Impact of treatment interval between neoadjuvant immunochemotherapy and surgery in lung squamous cell carcinoma.

OBJECTIVE: The optimal timing for surgery following neoadjuvant immunochemotherapy for lung squamous cell carcinoma appears to be a topic of limited data. Many clinical studies lack stringent guidelines regarding this timing. The objective of this study is to explore the effect of the interval between neoadjuvant immunochemotherapy and surgery on survival outcomes in patients with lung squamous cell carcinoma. METHODS: This study conducted a retrospective analysis of patients with lung squamous cell carcinoma who underwent neoadjuvant immunochemotherapy between January 2019 and October 2022 at The First Affiliated Hospital, Zhejiang University School of Medicine. Patients were divided into two groups based on the treatment interval: ≤33 days and > 33 days. The primary observational endpoints of the study were Disease-Free Survival (DFS) and Overall Survival (OS). Secondary observational endpoints included Objective response rate (ORR), Major Pathological Response (MPR), and Pathological Complete Remission (pCR). RESULTS: Using the Kaplan-Meier methods, the ≤ 33d group demonstrated a superior DFS curve compared to the > 33d group (p = 0.0015). The median DFS for the two groups was 952 days and 590 days, respectively. There was no statistical difference in the OS curves between the groups (p = 0.66), and the median OS was not reached for either group. The treatment interval did not influence the pathologic response of the tumor or lymph nodes. CONCLUSIONS: The study observed that shorter treatment intervals were associated with improved DFS, without influencing OS, pathologic response, or surgical safety. Patients should avoid having a prolonged treatment interval between neoadjuvant immunochemotherapy and surgery.

High-Performance Aluminum Fuels Induced by Monolayer Self-Assembly of Nano-Sized Energetic Fluoride Vesicles on the Surface.

Surface modification is frequently used to solve the problems of low combustion properties and agglomeration for aluminum-based fuels. However, due to the intrinsic incompatibility between the aluminum powder and the organic modifiers, the surface coating is usually uneven and disordered, which significantly deteriorates the uniformity and performances of the Al-based fuels. Herein, a new approach of monolayer nano-vesicular self-assembly is proposed to prepare high-performance Al fuels. Triblock copolymer G-F-G is produced by glycidyl azide polymer (GAP) and 2,2'-(2,2,3,3,4,5,5-Octafluorohexane-1,6-diyl) bis (oxirane) (fluoride) ring-open addition reaction. By utilizing G-F-G vesicular self-assembly in a special solvent, the nano-sized vesicles are firmly adhered to the surface of Al powder through the long-range attraction between the fluorine segments and Al. Meanwhile, the electrostatic repulsion between vesicles ensures an extremely thin coating thickness (≈15 nm), maintaining the monolayer coating structure. Nice ignition, combustion, anti-agglomeration, and water-proof properties of Al@G-F-G(DMF) are achieved, which are superior among the existing Al-based fuels. The derived Al-based fuel has excellent comprehensive properties, which can not only inspire the development of new-generation energetic materials but also provide facile but exquisite strategies for exquisite surface nanostructure construction via ordered self-assembly for many other applications.

Comparisons of short-term outcomes between robot-assisted, video-assisted, and open esophagectomy for resectable esophageal cancer after neoadjuvant treatment: a retrospective study.

Background: Robot-assisted esophagectomy (RAE), video-assisted minimally invasive esophagectomy (VAMIE), and open esophagectomy (OE) all have significant roles in the management of esophageal cancer (EC). Few studies have compared efficacy and safety between RAE, VAMIE, and OE for resectable EC after neoadjuvant treatment. Therefore, this study aimed to explore the short-term outcomes between RAE, VAMIE, and OE for resectable EC after neoadjuvant treatment. Methods: Ninety-eight patients were consecutively enrolled who underwent esophagectomy. A retrospective study was performed including 98 consecutive patients treated from January 2021 to August 2022 who received neoadjuvant treatment (including immunochemotherapy and chemoradiotherapy) followed by RAE, VAMIE or OE. Evaluated endpoints in the present study consisted of pathological outcomes, intraoperative and postoperative outcomes, as well as postoperative complications. Results: No significant differences were seen in the operating time, blood loss, length of intensive care unit (ICU) stay, R0 resection, and number of dissected lymph nodes between the three RAE, VAMIE, or OE groups. The achievement rate of right recurrent laryngeal nerve (RLN) lymph node removal (P=0.01) and the total cost (P<0.001) were higher in RAE. The postoperative hospital stay of OE was longer than the other two groups (P<0.05). There were no significant differences in postoperative complications. Conclusions: Compared to VAMIE, no clear benefit exists for RAE in the treatment of resectable EC after neoadjuvant therapy. OE resulted in a longer hospital stay. Although the rate of successful right RLN node removal was higher with RAE, the clinical relevance for this is yet unclear.

Reactive Oxygen Species-Responsive Composite Fibers Regulate Oxidative Metabolism through Internal and External Factors to Promote the Recovery of Nerve Function.

It is challenging to sufficiently regulate endogenous neuronal reactive oxygen species (ROS) production, reduce neuronal apoptosis, and reconstruct neural networks under spinal cord injury conditions. Here, hydrogel surface grafting and microsol electrospinning are used to construct a composite biomimetic scaffold with "external-endogenous" dual regulation of ROS. The outer hydrogel enhances local autophagy through responsive degradation and rapid release of rapamycin (≈80% within a week), neutralizing extracellular ROS and inhibiting endogenous ROS production, further reducing neuronal apoptosis. The inner directional fibers continuously supply brain-derived neurotrophic factors to guide axonal growth. The results of in vitro co-culturing show that the dual regulation of oxidative metabolism by the composite scaffold approximately doubles the neuronal autophagy level, reduces 60% of the apoptosis induced by oxidative stress, and increases the differentiation of neural stem cells into neuron-like cells by ≈2.5 times. The in vivo results show that the composite fibers reduce the ROS levels by ≈80% and decrease the formation of scar tissue. RNA sequencing results show that composite scaffolds upregulate autophagy-associated proteins, antioxidase genes, and axonal growth proteins. The developed composite biomimetic scaffold represents a therapeutic strategy to achieve neurofunctional recovery through programmed and accurate bidirectional regulation of the ROS cascade response.

Design Synthesis of Low-Silica SAPO-34 Nanocrystals by Constructing Isomorphous Core-Shell Structure: An Effective Catalyst for Improving Catalytic Performances in Methanol-to-Olefins Reaction.

It is well known that low-silica SAPO-34, with an extra porosity (meso- and/or macropores) system, affords excellent catalytic performance in the methanol-to-olefins (MTO) reaction, while the direct synthesis of low-silica SAPO-34 with a hierarchical structure is difficult to achieve, principally because the crystal impurities are usually formed under a low silica content in a gel precursor. Herein, low-silica SAPO-34 nanocrystals were successfully fabricated for the first time by constructing an isomorphous core-shell structure in an epitaxial growth manner. In which, low-silica, ultrasmall nanosquare-shaped SAPO-34 crystals with the same growth orientation along the (100) crystal plane compactly grow on the monocrystal SAPO-34 cores. Crucially, the external surface acid properties of the core SAPO-34 with the Si-rich outer layer are effectively modified by the low-silica SAPO-34 shell. Furthermore, the growth process and Si-substitution mechanism of the shell zeolite were comprehensively investigated. It was found that with the prolonged crystallization time, more and more coordinated Si(4Al) and Si(3Al) structures via two substitution mechanisms (SM2 and SM3) are generated in the nanocrystalline SAPO-34 shell, which endow moderate acidity of the core-shell SAPO-34. Compared to the uncoated SAPO-34, the core-shell SAPO-34 performs a longer lifespan and a higher average selectivity of light olefins (ethylene plus propylene) when applied to the MTO reaction, which is attributed to the positive effects of the luxuriant interstitial pores offering a fast diffusion channel and the moderate acid density depressing the hydrogen transfer reaction of light olefins. This work provides new insights into the fabrication of low-silica SAPO-34 nanocrystals, which are based on the rational design of the isomorphous core-shell zeolite.

A Genetically Engineered "Reinforced Concrete" Scaffold Regulates the N2 Neutrophil Innate Immune Cascade to Repair Bone Defects.

The innate immune response is crucial to inflammation, but how neutrophils and macrophages act in bone repair and tissue engineering treatment strategies await clarification. In this study, it is found that N2 neutrophils release stronger "eat me" signals to induce macrophage phagocytosis and polarize into the M2 anti-inflammatory phenotype. Guided by this biological mechanism, a mesoporous bioactive glass scaffold (MBG) is filled with hyaluronic acid methacryloyl (HAMA) hydrogel loaded with Transforming growth factor-ß1 (TGFß1) adenovirus (Ad@H), constructing a genetically engineered composite scaffold (Ad@H/M). The scaffold not only has good hydrophilicity and biocompatibility, but also provides mechanical stress support for bone repair. Adenovirus infection quickly induces N2 neutrophils, upregulating NF-κB and MAPK signaling pathways through Toll-like receptor 4 (TLR4) to promote the inflammatory response and macrophage phagocytosis. Macrophages perform phagocytosis and polarize towards the M2 phenotype, mediating the inflammatory response by inhibiting the PI3K-AKT-NF-κB pathway, maintaining homeostasis of the osteogenic microenvironment. The role of the Ad@H/M scaffold in regulating early inflammation and promoting long-term bone regeneration is further validated in vivo. In brief, this study focuses on the cascade of reactions between neutrophils and macrophage subtypes, and reports a composite scaffold that coordinates the innate immune response to promote bone repair.

A meta-analysis reveals increases in soil organic carbon following the restoration and recovery of croplands in Southwest China.

In China, the Grain for Green Program (GGP) is an ambitious project to convert croplands into natural vegetation, but exactly how changes in vegetation translate into changes in soil organic carbon remains less clear. Here we conducted a meta-analysis using 734 observations to explore the effects of land recovery on soil organic carbon and nutrients in four provinces in Southwest China. Following GGP, the soil organic carbon content (SOCc) and soil organic carbon stock (SOCs) increased by 33.73% and 22.39%, respectively, compared with the surrounding croplands. Similarly, soil nitrogen increased, while phosphorus decreased. Outcomes were heterogeneous, but depended on variations in soil and environmental characteristics. Both the regional land use and cover change indicated by the landscape type transfer matrix and net primary production from 2000 to 2020 further confirmed that the GGP promoted the forest area and regional mean net primary production. Our findings suggest that the GGP could enhance soil and vegetation carbon sequestration in Southwest China and help to develop a carbon-neutral strategy.

The Hippo-YAP signaling pathway drives CD24-mediated immune evasion in esophageal squamous cell carcinoma via macrophage phagocytosis.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in the world with poor prognosis. Despite the promising applications of immunotherapy, the objective response rate is still unsatisfactory. We have previously shown that Hippo/YAP signaling acts as a powerful tumor promoter in ESCC. However, whether Hippo/YAP signaling is involved in tumor immune escape in ESCC remains largely unknown. Here, we show that YAP directly activates transcription of the "don't eat me" signal CD24, and plays a crucial role in driving tumor cells to avoid phagocytosis by macrophages. Mechanistically, YAP regulates CD24 expression by interacting with TEAD and binding the CD24 promoter to initiate transcription, which facilitates tumor cell escape from macrophage-mediated immune attack. Our animal model data and clinical data show that YAP combined with CD24 in tumor microenvironment redefines the impact of TAMs on the prognosis of ESCC patients which will provide a valuable basis for precision medicine. Moreover, treatment with YAP inhibitor altered the distribution of macrophages and suppressed tumorigenesis and progression of ESCC in vivo. Together, our study provides a novel link between Hippo/YAP signaling and macrophage-mediated immune escape, which suggests that the Hippo-YAP-CD24 axis may act as a promising target to improve the prognosis of ESCC patients. A proposed model for the regulatory mechanism of Hippo-YAP-CD24-signaling axis in the tumor-associated macrophages mediated immune escape.

Effects of levosimendan on the outcome of veno-arterial extracorporeal membrane oxygenation: a systematic review and meta-analysis.

OBJECTIVES: For patients with severe cardiopulmonary failure, such as cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is primarily utilized to preserve their life by providing continuous extracorporeal respiration and circulation. However, because of the complexity of patients' underlying diseases and serious complications, successful weaning from ECMO is often difficult. At present, there have been limited studies on ECMO weaning strategies, so the principal purpose of this meta-analysis is to examine how levosimendan contributes to the weaning of extracorporeal membrane oxygenation. METHODS: The Cochrane Library, Embase, Web of Science, and PubMed were browsed for all potentially related research about clinical benefits of levosimendan in weaning patients receiving VA-ECMO and included 15 of them. The main outcome is success of weaning from extracorporeal membrane oxygenation, with the secondary outcomes of 1-month mortality (28 or 30 days), ECMO duration, hospital or intensive care unit (ICU) length of stay, and use of vasoactive drugs. RESULTS: 1772 patients altogether from 15 publications were incorporated in our meta-analysis. We used fixed and random-effect models to combine odds ratio (OR) and 95% confidence interval (CI) for dichotomous outcomes and standardized mean difference (SMD) for continuous outcomes. The weaning success rate in the levosimendan group was considerably higher in contrast to the comparison (OR = 2.78, 95% CI 1.80-4.30; P < 0.00001; I2 = 65%), and subgroup analysis showed that there was less heterogeneity in patients after cardiac surgery (OR = 2.06, 95% CI, 1.35-3.12; P = 0.0007; I2 = 17%). In addition, the effect of levosimendan on improving weaning success rate was statistically significant only at 0.2 mcg/kg/min (OR = 2.45, 95% CI, 1.11-5.40; P = 0.03; I2 = 38%). At the same time, the 28-day or 30-day proportion of deaths in the sample receiving levosimendan also decreased (OR = 0.47, 95% CI, 0.28-0.79; P = 0.004; I2 = 73%), and the difference was statistically significant. In terms of secondary outcomes, we found that individuals undergoing levosimendan treatment had a longer duration of VA-ECMO support. CONCLUSIONS: In patients receiving VA-ECMO, levosimendan treatment considerably raised the weaning success rate and helped lower mortality. Since most of the evidence comes from retrospective studies, more randomized multicenter trials are required to verify the conclusion.

Ligand-Screened Cerium-Based MOF Microcapsules Promote Nerve Regeneration via Mitochondrial Energy Supply.

Although mitochondria are crucial for recovery after spinal cord injury (SCI), therapeutic strategies to modulate mitochondrial metabolic energy to coordinate the immune response and nerve regeneration are lacking. Here, a ligand-screened cerium-based metal-organic framework (MOF) with better ROS scavenging and drug-loading abilities is encapsulated with polydopamine after loading creatine to obtain microcapsules (Cr/Ce@PDA nanoparticles), which reverse the energy deficits in both macrophages and neuronal cells by combining ROS scavenging and energy supplementation. It reprogrames inflammatory macrophages to the proregenerative phenotype via the succinate/HIF-1α/IL-1ß signaling axis. It also promotes the regeneration and differentiation of neural cells by activating the mTOR pathway and paracrine function of macrophages. In vivo experiments further confirm the effect of the microcapsules in regulating early ROS-inflammation positive-feedback chain reactions and continuously promoting nerve regeneration. This study provides a new strategy for correcting mitochondrial energy deficiency in the immune response and nerve regeneration following SCI.

A responsive hydrogel modulates innate immune cascade fibrosis to promote ocular surface reconstruction after chemical injury.

Following an ocular chemical injury, the release of neutrophil extracellular traps (NETs) triggers an innate immune cascade fibrotic effect involving macrophages (Mø), which limits corneal repair. However, the interplay and mechanisms between NETs and macrophages, as well as the coordination between the innate immunity and corneal repair, remain challenging issues. Using a co-culture system, we report that chemical stimulation exacerbates the accumulation of reactive oxygen species (ROS) within the polymorphonuclear neutrophils, leading to NET formation and the activation of M2 macrophages, ultimately inducing pathological fibrosis of the ocular surface through the IL-10/STAT3/TGF-ß1/Smad2 axis. Inspired by the locally formed acidic microenvironment mediated by innate acute inflammatory stimulation, we further integrate sericin with oxidized chitosan nanoparticles loaded with black phosphorus quantum dots (BPQDs) using Schiff base chemistry to construct a functional pH-responsive hydrogel. Following corneal injury, the hydrogel selectively releases BPQDs in response to the acidic environment, inhibiting the innate immune cascade fibrosis triggered by the PMN-ROS-NETs. Thus, corneal pathological fibrosis is alleviated and reshaping of the ocular surface takes place. These results represent a refinement of the mechanism of inherent immune effector cell interactions, and provide new research ideas for the construction of nano biomaterials that regulate pathological fibrosis.

Development of predictive models for assessing the progression and invasiveness of satellite lesions in patients with multiple pulmonary ground glass nodules.

Background: Currently, the appropriate treatment of satellite lesions is still controversial. With this study, we aimed to construct a set of nomograms to determine the characteristics of satellite lesions in patients with multiple pulmonary ground glass nodules (MPGGNs) and propose a reference for the management of satellite lesions. Methods: We retrospectively analyzed patients with MPGGNs who had undergone multiple rounds of surgical resection of primary and satellite lesions, including pathologic examinations after surgical resection. Results: A total of 125 lesions from 105 patients were included in the analysis; 85 lesions were advanced and 40 lesions were not advanced. Among them, 55 invasive pulmonary adenocarcinomas (IPA) and 70 noninvasive pulmonary adenocarcinomas were identified. After the final regression analysis, the patients' age, satellite lesion location, consolidation tumor ratio (CTR), lesion border clarity, and lesion diameter were used to predict satellite lesion progression. Patients' gender, satellite lesion location, lesion diameter, and computed tomography (CT) attenuation values were used to predict the invasiveness of the satellite lesion. The constructed nomograms showed strong discrimination with concordance indices (C indices) of 0.816 and 0.823, respectively. Conclusions: We developed a set of nomograms that can predict the risk of advanced or invasive satellite lesions in patients with MPGGNs. The area under the receiver operating characteristic (ROC) curve (AUC), the C-index, and the calibration curve suggest that the nomogram may be useful in the clinical setting. This model has the potential to help clinicians make treatment recommendations for the remaining lesions while treating the primary lesion in patients with MPGGNs.

YTHDC2 inhibits rat bone mesenchymal stem cells osteogenic differentiation by accelerating RUNX2 mRNA degradation via m6A methylation.

As the most abundant internal mRNA modification, N6-methyladenosine (m6A) RNA methylation has been found to influence many biological events including bone mesenchymal stem cells (BMSCs) osteogenic differentiation. YTH N6-methyladenosine RNA binding protein C2 （YTHDC2） is an m6A reading protein with the ability to mediate the decay of combined methylated mRNA, however its role in BMSCs osteogenic differentiation remains unknown. In this study, we first found an increase of RUNX family transcription factor 2 （RUNX2） expression and a decrease of YTHDC2 expression during the process of BMSCs osteogenic differentiation. Furthermore, we transfected BMSCs with YTHDC2 interference fragment, resulting in an increased content of RUNX2 mRNA and protein inside BMSCs. Finally, through RNA Immunoprecipitation experiments, we confirmed that YTHDC2 protein can bind to RUNX2 mRNA and accelerate its decomposition. Moreover, the immunofluorescence staining also showed a negative correlation between YTHDC2 and RUNX2. In conclusion, during BMSCs osteogenic differentiation, YTHDC2 protein showed decreased expression, resulting in a higher level of RUNX2 (mRNA and protein) expression inside cells, indicating YTHDC2 as a promising molecular target for the regulation of BMSCs osteogenic differentiation.

Long-term outcomes of moyamoya disease versus atherosclerosis-associated moyamoya vasculopathy using high-resolution MR vessel wall imaging.

OBJECTIVES: We aimed to compare the long-term outcomes and surgical benefits between moyamoya disease (MMD) and atherosclerosis-associated moyamoya vasculopathy (AS-MMV) using high-resolution MRI (HRMRI). METHODS: MMV patients were retrospectively included and divided into the MMD and AS-MMV groups according to vessel wall features on HRMRI. Kaplan-Meier survival and Cox regression were performed to compare the incidence of cerebrovascular events and prognosis of encephaloduroarteriosynangiosis (EDAS) treatment between MMD and AS-MMV. RESULTS: Of the 1173 patients (mean age: 42.4±11.0 years; male: 51.0%) included in the study, 881 were classified into the MMD group and 292 into the AS-MMV group. During the average follow-up of 46.0±24.7 months, the incidence of cerebrovascular events in the MMD group was higher compared with that in the AS-MMV group before (13.7% vs 7.2%; HR 1.86; 95% CI 1.17 to 2.96; p=0.008) and after propensity score matching (6.1% vs 7.3%; HR 2.24; 95% CI 1.34 to 3.76; p=0.002). Additionally, patients treated with EDAS had a lower incidence of events than those not treated with EDAS, regardless of whether they were in the MMD (HR 0.65; 95% CI 0.42 to 0.97; p=0.043) or AS-MMV group (HR 0.49; 95% CI 0.51 to 0.98; p=0.048). CONCLUSIONS: Patients with MMD had a higher risk of ischaemic stroke than those with AS-MMV, and patients with both MMD and AS-MMV could benefit from EDAS. Our findings suggest that HRMRI could be used to identify those who are at a higher risk of future cerebrovascular events.

Bronchiolar adenoma with squamous metaplasia: a distinct phenotype.

AIMS: Pulmonary bronchiolar adenoma is a benign lung tumour characterised by nodular proliferation of bilayered bronchiolar-type epithelium with a continuous layer of basal cells. The aim of this study was to describe a distinct and rare histological type of pulmonary bronchiolar adenoma: bronchiolar adenoma with squamous metaplasia. METHODS AND RESULTS: We examined the clinicopathological, immunohistochemical, and molecular characteristics of five cases (two cases from the same patient). The samples were histopathologically characterised by bilayered bronchiolar-type cells with sheets like spindle-oval and polygonal cells. Immunohistochemistry analysis revealed that columnar surface cells of the tumour were diffusely positive for TTF-1 and Napsin A, while basal cells were positive for P40 and P63. Moreover, the squamous metaplastic cells in the stroma were positive for P40, and P63, while being negative for TTF-1, Napsin A, S100, and SMA. Genomic analyses uncovered that all five samples had BRAF V600E mutations. Notably, both squamous metaplastic and basal cells were positive for BRAF V600E staining. CONCLUSION: We discovered a distinct subtype of pulmonary bronchiolar adenoma termed bronchiolar adenoma with squamous metaplasia. It is composed of columnar surface cells, basal cells, and sheet-like spindle-oval cells with squamous metaplasia in the stroma. All five samples harboured the BRAF V600E mutation. Importantly, BASM may be misdiagnosed as pulmonary sclerosing pneumocytoma upon frozen sections analysis. It may need further immunohistochemistry staining.

The Safety and Efficacy of Preoperative Immunotherapy Combined with Chemotherapy in Patients with Stage IIIA-IIIB Lung Squamous Cell Carcinoma.

OBJECTIVE: Data on preoperative immunotherapy combined with chemotherapy in potentially resectable lung squamous cell carcinoma (LUSC) remain scarce. This study was designed to investigate the safety and efficacy of preoperative immunotherapy and chemotherapy for stage IIIA-IIIB LUSC. METHODS: This study consecutively enrolled stage IIIA-IIIB LUSC who received preoperative immunotherapy combined with chemotherapy between January 2019 and July 2021. Patients received two to four cycles of immunotherapy combined with platinum-based doublet chemotherapy (platinum + paclitaxel) before surgery. Patients were assessed radiographically every one to two cycles until surgery. Postoperative pathological evaluation was also performed. Follow-up was performed until at least 3 months after surgery. RESULTS: Sixty-five patients with stage IIIA-IIIB LUSC were enrolled. The objective response rate was 78.46% (51/65), and no patients had progressive disease. Fifty-seven patients underwent surgery, and 55 patients achieved R0 resection. There were no perioperative deaths. The rate of pathological complete response (pCR) was 31.58% (18/57) and major pathological response was 68.42% (39/57). The incidence of grade 3 and 4 adverse reactions was 21.21 and 1.54%, respectively. CONCLUSION: Perioperative immunotherapy combined with chemotherapy followed by surgical resection for male patients with stage IIIA-IIIB LUSC was effective with a tolerable toxicity profile.

Vessel wall enhancement as a predictor of arterial stenosis progression and poor outcomes in moyamoya disease.

OBJECTIVES: This study aimed to determine the association between vessel wall enhancement and progression of arterial stenosis and clinical outcomes in patients with moyamoya (MMD) using high-resolution magnetic resonance (HRMR) vessel wall imaging. METHODS: Consecutive participants diagnosed with MMD were prospectively recruited and underwent HRMR at baseline and during follow-up, which had an interval period of ≥ 6 months and were clinically followed up for ≤ 24 months to record the occurrence of ischemic stroke. The relationship between vessel wall enhancement and arterial stenosis progression and stroke occurrence was evaluated. RESULTS: HRMR vessel wall imaging was used to identify 309 stenotic lesions at the internal carotid artery (ICA) in 170 participants (mean age: 37.7 ± 11.3 years old, male: 44.1%). The baseline presence (adjusted odds ratio [aOR] = 3.57, 95% CI = 1.97-6.44, p < 0.001) and progression (aOR = 2.96, 95% CI = 1.29-6.80, p = 0.010) of vessel wall enhancement and middle cerebral artery (MCA) involvement (aOR = 4.98, 95% CI = 1.50-16.52, p = 0.009) were significantly associated with rapid progression of arterial stenosis. Furthermore, vessel wall enhancement (adjusted HR = 3.59, 95% CI = 1.33-9.70, p = 0.011) and rapid progression of arterial stenosis (adjusted HR = 4.52, 95% CI = 1.48-13.81, p = 0.008) were correlated with future stroke occurrence. CONCLUSION: The baseline presence of vessel wall enhancement was associated with rapid progression of arterial stenosis and increased risk for stroke in MMD patients. Our findings suggest that vessel wall enhancement may serve as a predictor of disease progression and poor outcomes in MMD. KEY POINTS: • The baseline presence of vessel wall enhancement was significantly associated with the rapid progression of arterial stenosis. • The baseline presence of vessel wall enhancement and rapid progression of arterial stenosis were both correlated with increased risk for future occurrence of stroke. • Our findings suggest that vessel wall enhancement may serve as a predictor of rapid progression of arterial stenosis and poor outcomes in MMD patients.

Noval advance of histone modification in inflammatory skin diseases and related treatment methods.

Inflammatory skin diseases are a group of diseases caused by the disruption of skin tissue due to immune system disorders. Histone modification plays a pivotal role in the pathogenesis and treatment of chronic inflammatory skin diseases, encompassing a wide range of conditions, including psoriasis, atopic dermatitis, lupus, systemic sclerosis, contact dermatitis, lichen planus, and alopecia areata. Analyzing histone modification as a significant epigenetic regulatory approach holds great promise for advancing our understanding and managing these complex disorders. Additionally, therapeutic interventions targeting histone modifications have emerged as promising strategies for effectively managing inflammatory skin disorders. This comprehensive review provides an overview of the diverse types of histone modification. We discuss the intricate association between histone modification and prevalent chronic inflammatory skin diseases. We also review current and potential therapeutic approaches that revolve around modulating histone modifications. Finally, we investigated the prospects of research on histone modifications in the context of chronic inflammatory skin diseases, paving the way for innovative therapeutic interventions and improved patient outcomes.

Mutation of the glycine residue preceding the sixth tyrosine of the LAT adaptor severely alters T cell development and activation.

The LAT transmembrane adaptor is essential to transduce intracellular signals triggered by the TCR. Phosphorylation of its four C-terminal tyrosine residues (136, 175, 195, and 235 in mouse LAT) recruits several proteins resulting in the assembly of the LAT signalosome. Among those tyrosine residues, the one found at position 136 of mouse LAT plays a critical role for T cell development and activation. The kinetics of phosphorylation of this residue is delayed as compared to the three other C-terminal tyrosines due to a conserved glycine residue found at position 135. Mutation of this glycine into an aspartate residue (denoted LATG135D) increased TCR signaling and altered antigen recognition in human Jurkat T cells and ex vivo mouse T cells. Here, using a strain of LATG135D knockin mice, we showed that the LATG135D mutation modifies thymic development, causing an increase in the percentage of CD4+CD8+ double-positive cells, and a reduction in the percentage of CD4+ and CD8+ single-positive cells. Interestingly, the LATG135D mutation alters thymic development even in a heterozygous state. In the periphery, the LATG135D mutation reduces the percentage of CD8+ T cells and results in a small increment of γδ T cells. Remarkably, the LATG135D mutation dramatically increases the percentage of central memory CD8+ T cells. Finally, analysis of the proliferation and activation of T lymphocytes shows increased responses of T cells from mutant mice. Altogether, our results reinforce the view that the residue preceding Tyr136 of LAT constitutes a crucial checkpoint in T cell development and activation.