A survey of generative AI for de novo drug design: new frontiers in molecule and protein generation.

Artificial intelligence (AI)-driven methods can vastly improve the historically costly drug design process, with various generative models already in widespread use. Generative models for de novo drug design, in particular, focus on the creation of novel biological compounds entirely from scratch, representing a promising future direction. Rapid development in the field, combined with the inherent complexity of the drug design process, creates a difficult landscape for new researchers to enter. In this survey, we organize de novo drug design into two overarching themes: small molecule and protein generation. Within each theme, we identify a variety of subtasks and applications, highlighting important datasets, benchmarks, and model architectures and comparing the performance of top models. We take a broad approach to AI-driven drug design, allowing for both micro-level comparisons of various methods within each subtask and macro-level observations across different fields. We discuss parallel challenges and approaches between the two applications and highlight future directions for AI-driven de novo drug design as a whole. An organized repository of all covered sources is available at https://github.com/gersteinlab/GenAI4Drug.

Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis.

OBJECTIVE: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy. METHODS: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment. RESULTS: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis. CONCLUSIONS: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT05540275.

A critical review of biochar as an environmental functional material in soil ecosystems for migration and transformation mechanisms and ecological risk assessment.

At present, biochar has a large application potential in soil amelioration, pollution remediation, carbon sequestration and emission reduction, and research on the effect of biochar on soil ecology and environment has made positive progress. However, under natural and anthropogenic perturbations, biochar may undergo a series of environmental behaviors such as migratory transformation, mineralization and decomposition, and synergistic transport, thus posing certain potential risks. This paper outlines the multi-interfacial migration pathway of biochar in "air-soil-plant-animal-water", and analyzes the migration process and mechanism at different interfaces during the preparation, transportation and application of biochar. The two stages of the biochar mineralization process (mineralization of easily degradable aliphatic carbon components in the early stage and mineralization of relatively stable aromatic carbon components in the later stage) were described, the self-influencing factors and external environmental factors of biochar mineralization were analyzed, and the mineral stabilization mechanism and positive/negative excitation effects of biochar into the soil were elucidated. The proximity between field natural and artificially simulated aging of biochar were analyzed, and the change of its properties showed a trend of biological aging > chemical aging > physical aging > natural aging, and in order to improve the simulation and prediction, the artificially simulated aging party needs to be changed from a qualitative method to a quantitative method. The technical advantages, application scope and potential drawbacks of different biochar modification methods were compared, and biological modification can create new materials with enhanced environmental application. The stability performance of modified biochar was compared, indicating that raw materials, pyrolysis temperature and modification method were the key factors affecting the stability of biochar. The potential risks to the soil environment from different pollutants carried by biochar were summarized, the levels of pollutants released from biochar in the soil environment were highlighted, and a comprehensive selection of ecological risk assessment methods was suggested in terms of evaluation requirements, data acquisition and operation difficulty. Dynamic tracing of migration decomposition behavior, long-term assessment of pollution remediation effects, and directional design of modified composite biochar materials were proposed as scientific issues worthy of focused attention. The results can provide a certain reference basis for the theoretical research and technological development of biochar.

Impact of soil density on biomineralization using EICP and MICP techniques for earthen sites consolidation.

Enzyme-induced calcium carbonate precipitation (EICP) and microbially-induced calcium carbonate precipitation (MICP) techniques represent emerging trends in soil stabilization. However, the impact of soil density on biomineralization, particularly in historical earthen sites, remains unclear. This study compares the consolidation effects of EICP and MICP on cylindrical samples (10 cm × 5 cm) with three densities (1.5 g/cm3, 1.6 g/cm3, and 1.7 g/cm3) derived from the soil near the UNESCO World Cultural Heritage Site of Suoyang Ancient City, Gansu Province, China. Results showed that calcium carbonate production increased across all densities through bio-cementation, with higher densities producing more calcium carbonate. MICP-treated specimens exhibited larger increases in calcium carbonate production compared to those treated with EICP. Specimens with a density of 1.7 g/cm³ showed a wave velocity increase of 3.26% (EICP) and 7.13% (MICP), and an unconfined compressive strength increase of 8% (EICP) and 26% (MICP). These strength increases correlated with the generation of calcium carbonate. The findings suggest that biomineralization can be effectively utilized for in situ consolidation of earthen sites, emphasizing the importance of considering soil density in biologically-based conservation technologies. Furthermore, MICP shows potential advantages over EICP in providing stronger, compatible and more sustainable soil reinforcement.

Effects of biochar and compost on microbial community assembly and metabolic processes in glyphosate, imidacloprid and pyraclostrobin polluted soil under freezethaw cycles.

Biochar and organic compost are widely used in agricultural soil remediation as soil immobilization agents. However, the effects of biochar and compost on microbial community assembly processes in polluted soil under freezingthawing need to be further clarified. Therefore, a freezethaw cycle experiment was conducted with glyphosate (herbicide), imidacloprid (insecticide) and pyraclostrobin (fungicide) polluted to understand the effect of biochar and compost on microbial community assembly and metabolic behavior. We found that biochar and compost could significantly promote the degradation of glyphosate, imidacloprid and pyraclostrobin in freezethaw soil decrease the half-life of the three pesticides. The addition of immobilization agents improved soil bacterial and fungal communities and promoted the transformation from homogeneous dispersal to homogeneous selection. For soil metabolism, the combined addition of biochar and compost alleviated the pollution of glyphosate, imidacloprid and imidacloprid to soil through up-regulation of metabolites (DEMs) in amino acid metabolism pathway and down-regulation of DEMs in fatty acid metabolism pathway. The structural equation modeling (SEM) results showed that soil pH and DOC were the main driving factors affecting microbial community assembly and metabolites. In summary, the combined addition of biochar and compost reduced the adverse effects of pesticides residues.

Antitumor effects of IOX1 combined with bevacizumab-induced apoptosis and immunity on colorectal cancer cells.

Colorectal cancer (CRC), as a fatal cancer, is one of the most common cancers worldwide. Although the standard treatment for colorectal cancer is well researched and established, long-term patient survival remains poor, and mortality remains high. Therefore, more and more effective treatment options are needed. To evaluate the efficacy of bevacizumab, the histone demethylase inhibitor IOX1, or their combination for the treatment of colorectal cancer, we examined the effects of IOX1, bevacizumab, and IOX1 combined with bevacizumab on cell activity, proliferation, and migration of colorectal cancer cell lines HCT116, RKO, and CT26 by CCK8, colony formation assay, wound healing assay, and transwell assay. The effects of the drugs alone as well as in combination on apoptosis in colorectal cancer cell lines were examined by flow cytometry and further validated by Western blotting for apoptosis-related proteins. The antitumor effects of treatment alone or in combination on colorectal cancer cells were examined in animal models. Mice were injected subcutaneously with CT26 cells and the growth and immune infiltration in tumor tissues were detected by IHC after drug treatment. We found that IOX1 could effectively inhibit the activity of CRC cells and had a significant inhibitory effect on the proliferation and migration of CRC cells. The apoptosis rate increased in a dose-dependent manner after IOX1 treatment on colorectal cancer cells, and the expression of apoptosis-related proteins changed accordingly. Further combination with bevacizumab revealed that the combination had a more significant effect on the proliferation, migration, and apoptosis of CRC cells than either IOX1 or bevacizumab alone. In vivo experiments have found that both alone and combination drugs can inhibit the growth of mouse tumors, but the effect of combination inhibition is the most obvious. Combination therapy significantly inhibited the expression of proliferative marker (Ki67) in tumor xenograft models, and increased content of antigen-specific CD4+, CD8+T cell growth, and granzymeB (GZMB), which is associated with T cell cytotoxicity, was detected in combination therapy. Immunoassays suppressed the expression of relevant PD-1 and decreased. The anticancer drug bevacizumab and the histone demethylase inhibitor IOX1 may inhibit colon cancer cell growth by regulating apoptosis. The inhibitory effect of combination therapy on tumor growth may be achieved, in part, through upregulation of infiltration-mediated tumor immunity by T lymphocytes. The combination of IOX1 and bevacizumab produced significant synergistic effects. This study aims to provide a new direction for CRC combination therapy.

Effects and safety of endovascular recanalization for non-acute symptomatic intracranial vertebral artery occlusion with different risks.

There is no consensus on the optimal treatment for non-acute symptomatic intracranial vertebral artery occlusion, and endovascular recanalization is a challenging procedure. We report our clinical experience of endovascular recanalization in patients with non-acute symptomatic intracranial vertebral artery occlusion to assess the feasibility and safety of endovascular recanalization and determine the candidate patients for this procedure. Ninety-two patients with non-acute symptomatic intracranial vertebral artery occlusion who underwent endovascular recanalization from January 2019 to December 2021 were retrospectively analyzed. we grouped all patients according to imaging examination findings, occlusion length, duration, nature, calcification, and angulation to evaluate the risk of endovascular recanalization. The overall success rate of endovascular recanalization was 83.7% (77/92), and the perioperative complication rate was 10.9% (10/92). Among the 3 classification groups, the recanalization success rate gradually decreased from the low-risk group to the high-risk group (low-risk: 100%, medium-risk: 93.3%, high-risk group: 27.8%, P = .047), while the overall perioperative complication rate showed the opposite trend (0%, 10.0%, 38.9%, respectively, P = .001); the proportion of patients with 90-day modified Rankin Scale scores of 0-2 decreased successively (100%, 83.3%, and 22.2%, respectively, P < .026); 77 patients with successful recanalization were followed; the rate of restenosis/reocclusion increased sequentially (0%, 17.9%, and 80%, respectively, P = .000). Patients in the low- and medium-risk groups showed a good clinical course after endovascular recanalization. Among 88 patients (four patients lost to follow-up), with a median clinical follow-up of 13 months (interquartile range », 7-16), the rate of stroke or death after 30 days was 17.4% (16/92). Endovascular recanalization is safe and feasible for low- and medium-risk patients with non-acute symptomatic intracranial vertebral artery occlusion; it is also an alternative to conservative therapy for the patients.

Recycling of straw-biochar-biogas-electricity for sustainable food production pathways: Toward an integrated modeling approach.

As global greenhouse gas emissions increase and fossil energy sources decline dramatically, the energy transition is at the heart of many countries' development initiatives. As a biomass resource, straw plays a positive role in energy transformation and environmental improvement. However, there is still a challenge to explore the best options and models for straw production and utilization of green and efficient biomass energy in agricultural systems. This study establishes an economic-environmental-resource synergistic Straw Green recycling optimization model based on straw-electricity-biochar-biogas core (Straw Green recycling optimization model, SGROM). Firstly, we explore the effects of biochar return to the field on crop yield and greenhouse gas emission by Meta-analysis method, and on this basis, we construct SGROM to weigh the three objectives of economic-greenhouse gas emission-resource utilization, and explore the best allocation ratio between four utilization methods of straw: power generation, biochar preparation, biogas and derivatives preparation and sale, so as to obtain a straw recycling and efficient low-carbon utilization model. Exploring the response of straw green utilization patterns to crop market prices with the help of deep learning methods, SGROM has been applied to the main grain producing areas in the Sanjiang Plain of China, and the results of comparison with the traditional straw utilization (TSU) model show that the greenhouse gas emissions per unit of production value of SGROM are 19.66 % lower than that of TSU model, the electricity consumption is saved by 2.00 %, and the optimal ratios of straw for power generation, biogas and biochar production, and sale are 1.00 %, 10.75 %, 62.11 % and 26.14 %. The economic benefits and total greenhouse gas emissions of the integrated straw utilization mode are better than those of the single straw utilization mode, proving the superiority of SGROM in optimizing the straw utilization mode.

The boom era of emerging contaminants: A review of remediating agricultural soils by biochar.

Emerging contaminants (ECs) are widely sourced persistent pollutants that pose a significant threat to the environment and human health. Their footprint spans global ecosystems, making their remediation highly challenging. In recent years, a significant amount of literature has focused on the use of biochar for remediation of heavy metals and organic pollutants in soil and water environments. However, the use of biochar for the remediation of ECs in agricultural soils has not received as much attention, and as a result, there are limited reviews available on this topic. Thus, this review aims to provide an overview of the primary types, sources, and hazards of ECs in farmland, as well as the structure, functions, and preparation types of biochar. Furthermore, this paper emphasizes the importance and prospects of three remediation strategies for ECs in cropland: (i) employing activated, modified, and composite biochar for remediation, which exhibit superior pollutant removal compared to pure biochar; (ii) exploring the potential synergistic efficiency between biochar and compost, enhancing their effectiveness in soil improvement and pollution remediation; (iii) utilizing biochar as a shelter and nutrient source for microorganisms in biochar-mediated microbial remediation, positively impacting soil properties and microbial community structure. Given the increasing global prevalence of ECs, the remediation strategies provided in this paper aim to serve as a valuable reference for future remediation of ECs-contaminated agricultural lands.

Correction: Coating effect of renatured triple-helix lentinan on the morphology and antimicrobial activity of ZnO synthesized by hydrothermal method.

[This corrects the article DOI: 10.1039/D4RA01590H.].

Coating effect of renatured triple-helix lentinan on the morphology and antimicrobial activity of ZnO synthesized by hydrothermal method.

Polysaccharides are considered to be ideal green raw materials for enhancing biocompatibility and dispersion effects of nanoparticles. In this study, we coated and dispersed ZnO nanoparticles (NPs) using the denaturation-renaturation process of a triple helix glucan lentinan (LNT), induced by changes in pH value within the reaction system. Various ZnO/LNT composites with different particle sizes and crystal morphologies were prepared and characterized. The results demonstrated that renatured LNT (r-LNT) effectively encapsulated the {101̄0} crystal planes of ZnO, preventing crystal growth during the renaturation process and resulting in smaller, uniformly dispersed nanoparticles. Among the samples, ZnO/r-LNT-2 exhibited significantly higher antimicrobial activity, and it had a certain inhibitory effect on various plant pathogens. It also displayed the highest inhibitory effect against Candida albicans, with a minimum inhibitory concentration (MIC) of up to 8 µg mL-1. Consistently, ZnO/r-LNT-2 generated the highest amount of reactive oxygen species (ROS), thus exhibiting the most effective antimicrobial activity. However, excessive introduction of the dispersant LNT may reduce these activities. This study provides a foundation for further exploring the detailed mechanism of ROS generation catalyzed by ZnO and for harnessing the full potential of this type of antimicrobial agent.

Preparation of biocompatibility coating on magnesium alloy surface by sodium alginate and carboxymethyl chitosan hydrogel.

Magnesium alloy is an excellent material for biodegradable cerebrovascular stents. However, the rapid degradation rate of magnesium alloy will make stent unstable. To improve the biocompatibility of magnesium alloy, in this study, biodegradable sodium alginate and carboxymethyl chitosan (SA/CMCS) was used to coat onto hydrothermally treated the surface of magnesium alloy by a dipping coating method. The results show that the SA/CMCS coating facilitates the growth, proliferation, and migration of endothelial cells and promotes neovascularization. Moreover, the SA/CMCS coating suppresses macrophage activation while promoting their transformation into M2 type macrophages. Overall, the SA/CMCS coating demonstrates positive effects on the safety and biocompatibility of magnesium alloy after implantation, and provide a promising therapy for the treatment of intracranial atherosclerotic stenosis in the future.

Use of the Tubridge flow diverter in the treatment of intracranial aneurysms: a single center experience.

To investigate the safety and effect of Tubridge flow diverter deployment for the treatment of intracranial aneurysms, 85 patients with intracranial aneurysms treated with the Tubridge flow diverter were retrospectively enrolled. The clinical data including the baseline data, aneurysm parameters before and after treatment, and follow-up outcomes were assessed. Among 85 patients, there were 35 (41.2%) males and 50 females (58.8%) aged 17-77 (mean 56.7 ± 11.1) years with 110 aneurysms. Five (5.9%) patients initially presented with subarachnoid hemorrhage from aneurysm rupture. The aneurysm size was 2-30 (mean 8.6) mm, and the aneurysm neck was 2-10.6 (mean 5.7 ± 2.3) mm. Ninety-three Tubridge stents were deployed. Twenty-five (29.4%) patients experienced adjunctive loose coiling. Blood flow was significantly reduced from entering the aneurysm after stent deployment. Periprocedural complications occurred in three (3.5%) patients, including in-stent thrombosis during embolization in one patient (1.2%), conjunctiva edema on the right in one patient (1.2%), and acute multiple cerebral infarctions in one patient (1.2%). Angiographic follow-up was conducted in 67 (78.8%) patients 3-36 (mean 15.3 ± 5.6) months later. In 11 (16.4% or 11/67) patients, blood flow still entered the aneurysm with the O'Kelly-Marotta (OKM) grade B in two (3.0%) patients and grade C in nine (13.4%), whereas complete occlusion (OKM grade D) was achieved in the other 56 (83.6% or 56/67) aneurysms. In-stent stenosis was present in five (7.5%) patients with approximately 25% stenosis in three (4.5%) patients and 50% in two (3.0%). In conclusion, the Tubridge flow diverter can be safely and efficiently applied in the treatment of small and large intracranial aneurysms, with a low periprocedural complication rate, a high occlusion degree, and a low in-stent stenosis rate at follow-up even though large aneurysms may necessitate a longer surgical time and adjunctive coiling.

Vascular architecture characters and risk factors analysis of unstable moyamoya disease.

Background: In some MMD patients, the digital subtraction angiography (DSA) examination found, occlusion in the ipsilateral internal carotid artery or middle cerebral artery, accompanied by the formation of numerous moyamoya vessels. Conversely, the contralateral internal carotid artery or middle cerebral artery shows signs of stenosis without the presence of moyamoya vessels. Notably, cerebral perfusion studies reveal a similar or even more severe reduction in perfusion on the occluded side compared to the stenotic side. Importantly, clinical symptoms in these patients are typically attributed to ischemia caused by the stenotic side. This condition is referred to as unstable moyamoya disease (uMMD). Objective: This clinical research focuses on evaluating risk factors related to MMD and developing strategies to minimize postoperative complications. The study aims to analyze vascular characteristics and identify potential risk factors in patients with uMMD. Methods: The authors reviewed consecutive cases with complete clinical and radiological documentation of patients who underwent surgery between January 2018 and June 2023. Univariate analysis and multivariate logistic regression analysis were employed to understand the risk factors and prognosis of postoperative complications in uMMD. Results: Postoperative complications were retrospectively analyzed in 1481 patients (aged 14 to 65). Among them, 1,429 patients were assigned to the conventional treatment group, while 52 were in the unstable moyamoya disease group. The uMMD treatment group showed a significantly higher incidence of early postoperative complications such as RIND, cerebral infarction, and cerebral hemorrhage (p < 0.05). Univariate and multivariate logistic regression analyses were conducted on the postoperative complications of 52 uMMD patients. Initial symptoms of stenosis ≤50% (univariate: p = 0.008, multivariate: p = 0.015; OR [95% CI] =23.149 [1.853-289.217]) and choosing occluded side surgery (univariate: p = 0.043, multivariate: p = 0.018; OR [95% CI] =0.059 [0.006-0.617]) were identified as significant risk factors for postoperative neurological complications. Conclusion: Compared to the conventional treatment group, uMMD has higher complication rates, with vascular stenosis degree and surgical side selection identified as significant risk factors. A comprehensive understanding of preoperative clinical symptoms and vascular characteristics in moyamoya disease patients, coupled with the formulation of rational surgical plans, contributes positively to decreasing postoperative mortality and disability rates in uMMD.

Aspercitrininone A, novel antibacterial polyketide featuring unusual spiral skeleton from Aspergillus cristatus.

Aspercitrininone A (1), a novel polyketide featuring an unprecedented tetracyclic 6/6/6/5 spiral skeleton, was obtained from the rice fermentation cultures of the fungus Aspergillus cristatus together with five known compounds (2-6). Their structures were determined by HRESIMS data, 1D and 2D NMR spectroscopic analysis, and electronic circular dichroism (ECD) calculations. Aspercitrininone A was revealed as a new type of C/D cycle spiral structure and an unusual addition product of o-quinoid form citrinin with 2-methylterrefuranone. Compounds 1, 4, and 5 exhibited potent antibacterial activities with minimal inhibitory concentration (MIC) values from 13.2 to 67.3 µg/mL against four strains of human pathogenic bacteria in vitro.

Impact of premorbid hypertension and renin-angiotensin-aldosterone system inhibitors on the severity of aneurysmal subarachnoid haemorrhage: a multicentre study.

BACKGROUND: Hypertension is widely acknowledged as a significant contributory factor to the heightened risk of intracranial aneurysm rupture. Nevertheless, the impact of hypertension management on the outcomes subsequent to aneurysmal subarachnoid haemorrhage (aSAH), particularly concerning the severity of aSAH, remains an underexplored area. METHODS: We conducted a retrospective analysis using data from a prospectively multicentre cohort of 4545 patients with aSAH in China. Premorbid hypertension status and the utilisation of antihypertensive medications prior to admission were set as key exposure factors. The primary outcomes encompassed unfavourable clinical grading scales observed on admission. Employing multivariable logistic regression, we explored the association between premorbid hypertension status, preadmission use of renin-angiotensin-aldosterone system (RAAS) inhibitors and unfavourable clinical grading scales. RESULTS: In comparison to patients with normal blood pressure, only uncontrolled hypertension demonstrated a significant and independent association with an elevated risk of poor outcomes on the Hunt-Hess scale (OR=1.799, 95% CI 1.413 to 2.291, p<0.001) and the World Federation of Neurological Surgeons (WFNS) scale (OR=1.721, 95% CI 1.425 to 2.079, p<0.001). Furthermore, the antecedent use of RAAS inhibitors before admission was markedly and independently linked to a diminished risk of adverse outcomes on the Hunt-Hess scale (OR=0.653, 95% CI 0.430 to 0.992, p=0.046) and the WFNS scale (OR=0.656, 95% CI 0.469 to 0.918, p=0.014). CONCLUSIONS: Uncontrolled hypertension markedly elevates the risk of adverse clinical outcomes following an aSAH. Conversely, the preadmission utilisation of RAAS inhibitors demonstrates a noteworthy association with a favourable clinical outcome after aSAH.

Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.

To investigate the significance of atherosclerotic plaque location in hybrid surgery comprising both endovascular recanalization approaches and carotid endarterectomy for symptomatic atherosclerotic non-acute long-segment occlusion of the internal carotid artery (ICA), 162 patients were enrolled, including 120 (74.1%) patients in the proximal plaque group and 42 (25.9%) in the distal plaque group. Surgical recanalization was performed in all patients, with successful recanalization in 119 (99.2%) patients in the proximal and 39 (92.9%) in the distal plaque group. The total successful recanalization rate was 97.5% (158/162) with a failure rate of 2.5% (4/162). Periprocedural complications occurred in 5 (4.2% or 5/120) patients in the proximal plaque group, including neck infection in two (1.7%), recurrent nerve injury in 1 (0.8%), and laryngeal edema in 2 (1.7%), and 2 (4.8%) in the distal plaque group, including femoral puncture infection in 2 (4.8%). No severe complications occurred in either group. Univariate analysis showed plaque location was a significant (P = 0.018) risk factor for successful recanalization, and multivariate analysis indicated that the plaque location remained a significant independent risk factor for recanalization success (P = 0.017). In follow-up 6-48 months after the recanalization surgery, reocclusion occurred in two (2.8%) patients in the proximal plaque group and 4 (13.3%) in the distal plaque group. In conclusion, although hybrid surgery achieves similar outcomes in patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques, plaque location may be a significant risk factor for successful recanalization of symptomatic non-acute long-segment ICA occlusion.

TRPV3-Activated PARP1/AIFM1/MIF Axis through Oxidative Stress Contributes to Atopic Dermatitis.

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.

Effects of percutaneous endovascular angioplasty for severe stenosis or occlusion of subclavian artery.

To investigate the effect and safety of percutaneous endovascular angioplasty (PEA) with optional stenting for the treatment of severe stenosis or occlusion of subclavian artery, patients with severe stenosis ≥ 70% or occlusion of subclavian artery treated with PEA were retrospectively enrolled. The clinical data were analyzed. A total of 222 patients were retrospectively enrolled, including 151 males (68.0%) and 71 females (32.0%) aged 48-86 (mean 63.9 ± 9.0) years. Forty-seven (21.2%) patients had comorbidities. Subclavian artery stenosis ≥ 70% was present in 201 (90.5%) patients and complete subclavian occlusion in 21 (9.5%) cases. Angioplasty was successfully performed in all (100%) patients. Balloon-expandable stents were used in 190 (85.6%) cases, and self-expandable stents in 20 (9.0%) cases. Only 12 (5.4%) cases were treated with balloon dilation only. Among 210 patients treated with stent angioplasty, 71 (33.8% or 71/210) cases underwent balloon pre-dilation, 139 (66.2% or 139/210) had direct deployment of balloon-expandable stents, and 2 (1.0% or 2/210) experienced balloon post-dilation. Distal embolization protection devices were used in 5 (2.3% or 5/222) cases. Periprocedural complications occurred in 3 (1.4%) patients, including aortic dissection in 2 (0.9%) cases and right middle cerebral artery embolism in 1 (0.5%). No hemorrhage occurred. Among 182 (82.0%) patients with 6-month follow-up, restenosis > 70% occurred in 1 (0.5%) patient, and among 68 (30.6%) patients with 12-month follow-up, restenosis > 70% took place in 11 (16.2%) patients. Percutaneous endovascular angioplasty can be safely and efficiently performed for the treatment of severe stenosis ≥ 70% or occlusion of subclavian artery.

Intracranial Aneurysms Managed by Parent Artery Reconstruction Using Tubridge Flow Diverter study: 1-year outcomes.

OBJECTIVE: Previous randomized controlled trials have reported a significantly higher occlusion rate of large and giant aneurysms when utilizing the Tubridge flow diverter (FD). In the present trial, the safety and efficacy of the Tubridge FD in treating unruptured internal carotid artery (ICA) or vertebral artery (VA) aneurysms were assessed in a real-world setting. METHODS: The Intracranial Aneurysms Managed by Parent Artery Reconstruction Using Tubridge Flow Diverter (IMPACT) study is a prospective, multicenter, single-arm clinical trial assessing the efficacy of the Tubridge FD in the management of unruptured aneurysms located in the ICA or VA. The primary endpoint was the complete occlusion (Raymond-Roy class 1) rate at the 1-year follow-up. The secondary endpoints included the technical success rate, the successful occlusion rate of the aneurysm, which is the degree of aneurysm embolization scored as Raymond-Roy class 1 or 2, major (> 50%) in-stent stenosis, and incidence of disabling stroke or neurological death associated with the target aneurysms. RESULTS: This study included 14 interventional neuroradiology centers, with 200 patients and 240 aneurysms. According to angiographic core laboratory assessment, 205 (85.4%) aneurysms were located in the ICA, 34 (14.2%) in the VA, and 1 (0.4%) in the middle cerebral artery. Additionally, 189 (78.8%) aneurysms were small (< 10 mm). At the 12-month follow-up, the total occlusion rate was 79.0% (166/210, 95% CI 72.91%-84.34%). Additionally, the occurrence of disabling stroke or neurological death related to the specified aneurysms was 1% (2/200). CONCLUSIONS: The 1-year results from the IMPACT trial affirm the safety record of use of the Tubridge FD in the treatment of intracranial aneurysms in real-world scenarios. These results reveal low morbidity and mortality rates of 3.5% and 1.5%, respectively. Furthermore, they provide evidence of the effectiveness of the Tubridge FD, as demonstrated by the complete occlusion achieved in 166 of 210 (79%) cases.