Characterization of distinct microbiota associated with androgenetic alopecia patients treated and untreated with platelet-rich plasma (PRP).

BACKGROUND: Androgenic alopecia (AGA) is the most common type of hair loss in men, and there are many studies on the treatment of hair loss by platelet-rich plasma (PRP). The human scalp contains a huge microbiome, but its role in the process of hair loss remains unclear, and the relationship between PRP and the microbiome needs further study. Therefore, the purpose of this study was to investigate the effect of PRP treatment on scalp microbiota composition. METHODS: We performed PRP treatment on 14 patients with AGA, observed their clinical efficacy, and collected scalp swab samples before and after treatment. The scalp microflora of AGA patients before and after treatment was characterized by amplifying the V3-V4 region of the 16 s RNA gene and sequencing for bacterial identification. RESULTS: The results showed that PRP was effective in the treatment of AGA patients, and the hair growth increased significantly. The results of relative abundance analysis of microbiota showed that after treatment, g_Cutibacterium increased and g_Staphylococcus decreased, which played a stable role in scalp microbiota. In addition, g_Lawsonella decreased, indicating that the scalp oil production decreased after treatment. CONCLUSIONS: The findings suggest that PRP may play a role in treating AGA through scalp microbiome rebalancing.

Development of an atmospheric pressure plasma-based OES device for in-situ mapping of Cd and related elements in plants.

We have developed an innovative optical emission spectrometry imaging device integrating a diode laser for sample introduction and an atmospheric pressure plasma based on dielectric barrier discharge for atomization and excitation. By optimizing the device parameters and ensuring appropriate leaf moisture, we achieved effective imaging with a lateral resolution as low as 50 µm. This device allows for tracking the accumulation of Cd and related species such as K, Zn, and O2+∙, in plant leaves exposed to different Cd levels and culture times. The results obtained are comparable to established in-lab imaging and quantitative methods. With its features of compact construction, minimal sample preparation, ease of operation, and low limit of detection (0.04 µg/g for Cd), this novel methodology shows promise as an in-situ elemental imaging tool for interdisciplinary applications.

Rapid detection of hypobromous acid by a tetraphenylethylene-based turn-on fluorescent AIE probe and its applications.

BACKGROUND: Similar to hypochlorous acid (HClO), hypobromous acid (HBrO) is one of the most notable reactive oxygen species (ROS). Overexpression of HBrO is linked to various diseases causing organ and tissue loss. Due to HBrO's role in the oxidation of micropollutants, real-time monitoring of HBrO in water-based systems is essential. Tetraphenylethylene (TPE)-based organic aggregation-induced emission luminophores (AIEgens) are an emerging category of fluorescent probe materials that have attracted considerable attentions. However, AIE probes are rarely applied to detect HBrO. Developing faster, more precise, and more sensitive AIE probes is thus crucial for detecting biological and environmental HBrO. RESULTS: A small molecule fluorescent probe 4-(1,2,2-triphenylvinyl)benzamidoxime (SWJT-21) was synthesized for the sensitive and selective detection of hypobromous acid (HBrO) based on aggregation-induced emission (AIE). The amidoxime unit of SWJT-21 would undergo an oxidation reaction with HBrO, leading to a structure differentiation between the probe and the product, and therefore the turn-on fluorescence by the AIE effect. The probe could recognize hypobromous acid rapidly (less than 3 s) in high aqueous phase (99 % water) with a turn-on fluorescence response. It was determined that the limit of detection for HBrO was 5.47 nM. Moreover, SWJT-21 demonstrates potential as a test strip for the detection of HBrO. SWJT-21 was also successfully used for the monitoring of HBrO in water samples and for the detection of endogenous/exogenous HBrO in living cells and zebrafish. SIGNIFICANCE: A special AIE fluorescence turn-on probe SWJT-21 based on tetraphenylethylene was designed for detecting HBrO in the environmental and biological systems. This probe has an extremely low detection limit of 5.47 nM and is able to detect HBrO in 99 % aqueous phase in less than 3 s.

Neural mechanisms of respiratory interoception.

Respiratory interoception is one of the internal bodily systems that is comprised of different types of somatic and visceral sensations elicited by different patterns of afferent input and respiratory motor drive mediating multiple respiratory modalities. Respiratory interoception is a complex system, having multiple afferents grouped into afferent clusters and projecting into both discriminative and affective centers that are directly related to the behavioral assessment of breathing. The multi-afferent system provides a spectrum of input that result in the ability to interpret the different types of respiratory interceptive sensations. This can result in a response, commonly reported as breathlessness or dyspnea. Dyspnea can be differentiated into specific modalities. These respiratory sensory modalities lead to a general sensation of an Urge-to-Breathe, driven by a need to compensate for the modulation of ventilation that has occurred due to factors that have affected breathing. The multiafferent system for respiratory interoception can also lead to interpretation of the sensory signals resulting in respiratory related sensory experiences, including the Urge-to-Cough and Urge-to-Swallow. These behaviors are modalities that can be driven through the differentiation and integration of multiple afferent input into the respiratory neural comparator. Respiratory sensations require neural somatic and visceral interoceptive elements that include gated attention and detection leading to respiratory modality discrimination with subsequent cognitive decision and behavioral compensation. Studies of brain areas mediating cortical and subcortical respiratory sensory pathways are summarized and used to develop a model of an integrated respiratory neural network mediating respiratory interoception.

Inhibition of PbeXTH1 and PbeSEOB1 is required for the Valsa canker resistance contributed by Wall-associated kinase gene MbWAK1.

Wall-associated kinases (WAKs) have been determined to recognize pathogenic signals and initiate plant immune responses. However, the roles of the family members in host resistance against Valsa canker, a serious fungal disease of apples and pears, are largely unknown. Here, we identified MbWAK1 in Malus baccata, a resistant germplasm differentially expressed during infection by Valsa mali (Vm). Over-expression of MbWAK1 enhanced the Valsa canker resistance of apple and pear fruits and 'Duli-G03' (Pyrus betulifolia) suspension cells. A large number of phloem, cell wall, and lipid metabolic process-related genes were differentially expressed in overexpressed suspension cell lines in response to Valsa pyri (Vp) signals. Among these, the expression of xyloglucan endotransglucosylase/hydrolase (XTH) gene PbeXTH1 and sieve element occlusion B-like (SEOB) gene PbeSEOB1 were significantly inhibited. Transient expression of PbeXTH1 or PbeSEOB1 compromised the expressional induction of MbWAK1 and the resistance contributed by MbWAK1. In addition, PbeXTH1 and PbeSEOB1 suppressed the immune response induced by MbWAK1. Our results enriched the molecular mechanisms for MbWAK1 against Valsa canker and resistant breeding.

High Blood Pressure in Children Aged 3 to 12 Years Old With Overweight or Obesity.

Objective: (1) To describe the prevalence of high blood pressure (BP) and the association with BMI in young children with overweight/obesity; (2) to evaluate the accuracy of a single high BP to diagnose sustained hypertension over three visits. Methods: We used pre-intervention data from the Improving Pediatric Obesity Practice Using Prompts (iPOP-UP) trial. We included children aged 3-12 years with BMI ≥85th percentile at well-visits in 2019-2021 at 84 primary care practices in 3 US health systems in the Northeast, Midwest, and South. BP percentiles were calculated from the first visit with BP recorded during the study period. Hypertensive-range BP was defined by the 2017 American Academy of Pediatrics guideline. We tested the association between BMI classification and hypertensive BP using multivariable logistic regression. Results: Of 78,280 children with BMI ≥85th percentile, 76,214 (97%) had BP recorded during the study period (mean 7.4 years, 48% female, 53% with overweight, and 13% with severe obesity). The prevalence of elevated or hypertensive BP was 31%, including 27% in children with overweight and 33%, 39%, and 49% with class I, II, and III obesity, respectively. Higher obesity severity was associated with higher odds of hypertensive BP in the multivariable model. Stage 2 hypertensive BP at the initial visit had specificity of 99.1% (95% confidence interval 98.9-99.3) for detecting sustained hypertension over ≥3 visits. Conclusions: High BP is common in 3- to 12-year-olds with overweight/obesity, with higher obesity severity associated with greater hypertension. Children with overweight/obesity and stage 2 BP are likely to have sustained hypertension and should be prioritized for evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT05627011.

Correlation of epicardial adipose tissue and inflammatory indices in patients with STEMI and implications for atrial arrhythmias.

BACKGROUND: Epicardial adipose tissue(EAT) is associated with inflammation in previous studies but is unknown in patients with ST-segment elevation myocardial infarction(STEMI).This study investigated the correlation between epicardial fat and inflammatory cells obtained by cardiac magnetic resonance (CMR) and the effect on atrial arrhythmias in patients with STEMI. METHODS: This was a single-center, retrospective study. We consecutively selected patients who all completed CMR after Percutaneous Coronary Intervention (PCI) from January 2019 to December 2022 and then had regular follow-ups at 1, 3, 6, 9, and 12 months. The enrolled patients were grouped according to the presence or absence of atrial arrhythmia and divided into atrial and non-atrial arrhythmia groups. RESULTS: White blood cell, neutrophil, lymphocyte, C-reactive protein, EATV, LVES, LVED were higher in the atrial arrhythmia group than in the non-atrial arrhythmia group, and LVEF was lower than that in the non-atrial arrhythmia group (p < 0.05); EATV was significantly positively correlated with each inflammatory indices (white blood cell: r = 0.415 p < 0.001, neutrophil:r = 0.386 p < 0.001, lymphocyte:r = 0.354 p < 0.001, C-reactive protein:r = 0.414 p < 0.001); one-way logistic regression analysis showed that risk factors for atrial arrhythmias were age, heart rate, white blood cell, neutrophil, lymphocyte, C-reactive protein, EATV, LVES, LVED; multifactorial logistic regression analysis showed that neutrophil, lymphocyte, C-reactive protein, EATV, and LVES were independent risk factors for atrial arrhythmias; ROC analysis showed that the area under the curve (AUC) for neutrophil was 0.862; the AUC for lymphocyte was 1.95; and the AUC for C-reactive protein was 0.862. reactive protein was 0.852; AUC for LVES was 0.683; and AUC for EATV was 0.869. CONCLUSION: In patients with STEMI, EAT was significantly and positively correlated with inflammatory indices; neutrophil, lymphocyte, C-reactive protein, EATV, and LVES were independent risk factors for atrial arrhythmias and had good predictive value.

Hypertension Trends and Disparities Over 12 Years in a Large Health System: Leveraging the Electronic Health Records.

BACKGROUND: The digital transformation of medical data enables health systems to leverage real-world data from electronic health records to gain actionable insights for improving hypertension care. METHODS AND RESULTS: We performed a serial cross-sectional analysis of outpatients of a large regional health system from 2010 to 2021. Hypertension was defined by systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or recorded treatment with antihypertension medications. We evaluated 4 methods of using blood pressure measurements in the electronic health record to define hypertension. The primary outcomes were age-adjusted prevalence rates and age-adjusted control rates. Hypertension prevalence varied depending on the definition used, ranging from 36.5% to 50.9% initially and increasing over time by ≈5%, regardless of the definition used. Control rates ranged from 61.2% to 71.3% initially, increased during 2018 to 2019, and decreased during 2020 to 2021. The proportion of patients with a hypertension diagnosis ranged from 45.5% to 60.2% initially and improved during the study period. Non-Hispanic Black patients represented 25% of our regional population and consistently had higher prevalence rates, higher mean systolic and diastolic blood pressure, and lower control rates compared with other racial and ethnic groups. CONCLUSIONS: In a large regional health system, we leveraged the electronic health record to provide real-world insights. The findings largely reflected national trends but showed distinctive regional demographics and findings, with prevalence increasing, one-quarter of the patients not controlled, and marked disparities. This approach could be emulated by regional health systems seeking to improve hypertension care.

Long COVID Characteristics and Experience: A Descriptive Study from the Yale LISTEN Research Cohort.

OBJECTIVE: To describe the experience of people with long COVID symptomatology and characterize the psychological, social, and financial challenges they experience. BACKGROUND: The experience of people with long COVID needs further amplification, especially with a comprehensive focus on symptomatology, treatments, and impact on daily life and finances. METHODS: We collected data from individuals aged 18 and older reporting long COVID as participants in the Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study. The sample population included 441 participants surveyed between May 2022 and July 2023. We evaluated their demographic characteristics, socioeconomic and psychological status, index infection period, health status, quality of life, symptoms, treatments, pre-pandemic comorbidities, and new-onset conditions. RESULTS: Overall, the median age of the participants with long COVID was 46 years (IQR: 38 to 57 years); 74% were women, 86% were Non-Hispanic White, and 93% were from the United States. Participants reported low health status measured by the Euro-QoL visual analogue scale, with a median score of 49 (IQR: 32 to 61). Participants documented a diverse range of symptoms, with all 96 possible symptom choices being reported. Additionally, participants had tried many treatments (median number of treatments: 19, IQR: 12 to 28). They were also experiencing psychological distress, social isolation, and financial stress. CONCLUSIONS: Despite having tried numerous treatments, participants with long COVID continued to experience an array of health and financial challenges-findings that underscore the failure of the healthcare system to address the medical needs of people with long COVID. These insights highlight the need for crucial medical, mental health, financial, and community support services, as well as further scientific investigation, to address the complex impact of long COVID.

Engineering Streptomyces sp. CPCC 204095 for the targeted high-level production of isatropolone A by elucidating its pathway-specific regulatory mechanism.

BACKGROUND: Isatropolone A and C, produced by Streptomyces sp. CPCC 204095, belong to an unusual class of non-benzenoid aromatic compounds and contain a rare seven-membered ring structure. Isatropolone A exhibits potent activity against Leishmania donovani, comparable to the only oral drug miltefosine. However, its variably low productivity represents a limitation for this lead compound in the future development of new anti-leishmaniasis drugs to meet unmet clinical needs. RESULTS: Here we first elucidated the regulatory cascade of biosynthesis of isatropolones, which consists of two SARP family regulators, IsaF and IsaJ. Through a series of in vivo and in vitro experiments, IsaF was identified as a pathway-specific activator that orchestrates the transcription of the gene cluster essential for isatropolone biosynthesis. Interestingly, IsaJ was found to only upregulate the expression of the cytochrome P450 monooxygenase IsaS, which is crucial for the yield and proportion of isatropolone A and C. Through targeted gene deletions of isaJ or isaS, we effectively impeded the conversion of isatropolone A to C. Concurrently, the facilitation of isaF overexpression governed by selected promoters, prompted the comprehensive activation of the production of isatropolone A. Furthermore, meticulous optimization of the fermentation parameters was conducted. These strategies culminated in the attainment of an unprecedented maximum yield-980.8 mg/L of isatropolone A-achieved in small-scale solid-state fermentation utilizing the genetically modified strains, thereby establishing the highest reported titer to date. CONCLUSION: In Streptomyces sp. CPCC 204095, the production of isatropolone A and C is modulated by the SARP regulators IsaF and IsaJ. IsaF serves as a master pathway-specific regulator for the production of isatropolones. IsaJ, on the other hand, only dictates the transcription of IsaS, the enzyme responsible for the conversion of isatropolone A and C. By engineering the expression of these pivotal genes, we have devised a strategy for genetic modification aimed at the selective and high-yield biosynthesis of isatropolone A. This study not only unveils the unique regulatory mechanisms governing isatropolone biosynthesis for the first time, but also establishes an essential engineering framework for the targeted high-level production of isatropolone A.

Nanoconfinement Enables Photoelectrochemical Selective Oxidation of Glycerol via the Microscale Fluid Effect.

The glycerol oxidation reaction (GOR) run with photoelectrochemical cells (PECs) is one of the most promising ways to upgrade biomass because it is thermodynamically favorable, while irreversible overoxidation leads to unsatisfactory product selectivities. Herein, a tunable one-dimensional nanoconfined environment was introduced into the GOR process, which accelerated mass transfer of glycerol via the microscale fluid effect and changed the main oxidation product from formic acid (FA) to glyceraldehyde (GLD), which led to retention of the heavier multicarbon products. The rate of glycerol diffusion in the nanochannels increased by a factor of 4.92 with decreasing inner diameters. The main product from the PEC-selective oxidation of glycerol changed from the C1 product FA to the C3 product GLD with a great selectivity of 60.7%. This work provides a favorable approach for inhibiting further oxidation of multicarbon products and illustrates the importance of microenvironmental regulation in biomass oxidation.

Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of <12% due to the lack of effective treatments. Novel treatment strategies are urgently needed. Here, PKMYT1 is identified through genome-wide CRISPR screens as a non-mutant, genetic vulnerability of PDAC. Higher PKMYT1 expression levels indicate poor prognosis in PDAC patients. PKMYT1 ablation inhibits tumor growth and proliferation in vitro and in vivo by regulating cell cycle progression and inducing apoptosis. Moreover, pharmacological inhibition of PKMYT1 shows efficacy in multiple PDAC cell models and effectively induces tumor regression without overt toxicity in PDAC cell line-derived xenograft and in more clinically relevant patient-derived xenograft models. Mechanistically, in addition to its canonical function of phosphorylating CDK1, PKMYT1 functions as an oncogene to promote PDAC tumorigenesis by regulating PLK1 expression and phosphorylation. Finally, TP53 function and PRKDC activation are shown to modulate the sensitivity to PKMYT1 inhibition. These results define PKMYT1 dependency in PDAC and identify potential therapeutic strategies for clinical translation.

Near-Infrared Triggered Biodegradable Microneedle Patch for Controlled Macromolecule Drug Release.

Transdermal drug delivery of macromolecule drugs attracts significant attention due to the advantage of convenience and biocompatibility. However, the practical usage of it is limited by the low delivery efficiency and poor drug absorption. To develop an efficient, safe, and controllable transdermal delivery method, the near-infrared (NIR) triggered calcium sulfate and gelatin biodegradable composite microneedle (MN) patches are developed. The MN patches are fabricated by polydimethylsiloxane (PDMS) molds, and the structure data can be adjusted by changing the molds. Such an MN patch can release both macro and micro molecule drugs. After loading with photothermal converter IR780, which can transfer energy of light to heat, the release of macromolecule drugs in MNs can be controlled by applying NIR irradiation. The control effect can be enhanced by spraying 1-tetradecanol (TD) coating and optimizing the ratio (weight) of gelatin and calcium sulfate to 2:6. Besides, the MN patch can deliver drugs through the skin barrier, and the process can be controlled by NIR. Moreover, the insulin-loaded MN patch exhibits some therapeutic effects on healthy mice. This work suggests that biodegradable MNs can achieve controllable drug delivery and potentially be applied in individual treatment via transdermal ingestion.

Anti-EGFR ScFv functionalized exosomes delivering LPCAT1 specific siRNAs for inhibition of lung cancer brain metastases.

Brain metastasis (BM) is one of the leading causes of cancer-related deaths in patients with advanced non-small cell lung cancer (NSCLC). However, limited treatments are available due to the presence of the blood-brain barrier (BBB). Upregulation of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in NSCLC has been found to promote BM. Conversely, downregulating LPCAT1 significantly suppresses the proliferation and metastasis of lung cancer cells. In this study, we firstly confirmed significant upregulation of LPCAT1 in BM sites compared to primary lung cancer by analyzing scRNA dataset. We then designed a delivery system based on a single-chain variable fragment (scFv) targeting the epidermal growth factor receptor (EGFR) and exosomes derived from HEK293T cells to enhance cell-targeting capabilities and increase permeability. Next, we loaded LPCAT1 siRNA (siLPCAT1) into these engineered exosomes (exoscFv). This novel scFv-mounted exosome successfully crossed the BBB in an animal model and delivered siLPCAT1 to the BM site. Silencing LPCAT1 efficiently arrested tumor growth and inhibited malignant progression of BM in vivo without detectable toxicity. Overall, we provided a potential platform based on exosomes for RNA interference (RNAi) therapy in lung cancer BM.

Is ALPPS still appropriate for large or locally advanced hepatocellular carcinoma in an era of targeted agents and immunotherapy?

Therapeutic options for large or locally advanced hepatocellular carcinoma (HCC) have limited efficacy. This study investigated the efficacy and safety of drug-eluting beads trans-arterial chemo-embolization (dTACE), portal vein embolization (PVE), tyrosine kinase inhibitor (TKI), and immune checkpoint inhibitors (ICI) compared to Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) for large or locally advanced HCC.Data regarding clinicopathological details, safety, and oncological outcomes were reviewed for the quadruple therapy (dTACE-PVE-TKI-ICI) and compared with ALPPS.From 2019 to 2020, 10 patients with large or locally advanced HCC underwent future remnant liver (FRL) modulation (dTACE-PVE-TKI-ICI: 5; ALPPS: 5). All five dTACE-PVE-TKI-ICI cases responded well, with patients #4 and #5 achieving complete tumor necrosis. The overall response rate (ORR) was 5/5. Patients #1-4 underwent hepatectomy, while #5 declined surgery due to complete tumor necrosis. Mean FRL volume increased by 75.3% (range 60.0%-89.4%) in 2-4 months, compared to 104.6% (range 51.3%-160.8%) in 21-37 days for ALPPS (P = 0.032). Major postoperative complications occurred in 1/5 ALPPS patients. Resection rates were 4/4 for quadruple therapy and 5/5 for ALPPS. 2-year progression free survival for dTACE-PVE-TKI-ICI and ALPPS were 5/5 and 3/5, respectively.Quadruple therapy is a feasible, effective strategy for enhancing resectability by downsizing tumors and inducing FRL hypertrophy, with manageable complications and improved long-term prognosis. In addition, it provokes the re-examination of the application of ALPPS in an era of molecular and immune treatments.

Cycloplatinated (II) Complex Based on Isoquinoline Alkaloid Elicits Ferritinophagy-Dependent Ferroptosis in Triple-Negative Breast Cancer Cells.

The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.

Collective Molecular Machines: Multidimensionality and Reconfigurability.

Molecular machines are key to cellular activity where they are involved in converting chemical and light energy into efficient mechanical work. During the last 60 years, designing molecular structures capable of generating unidirectional mechanical motion at the nanoscale has been the topic of intense research. Effective progress has been made, attributed to advances in various fields such as supramolecular chemistry, biology and nanotechnology, and informatics. However, individual molecular machines are only capable of producing nanometer work and generally have only a single functionality. In order to address these problems, collective behaviors realized by integrating several or more of these individual mechanical units in space and time have become a new paradigm. In this review, we comprehensively discuss recent developments in the collective behaviors of molecular machines. In particular, collective behavior is divided into two paradigms. One is the appropriate integration of molecular machines to efficiently amplify molecular motions and deformations to construct novel functional materials. The other is the construction of swarming modes at the supramolecular level to perform nanoscale or microscale operations. We discuss design strategies for both modes and focus on the modulation of features and properties. Subsequently, in order to address existing challenges, the idea of transferring experience gained in the field of micro/nano robotics is presented, offering prospects for future developments in the collective behavior of molecular machines.

METTL3 and METTL14-mediated N6-methyladenosine modification of SREBF2-AS1 facilitates hepatocellular carcinoma progression and sorafenib resistance through DNA demethylation of SREBF2.

As the most prevalent epitranscriptomic modification, N6-methyladenosine (m6A) shows important roles in a variety of diseases through regulating the processing, stability and translation of target RNAs. However, the potential contributions of m6A to RNA functions are unclear. Here, we identified a functional and prognosis-related m6A-modified RNA SREBF2-AS1 in hepatocellular carcinoma (HCC). The expression of SREBF2-AS1 and SREBF2 in HCC tissues and cells was measured by RT-qPCR. m6A modification level of SREBF2-AS1 was measured by methylated RNA immunoprecipitation assay. The roles of SREBF2-AS1 in HCC progression and sorafenib resistance were investigated by proliferation, apoptosis, migration, and cell viability assays. The regulatory mechanisms of SREBF2-AS1 on SREBF2 were investigated by Chromatin isolation by RNA purification, RNA immunoprecipitation, CUT&RUN, and bisulfite DNA sequencing assays. Our findings showed that the expression of SREBF2-AS1 was increased in HCC tissues and cells, and positively correlated with poor survival of HCC patients. m6A modification level of SREBF2-AS1 was also increased in HCC and positively correlated with poor prognosis of HCC patients. METTL3 and METTL14-induced m6A modification upregulated SREBF2-AS1 expression through increasing SREBF2-AS1 transcript stability. Functional assays showed that only m6A-modified, but not non-modified SREBF2-AS1 promoted HCC progression and sorafenib resistance. Mechanistic investigations revealed that m6A-modified SREBF2-AS1 bound and recruited m6A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1 to SREBF2 promoter, leading to DNA demethylation at SREBF2 promoter and the upregulation of SREBF2 transcription. Functional rescue assays showed that SREBF2 was the critical mediator of the oncogenic roles of SREBF2-AS1 in HCC. Together, this study showed that m6A-modified SREBF2-AS1 exerted oncogenic roles in HCC through inducing DNA demethylation and transcriptional activation of SREBF2, and suggested m6A-modified SREBF2-AS1 as a prognostic biomarker and therapeutic target for HCC.

Hinged External Fixation Combined with Open Debridement for Post-traumatic Elbow Stiffness: A Systematic Review and Meta-analysis.

Background: Open debridement remains the gold standard for the clinical treatment of post-traumatic elbow stiffness. However, postoperative complications, such as re-contraction and heterotopic ossification of the elbow joint, are highly prevalent. Hinged external fixation appears to offer the potential for greater improvement of joint function and reduction of complications. The purpose of this article is to provide the latest evidence on the effectiveness and safety of hinged external fixation combined with open debridement for the treatment of post-traumatic elbow stiffness. Methods: We searched for randomized controlled trials (RCTs) from the China National Knowledge Infrastructure, MEDLINE, PubMed, Web of Science, EMBASE, and Cochrane Library databases until December 31, 2022. STATA 15.1 software was used to analyze all the data for this article. The quality of the included articles was evaluated using the Cochrane Reviewer's Handbook 5.3. Results: Finally, we selected 8 high-quality RCTs for our meta-analysis, which included 555 patients. The meta-analysis demonstrated that hinged external fixation combined with open debridement for post-traumatic elbow stiffness (treatment group) showed a significant increase in elbow flexion and extension mobility (WMD = 5.16, 95% CI 4.39-5.49, Z = 13.02, P = 0.000), Mayo elbow function scores (WMD = 5.25, 95% CI 4.33-6.17, Z = 11.15, P = 0.000), and Mayo excellent rate (RR = 1.25, 95% CI 1.14-1.37, Z = 4.87, P = 0.000). Additionally, there was a significant decrease in the complication rate (RR = 1.11, 95% CI 1.02-1.20, Z = 2.54, P = 0.011) compared to open debridement alone (control group). Furthermore, the results of the publication bias test showed no significant bias. Conclusions: With the assistance of hinged external fixation, open debridement for post-traumatic elbow stiffness can lead to increased elbow mobility and a reduced complication rate. However, due to the small sample size, a multicenter randomized controlled trial with a larger sample size is still necessary to further confirm the effectiveness and safety of hinged external fixation combined with open debridement for post-traumatic elbow stiffness. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-023-01087-y.