.05 in univariate analysis or of particular importance, the HR was 0.335 (95% CI 0.114 to 0.986, p=0.047), compared with the control group. CONCLUSIONS: In our study, PCSK9 inhibitors add-on therapy further reduced LDL-C levels and ERS in patients with symptomatic ICAS.

POLR3G promotes EMT via PI3K/AKT signaling pathway in bladder cancer.

RNA Polymerase III Subunit G (POLR3G) promotes tumorigenesis, metastasis, cancer stemness, and chemoresistance of breast cancer and lung cancer; however, its biological function in bladder cancer (BLCA) remains unclear. Through bioinformatic analyses, we found that POLR3G expression was significantly elevated in BLCA tumor tissues and was associated with decreased survival. Multivariate Cox analysis indicated that POLR3G could serve as an independent prognostic risk factor. Our functional investigations revealed that POLR3G deficiency resulted in reduced migration and invasion of BLCA cells both in vitro and in vivo. Additionally, the expressions of EMT-related mesenchymal markers were also downregulated in POLR3G knockdown cells. Mechanistically, we showed that POLR3G could activate the PI3K/AKT signaling pathway. Inhibition of this pathway with LY294002 reduced the enhanced migration and invasion of BLCA cells induced by POLR3G overexpression, whereas the activation of this pathway using 740Y-P restored the abilities that were inhibited by POLR3G knockdown. Taken together, our findings suggested that POLR3G is a prognostic predictor for BLCA and promotes EMT of BLCA through activation of the PI3K/AKT signaling pathway.

Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial.

Importance: For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective: To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Interventions: Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Results: Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Conclusions: Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

Crosstalk between Mesenchymal Stem Cells and Cancer Stem Cells Reveals a Novel Stemness-Related Signature to Predict Prognosis and Immunotherapy Responses for Bladder Cancer Patients.

Mesenchymal stem cells (MSCs) and cancer stem cells (CSCs) maintain bladder cancer (BCa) stemness and facilitate the progression, metastasis, drug resistance, and prognosis. Therefore, we aimed to decipher the communication networks, develop a stemness-related signature (Stem. Sig.), and identify a potential therapeutic target. BCa single-cell RNA-seq datasets (GSE130001 and GSE146137) were used to identify MSCs and CSCs. Pseudotime analysis was performed by Monocle. Stem. Sig. was developed by analyzing the communication network and gene regulatory network (GRN) that were decoded by NicheNet and SCENIC, respectively. The molecular features of the Stem. Sig. were evaluated in TCGA-BLCA and two PD-(L)1 treated datasets (IMvigor210 and Rose2021UC). A prognostic model was constructed based on a 101 machine-learning framework. Functional assays were performed to evaluate the stem traits of the hub gene. Three subpopulations of MSCs and CSCs were first identified. Based on the communication network, the activated regulons were found by GRN and regarded as the Stem. Sig. Following unsupervised clustering, two molecular subclusters were identified and demonstrated distinct cancer stemness, prognosis, immunological TME, and response to immunotherapy. Two PD-(L)1 treated cohorts further validated the performance of Stem. Sig. in prognosis and immunotherapeutic response prediction. A prognostic model was then developed, and a high-risk score indicated a poor prognosis. Finally, the hub gene SLC2A3 was found exclusively upregulated in extracellular matrix-related CSCs, predicting prognosis, and shaping an immunosuppressive tumor microenvironment. Functional assays uncovered the stem traits of SLC2A3 in BCa by tumorsphere formation and western blotting. The Stem. Sig. derived from MSCs and CSCs can predict prognosis and response to immunotherapy for BCa. Besides, SLC2A3 may serve as a promising stemness target facilitating cancer effective management.

Age-Related Changes in Cerebral Hemodynamics in Children Undergoing Congenital Cardiac Surgery: A Prospective Observational Study.

OBJECTIVE: To explore age-related cerebral hemodynamic characteristics before and after pediatric cardiac surgery. DESIGN: Prospective observational study. SETTING: Single-center study based at a tertiary care center in Shanghai, China. PATIENTS: Fifty-three children with congenital heart disease (CHD) aged zero-to-six years undergoing cardiac surgery with cardiopulmonary bypass were enrolled, and 44 children finally were analyzed. INTERVENTION: Cerebral hemodynamics were measured by transcranial color-coded duplex sonography in the right temporal window before and after surgery. The resistance index (RI), pulsatility index (PI), and cerebral blood flow velocity (CBFV), including time average maximum flow velocity (Vtamax), mean blood flow velocity (Vmean), and the peak systolic flow velocity (Vpeak), of the right middle cerebral artery (MCA) and regional cerebral oxygen saturation (rScO2) of the right frontal lobe were measured and analyzed. Heart rate and mean arterial pressure were also recorded during ultrasound. MEASUREMENTS AND MAIN RESULTS: RI and PI decreased exponentially with age before and after cardiac surgery. While PI remained unchanged after cardiac surgery, RI was significantly reduced. Furthermore, RI reduction after cardiac surgery was more significant in children >18 months compared to those ≤18 months. CBFV of the right MCA also showed exponential increase with age, but rScO2 linearly increased. Cardiac surgery significantly changed the cerebral hemodynamics, but it did not affect rScO2 in children regardless of age. CONCLUSIONS: Age-related cerebral hemodynamic changes exist in children with CHD. Cardiopulmonary bypass surgery led to greater cerebrovascular dilation in children aged ≤18 months than those >18 months.

Integrated Analysis Revealed an Inflammatory Cancer-Associated Fibroblast-Based Subtypes with Promising Implications in Predicting the Prognosis and Immunotherapeutic Response of Bladder Cancer Patients.

Inflammatory cancer-associated fibroblasts (iCAFs) are closely related to progression, anticancer therapeutic resistance, and poor prognosis of bladder cancer (BCa). However, the functional role of iCAFs in BCa has been poorly studied. In our study, two BCa scRNA-seq datasets (GSE130001 and GSE146137) were obtained and integrated by the Seurat pipeline. Based on reported markers (COL1A1 and PDGFRA), iCAFs were identified and the related signature of 278 markers was developed. Following unsupervised consensus clustering, two molecular subtypes of TCGA-BLCA were identified and characterized by distinct dysregulated cancer hallmarks, immunological tumor microenvironments, prognoses, responses to chemotherapy/immunotherapy, and stemness. Subsequently, the robustness of the signature-based clustering, in terms of prognosis and therapeutic response prediction, was validated in a GEO-meta cohort with seven independent GEO datasets of 519 BCa patients, and three immune checkpoint inhibitor (ICI)-treated cohorts. Considering the heterogeneity, re-clustering of iCAFs was performed and a subpopulation, named "LOXL2+ iCAFs", was identified. Co-culture CM derived from LOXL2 overexpression/silencing CAFs with T24 cells revealed that overexpression of LOXL2 in CAFs promoted while silencing LOXL2 inhibited the proliferation, migration, and invasion of T24 cells through IL32. Moreover, the positive correlation between LOXL2 and CD206, an M2 macrophage polarization marker, has been observed and validated. Collectively, integrated single-cell and bulk RNA sequencing analyses revealed an iCAF-related signature that can predict prognosis and response to immunotherapy for BCa. Additionally, the hub gene LOXL2 may serve as a promising target for BCa treatment.

Is electronic follow-up using a mobile phone application after mid-urethral sling placement feasible and efficient?

PURPOSE: To assess and report the feasibility and efficacy of electronic follow-up in patients after mid-urethral sling (MUS) operation. METHODS: All 235 patients after MUS operation for stress urinary incontinence (SUI) were divided into the WeChat follow-up (WFU) and the outpatient follow-up (OFU) groups. Patients completed electronic or paper-validated questionnaires. Demographic and clinical characteristics, questionnaire scores, loss to follow-up rate, patient satisfaction, and complications were compared and analyzed. RESULTS: Overall, 189 patients completed the follow-up assessment. The OFU group showed a higher rate of loss to follow-up (25.6% vs. 13.2%, p = 0.016). The mean preoperative International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores were 18.22 ± 2.64 and 18.06 ± 2.75 in the WFU and OFU groups, respectively (p = 0.672). The mean postoperative ICIQ-UI SF scores were 3.70 ± 1.65 and 3.86 ± 1.48, respectively (p = 0.489). There were 84.8% of WFU patients and 80% of OFU patients reported "very much better" or "much better" on the Patient Global Impression of Improvement (PGI-I) scale (p = 0.381). Patient satisfaction rate was higher in the WFU group than in the OFU group (87.9% vs. 74.4%, p = 0.018). Seventeen patients reported postoperative complications (9 and 8 patients in the WFU and OFU groups, respectively, p = 0.961). CONCLUSIONS: It appears that electronic follow-up using a mobile phone application is feasible and efficient for patients after MUS operation, and may be associated with improved rates of satisfaction and retention.

Diabetes Mellitus Might Not Be Associated with Any Stone Component in a Local District.

BACKGROUND: Type II diabetes mellitus (DM) is a risk factor for urinary stones, but the pathogenesis remains unclear. The aim of our study was to present the distribution of stone components between DM and no DM group from a local stone center in China and to help the prevention department in decision-making. METHODS: We reviewed the records of patients with upper urinary stones attending our hospital from January 2015 to September 2018. The patients with complete information were divided into 2 groups: type II DM group (DM group) and without DM group (no DM group). The distribution of stone components was analyzed. RESULTS: Two hundred twenty-two patients were complicated with DM, whereas 1,894 (89%) were not. Significant difference was found in the distribution of hypertension and BMI (p = 0, p = 0, respectively). Distribution of sex, age, and stone components did not differ between the 2 groups. By the binary logistic analysis, increasing age and sex seemed to be the main risk factors influencing the stone components. Only the calcium stone seemed to be free of the -impact from age and sex. Occurrence of hypertension is a single risk factor for calcium stone from our analysis. Presence of diabetes and increasing BMI was not found to be significantly associated with the risk for any stone component. CONCLUSIONS: In a local district, DM might not be the main factor associated with an increased risk for uric acid stone formation or any stone component. We should also consider the local characteristics of the stone distribution.

Metabolic response of bok choy leaves under chromium pollution stress.

Chromium (Cr) pollution in farmlands is a common environmental issue, that can seriously inhibit plant growth, damage plant cells, and even cause plant death. In this study, bok choy (Brassica campestris L. ssp. chinensis Makino (var. communis Tsen et Lee)) was selected as a model plant to investigate the metabolic response to Cr stress at concentrations of 2.0 mg/L and 8.0 mg/L. Metabolites were identified using gas chromatography-mass spectrometry. Principal component analysis and orthogonal projections to latent structure discriminant analysis revealed the notable effect of Cr stress on the metabolites of bok choy. Under Cr stress, 145 metabolites were identified in the bok choy leaves. At 2.0 mg/L Cr stress, 10 and 26 metabolites changed compared to the control after 7 d and 14 d, respectively. At 8.0 mg/L Cr stress, 24 and 24 metabolites changed significantly after 7 and 14 d, respectively. The data showed that metabolism was affected by the Cr stress concentration and exposure time. Specifically, under the Cr stress, the tricarboxylic acid cycle, glutamine synthetase/glutamate synthase cycle, and partial amino acid metabolic pathways were blocked, inhibiting the normal growth and development of bok choy. The change of citric acid content was the most significant, and the accumulation of citric acid indicated the degree of plant Cr toxicity and resistance. These results would facilitate further dissection of the mechanisms of heavy metal accumulation/tolerance in plants and the effective management of such contamination in vegetable crops by genetic manipulation.

The feasibility of one-stage flexible ureteroscopy lithotripsy in solitary kidney patients with 1-3 cm renal stones and risk factors of renal function changes.

PURPOSE: To compare perioperative outcomes and long-term renal function changes between prior stenting (PS) and not prior stenting (NPS) before flexible ureteroscopy lithotripsy (f-URS) for solitary kidney patients. METHODS: Solitary kidney patients with 10-30 mm renal stones were enrolled in this historical control study. Perioperative parameters and complications were compared. Stone-free was defined as the absence of any residual stones on a CT scan. Renal function changes were evaluated by estimated glomerular filtration rate (eGFR) and adjusted for body surface area. A decrease in the eGFR over 20% was identified as 'deterioration' in renal function. The follow-up period was at least 6 months. Logistic regression was used to identify risk factors of renal function deterioration. RESULTS: Of the 76 patients included, 40 cases experienced prior stenting before f-URS. The average stone diameter was 16.8 ± 4.7 mm, ranging from 10.0 to 28.4 mm. Initial SFR was 85.0 and 83.3% in the PS and NPS groups, respectively (p = 0.842), while SFR after the second procedure was 97.5 and 94.4% (p = 0.926). Seven PS and 5 NPS patients developed complications (p = 0.666). At the postoperative 6 months, seven patients showed a deteriorated renal function. Surgical time in minutes was identified as a risk factor for renal function deterioration after the operation (OR = 1.061, 95% CI: 1.015-1.109, p = 0.009, per minute). CONCLUSION: It appears that one-stage f-URS without PS could be feasible for 10-30 mm renal stones in solitary kidney patients, and less surgical time might be beneficial to protect renal function.

The left ureterocele and stone of calyceal diverticulum in the patient with bilateral incomplete duplex kidneys managed by flexible ureteroscopy: a case report and literature review.

BACKGROUND: Duplex kidneys are one of the most common renal congenital abnormalities, mostly asymptomatic and of no clinical significance. There are little reports about the left ureterocele and stone of calyceal diverticulum in patients with bilateral incomplete duplex kidneys managed by flexible ureteroscopy. CASE PRESENTATION: A 69-year-old Chinese woman was presented with left waist pain for 1 month. A preoperative computed tomography (CT) scan and intravenous pyelogram revealed the left ureterocele which located in the left ureterovesical junction, and stone of calyceal diverticulum which located in the upper kidney of left incomplete duplex kidneys. The ureterocele was confirmed in view of ureteroscopy and the holmium laser was used for the resection of ureterocele. It took us a lot of efforts to find out the stone because of diverticular neck stenosis. Fortunately, when diverticular neck stenosis was incised internally by holmium laser, the stone was discovered clearly and removed using the holmium laser and nitinol stone basket through flexible ureteroscopy. A double-J ureteral stent was inserted and remained in place for 1 month. The symptom disappeared postoperatively and no complications were developed during the placement of the stent. There were no stone residents observed on CT scan before removing the ureteral stent 1 month later. CONCLUSIONS: Flexible ureteroscopy with holmium laser is feasible to manage the ureterocele and calyceal diverticulum stones in patients with bilateral incomplete duplex kidneys in one operation.

No Wound for Stones <2 cm in Horseshoe Kidney: A Systematic Review of Comparative Studies.

INTRODUCTION: No wound to the patients is the pursuit of surgeons. Extracorporeal shock wave lithotripsy (SWL) and ureteroscopy (URS) are minimally invasive modalities for treating horseshoe kidney (HSK) stone <2 cm. We aimed to review the outcomes and complications of comparing SWL and URS in HSK stone. METHODS: The literature was reviewed in the Embase, PubMed, and Cochrane Library up to March 1, 2018. Only 4 articles were available for analysis. Inclusion criteria were all English language articles reporting on the comparison between SWL and URS. RESULTS: URS tends to be performed in a relatively heavier stone burden. The higher initial stone-free rate and success rate were demonstrated for URS than for SWL (p < 0.00001, p = 0.02, respectively). The less retreatment rate was found in URS than SWL (p = 0.04). There was no difference in minor complications in the 2 groups (p = 0.57). Renal colic episodes were more likely to be observed in the SWL group (p = 0.02). There were no major complications found in the review. CONCLUSION: For a stone <2 cm in HSK, both SWL and URS are safe treatment modalities. URS alone is a more feasible and sufficient option for stone in HSK <2 cm than SWL with possibilities of a second session.

Removal efficiency of hexavalent chromium from wastewater using starch-stabilized nanoscale zero-valent iron.

In this study, starch-stabilized nanoscale zero-valent iron (S-nZVI) was produced using the liquid-phase reduction method. It was used to remove chromium from wastewater, and compared to a commercial nanoscale zero-valent iron (C-nZVI). Both nZVIs were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The characterization results showed that S-nZVI had smaller particles and a more uniform particle size distribution than C-nZVI. Both nZVIs showed a core-shell structure with the Fe0 core prominently surrounded by less iron oxides of Fe2+ and Fe3+. The optimal application methods to remove Cr(VI) from wastewater were also explored. The results showed that both the removal efficiencies of total Cr and Cr(VI) increased with increases in the addition of nZVIs, while the removal efficiencies of total Cr and Cr(VI) by S-nZVI were clearly higher than that of C-nZVI, especially in a low pH range (pH = 1.0-6.0). This research indicated that starch-stabilized nanoscale zero-valent iron is a valuable material to remove heavy metals from wastewater due to its stability and high reactivity.

Silence of HDAC6 suppressed esophageal squamous cell carcinoma proliferation and migration by disrupting chaperone function of HSP90.

Esophageal carcinoma is aggressive in nature and its prognosis is largely dependent on the degree of invasion. Histone deacetylase 6 (HDAC6), as the most unique member of HDACs family, has the positive activity to promote initiation and progression of various cancers via targeting multiple non-histone proteins in cytoplasm. In this study, we found that HDAC6 was over-expressed in three esophageal cancer cell lines (KYSE140, KYSE170, KYSE180) when compared to non-carcinoma esophageal epithelial cell HEEC-1. Then two HDAC6 specific siRNAs and HDAC6 inhibitor tubastatin A greatly suppressed KYSE140 and KYSE180 cells proliferation and migration, and the inhibition of cell motility was accompanied by elevated acetylation of α-tubulin, a target of HDAC6. Consistently, the microtubulin skeleton was stabilized after HDAC6 knockdown or inhibition. In addition, acetylation status of HSP90, another HDAC6 target, was also increased towards HDAC6 knockdown or inhibition by co-immunoprecipitation assay. Besides, co-treatment of HSP90 inhibitor (PU-H71) and HDAC6 inhibitor (tubastatin A) induced a stronger cell migration inhibition compared to administration of either drug alone. Furthermore, cell proliferation of KYSE140 and KYSE180 were also compromised in response to combination of HDAC6 and HSP90 inhibitors. Additionally, co-administration of HSP90 inhibitor and HDAC6 inhibitor strongly inhibited tumor growth in vivo. Taken together, our results indicated that HDAC6 is a promising target by inhibiting HSP90 function in ESCC.

Electrolysis of metal oxides in MgCl2 based molten salts with an inert graphite anode.

Electrolysis of solid metal oxides has been demonstrated in MgCl2-NaCl-KCl melt at 700 °C taking the electrolysis of Ta2O5 as an example. Both the cathodic and anodic processes have been investigated using cyclic voltammetry, and potentiostatic and constant voltage electrolysis, with the cathodic products analysed by XRD and SEM and the anodic products by GC. Fast electrolysis of Ta2O5 against a graphite anode has been realized at a cell voltage of 2 V, or a total overpotential of about 400 mV. The energy consumption was about 1 kW h kgTa(-1) with a nearly 100% Ta recovery. The cathodic product was nanometer Ta powder with sizes of about 50 nm. The main anodic product was Cl2 gas, together with about 1 mol% O2 gas and trace amounts of CO. The graphite anode was found to be an excellent inert anode. These results promise an environmentally-friendly and energy efficient method for metal extraction by electrolysis of metal oxides in MgCl2 based molten salts.

The oncogene MYBL2 promotes the malignant phenotype and suppresses apoptosis through hedgehog signaling pathway in clear cell renal cell carcinoma.

Multiple cancers have been associated with MYB-related protein B (MYBL2), its involvement in clear cell renal cell carcinoma (ccRCC) has yet to be demonstrated. Our study revealed a significant upregulation of MYBL2 in ccRCC tissues, correlating with clinicopathological features and patient prognosis. Increased MYBL2 expression promoted cell proliferation and suppressed apoptosis. RNA-seq analysis unveiled a reduction in smoothened (SMO) expression upon MYBL2 silencing. However, luciferase and chromatin immunoprecipitation (ChIP) assays demonstrated MYBL2's positive regulation of SMO expression by directly targeting the SMO promoter. Reintroduction of SMO expression in MYBL2-knocked down cells partially restored cell proliferation and mitigated apoptosis inhibition. Overall, these results indicate that MYBL2 facilitates ccRCC progression by enhancing SMO expression, suggesting its potential as an intriguing drug target for ccRCC therapy.

Impact of lymphadenectomy extent on immunotherapy efficacy in postresectional recurred non-small cell lung cancer: a multi-institutional retrospective cohort study.

BACKGROUND: Lymph node (LN) dissection is a common procedure for non-small cell lung cancer (NSCLC) to ascertain disease severity and treatment options. However, murine studies have indicated that excising tumor-draining LNs diminished immunotherapy effectiveness, though its applicability to clinical patients remains uncertain. Hence, the authors aim to illustrate the immunological implications of LN dissection by analyzing the impact of dissected LN (DLN) count on immunotherapy efficacy, and to propose a novel 'immunotherapy-driven' LN dissection strategy. MATERIALS AND METHODS: The authors conducted a retrospective analysis of NSCLC patients underwent anti-PD-1 immunotherapy for recurrence between 2018 and 2020, assessing outcomes based on DLN count stratification. RESULTS: A total of 144 patients were included, of whom 59 had a DLN count less than or equal to 16 (median, IQR: 11, 7-13); 66 had a DLN count greater than 16 (median, IQR: 23, 19-29). With a median follow-up time of 14.3 months (95% CI: 11.0-17.6), the overall median progression-free survival (PFS) was 7.9 (95% CI: 4.1-11.7) months, 11.7 (95% CI: 7.9-15.6) months in the combination therapy subgroup, and 4.8 (95% CI: 3.1-6.4) months in the immunotherapy alone subgroup, respectively. In multivariable Cox analysis, DLN count less than or equal to 16 is associated with an improved PFS in all cohorts [primary cohort: HR=0.26 (95% CI: 0.07-0.89), P =0.03]; [validation cohort: HR=0.46 (95% CI: 0.22-0.96), P =0.04]; [entire cohort: HR=0.53 (95% CI: 0.32-0.89), P =0.02]. The prognostic benefit of DLN count less than or equal to 16 was more significant in immunotherapy alone, no adjuvant treatment, pN1, female, and squamous carcinoma subgroups. A higher level of CD8+ central memory T cell (Tcm) within LNs was associated with improved PFS (HR: 0.235, 95% CI: 0.065-0.845, P =0.027). CONCLUSIONS: An elevated DLN count (cutoff: 16) was associated with poorer immunotherapy efficacy in recurrent NSCLC, especially pronounced in the immunotherapy alone subgroup. CD8+Tcm proportions in LNs may also impact immunotherapy efficacy. Therefore, for patients planned for adjuvant immunotherapy, a precise rather than expanded lymphadenectomy strategy to preserve immune-depending LNs is recommended.

Myeloprotection with trilaciclib in Chinese patients with extensive-stage small cell lung cancer receiving chemotherapy: Results from a randomized, double-blind, placebo-controlled phase III study (TRACES).

INTRODUCTION: Trilaciclib is a transient cyclin-dependent kinase 4/6 inhibitor that decreases the incidence of chemotherapy-induced myelosuppression in extensive-stage small cell lung cancer (ES-SCLC). TRACES study was designed to assess the safety, efficacy and pharmacokinetics (PK) of trilaciclib before chemotherapy in Chinese patients with ES-SCLC. METHODS: The study included an open-label safety run-in part (Part 1) and double-blinded, placebo-controlled part (Part 2) where patients received trilaciclib or placebo before chemotherapy. Treatment-naïve or previously treated ES-SCLC patients received intravenous trilaciclib (240 mg/m2) or placebo before etoposide/carboplatin or topotecan, respectively. Primary endpoints were PK, safety and duration of severe neutropenia (DSN) in Cycle 1 in Part 1 and Part 2. Exploratory endpoints included the effect of trilaciclib on other myeloprotection endpoints, safety and antitumor efficacy. RESULTS: Overall, 95 Chinese patients were enrolled, of which 12 and 83 patients were in Part 1 and Part 2, respectively. In Part 1, trilaciclib was well tolerated. Non-compartmental analysis results revealed no substantial differences in the main exposure parameters. In Part 2, 41 patients received trilaciclib, and 42 received placebo. Patients in trilaciclib arm vs placebo arm had a clinically and statistically significant decrease in DSN (mean [SD]) in Cycle 1 (0 [1.7] vs 2 [3.0] days; P = 0.0003), with improvements in additional neutrophil, red blood cell, and platelet measures. After a median follow-up of 14.1 months, the median overall survival was 12.0 months in trilaciclib arm and 8.8 months in placebo arm (HR, 0.69; 95 % CI: 0.40-1.22). Median progression-free survival was 4.8 months and 4.3 months, respectively (HR, 0.86; 95 % CI: 0.53-1.39). Trilaciclib had a well-tolerated safety profile. CONCLUSIONS: Trilaciclib in the Chinese population demonstrated a similar PK and safety profile as seen in other global trials. There was significant reduction of DSN in Cycle 1, thereby substantiating the myeloprotective effects of trilaciclib in Chinese ES-SCLC patients.

Machine learning-based identification of tumor-infiltrating immune cell-associated model with appealing implications in improving prognosis and immunotherapy response in bladder cancer patients.

Background: Immune cells are crucial components of the tumor microenvironment (TME) and regulate cancer cell development. Nevertheless, the clinical implications of immune cell infiltration-related mRNAs for bladder cancer (BCa) are still unclear. Methods: A 10-fold cross-validation framework with 101 combinations of 10 machine-learning algorithms was employed to develop a consensus immune cell infiltration-related signature (IRS). The predictive performance of IRS in terms of prognosis and immunotherapy was comprehensively evaluated. Results: The IRS demonstrated high accuracy and stable performance in prognosis prediction across multiple datasets including TCGA-BLCA, eight independent GEO datasets, our in-house cohort (PUMCH_Uro), and thirteen immune checkpoint inhibitors (ICIs) cohorts. Additionally, IRS was superior to traditional clinicopathological features (e.g., stage and grade) and 94 published signatures. Furthermore, IRS was an independent risk factor for overall survival in TCGA-BLCA and several GEO datasets, and for recurrence-free survival in PUMCH_Uro. In the PUMCH_Uro cohort, patients in the high-IRS group were characterized by upregulated CD8A and PD-L1 and TME of inflamed and immunosuppressive phenotypes. As predicted, these patients should benefit from ICI therapy and chemotherapy. Furthermore, in the ICI cohorts, the high-IRS group was related to a favorable prognosis and responders have dramatically higher IRS compared to non-responders. Conclusions: Generally, these indicators suggested the promising application of IRS in urological practices for the early identification of high-risk patients and potential candidates for ICI application to prolong the survival of individual BCa patients.

PLAGL2 promotes bladder cancer progression via RACGAP1/RhoA GTPase/YAP1 signaling.

PLAGL2 is upregulated in various tumors, including bladder cancer (BCa). However, the mechanisms underlying the tumorigenic effects of PLAGL2 in BCa remain unclear. In our study, we proved that PLAGL2 was overexpressed in BCa tissues and correlated with decreased survival. Functionally, PLAGL2 deficiency significantly suppressed the proliferation and metastasis of BCa cells in vitro and in vivo. RNA sequencing, qRT‒PCR, immunoblotting, immunofluorescence staining, luciferase reporter, and ChIP assays revealed that overexpressed PLAGL2 disrupted the Hippo pathway and increased YAP1/TAZ activity by transactivating RACGAP1. Further investigations demonstrated that PLAGL2 activated YAP1/TAZ signaling via RACGAP1-mediated RhoA activation. Importantly, the RhoA inhibitor simvastatin or the YAP1/TAZ inhibitor verteporfin abrogated the proproliferative and prometastatic effects of BCa enhanced by PLAGL2. These findings suggest that PLAGL2 promotes BCa progression via RACGAP1/RhoA GTPase/YAP1 signaling. Hence, the core nodes of signaling may be promising therapeutic targets for BCa.