Extracellular Vesicles From Primed Adipose-Derived Stem Cells Enhance Achilles Tendon Repair by Reducing Inflammation and Promoting Intrinsic Healing.

Achilles tendon rupture is a common sports-related injury. Even with advanced clinical treatments, many patients suffer from long-term pain and functional deficits. These unsatisfactory outcomes result primarily from an imbalanced injury response with excessive inflammation and inadequate tendon regeneration. Prior studies showed that extracellular vesicles from inflammation-primed adipose-derived stem cells (iEVs) can attenuate early tendon inflammatory response to injury. It remains to be determined if iEVs can both reduce inflammation and promote regeneration in the later phases of tendon healing and the underlying mechanism. Therefore, this study investigated the mechanistic roles of iEVs in regulating tendon injury response using a mouse Achilles tendon injury and repair model in vivo and iEV-macrophage and iEV-tendon cell coculture models in vitro. Results showed that iEVs promoted tendon anti-inflammatory gene expression and reduced mononuclear cell accumulation to the injury site in the remodeling phase of healing. iEVs also increased collagen deposition in the injury center and promoted tendon structural recovery. Accordingly, mice treated with iEVs showed less peritendinous scar formation, much lower incidence of postoperative tendon gap or rupture, and faster functional recovery compared to untreated mice. Further in vitro studies revealed that iEVs both inhibited macrophage M1 polarization and increased tendon cell proliferation and collagen production. The iEV effects were partially mediated by miR-147-3p, which blocked the toll-like receptor 4/NF-κB signaling pathway that activated the M1 phenotype of macrophages. The combined results demonstrate that iEVs are a promising therapeutic agent that can enhance tendon repair by attenuating inflammation and promoting intrinsic healing.

Synthesis, Screening, and Evaluation of Theranostic Molecular CPCR4-Based Probe Targeting CXCR4.

Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [68Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [177Lu]Lu-pentixather, the therapeutic companion of [68Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4) and [124I]I-6 ([124I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [124I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [68Ga]Ga-pentixafor group with the [124I]I-6 group, we found that the [124I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (131I) labeling, and the tumor-bearing animal models were treated with [131I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [124I]I-6 and [131I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.

Construction of Si-Stereogenic Silanols by Palladium-Catalyzed Enantioselective C-H Alkenylation.

The construction of silicon-stereogenic silanols via Pd-catalyzed intermolecular C-H alkenylation with the assistance of a commercially available L-pyroglutamic acid has been realized for the first time. Employing oxime ether as the directing group, silicon-stereogenic silanol derivatives could be readily prepared with excellent enantioselectivities, featuring a broad substrate scope and good functional group tolerance. Moreover, parallel kinetic resolution with unsymmetric substrates further highlighted the generality of this protocol. Mechanistic studies indicate that L-pyroglutamic acid could stabilize the Pd catalyst and provide excellent chiral induction. Preliminary computational studies unveil the origin of the enantioselectivity in the C-H bond activation step.

Reconsidering N component of cancer staging for T1-2N0-2M0 small-cell lung cancer: a retrospective study based on multicenter cohort.

BACKGROUND: The current nodal (pN) classification still has limitations in stratifying the prognosis of small cell lung cancer (SCLC) patients with pathological classifications T1-2N0-2M0. Thus. This study aimed to develop and validate a modified nodal classification based on a multicenter cohort. MATERIALS AND METHODS: We collected 1156 SCLC patients with pathological classifications T1-2N0-2M0 from the Surveillance, Epidemiology, and End Results database and a multicenter database in China. The X-tile software was conducted to determine the optimal cutoff points of the number of examined lymph nodes (ELNs) and lymph node ratio (LNR). The Kaplan-Meier method, the Log-rank test, and the Cox regression method were used in this study. We classified patients into three pathological N modification categories, new pN#1 (pN0-#ELNs > 3), new pN#2 (pN0-#ELNs ≤ 3 or pN1-2-#LNR ≤ 0.14), and new pN#3 (N1-2-#LNR > 0.14). The Akaike information criterion (AIC), Bayesian Information Criterion, and Concordance index (C-index) were used to compare the prognostic, predictive ability between the current pN classification and the new pN component. RESULTS: The new pN classification had a satisfactory effect on survival curves (Log-rank P < 0.001). After adjusting for other confounders, the new pN classification could be an independent prognostic indicator. Besides, the new pN component had a much more accurate predictive ability in the prognostic assessment for SCLC patients of pathological classifications T1-2N0-2M0 compared with the current pN classification in the SEER database (AIC: 4705.544 vs. 4731.775; C-index: 0.654 vs. 0.617, P < 0.001). Those results were validated in the MCDB from China. CONCLUSIONS: The multicenter cohort developed and validated a modified nodal classification for SCLC patients with pathological category T1-2N0-2M0 after surgery. Besides, we propose that an adequate lymph node dissection is essential; surgeons should perform and consider the situation of ELNs and LNR when they evaluate postoperative prognoses of SCLC patients.

Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is currently the standard first-line therapy for EGFR-mutated advanced non-small cell lung cancer (NSCLC). The life quality and survival of this subgroup of patients were constantly improving owing to the continuous iteration and optimization of EGFR-TKI. Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was initially approved for the treatment of NSCLC patients carrying EGFR T790M mutations, and has currently become the dominant first-line targeted therapy for most EGFR mutant lung cancer. Unfortunately, resistance to osimertinib inevitably develops during the treatment and therefore limits its long-term effectiveness. For both fundamental and clinical researchers, it stands for a major challenge to reveal the mechanism, and a dire need to develop novel therapeutics to overcome the resistance. In this article, we focus on the acquired resistance to osimertinib caused by EGFR mutations which account for approximately 1/3 of all reported resistance mechanisms. We also review the proposed therapeutic strategies for each type of mutation conferring resistance to osimertinib and give an outlook to the development of the next generation EGFR inhibitors. Video Abstract.

A two-level copula joint model for joint analysis of longitudinal and competing risks data.

In this article, we propose a two-level copula joint model to analyze clinical data with multiple disparate continuous longitudinal outcomes and multiple event-times in the presence of competing risks. At the first level, we use a copula to model the dependence between competing latent event-times, in the process constructing the submodel for the observed event-time, and employ the Gaussian copula to construct the submodel for the longitudinal outcomes that accounts for their conditional dependence; these submodels are glued together at the second level via the Gaussian copula to construct a joint model that incorporates conditional dependence between the observed event-time and the longitudinal outcomes. To have the flexibility to accommodate skewed data and examine possibly different covariate effects on quantiles of a non-Gaussian outcome, we propose linear quantile mixed models for the continuous longitudinal data. We adopt a Bayesian framework for model estimation and inference via Markov Chain Monte Carlo sampling. We examine the performance of the copula joint model through a simulation study and show that our proposed method outperforms the conventional approach assuming conditional independence with smaller biases and better coverage probabilities of the Bayesian credible intervals. Finally, we carry out an analysis of clinical data on renal transplantation for illustration.

Efficacy and safety of low-dose oral isotretinoin monotherapy versus combined therapy with picosecond laser for the treatment of acne scars in Asian population.

PURPOSE: Acne scars are common in patients with moderate to severe acne. Isotretinoin is the first-line treatment for those patients, but whether oral isotretinoin can improve acne scar is not clear. Picosecond lasers (FxPico) has been reported to improve acne scars. In the present study, we evaluated the clinical efficacy of low-dose isotretinoin with or without FxPico treatment for acne scars. MATERIALS AND METHODS: A total of 48 patients with acne scars were enrolled and were randomly assigned to receive low dose oral isotretinoin or not. For all the patients in both treatment groups, one side of face were randomly assigned to be treated with picosecond laser. Assessments, including photos, échelle d'évaluation clinique des cicatrices d'acné (ECCA) and Global Acne Grading System (GAGS) score, the number of lesions, melanin and erythema indexes, transepidermal water loss were assessed at 0, 1, 2, and 3 month. Side effects, Dermatology Life Quality Index (DLQI) and satisfaction were recorded before and after the study. RESULTS: A total of 44 patients completed the study (24 received oral low dose isotretinoin and 20 did not). Low dose oral isotretinoin treated group showed significant improvement on ECCA (from 112.5 [50-180] to 105 [50-160]), GAGS score (from 12.6 ± 3.3 to 10.1 ± 3.0), the count of papules (from 4.3 ± 3.7 to 1.0 ± 1.5) than the blank group, and higher improvement were noticed after isotretinoin combined with FxPico. All the side effects were temporary and tolerable, no adverse effects were observed. Higher DLQI and patients' satisfaction were achieved by oral isotretinoin alone and isotretinoin combined with FxPico. CONCLUSIONS: This is the first paper showing the improvement of scars by early low dose-isotretinoin intervention with or without the combination of picosecond laser. Early intervention with oral low-dose isotretinoin is effective for the treatment and prevention of acne scars, the combined therapy with FxPico can achieve better outcome.

Abnormal adenosine metabolism of neutrophils inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus.

BACKGROUND: Neutrophils consume a large amount of energy when performing their functions. Compared with other white blood cells, neutrophils contain few mitochondria and mainly rely on glycolysis and gluconeogenesis to produce ATP. The inflammatory site is hypoxic and nutrient poor. Our aim is to study the role of abnormal adenosine metabolism of neutrophils in the asthmatic airway inflammation microenvironment. METHOD: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene-knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5'-(α, ß-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. RESULT: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic knockdownof CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. CONCLUSION: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.

Toxicological Assessment of Higher Olefins in OECD TG 422 Repeated Dose and Reproductive /Developmental Toxicity Screening Tests in Han Wistar Rats.

Higher olefins (HO) are used primarily as intermediates in the production of other chemicals, such as polymers, fatty acids, plasticizer alcohols, surfactants, lubricants, amine oxides, and detergent alcohols. The potential toxicity of five HO (i.e., 1-Octene, Nonene, Decene, Hexadecene, and 1-Octadecene) with carbon ranging from C8 to C18 was examined in a combined repeated dose and reproduction/developmental toxicity screening study (OECD TG 422). These five HO were administered to Han Wistar rats by gavage at 0 (controls), 100, 300, and 1000 mg/kg bw/day. As a group of substances, adaptive changes in the liver (liver weight increase without pathological evidence), as well as increased kidney weight in male rats, were observed in HO with carbon numbers from C8 to C10. The overall systemic no observed adverse effect level (NOAEL) for all HO was determined at 1000 mg/kg bw/day. In the reproductive/developmental toxicity assessment, offspring viability, size, and weights were reduced in litters from females treated with Nonene at 1000 mg/kg bw/day. The overall no observed effects level (NOEL) for reproductive toxicity was considered to be 300 mg/kg bw/day for Nonene and 1000 mg/kg bw/day for the other four HO, respectively. These data significantly enrich the database on the toxicity of linear and branched HO, allowing comparison with similar data published on a range of linear and branched HO. Comparisons between structural class and study outcome provide further supportive data in order to validate the read-across hypothesis as part of an overall holistic testing strategy.

A Privacy-Preserving Trajectory Publishing Method Based on Multi-Dimensional Sub-Trajectory Similarities.

With the popularity of location services and the widespread use of trajectory data, trajectory privacy protection has become a popular research area. k-anonymity technology is a common method for achieving privacy-preserved trajectory publishing. When constructing virtual trajectories, most existing trajectory k-anonymity methods just consider point similarity, which results in a large dummy trajectory space. Suppose there are n similar point sets, each consisting of m points. The size of the space is then mn. Furthermore, to choose suitable k- 1 dummy trajectories for a given real trajectory, these methods need to evaluate the similarity between each trajectory in the space and the real trajectory, leading to a large performance overhead. To address these challenges, this paper proposes a k-anonymity trajectory privacy protection method based on the similarity of sub-trajectories. This method not only considers the multidimensional similarity of points, but also synthetically considers the area between the historic sub-trajectories and the real sub-trajectories to more fully describe the similarity between sub-trajectories. By quantifying the area enclosed by sub-trajectories, we can more accurately capture the spatial relationship between trajectories. Finally, our approach generates k-1 dummy trajectories that are indistinguishable from real trajectories, effectively achieving k-anonymity for a given trajectory. Furthermore, our proposed method utilizes real historic sub-trajectories to generate dummy trajectories, making them more authentic and providing better privacy protection for real trajectories. In comparison to other frequently employed trajectory privacy protection methods, our method has a better privacy protection effect, higher data quality, and better performance.

Long read sequencing and expression studies of AHDC1 deletions in Xia-Gibbs syndrome reveal a novel genetic regulatory mechanism.

Xia-Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein-truncating mutations in the AT-Hook DNA binding motif containing 1 (AHDC1) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity. We analyzed 19 individuals with large contiguous deletions involving AHDC1, along with other genes. One individual bore the smallest known contiguous AHDC1 deletion (∼350 Kb), encompassing eight other genes within chr1p36.11 (Feline Gardner-Rasheed, IFI6, FAM76A, STX12, PPP1R8, THEMIS2, RPA2, SMPDL3B) and terminating within the first intron of AHDC1. The breakpoint junctions and phase of the deletion were identified using both short and long read sequencing (Oxford Nanopore). Quantification of RNA expression patterns in whole blood revealed that AHDC1 exhibited a mono-allelic expression pattern with no deficiency in overall AHDC1 expression levels, in contrast to the other deleted genes, which exhibited a 50% reduction in mRNA expression. These results suggest that AHDC1 expression in this individual is compensated by a novel regulatory mechanism and advances understanding of mutational and regulatory mechanisms in neurodevelopmental disorders.

Parthenolide alleviates peritoneal fibrosis by inhibiting inflammation via the NF-κB/ TGF-ß/Smad signaling axis.

Peritoneal fibrosis is a common complication of peritoneal dialysis (PD) with a complicated pathogenesis and limited treatments. Parthenolide (PTL), a recognized nuclear factor-κB (NF-κB) inhibitor extracted from Tanacetum balsamita, has been widely used to treat various inflammatory diseases and has been proven to improve peritoneal fibrosis in PD mice by selectively inhibiting the phosphorylation of Smad2/3. Transforming growth factor-ß1 (TGF-ß1), via Smad-dependent signaling, has a pivotal role in promoting pathogenic of fibrosis. To investigate whether PTL can inhibit peritoneal fibrosis, we affected the interaction between NF-κB and the TGF-ß/Smad2/3 pathway. Long dwell peritoneal dialysis fluid (PDF) and peritoneum tissues were collected from continuous ambulatory peritoneal dialysis (CAPD) patients. PTL was administered intragastrically into a PD mouse model by daily infusion of 4.25% dextrose-containing PDF. Treated HMrSV5 cells or rat peritoneal mesothelial cells (RPMCs) were treated with high glucose(138 mM) at the same concentration as 2.5% dextrose-containing PDF and PTL. PD-related peritoneal fibrosis samples indicated an increase in inflammation, and PTL decreased the levels of inflammatory cytokines (L-6, TNF-α, and MCP-1). PTL inhibited high glucose-induced mesothelial-to-mesenchymal transition (MMT), as indicated by a reduced expression of fibrosis markers (fibronectin, collagen I, and α-SMA) and increased expression of the epithelial marker E-cadherin. PTL also significantly decreased TGF-ß1 expression and the phosphorylation of IκBα and NF-κBp65. The changes in the levels of TGF-ß1 expression and p-p65 or p65 showed similar trends according to western blot, immunohistochemistry, and immunofluorescence assays in vitro and in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to confirm that PTL regulates the transcription of TGF-ß1 induced by high glucose through NF-κBp65. In summary, PTL induces a therapeutic effect in peritoneal fibrosis by inhibiting inflammation via the NF-κB/ TGF-ß/Smad signaling axis.

Comparison of Short-Term DAPT and Long-Term DAPT on the Prognosis of PCI Patients: A Meta-Analysis of Randomized Controlled Trials.

Background: Dual antiplatelet therapy (DAPT) is the primary medication for patients after percutaneous coronary intervention (PCI). However, the best DAPT duration is still controversial. This systematic review and meta-analysis aims to assess the safety and effectiveness of short-term (3-6 months) DAPT compared to long-term (12 months) DAPT. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science systematically for all the randomized controlled trials (RCTs) which compared the different strategies for DAPT in patients undergoing PCI within ten years prior to January 2021. Major bleeding and any bleeding were identified as the safe endpoints. All causes of death, cardiac death, myocardial infarction, definite/probable stent thrombosis, target vessel revascularization, and stroke were identified as the efficacy endpoints. The hazard ratio (HR) and 95% confidence interval (CI) in each study were abstracted. Results: Overall, 11 trials and 24,242 patients were included in this meta-analysis with 15-month median follow-up time. Short-term DAPT was related to reduced risks of major bleeding (HR 0.65, 95% CI 0.48-0.89) and any bleeding (HR 0.64, 95% CI 0.53-0.79). No obvious differences in any of the other endpoints were observed. In acute coronary syndrome (ACS) patients with drug-eluting stents (DES), short-term compared with long-term DAPT was related to a decreased risk of major bleeding (HR 0.57, 95% CI 0.37-0.87) without significant increasing in the risks of any bleeding and ischemic endpoints. Furthermore, short-term DAPT followed by P2Y12 receptor inhibitor monotherapy appreciably lowered the risk of major bleeding (HR 0.64, 95% CI 0.42-0.96) and any bleeding (HR 0.58, 95% CI 0.36-0.93). There were no obvious differences concerning death between the different strategies for DAPT. Conclusions: After PCI with DES, short-term DAPT is safer than long-term DAPT, and is not inferior in effectiveness, even in ACS patients. P2Y12 receptor inhibitor monotherapy following short-term DAPT is also related to a decreased risk of bleeding and may be an alternative anti-platelet strategy.

Predictive Value of Free Triiodothyronine in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Background: Homeostasis of thyroid hormones has significant effects on the cardiovascular system. The aim of this study was to investigate the association between free triiodothyronine (FT3) and adverse cardiovascular events in patients with acute coronary syndrome (ACS) who were undergoing percutaneous coronary intervention (PCI). Methods: A total of 1701 patients with ACS undergoing PCI were included in this study. All patients were divided into three groups according to the tertiles of FT3 level: the lowest tertile (FT3 < 4.51 pmol/L), the middle tertile (4.51 pmol/L ≤ FT3 < 4.89 pmol/L) and the highest tertile group (FT3 ≥ 4.89 pmol/L). The primary study endpoint was a composite of major adverse cardiovascular events (MACE), which included all-cause death, ischemic stroke, myocardial infarction, or unplanned repeat revascularization. Results: During a median follow-up period of 927 days, 349 patients had at least one event. Compared with patients with the highest tertile, those with the lowest tertile had a significantly higher incidence of MACE, all-cause death, MI, ischemic stroke and repeat revascularization (all p values < 0.05). In the multivariate Cox regression analysis, the middle tertile had similar risk of MACE (HR = 0.986, 95% CI 0.728-1.336, p = 0.929) as the highest tertile, but the patients with the lowest tertile had a 92.9% higher risk of MACE (HR = 1.929, 95% CI 1.467-2.535, p < 0.001). There was a non-linear relationship between FT3 and MACE and unplanned repeat revascularization (all p values for non-linear association < 0.001). Adding the tertiles of FT3 level into the baseline model yielded a significant improvement in discrimination for predicting MACE ( Δ AUC = 0.013, p = 0.025). Conclusions: A significantly reduced FT3 level was independently associated with a worse prognosis in patients with ACS undergoing PCI.

Efficient taper optical hydrogel fiber coupler drawn from suspended photocuring 3D printing.

Integrating bio-friendly optical hydrogel fibers (HFs) with solid-state fibers (SFs) could expand the horizons of fiber-optic technology for bio-photonics. However, methods for coupling HF and SF-based systems are inefficient due to the mode field mismatch. Here, a hydrogel fiber coupler with a taper core-cladding structure is demonstrated for efficiently coupling HF to SF and fabricated through suspended photocuring 3D printing. Coupling efficiencies of 8.3 and 9.4 dB are obtained at 632 and 473 nm, respectively, which are 22% better than those of conventional couplers. The working bandwidth covers visible wavelengths, satisfying bioengineering requirements. This research removes obstacles to optical fiber applications in bioscience.

Investigation of miR-126-3p loaded on adipose stem cell-derived exosomes for wound healing of full-thickness skin defects.

OBJECTIVE: To investigate the function of miR-126-3p loaded on adipose stem cell (ADSC)-derived exosomes (ADSC-Exos) in wound healing of full-thickness skin defects. METHODS: ADSCs transfected with miR-126-3p mimic, miR-126-3p inhibitor or pcDNA3.1-PIK3R2, or PKH26-marked ADSC-Exos were cultured with fibroblasts or human umbilical vein endothelial cells (HUVECs). The proliferation and migration rates of fibroblasts and angiogenesis of HUVECs were measured. Rats with full-thickness skin defects were injected with ADSC-Exos or exosomes extracted from ADSCs transfected with miR-126-3p inhibitor and the wound healing rates were measured. The wound bed, collagen deposition and angiogenesis in injured rats were assessed. RESULTS: ADSC-Exos could be ingested by fibroblasts and HUVECs. Co-incubation with ADSCs or ADSC-Exos promoted the proliferation and migration of fibroblasts and angiogenesis of HUVECs, which was further enhanced by miR-126-3p overexpression. Inhibition of ADSC-Exos or miR-126-3p or PIK3R2 overexpression suppressed the proliferation and migration of fibroblasts and angiogenesis of HUVECs. ADSC-derived exosomal miR-126-3p increased wound healing rate, collagen deposition and newly formed vessels in the injured rats. CONCLUSION: ADSC-derived exosomal miR-126-3p promotes wound healing of full-thickness skin defects by targeting PIK3R2.

Prognostic value of preoperative C-reactive protein to albumin ratio in patients with thymic epithelial tumors: a retrospective study.

BACKGROUND: The C-reactive protein to albumin ratio (CAR) is associated with poor prognosis in various cancers. However, its value in thymic epithelial tumors remains to be elucidated, we aimed to evaluate the prognostic significance of preoperative CAR in patients with surgically resected thymic epithelial tumors (TETs). METHODS: We retrospectively collected data from 125 patients with TETs who underwent thymoma resection at our center. The best cutoff values ​​for the continuous variable, CAR, were obtained using X-tile software. Univariate and multivariate Cox regression analyses were used to evaluate CAR as an independent predictor of overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier analysis and log-rank tests were used to present risk stratification of patients based on CAR and the Glasgow-prognostic-score (GPS). The prognostic effect of CAR was assessed using a receiver operating characteristic curve. RESULTS: Patients were categorized into high (≥ 0.17) and low (< 0.17) CAR groups according to the optimal cutoff value of 0.17. Univariate and multivariate analyses showed that CAR was an independent predictor of prognosis. World health organization stage, CAR level, GPS score, and drinking history were important independent prognostic factors for OS (p < 0.05). T stage, CAR level, and drinking history were important independent prognostic factors for RFS (p < 0.05). The area under the curve value of CAR to predict prognosis was 0.734 for OS and 0.680 for RFS. CONCLUSIONS: Elevated preoperative CAR was independently associated with poor OS and RFS after thymectomy. Therefore, CAR may be a valuable biomarker for the postoperative prognosis of TETs.

Assessment of the Intestinal Absorption of Higher Olefins by the Everted Gut Sac Model in Combination with In Silico New Approach Methodologies.

To reduce the number of animals and studies needed to fulfill the information requirements as required by Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (EC no. 1907/2006), a read-across approach was used to support approximately 30 higher olefins. This study aimed to assess the absorption potential of higher olefins through the gut wall as the experimentally determined bioavailability which would strengthen the read-across hypothesis and justification, reducing the need for toxicity studies on all of the higher olefins. The absorption potential of a series of higher olefins (carbon range from 6 to 28, with five configurations of the double bond) was determined in the in vitro everted rat small intestinal sac model and subsequently ranked. In addition, in silico approaches were applied to predict the reactivity, lipophilicity, and permeability of higher olefins. In the in vitro model, everted sacs were incubated in "fed-state simulated small intestinal fluid" saturated with individual higher olefins. The sac contents were then collected, extracted, and analyzed for olefin content using gas chromatography with a flame ionization detector. The C6 to C10 molecules were readily absorbed into the intestinal sacs. Marked inter-compound differences were observed, with the amount of absorption generally decreasing with the increase in carbon number. Higher olefins with ≥C14 carbons were either not absorbed or very poorly absorbed. In the reactivity simulation study, the reactivity is well described by the position of the double bond rather than the number of carbon atoms. In the lipophilicity and permeability analysis, both parameter descriptors depend mainly on the number of carbon atoms and less on the position of the double bond. In conclusion, these new approach methodologies provide supporting information on any trends or breakpoints in intestinal uptake and a hazard matrix based on carbon number and position of the double bond. This matrix will further assist in the selection of substances for inclusion in the mammalian toxicity testing programme.

Exosomal circ_0007385 enhances non-small cell lung cancer cell proliferation and stemness via regulating miR-1253/FAM83A axis.

Exosomes are critical mediators of intercellular communication in the tumor microenvironment. Exosomal circular RNAs (circRNAs) can act as biomarkers and play crucial roles in many cancers, including non-small cell lung cancer (NSCLC). The aim of this study was to explore the functions and regulatory mechanism of exosomal circ_0007385 in NSCLC. The expression levels of circ_0007385, microRNA-1253 (miR-1253), family with sequence similarity 83, member A (FAM83A) mRNA were determined by quantitative real-time PCR (qRT-PCR). Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (Edu), and colony formation assays were utilized to determine cell proliferation ability. Sphere formation efficiency was determined by sphere formation assay. All protein levels were detected by western blot assay. Exosomes were detected using transmission electron microscopy analysis. Size distribution of exosomes was analyzed by nanoparticle tracking analysis. The interaction between miR-1253 and circ_0007385 or FAM83A was confirmed by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. Mice xenograft model was established to verify the function of circ_0007385 in vivo. Circ_0007385 was upregulated in NSCLC tissues and cells. Knockdown of circ_0007385 inhibited NSCLC cell proliferation and stemness, while exosomal circ_0007385 facilitated NSCLC cell proliferation and stemness. In addition, miR-1253 was a direct target of circ_0007385, and miR-1253 reversed the inhibitory effects of circ_0007385 on cell proliferation and stemness in NSCLC cells. Moreover, FAM83A was a direct target of miR-1253, and miR-1253 suppressed NSCLC cell proliferation and stemness by targeting FAM83A. Furthermore, circ_0007385 knockdown inhibited tumor growth in vivo. Exosomal circ_0007385 promoted NSCLC cell proliferation and stemness by regulating miR-1253/FAM83A axis.

The Prognostic Value of Preoperative Serum D-dimer Levels After Surgical Resection of Thymic Epithelial Tumors.

INTRODUCTION: Thymic epithelial tumors are the most common mediastinal tumors. Despite the high survival rate after surgery, some patients still require postoperative adjuvant therapy and closer follow-up. Hematological indicators such as biochemical routines and coagulation indicators have been reported to be independently associated with the prognosis of various malignancies. Therefore, we included hematological indicators in the analysis. METHODS: The data of 105 patients with thymic epithelial tumors were retrospectively collected from Sun Yat-sen University Cancer Center, and the patients with missing preoperative hematological indicators were excluded. X-tile software was used to obtain the best cutoff value of each preoperative hematological indicator, and COX regression analysis and Kaplan-Meier survival curves were used to demonstrate statistically significant results. RESULTS: COX univariate regression analysis of all patients showed that Masaoka stage, T stage, WHO histologic types, D-dimer, albumin-fibrinogen ratio (AFR), Fibrinogen (Fbg) were associated with postoperative overall survival (P < .05). T stage, WHO histologic types, D-dimer, and AFR were associated with postoperative recurrence-free survival (P < .05). Finally, multivariate regression analysis showed that T stage, D-dimer levels were independently associated with postoperative overall survival (OS) and recurrence-free survival (RFS) in patients with thymic epithelial tumors. CONCLUSIONS: For thymic epithelial tumors, higher preoperative D-dimer levels predict poorer survival and shorter recurrence-free survival. This may help guide postoperative adjuvant therapy and follow-up patterns in patients with thymic epithelial tumors.