Interlesional response heterogeneity is associated with the prognosis of abiraterone treatment in metastatic castration-resistant prostate cancer.

BACKGROUND: Interlesional response heterogeneity (ILRH) poses challenges to the treatment of metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no prospective clinical trials exploring the prognostic significance of ILRH on paired positron emission tomography/computed tomography (PET/CT) in the context of abiraterone therapy. METHODS: In this prospective study, we enrolled patients with mCRPC treated with abiraterone (ClinicalTrials.gov: NCT05188911; ChiCTR.org.cn: ChiCTR2000034708). 68Ga-prostate-specific membrane antigen (PSMA)+18F-fluorodeoxyglucose (FDG) PET/CT and circulating tumor DNA (ctDNA) monitoring were performed at baseline and week 13. Patients were grouped by their early ILRH measurement. The primary endpoint was to evaluate the predictive role of ILRH for conventional progression-free survival (PFS) through the concordance index (C-index) assessment. Conventional PFS was defined as the time from medication to conventional radiographic progression, clinical progression, or death. FINDINGS: Ultimately, 33 patients were included with a median follow-up of 28.7 months. Baseline+week 13 PSMA PET/CT revealed that 33.3% of patients showed ILRH. Those patients with hetero-responding disease had significantly different PFS compared to the responding and non-responding groups (hazard ratio: responding group = reference, hetero-responding group = 4.0, non-responding group = 5.8; p < 0.0001). The C-index of ILRH on paired PSMA PET/CT (0.742 vs. 0.660) and FDG PET/CT (0.736 vs. 0.668) for conventional PFS was higher than that of PSA response. In an exploratory analysis, PSMA-/FDG+ lesions at week 13 were identified as a strong surrogate for poor conventional PFS (p = 0.039). CONCLUSIONS: ILRH on both baseline+week 13 PSMA and FDG PET/CT strongly associated with conventional PFS. FUNDING: This study was funded by the Ministry of Science and Technology of China and Shanghai.

Causal association of genetically determined plasma metabolites with osteoarthritis: a two-sample Mendelian randomization study.

Background: We aimed to elucidate the causal relationship between plasma metabolites and the vulnerability to Osteoarthritis (OA), encompassing both hip OA and knee OA. Methods: We conducted a two-way two-sample Mendelian randomization (MR) analysis to investigate the association of 1,400 plasma metabolites with OA. The Inverse Variance Weighted (IVW) model served as the primary two-sample MR Analysis method, with supplementary analysis using the Weighted Median (WM) and MR Egger methods. To ensure the robustness of our findings, sensitivity analyses were performed, incorporating Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and Leave-One-Out analyses. To validate the identified metabolites, we utilized the Steiger test and linkage disequilibrium score regression. Results: A total of 94 plasma metabolites were associated with osteoarthritis, with 60 associated with hip OA and 106 associated with knee OA. IVW analysis revealed that tryptophan levels showed the strongest positive association with hip OA (OR [95% CI]: 1.119 [1.024, 1.223]), while X-24757 levels exhibited the highest positive association with knee osteoarthritis (OR [95% CI]: 1.095 [1.032, 1.162]). Ethylparaben sulfate levels were found to have the greatest positive association with hip OA (OR [95% CI]: 1.118 [1.015, 1.231]). Notably, the plasma metabolite X-2475 showed a strong robust random effect across all three types of osteoarthritis. Metabolic pathway analysis revealed that the pathogenesis of osteoarthritis in the hip was mediated by acetylarginine, specifically in four important metabolic pathways: ethanol degradation (p = 0.044), amino sugar metabolism (p = 0.090), fatty acid biosynthesis (p = 0.095), and aspartate metabolism (p = 0.097816). Conclusion: There is a significant association between tryptophan levels and the risk of hip OA, as well as X-24757 levels and the risk of knee osteoarthritis. Additionally, X-24757 levels are also linked to the risk of hip OA. Moreover, this study has identified four crucial metabolic pathways in hip osteoarthritis, which are all regulated by acetylarginine. These findings provide valuable insights into potential biomarkers for OA and highlight potential pathways for its prevention and clinical intervention.

Apoptotic signaling pathways in bone metastatic lung cancer: a comprehensive analysis.

This review provides a comprehensive analysis of apoptotic signaling pathways in the context of bone metastatic lung cancer, emphasizing the intricate molecular mechanisms and microenvironmental influences. Beginning with an overview of apoptosis in cancer, the paper explores the specific molecular characteristics of bone metastatic lung cancer, highlighting alterations in apoptotic pathways. Focused discussions delve into key apoptotic signaling pathways, including the intrinsic and extrinsic pathways, and the roles of critical molecular players such as Bcl-2 family proteins and caspases. Microenvironmental factors, such as the tumor microenvironment, extracellular matrix interactions, and immune cell involvement, are examined in depth. The review also addresses experimental approaches and techniques employed in studying apoptotic signaling, paving the way for a discussion on current therapeutic strategies, their limitations, and future prospects. This synthesis contributes a holistic understanding of apoptosis in bone metastatic lung cancer, offering insights for potential therapeutic advancements.

Protocol for CHAMPION study: a prospective study of maximal-cytoreductive therapies for patients with de novo metastatic hormone-sensitive prostate cancer who achieve oligopersistent metastases during systemic treatment with apalutamide plus androgen deprivation therapy.

BACKGROUND: The proposed trial is to examine the feasibility of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided cytoreduction plus apalutamide and androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) at oligometastatic state. METHODS: CHAMPION (NCT05717582) is an open-label, single-arm, phase II trial, planning to enroll newly diagnosed mHSPC cases with oligometastases (≤ 10 distant metastatic sites in conventional imaging). Patients will receive 6 cycles of apalutamide plus ADT. Patients with oligometastatic disease at PSMA PET/CT after 3 treatment cycles will receive cytoreductive radical prostatectomy. PSMA PET/CT-guided metastasis-directed external radiation therapy will be determined by the investigators. Apalutamide plus ADT will be continued for 2 weeks postoperatively. The primary endpoint is the proportion of patients with undetectable prostate-specific antigen (PSA), no disease progression, and no symptom deterioration after 6 cycles of apalutamide plus ADT. Secondary endpoints include the percentage of patients with PSA ≤ 0.2 ng/mL and oligometastases by the end of 3 treatment cycles, PSA response rate, and safety. Fleming's two-stage group sequential design will be adopted in the study, where the null hypothesis is that the rate of patients with an undetectable PSA is ≤ 40% after 6 cycles of treatment, while the alternate hypothesis is an undetectable PSA of > 60%; with one-sided α = 0.05, power = 0.80, and an assumed dropout rate of 10%, the required number of patients for an effective analysis is 47. Enrolment in the study commenced in May 2023. DISCUSSION: The multi-modal therapy based on treatment response may improve the prognosis of newly diagnosed mHSPC patients with oligometastases. TRIAL REGISTRATION: The study is registered with Clinical Trials.Gov (NCT05717582). Registered on 8th February 2023.

Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer.

This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e ., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.

[Digital study on proximal clavicle anatomical plate based on 3D printing technology].

OBJECTIVE: To explore feasibility of 3D metal printing technology combined with virtual design proximal clavicle anatomical plate. METHODS: A 52-year-old male healthy volunteer was retrospectively selected to design proximal clavicle anatomical plate system by using Mimics15.01,NX12.0 and other software. STL data were input into 3D printer to print 1:1 clavicle model and proximal clavicle anatomical plate. The fit of the plate was tested in vitro and the accuracy of screw position was evaluated by imaging. Printing time of model,nail path design and fabrication time of the anatomical plate at proximal clavicle were recorded. RESULTS: The 3D metal printing proximal clavicle anatomical plate fitted well to clavicle model,orientation of proximal clavicle locking screw was accurate,and X-ray and CT scan showed the screw position was good. Printing time of model,the time of nail path design,and the time of making anatomical plate of proximal clavicle were 120,15 and 300 min respectively. CONCLUSION: The proximal clavicular anatomical plate system based on 3D metal printing technology could achieve good lamination of proximal clavicular fracture plate and precise screw placement,providing a new and accurate surgical method for the treatment of the proximal clavicular fracture.

Clinical effectiveness of a multitarget urine DNA test for urothelial carcinoma detection: a double-blinded, multicenter, prospective trial.

Urine-based testing is promising for noninvasive diagnosis of urothelial carcinoma (UC) but has suboptimal sensitivity for early-stage tumors. Herein, we developed a multitarget urine tumor DNA test, UI-Seek, for UC detection and evaluated its clinical feasibility. The prediction model was developed in a retrospective cohort (n = 382), integrating assays for FGFR3 and TERT mutations and aberrant ONECUT2 and VIM methylation to generate a UC-score. The test performance was validated in a double-blinded, multicenter, prospective trial (n = 947; ChiCTR2300076543) and demonstrated a sensitivity of 91.37% and a specificity of 95.09%. The sensitivity reached 75.81% for low-grade Ta tumors and exceeded 93% in high-grade Ta and higher stages (T1 to T4). Simultaneous identification of both bladder and upper urinary tract tumors was enabled with sensitivities exceeding 90%. No significant confounding effects were observed regarding benign urological diseases or non-UC malignancies. The test showed improved sensitivities over urine cytology, the NMP22 test, and UroVysion FISH alongside comparable specificities. The single-target accuracy was greater than 98% as confirmed by Sanger sequencing. Post-surgery UC-score decreased in 97.7% of subjects. Overall, UI-Seek demonstrated robust performance and considerable potential for the early detection of UC.

Nomogram to predict the presence of PSMA-negative but FDG-positive lesion in castration-resistant prostate cancer: a multicenter cohort study.

Background: PSMA-negative but FDG-positive (PSMA-/FDG+) lesion in dual-tracer (68Ga-PSMA and 18F-FDG) positron emission tomography/computed tomography (PET/CT) is associated with an unfavorable response to Lutetium-177 (177Lu)-PSMA-617. This study sought to develop both radiomics and clinical models for the precise prediction of the presence of PSMA-/FDG+ lesions in patients with castration-resistant prostate cancer (CPRC). Methods: A cohort of 298 patients who underwent dual-tracer PET/CT with a less than 5-day interval was included. The evaluation of the prognostic performance of the radiomics model drew upon the survival data derived from 40 patients with CRPC treated with 177Lu-PSMA-617 in an external cohort. Two endpoints were evaluated: (a) prostate-specific antigen (PSA) response rate, defined as a reduction exceeding 50% from baseline and (b) overall survival (OS), measured from the initiation of 177Lu-PSMA-617 to death from any cause. Results: PSMA-/FDG+ lesions were identified in 56 (18.8%) CRPC patients. Both radiomics (area under the curve [AUC], 0.83) and clinical models (AUC, 0.78) demonstrated robust performance in PSMA-/FDG+ lesion prediction. Decision curve analysis revealed that the radiomics model yielded a net benefit over the 'screen all' strategy at a threshold probability of ⩾4%. At a 5% probability threshold, the radiomics model facilitated a 21% reduction in 18F-FDG PET/CT scans while only missing 2% of PSMA-/FDG+ cases. Patients with a low estimated score exhibited significantly prolonged OS (hazard ratio = 0.49, p = 0.029) and a higher PSA response rate (75% versus 35%, p = 0.011) compared to those with a high estimated score. Conclusion: This study successfully developed two models with accurate estimations of the risk associated with PSMA-/FDG+ lesions in CRPC patients. These models held potential utility in aiding the selection of candidates for 177Lu-PSMA-617 treatment and guiding 68Ga-PSMA PET/CT-directed radiotherapy.

Predictive nomogram for PSMA-/FDG+ lesion This study developed two models with accurate estimations of the risk associated with specific lesions in prostate cancer.

Transient Compression Injury Triggers Neuroinflammation in a New Rat Model of Acute Peripheral Neuropathic Pain.

BACKGROUND: Peripheral neuropathic pain (NeP), induced by surgical intervention, is a well-known complication or sequela that remains a clinical challenge with few effective treatments. Ideal animal models that can recapitulate surgery-associated NeP remain to be established for both mechanistic studies and drug discovery. OBJECTIVES: We aimed to establish a new rat model of postsurgical NeP and describe its characteristics, as well as screen-promising therapeutic analgesics. STUDY DESIGN: Experimental research in rats. SETTING: The research took place in the laboratory of Xinqiao Hospital of the Third Military Medical University. METHODS: To mimic the surgical procedure associated with peripheral nerve injury (PNI), we established a transient compression injury (TCI) in the sciatic nerve. Behavioral tests of nociception were used to confirm the effect and the time course of this pain model. Histological assessments (transmission electron microscopy evaluation and immunohistochemistry) were performed to observe the neuropathological and immunological features. RNA sequencing (RNA-seq) of injured nerves and dorsal root ganglia (DRGs) was conducted to reveal the underlying mechanism in the newly established animal model and screen promising therapeutic targets. RESULTS: We established a rat model of TCI of the PN and detected nociceptive hypersensitivity of the injured (ipsilateral) nerve by behavioral tests. This animal model of NeP was further confirmed by observing time-dependent changes in mechanical allodynia and thermal hyperalgesia, as well as by examining the activation of microglia in the ipsilateral spinal dorsal horn. Pathophysiologically, TCI induced macroscopic nerve swelling and demyelination, which resulted in inflammatory responses in ipsilateral nerves. We also found inflammatory cell infiltration in the ipsilateral nerve that was sustained for several weeks, which further exacerbated local inflammation and oxidative stress. Moreover, RNA-seq revealed remarkably upregulated inflammatory reactions in PNs and the DRGs. Notably, the overexpression of inflammatory mediators and the infiltration of macrophages and microglia triggered remote immune responses in DRGs. Based on the RNA-seq results, we also confirmed that gabapentin (GBP) exerts therapeutic effects in TCI-induced NeP by regulating alpha2delta-1. LIMITATIONS: We did not compare the new rat model with the classical pain model (like chronic constriction injury or spared nerve injury) in histology or transcriptomics. CONCLUSIONS: We established a new rat model of NeP and thoroughly characterized neuroinflammation in the injured nerve and DRGs. Based on the upregulated genes in DRGs in this model, we screened a promising analgesic (GBP) capable of reducing pain hypersensitivity in surgery-associated NeP.

Heterogeneity of Radiological Progression Patterns and Association with Outcomes in Patients with Metastatic Prostate Cancer.

BACKGROUND: With an increasing number of clinical trials using radiographic progression-free survival (rPFS) instead of overall survival as the primary study endpoint, the heterogeneity of different radiological progression patterns in rPFS and postprogression survival (PPS) remains unclear. OBJECTIVE: Herein, we investigate the proportion of various radiological progression patterns in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC), and further explore the differences in rPFS and PPS between patients exhibiting single- or multicategory progression patterns. DESIGN, SETTING, AND PARTICIPANTS: This post hoc, retrospective secondary analysis was based on individual patient data from LATITUDE (phase 3 randomized mHSPC study) and COU-AA-302 (phase 3 randomized mCRPC study). Patients with complete imaging follow-up data and radiological progression were included in the analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The rPFS and PPS in LATITUDE and COU-AA-302 were evaluated. The proportion of patients exhibiting each progression pattern was calculated, and a survival analysis was conducted using the Kaplan-Meier method. RESULTS AND LIMITATIONS: Of the 489 mHSPC patients studied, 366 experienced single-category progression, while the remaining 123 patients (25.2%) exhibited simultaneous occurrence of different progressive events (multicategory radiological progression). Of the 534 mCRPC patients studied, 390 experienced single-category progression, while the remaining 144 patients (27.0%) experienced multicategory progressive events. Among mCRPC patients, the rPFS of bone progression was the shortest. In contrast, among mHSPC patients, the rPFS of target lesion enlargement is the shortest, followed by bone progression. Notably, patients experiencing a single-category progression pattern displayed comparable rPFS to but significantly longer PPS than those experiencing multicategory progression patterns (PPS mHSPC cohort: 21.5 vs 6.9 mo, p < 0.0001; mCRPC cohort: 23.6 vs 15.7 mo, p < 0.0001). The study is limited by its hypothesis-generating nature. Therefore, the observed phenomena in our research necessitate validation through future prospective studies. CONCLUSIONS: Patients who experience multicategory radiological progression represent a significant proportion, accounting for approximately 25% of all men with mHSPC or mCRPC. Patients with multicategory radiological progression patterns had similar rPFS to but significantly shorter PPS than those experiencing single-category progression patterns. In future clinical trials and clinical practice, radiological progression patterns should be recognized as a crucial determinant of prognosis, while also serving as the stratification or inclusion criteria for second-line treatment clinical trials. PATIENT SUMMARY: In this study, we observed that among men with metastatic prostate cancer, those who experienced two or more radiological events during a single visit had a worse prognosis than those who experienced isolated radiological events.

Intelligent-Critic-Based Tracking Control of Discrete-Time Input-Affine Systems and Approximation Error Analysis With Application Verification.

In recent years, the application of function approximators, such as neural networks and polynomials, has ushered in a new stage of development in solving optimal control problems. However, considering the existence of approximation errors, the stability of the controlled system cannot be guaranteed. Therefore, in view of the prevalence of approximation errors, we investigate optimal tracking control problems for discrete-time systems. First, a novel value function is introduced into the intelligent critic framework. Second, an implicit method is utilized to demonstrate the boundedness of the iterative value functions with approximation errors. An explicit method is applied to prove the stability of the system with approximation errors. Furthermore, an evolving policy is designed to iteratively tackle the optimal tracking control problem and demonstrate the stability of the system. Finally, the effectiveness of the developed method is verified through numerical as well as practical examples.

The effect of anthocyanin from Dioscorea alata L. after purification, identification on antioxidant capacity in mice.

Increasing findings devote to searching for natural active compositions as additives to ameliorate health status. Anthocyanin, water-soluble natural pigment, has been concerned due to its favorable antioxidant activity. In this study, we purified anthocyanin from Dioscorea alata L., identified its compounds, and evaluated its antioxidant properties. The results indicated that the purity of anthocyanin increased to 39.59 ± 1.56%, 60.18 ± 1.97%, and 81.08 ± 1.97% after purification via AB-8 macroporous resin, Sep-Pak C18 solid phase, and LH-20 Sephadex stepwise. Ultra-performance liquid chromatography tandem mass spectrometer results indicated that paeoniflorin-3,5-O-dihexoside, petunin-3-O-feruloyl-glucoside-5-O-glucoside, cyanidin-3-O-feruloyl glucoside-5-O-glucoside, cyanidin-3-O-sophoroside, and petunin-3,5-O-dihexoside were the major compounds. The purified anthocyanin exhibited stronger antioxidant activity than the unpurified extract and ascorbic acid, whereas weaker than that of cyanidin-3-O-glucoside in general, which was assessed using DPPH, ABTS, and Fe3+ reducing capacity methods. Moreover, the purified anthocyanin increased GSH-Px, total antioxidant capacity, and superoxide dismutase activities and decreased malondialdehyde concentration on serum in mice after administering lipopolysaccharide for 24 h (p < .05). To summarize, the purified anthocyanin boasts more outstanding antioxidant properties than that of crude extracts. These results provide a reference with source of anthocyanin and it is conducive to use Dioscorea alata L. resources.

Prospective clinical sequencing of 1016 Chinese prostate cancer patients: uncovering genomic characterization and race disparity.

Although there is a well-known disparity in prostate cancer (PC) incidence and mortality between Chinese and Western patients, the underlying genomic differences have been investigated only sparsely. This clinicogenomic study was conducted to reveal the genomic mutations contributing to the PC disparity across ethnicities and investigate the mutational profile of Chinese PC patients. A total of 1016 Chinese PC patients were prospectively enrolled and subjected to targeted sequencing, resulting in usable sequencing data for 41 genes from 859 patients. Genomic data retrieved from The Cancer Genome Atlas (TCGA; locoregional PC), Memorial Sloan Kettering Cancer Center [MSKCC; metastatic castration-sensitive PC (mCSPC)], and Stand Up To Cancer [SU2C; metastatic castration-resistant PC (mCRPC)] cohorts were used as comparators representing Western men. Genomic mutations were analyzed using an integrated bioinformatic strategy. A comparison of the disease stages revealed that mutations in tumor protein 53 (TP53), androgen receptor (AR), forkhead box A1 (FOXA1), and genes involved in the cell cycle pathway were enriched in mCRPC. Mutations in adenomatous polyposis coli (APC) gene were found to be more prevalent in patients with visceral metastasis. Genomic differences between Western and Chinese men were mainly observed in castration-sensitive PC, with tumors from Chinese men having more FOXA1 (11.4% vs. 4.2%) but fewer TP53 (4.8% vs. 13%) mutations in locoregional PC and harboring fewer TP53 (11% vs. 29.2%), phosphatase and tensin homolog (PTEN; 2.5% vs. 10.3%), and APC (1.7% vs. 7.4%) mutations in the mCSPC stage than those of Western men. Patients of both ethnicities with mCRPC had similar mutational spectra. Furthermore, FOXA1 class-2 was less common than FOXA1 class-1 and showed no enrichment in metastasis, contrary to the findings in the Western cohort. Our study provides a valuable resource for a better understanding of PC in China and reveals the genomic alterations associated with PC disparity across races.

Intravenous application of tranexamic acid in intramedullary nailing for the treatment of geriatric intertrochanteric fractures: a systematic review and meta-analysis.

BACKGROUND: Meta-analyses on the use of tranexamic acid (TXA) in intertrochanteric fractures have shown inconsistent results due to variations in inclusion criteria and clinical heterogeneity. To address these limitations, we conducted a rigorous analysis of recent randomized controlled trials (RCTs) with strict inclusion criteria. The aim of this study was to objectively evaluate the effects and safety of intravenous TXA administration in the treatment of geriatric intertrochanteric femoral fractures with intramedullary nailing. METHODS: PubMed, Embase, and the Cochrane Library were searched for RCTs published from the database inception to August 2022. The date of total blood loss (TBL), intra-operative blood loss (IBL), hidden blood loss (HBL), transfusion rate, transfusion units, thromboembolic events, and mortality were extracted. Review Manager 5.3 was used for the analysis. RESULTS: A total of six RCTs involving 689 patients were included. Meta-analyses indicated that TXA can significantly reduce TBL (WMD = -232.82; 95% CI -312.81 to -152.84; p < 0.00001), IBL (WMD = -36.33; 95% CI -51.38 to -21.28; p < 0.00001), HBL (WMD = -189.23; 95% CI -274.92 to -103.54; p < 0.0001), transfusion rate (RR = 0.53; 95% CI 0.33 to 0.85; p = 0.008), and transfusion units (WMD = -0.58; 95% CI -0.75 to -0.41; p < 0.01). No increase in thromboembolic events rate (RR = 0.75; 95% CI 0.38 to 1.50; p = 0.42) and mortality (RR = 1.36; 95% CI 0.61 to 3.04; p = 0.45) was observed. CONCLUSIONS: Our meta-analysis provides robust evidence supporting the efficacy and safety of intravenous TXA administration in treating geriatric intertrochanteric femoral fractures with intramedullary nailing. TXA significantly reduces blood loss and transfusion requirements without increasing the risk of thromboembolic events or mortality.

Topical application of a novel anti-interleukin-17A antibody fragment penetrates psoriatic skin: Results of a randomised, double-blind, placebo-controlled Phase Ib study.

Interleukin (IL)-17A underlies the pathogenesis of chronic plaque psoriasis (CPP). Well-tolerated, effective IL-17A inhibitors for mild-to-moderate CPP are needed. ZL-1102 is a novel antibody fragment targeting IL-17A. To assess the safety, tolerability, preliminary efficacy and skin penetration of a topical 1% ZL-1102 hydrogel in patients with mild-to-moderate CPP, a two-part, Phase Ib study was conducted. Open-label Part A: six patients received a single topical application of ZL-1102 onto a psoriatic plaque; double-blind Part B: 53 patients were randomised 1:1 to twice-daily ZL-1102 or vehicle for 4 weeks. Key primary endpoints included treatment-emergent adverse events (TEAEs), tolerability and changes in local psoriasis area and severity index (PASI). TEAEs occurred in two (33.3%) patients in Part A and in 16 (59.3%) and 13 (50.0%) patients in the ZL-1102 and vehicle arms, respectively, in Part B. No grade ≥3 TEAEs were seen with ZL-1102. ZL-1102 led to numerically greater changes in local PASI versus vehicle (-28.8% vs. -17.2%), with good local tolerability. The trend towards local PASI improvement was accompanied by biomarker changes based on RNA sequencing, indicative of ZL-1102 penetration into psoriatic plaques. Topical ZL-1102 showed good safety, local tolerability and a trend towards improved local PASI; skin penetration was observed without measurable systemic exposure. ACTRN12620000700932.

Immune Co-inhibitory Receptors CTLA-4, PD-1, TIGIT, LAG-3, and TIM-3 in Upper Tract Urothelial Carcinomas: A Large Cohort Study.

Programmed cell death 1 ligand 1), programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3, lymphocyte activation gene-3, and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in upper tract urothelial carcinoma (UTUC). The aim of this Cohort Study was to provide evidence concerning expression profiles and the clinical significance of CIRs among Chinese UTUC patients. A total of 175 UTUC patients who received radical surgery in our center were included. We used immunohistochemistry to evaluate CIR expressions in tissue microarrays (TMAs). Clinicopathological characteristics and prognostic correlations of CIR proteins were retrospectively analyzed. TIGIT, T-cell immunoglobulin and mucin-domain containing-3, PD-1, CTLA-4, Programmed cell death 1 ligand 1, and lymphocyte activation gene-3 high expression was examined in 136(77.7%), 86(49.1%), 57(32.6%), 18(10.3%), 28(16.0%), and 18(10.3%) patients, respectively. Log-rank tests and Multivariate Cox analysis both implied CTLA-4 and TIGIT expression was associated with worse relapse-free survival. In conclusion, this is the largest Chinese UTUC cohort study, and we analyzed the Co-inhibitory receptor expression profiles in UTUC. We identified CTLA-4 and TIGIT expression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced UTUCs are probably immunogenic, for which single or combined immunotherapy may be potential therapeutic approaches in the future.

A novel necroptosis-associated miRNA signature predicting prognosis of endometrial cancer and correlated with immune infiltration.

OBJECTIVE: Necroptosis is a form of programmed cell death identified irrelevant to caspases, which plays an important role in the tumorigenesis and development of cancer. MicroRNAs (miRNAs) are important regulators of both necroptosis and cancer. MATERIALS AND METHODS: Expression of sixteen necroptosis-associated miRNAs were analyzed in 546 endometrial cancer (EC) tissues and 33 paracancerous samples from the Cancer Genome Atlas (TCGA). Cox regression analysis was used to evaluate the correlations between miRNAs and overall survival. MiRNAs risk score (Mrs) and nomogram were established to assess the potential value of necroptosis-related miRNAs on prognosis. Expression of miRNA-148a-3p in endometrial cancer cells and endometrial epithelial cells was detected by quantitative real-time PCR (qRT-PCR). The targets genes of miR-148a-3p were predicted using miRDB, miRTarBase and TargetScan and the prognostic-related genes were screened. Immune infiltration analysis was conducted to explore the potential mechanism of these target genes. RESULTS: We identified fourteen differentially expressed miRNAs and selected seven miRNAs (miR-15a-5p, miR148a-3p, miR-7-5p, miR-141-3p, miR-200a-5p, miR-223-3p, miR-16-5p) for prognostic-model construction. The area under the curve (AUC) of receiver operating characteristic (ROC) curve for 1-, 2- and 5-year survival were 0.678, 0.652 and 0.656 respectively. Multivariate analysis revealed that the Mrs was an independent prognostic factor considering other risk factors (HR = 1.928, 95% CI = 1.072-3.467, P = 0.028). Among these miRNAs, miRNA-148a-3p was up-regulated in cancer tissues and cells, and Kaplan-Meier analysis showed its significance in overall survival (OS). The target genes, DNAJB4 and PRNP, were associated with poor prognosis and correlated with tumor immune infiltration. CONCLUSIONS: Our study constructed a novel necroptosis-associated miRNAs model for prognosis prediction, and DNAJB4 and PRNP may be therapeutic targets for EC.

Letter to the Editor: clinical utility of urine DNA for noninvasive detection and minimal residual disease monitoring in urothelial carcinoma.

Current methods for the early detection and minimal residual disease (MRD) monitoring of urothelial carcinoma (UC) are invasive and/or possess suboptimal sensitivity. We developed an efficient workflow named urine tumor DNA multidimensional bioinformatic predictor (utLIFE). Using UC-specific mutations and large copy number variations, the utLIFE-UC model was developed on a bladder cancer cohort (n = 150) and validated in The Cancer Genome Atlas (TCGA) bladder cancer cohort (n = 674) and an upper tract urothelial carcinoma (UTUC) cohort (n = 22). The utLIFE-UC model could discriminate 92.8% of UCs with 96.0% specificity and was robustly validated in the BLCA_TCGA and UTUC cohorts. Furthermore, compared to cytology, utLIFE-UC improved the sensitivity of bladder cancer detection (p < 0.01). In the MRD cohort, utLIFE-UC could distinguish 100% of patients with residual disease, showing superior sensitivity compared to cytology (p < 0.01) and fluorescence in situ hybridization (FISH, p < 0.05). This study shows that utLIFE-UC can be used to detect UC with high sensitivity and specificity in patients with early-stage cancer or MRD. The utLIFE-UC is a cost-effective, rapid, high-throughput, noninvasive, and promising approach that may reduce the burden of cystoscopy and blind surgery.

Topical tranexamic acid in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly: A protocol for systematic review and meta-analysis.

BACKGROUND: Numerous studies have demonstrated that the use of tranexamic acid (TXA) intravenously minimizes bleeding, lowers transfusion rates, and does not raise the risk of complications during major orthopedic surgery. Concerning the effectiveness of the topical application, there are, nevertheless, inconsistent findings. We aimed to develop a protocol for systematic review and meta-analysis on the benefits and safety of topical TXA in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly. METHODS: PubMed, Embase, and the Cochrane Library will all be searched for randomized controlled trials published from the database inception to October 15, 2022. The primary outcomes will be intraoperative blood loss, hidden blood loss, total blood loss, transfusion rate, transfusion units, operative time, thromboembolic events, and mortality. The risk of bias will be evaluated using the Cochrane risk of bias assessment tool. Review Manager 5.3 will be used for the analysis. RESULTS: The effects and safety of topical TXA in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly will be quantified in this study. CONCLUSIONS: The study's findings will assist doctors in determining if topical TXA use is secure and efficient.