Efficacy and safety of combined stent retriever and contact aspiration vs. stent retriever alone on revascularization in patients with acute ischemic stroke: a systematic review and meta-analysis.

Objective: Whether the efficacy of combined stent retriever and contact aspiration (S + A) is superior to stent retriever (S) alone for revascularisation in patients with large vessel occlusive stroke remains uncertain. The aim of this meta-analysis was to assess the safety and efficacy of combined stent retriever and contact aspiration for the treatment of acute ischaemic stroke with large vessel occlusion by comparing it with stent retriever alone. Methods: We systematically searched the PubMed, Embase, Web of Science, and The Cochrane Library databases for randomised controlled trials and observational studies (case-control and cohort studies) published before 1 October 2023 comparing the efficacy of combined stent retriever and contact aspiration versus tent retriever alone in patients with large vessel occlusive stroke. The end point of the primary efficacy observed in this meta-analysis study was the rate of first pass nearly complete or complete recanalisation (mTICI 2c-3). Secondary effectiveness nodes were: rate of first pass successful recanalisation (mTICI 2b-3), rate of near-complete or complete recanalisation of the postoperative vessel, rate of successful recanalisation of the postoperative vessel, and MRS 0-2 within 90 days. Safety endpoints were interoperative embolism, symptomatic intracranial haemorrhage, and mortality within 90 days. Results: A total of 16 studies were included in the literature for this meta-analysis, with a total of 7,320 patients (S + C group: 3,406, S group: 3,914). A comprehensive analysis of the included literature showed that combined stent retriever and contact aspiration had a higher rate of near-complete or complete recanalisation of the postoperative vessel [OR = 1.53, 95% CI (1.24, 1.88), p < 0.0001] and rate of successful recanalisation of the postoperative vessel compared to stent retriever alone [OR = 1.83, 95% CI (1.55, 2.17), p < 0.00001]; there were no statistically significant differences between the two groups in terms of the rate of first pass nearly complete or complete recanalisation [OR = 1.00, 95% CI (0.83, 1.19), p = 0.96], rate of first pass successful recanalisation [OR = 1.02, 95% CI (0.85, 1.24), p = 0.81], interoperative embolism [OR = 0.93, 95% CI (0.72, 1.20), p = 0.56], symptomatic intracranial haemorrhage [OR = 1.14, 95% CI (0.87, 1.48), p = 0.33], MRS 0-2 within 90 days [OR = 0.89, 95% CI (0.76, 1.04), p = 0.14] and mortality within 90 days [OR = 1.11, 95% CI (0.94, 1.31), p = 0.22]. Conclusion: Combined stent retriever and contact aspiration has a higher rate of postprocedural revascularisation (mTICI 2c-3/mTICI 2b-3) compared with stent retriever alone in patients with large vessel occlusion stroke. In addition, it was not superior to stenting alone in terms of the rate of first pass recanalisation (mTICI 2c-3/mTICI 2b-3), interoperative embolisation, symptomatic intracranial haemorrhage, good functional prognosis within 90 days and mortality within 90 days.

SCFFBXW11 Complex Targets Interleukin-17 Receptor A for Ubiquitin-Proteasome-Mediated Degradation.

Interleukin-17 (IL-17) is a pro-inflammatory cytokine that participates in innate and adaptive immune responses and plays an important role in host defense, autoimmune diseases, tissue regeneration, metabolic regulation, and tumor progression. Post-translational modifications (PTMs) are crucial for protein function, stability, cellular localization, cellular transduction, and cell death. However, PTMs of IL-17 receptor A (IL-17RA) have not been investigated. Here, we show that human IL-17RA was targeted by F-box and WD repeat domain-containing 11 (FBXW11) for ubiquitination, followed by proteasome-mediated degradation. We used bioinformatics tools and biochemical techniques to determine that FBXW11 ubiquitinated IL-17RA through a lysine 27-linked polyubiquitin chain, targeting IL-17RA for proteasomal degradation. Domain 665-804 of IL-17RA was critical for interaction with FBXW11 and subsequent ubiquitination. Our study demonstrates that FBXW11 regulates IL-17 signaling pathways at the IL-17RA level.

Comparative Analysis of the Efficacy of Spinal Cord Stimulation and Traditional Debridement Care in the Treatment of Ischemic Diabetic Foot Ulcers: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Spinal cord stimulation (SCS) is an effective treatment for diabetic peripheral neuropathy. The purpose of this study was to investigate the effectiveness of SCS in the treatment of ischemic diabetic foot ulcers. METHODS: In this retrospective study, the SCS group comprised 102 patients with ischemic diabetic foot who were treated with SCS for foot ulcers and nonhealing wounds due to severe lower limb ischemia. The traditional debridement care (TDC) group comprised 104 patients with ischemic diabetic foot who received only TDC. Strict screening criteria were applied. The assignment of patients to either group depended solely on their willingness to be treated with SCS. Secondary end points were transcutaneous partial pressure of oxygen (PtcO 2 ), ankle-brachial index (ABI), and color Doppler of the lower limb arteries in the feet at 6 months and 12 months after treatment. The primary end point was the amputation. RESULTS: The dorsal foot PtcO 2 and ABI of the patients in the SCS group were significantly improved at 6 months and 12 months postoperation ( P < .05). The therapeutic efficacy was significantly better than that of the TDC group over the same period of time ( P < .05). The degree of vasodilation of the lower limb arteries (ie, femoral, popliteal, posterior tibial, and dorsalis pedis arteries) on color Doppler was higher in the SCS group than in the TDC group ( P < .05). The odds ratios for total amputation at 6 and 12 months postoperatively in the SCS group were 0.45 (95% CI, 0.19-1.08) and 0.17 (95% CI, 0.08-0.37), respectively, compared with the TDC group. CONCLUSION: SCS improved symptoms of lower limb ischemia in ischemic diabetic feet and reduced the rate of toe amputation by increasing PtcO 2 , ABI, and arterial vasodilation in the lower limbs.

Genetic Profiling of African American Patients With Prostatic Adenocarcinoma Metastatic to the Lymph Nodes: A Pilot Study.

CONTEXT.­: Genetic profiling data of prostatic adenocarcinoma are derived from predominantly White patients. In African Americans, prostatic adenocarcinoma has a poorer prognosis, raising the possibility of distinct genetic alterations. OBJECTIVE.­: To investigate the genomic alterations of prostatic adenocarcinoma metastatic to regional lymph nodes in African American patients, with an emphasis on SPOP mutation. DESIGN.­: We retrospectively reviewed African American patients with pN1 prostatic adenocarcinoma managed with radical prostatectomy and lymph node dissection. Comprehensive molecular profiling was performed, and androgen receptor signaling scores were calculated. RESULTS.­: Nineteen patients were included. The most frequent genetic alteration was SPOP mutations (5 of 17; 29.4% [95% CI: 10.3-56.0]). While most alterations were associated with a high androgen receptor signaling score, mutant SPOP was exclusively associated with a low median and interquartile range (IQR) androgen receptor signaling score (0.788 [IQR 0.765-0.791] versus 0.835 [IQR 0.828-0.842], P = .003). In mutant SPOP, mRNA expression of SPOP inhibitor G3BP1 and SPOP substrates showed a significantly decreased expression of AR (33.40 [IQR 28.45-36.30] versus 59.53 [IQR 53.10-72.83], P = .01), TRIM24 (3.95 [IQR 3.28-5.03] versus 9.80 [IQR 7.39-11.70], P = .008), and NCOA3 (15.19 [IQR 10.59-15.93] versus 21.88 [IQR 18.41-28.33], P = .046). CONCLUSIONS.­: African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.

Role(s) of G3BPs in Human Pathogenesis.

Ras-GTPase-activating protein (SH3 domain)-binding proteins (G3BP) are RNA binding proteins that play a critical role in stress granule (SG) formation. SGs protect critical mRNAs from various environmental stress conditions by regulating mRNA stability and translation to maintain regulated gene expression. Recent evidence suggests that G3BPs can also regulate mRNA expression through interactions with RNA outside of SGs. G3BPs have been associated with a number of disease states, including cancer progression, invasion, metastasis, and viral infections, and may be useful as a cancer therapeutic target. This review summarizes the biology of G3BP including their structure, function, localization, role in cancer progression, virus replication, mRNA stability, and SG formation. We will also discuss the potential of G3BPs as a therapeutic target. SIGNIFICANCE STATEMENT: This review will discuss the molecular mechanism(s) and functional role(s) of Ras-GTPase-activating protein (SH3 domain)-binding proteins in the context of stress granule formation, interaction with viruses, stability of RNA, and tumorigenesis.

Clinical Effect Analysis of Spinal Cord Electrical Stimulator Implantation for Diabetic Foot.

OBJECTIVE: To investigate the clinical effect of spinal cord electrical stimulator implantation in the treatment of a diabetic foot (DF). MATERIALS AND METHODS: We recruited 19 patients with DF who were admitted to Shengjing Hospital of China Medical University between January 2018 and May 2020. All the patients were treated with spinal cord electrical stimulator implantation. Skin temperature, degree of pain, quality of life (QOL) score, limb (toe) preservation, and nerve conduction velocity of the patients were compared pre- and postoperatively. RESULTS: The diameter and peak velocity of multisegment arteries in the lower limbs had significantly increased post surgery. Foot skin temperature significantly increased in patients with good effect. The postoperative visual analog scale score of the patients was significantly lower than that noted preoperatively (p < 0.05). The conduction velocities of the lower limb sensory nerves (eg, superficial peroneal nerve and sural nerve) and motor nerves (eg, common peroneal nerve and tibial nerve) had improved post surgery. Moreover, patients' QOL score had significantly improved postoperatively (p < 0.05). The limb (toe) salvage rate was 94.74%. CONCLUSION: The implantation of a spinal cord electrical stimulator for treating DF can effectively relieve pain and other associated symptoms. Additionally, this device can promote nerve function recovery and lower limb blood supply and reduce the risk of toe amputation; therefore, it is clinically effective and should be considered in the treatment of DF.

GC-MLP: Graph Convolution MLP for Point Cloud Analysis.

With the objective of addressing the problem of the fixed convolutional kernel of a standard convolution neural network and the isotropy of features making 3D point cloud data ineffective in feature learning, this paper proposes a point cloud processing method based on graph convolution multilayer perceptron, named GC-MLP. Unlike traditional local aggregation operations, the algorithm generates an adaptive kernel through the dynamic learning features of points, so that it can dynamically adapt to the structure of the object, i.e., the algorithm first adaptively assigns different weights to adjacent points according to the different relationships between the different points captured. Furthermore, local information interaction is then performed with the convolutional layers through a weight-sharing multilayer perceptron. Experimental results show that, under different task benchmark datasets (including ModelNet40 dataset, ShapeNet Part dataset, S3DIS dataset), our proposed algorithm achieves state-of-the-art for both point cloud classification and segmentation tasks.

A common intronic single nucleotide variant modifies PKD1 expression level.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 and PKD2 (PKD1/2), has unexplained phenotypic variability likely affected by environmental and other genetic factors. Approximately 10% of individuals with ADPKD phenotype have no causal mutation detected, possibly due to unrecognized risk variants of PKD1/2. This study was designed to identify risk variants of PKD genes through population genetic analyses. We used Wright's F-statistics (Fst) to evaluate common single nucleotide variants (SNVs) potentially favored by positive natural selection in PKD1 from 1000 Genomes Project (1KG) and genotyped 388 subjects from the Rogosin Institute ADPKD Data Repository. The variants with >90th percentile Fst scores underwent further investigation by in silico analysis and molecular genetics analyses. We identified a deep intronic SNV, rs3874648G> A, located in a conserved binding site of the splicing regulator Tra2-ß in PKD1 intron 30. Reverse-transcription PCR (RT-PCR) of peripheral blood leukocytes (PBL) from an ADPKD patient homozygous for rs3874648-A identified an atypical PKD1 splice form. Functional analyses demonstrated that rs3874648-A allele increased Tra2-ß binding affinity and activated a cryptic acceptor splice-site, causing a frameshift that introduced a premature stop codon in mRNA, thereby decreasing PKD1 full-length transcript level. PKD1 transcript levels were lower in PBL from rs3874648-G/A carriers than in rs3874648-G/G homozygotes in a small cohort of normal individuals and patients with PKD2 inactivating mutations. Our findings indicate that rs3874648G > A is a PKD1 expression modifier attenuating PKD1 expression through Tra2-ß, while the derived G allele advantageously maintains PKD1 expression and is predominant in all subpopulations.

UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer.

UBR5, a HECT-domain E3 ubiquitin ligase, is an attractive therapeutic target for aggressive breast cancers. Defining the substrates of UBR5 is crucial for scientific understanding and clinical intervention. Here, we demonstrate that CDC73, a component of the RNA polymerase II-associated factor 1 complex, is a key substrate that impedes UBR5's profound tumorigenic and metastatic activities in triple-negative breast cancer (TNBC) via mechanisms of regulating the expression of ß-catenin and E-cadherin, tumor cell apoptosis and CD8+ T cell infiltration. Expression of CDC73 is also negatively associated with the progression of breast cancer patients. Moreover, we show that UBR5 destabilizes CDC73 by polyubiquitination at Lys243, Lys247, and Lys257 in a non-canonical manner that is dependent on the non-phosphorylation state of CDC73 at Ser465. CDC73 could serve as a molecular switch to modulate UBR5's pro-tumor activities and may provide a potential approach to developing breast cancer therapeutic interventions.

G3BP1 modulates SPOP to promote prostate tumorigenesis.

Speckle-type POZ protein (SPOP), a Cullin 3-based ubiquitin ligase (CUL3SPOP), acts as a prostate-specific tumor suppressor. Loss-of-function mutations in SPOP occur in 10% of primary prostate cancer with a high Gleason grade and poor prognosis. However, it is unclear how the ubiquitin ligase activity of SPOP is controlled and how dysregulation of SPOP contributes to malignant transformation. Here, we identified GTPase Activating Protein (SH3 Domain) Binding Protein 1 (G3BP1) as an interactor and upstream regulator of CUL3SPOP, and it functions as an inhibitor of CUL3SPOP ubiquitin ligase, suggesting a distinctive mode of CUL3SPOP inactivation that aggravates prostate cancer.