The timing of durvalumab administration affects the risk of pneumonitis in patients with locally advanced non-small cell lung cancer: a systematic review and meta-analysis.

PURPOSE: The PACIFIC study has demonstrated that the administration of durvalumab following concurrent chemoradiotherapy can significantly improve both overall survival and progression-free survival rates in patients with locally advanced unresectable non-small cell lung cancer. While the latest NCCN guidelines recommend this combination regimen, they do not specify the optimal timing for administering durvalumab after completing radiotherapy. The PACIFIC study suggested initiating durvalumab within 42 days of completing radiotherapy, but early administration of the drug may increase the incidence of pneumonitis. Therefore, we conducted this study to investigate whether the time interval between completion of radiotherapy and initiation of durvalumab treatment is associated with the risk of pneumonitis (Grade ≥ 3), which is the primary endpoint, as well as progression-free survival, which is the secondary endpoint. METHODS: A comprehensive search of clinical trials in PubMed and EMBASE was conducted up to March 2023 to identify clinical trials involving locally advanced unresectable non-small cell lung cancer patients who were treated with durvalumab following chemoradiotherapy. Meta-analysis was performed on single-arm studies to estimate the incidence of pneumonitis (Grade ≥ 3) and progression-free survival in all studies, as well as in studies that administered durvalumab within 42 days after completion of radiotherapy. RESULTS: This meta-analysis consisted of nine studies with a total of 2560 patients. The analysis showed that the incidence of pneumonitis (Grade ≥ 3) was 5.36% [95%CI (0.03, 0.08), I2 = 18.41%, p = 0.29], while the 1-year progression-free survival rate was 57.91% [95%CI (0.53, 0.63), I2 = 10.57%, p = 0.35]. Furthermore, when the duration between completion of radiotherapy and initiation of durvalumab treatment was shorter than 42 days, the incidence of pneumonitis (Grade ≥ 3) was 4.12% [95%CI (0.02, 0.06), I2 = 0.00%, p = 0.56], with a 1-year progression-free survival rate of 61.03% [95%CI (0.51, 0.71), I2 = 59.06%, p = 0.09]. CONCLUSION: Overall, based on the available evidence, it appears that there is no significant increase in pneumonitis or decrease in progression-free survival (PFS) when the time interval is less than 42 days and a shorter interval between treatment sessions does not necessarily have a detrimental effect on the rate of pneumonitis. We recommend that clinicians carefully evaluate the specific circumstances of each patient to determine the optimal timing for initiating immunotherapy.

Fabrication of a Large-Area Flexible Scintillating Membrane for High-Resolution X-ray Imaging Using an AIEgen-Functionalized Metal-Organic Framework.

With the growing demand for X-ray imaging, especially for three-dimensional objects with curved surfaces, a large-area flexible X-ray imaging membrane based on scintillating materials becomes the focus of vigorous investigation. Among the developed scintillators, metal-organic frameworks (MOFs) featuring tunable photophysical properties and marked luminescence stability hold great promise for serving as ideal X-ray scintillators. Here, we report a flexible composite scintillating membrane with superior imaging performance. The membrane is achieved by embedding an aggregation-induced emission (AIE) luminogen (AIEgen, H4ETTC)-functionalized MOF scintillator (Y-PCN-94) into a polymer matrix (PDMS). Notably, Y-PCN-94 exhibits a strong AIE effect under both ultraviolet (UV) light and X-ray irradiation, which is also the first time that the AIE effect was observed in the MOF system under an ionizing radiation field. This also gives the material promising radioluminescence properties, such as a low X-ray detection limit (1.6 µGy s-1) and high imaging resolution (>14.3 lp mm-1), which can be mainly attributed to the combination of the AIE effect and strong X-ray stopping power. This work demonstrates that incorporating AIEgens into MOFs or other frameworks can offer an alternative approach for producing high-performance X-ray scintillators.

The emerging role of exosomes in radiotherapy.

Presently, more than half of cancer patients receive radiotherapy to cure localized cancer, palliate symptoms, or control the progression of cancer. However, radioresistance and radiation-induced bystander effects (RIBEs) are still challenging problems in cancer treatment. Exosomes, as a kind of extracellular vesicle, have a significant function in mediating and regulating intercellular signaling pathways. An increasing number of studies have shown that radiotherapy can increase exosome secretion and alter exosome cargo. Furthermore, radiation-induced exosomes are involved in the mechanism of radioresistance and RIBEs. Therefore, exosomes hold great promise for clinical application in radiotherapy. In this review, we not only focus on the influence of radiation on exosome biogenesis, secretion and cargoes but also on the mechanism of radiation-induced exosomes in radioresistance and RIBEs, which may expand our insight into the cooperative function of exosomes in radiotherapy. Video abstract.

Comparing upfront surgery with neoadjuvant treatments in patients with resectable, borderline resectable or locally advanced pancreatic cancer: a systematic review and network meta-analysis of randomized clinical trials.

BACKGROUND: The aim was to explore the optimal neoadjuvant therapy strategy for resectable, borderline resectable, and locally advanced pancreatic cancer, in order to provide a theoretical basis for the development of new neoadjuvant treatment protocols for clinical use. PATIENTS AND METHODS: The authors reviewed literature titles and abstracts comparing three treatment strategies (neoadjuvant chemoradiotherapy, neoadjuvant chemotherapy, and upfront surgery) in PubMed, Embase, The Cochrane Library, Web of Science from 2009 to 2023 to estimate relative odds ratios for resection rate and hazard ratios (HRs) for overall survival (OS) in all include trials. RESULTS: A total of nine studies involving 889 patients were included in the analysis. The treatment methods included upfront surgery, neoadjuvant chemotherapy, and neoadjuvant chemoradiotherapy followed by surgery. The network meta-analysis results demonstrated that neoadjuvant chemoradiotherapy followed by surgery was an effective approach in improving OS for resectable and borderline resectable pancreatic cancer (RPC) patients compared to upfront surgery (HR: 0.79, 95% CI: 0.64-0.98) and neoadjuvant chemotherapy (HR: 0.79, 95% CI: 0.64-0.98). Additionally, neoadjuvant chemoradiotherapy significantly increased the margin negative resection (R0) rate and pathological negative lymph node (pN0) rate in patients with resectable and borderline RPC. However, it is worth noting that neoadjuvant chemoradiotherapy increased the risk of grade 3 or higher treatment-related adverse events, including in patients with locally advanced pancreatic cancer. CONCLUSIONS: The current evidence suggests that neoadjuvant chemoradiotherapy followed by surgery is the optimal choice for treating patients with resectable and borderline RPC. Future research should focus on optimizing neoadjuvant chemoradiotherapy regimens to effectively improve OS while reducing the occurrence of adverse events.

Structural and functional prediction, evaluation, and validation in the post-sequencing era.

The surge of genome sequencing data has underlined substantial genetic variants of uncertain significance (VUS). The decryption of VUS discovered by sequencing poses a major challenge in the post-sequencing era. Although experimental assays have progressed in classifying VUS, only a tiny fraction of the human genes have been explored experimentally. Thus, it is urgently needed to generate state-of-the-art functional predictors of VUS in silico. Artificial intelligence (AI) is an invaluable tool to assist in the identification of VUS with high efficiency and accuracy. An increasing number of studies indicate that AI has brought an exciting acceleration in the interpretation of VUS, and our group has already used AI to develop protein structure-based prediction models. In this review, we provide an overview of the previous research on AI-based prediction of missense variants, and elucidate the challenges and opportunities for protein structure-based variant prediction in the post-sequencing era.

Robust positive association between serum urate and the risk of chronic obstructive pulmonary disease: hospital-based cohort and Mendelian randomisation study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and hyperuricaemia are both characterised by systemic inflammation. Preventing chronic diseases among the population with common metabolic abnormality is an effective strategy. However, the association of hyperuricaemia with the higher incidence and risk of COPD remains controversial. Therefore, replicated researches in populations with distinct characteristics or demographics are compellingly warranted. METHODS: This cohort study adopted a design of ambispective hospital-based cohort. We used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to minimise the effects of potential confounding factors. A Cox regression model and restricted cubic spline (RCS) model were applied further to assess the effect of serum urate on the risk of developing COPD. Finally, we conducted a two-sample Mendelian randomisation (MR) analysis to explore evidence of causal association. RESULTS: There is a higher incidence in the population with hyperuricaemia compared with the population with normal serum urate (22.29/1000 person-years vs 8.89/1000 person-years, p=0.009). This result is robust after performing PSM (p=0.013) and IPTW (p<0.001). The Cox model confirms that hyperuricaemia is associated with higher risk of developing COPD (adjusted HR=3.35 and 95% CI=1.61 to 6.96). Moreover, RCS shows that the risk of developing COPD rapidly increases with the concentration of serum urate when it is higher than the reference (420 µmol/L). Finally, in MR analysis, the inverse variance weighted method evidences that a significant causal effect of serum urate on COPD (OR=1.153, 95% CI=1.034 to 1.289) is likely to be true. The finding of MR is robust in the repeated analysis using different methods and sensitivity analysis. CONCLUSIONS: Our study provides convincing evidence suggesting a robust positive association between serum urate and the risk of developing COPD, and indicates that the population with hyperuricaemia is at high risk of COPD in the Chinese population who seek medical advice or treatment in the hospital.

Red ginseng extracts ameliorate high-fat diet-induced obesity and insulin resistance by activating the intestinal TGR5-mediated bile acids signaling pathway.

BACKGROUND: Obesity has emerged as a worldwide metabolic disease, given its rapid growth in global prevalence. Red ginseng extracts (RGS), one of the traditional processed products of ginseng, show the potential to improve the metabolic phenotype of obesity. However, the RGS mechanism for regulating obesity and late insulin resistance remains to be clarified. PURPOSE: This study aimed to emphasize the potential use of RGS in treatment of obesity and insulin resistance (IR) and explore the underlying mechanism affecting glucose and lipid metabolism improvements. METHODS: The role of RGS was evaluated in a high-fat diet (HFD) rodent model. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to characterize the glucose metabolism level. The expression of lipolysis proteins and uncoupling protein-1 (UCP-1) were investigated by western blot. Glucagon-like peptide-1 (GLP-1) and apical sodium-dependent bile acid transporter (ASBT) protein expression in the intestine were determined via immunofluorescence. UPLC-Q-TOF-MS were used to detect the alterations in bile acids (BAs) levels in serum, ileum, and inguinal white adipose tissue (iWAT). In addition, intestine-specific Tgr5 knockout mice were employed to verify the efficacy of RGS in improving obesity. RESULTS: RGS treatment alleviated dietary-induced dyslipidemia and IR in obese mice in a dose-dependent manner and improved glucose and insulin tolerance, and energy expenditure. RGS treatment significantly reduced lipid deposition and induced GLP-1 secretion in the intestine of wild-type mice but not in Tgr5ΔIN obese mice. Furthermore, RGS intervention increased BA levels in serum, ileum, and iWAT. The increase of circulating BAs in mice was related to the activation of ileal TGR5 and the promotion of ASBT translocation to the plasma membrane, thus affecting BA transport. Next, the increased level of circulating BAs entered the periphery, which might facilitate lipolysis and energy consumption by activating TGR5 in iWAT. CONCLUSION: Our results demonstrated that RGS significantly alleviated HFD-induced obesity and insulin resistance in mice. RGS intervention improved glucose metabolism, promoted lipolysis, and energy metabolism by activating TGR5 in the intestine. In addition, we found that activating intestinal TGR5 facilitated the localization of ASBT to the plasma membrane, which ultimately promoted the transport of BAs to regulate metabolic phenotype.

Hybrid Cycloalkyl-Alkyl Chain-Based Symmetric/Asymmetric Acceptors with Optimized Crystal Packing and Interfacial Exciton Properties for Efficient Organic Solar Cells.

Hybrid cycloalkyl-alkyl side chains are considered a unique composite side-chain system for the construction of novel organic semiconductor materials. However, there is a lack of fundamental understanding of the variations in the single-crystal structures as well as the optoelectronic and energetic properties generated by the introduction of hybrid side chains in electron acceptors. Herein, symmetric/asymmetric acceptors (Y-C10ch and A-C10ch) bearing bilateral and unilateral 10-cyclohexyldecyl are designed, synthesized, and compared with the symmetric acceptor 2,2'-((2Z,2'Z)-((12,13-bis(2-butyloctyl)-3,9 bis(ethylhexyl)-12,13-dihydro-[1,2,5]thiadiazolo[3,4-e]thieno[2″,3″':4',5']thieno[2',3':4,5] pyrrolo[3,2-g]thieno[2',3':4,5]thieno[3,2-b]indole-2,10- diyl)bis(methanylylidene))bis(5,6-difluoro-3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile (L8-BO). The stepwise introduction of 10-cyclohexyldecyl side chains decreases the optical bandgap, deepens the energy level, and enables the acceptor molecules to pack closely in a regular manner. Crystallographic analysis demonstrates that the 10-cyclohexyldecyl chain endows the acceptor with a more planar skeleton and enforces more compact 3D network packing, resulting in an active layer with higher domain purity. Moreover, the 10-cyclohexyldecyl chain affects the donor/acceptor interfacial energetics and accelerates exciton dissociation, enabling a power conversion efficiency (PCE) of >18% in the 2,2'-((2Z,2'Z)-((12,13-bis(2-ethylhexyl)-3,9-diundecyl12,13-dihydro-[1,2,5]thiadiazolo[3,4-e]thieno[2″,3″':4',5']thieno[2',3':4,5]pyrrolo[3,2-g]thieno[2',3':4,5]thieno[3,2-b]indole-2,10-diyl)bis(methanylylidene))bis(5,6-difluoro-3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile (Y6) (PM6):A-C10ch-based organic solar cells (OSCs). Importantly, the incorporation of Y-C10ch as the third component of the PM6:L8-BO blend results in a higher PCE of 19.1%. The superior molecular packing behavior of the 10-cyclohexyldecyl side chain is highlighted here for the fabrication of high-performance OSCs.

Urban living and chronic diseases in the presence of economic growth: Evidence from a long-term study in southeastern China.

High-speed urban development has brought about an increase in per capita income in low- and middle-income countries (LMICs) as well as the high prevalence rate of chronic diseases. Based on a study of chronic diseases from 2011 to 2021 in southeastern China, we used multivariate adjusted logistic regression method to analyze the effect of urban living on the incidence of typical chronic diseases and the trend of such effect with the improvement of public healthcare system. We adopted potential mediating risk factors of urban lifestyles including body mass index (BMI), frequency of dining out, sedentary time, and psychological distress in the adjusted estimation. Baseline results indicate a positive relationship between living in urban areas and the prevalence of type 2 diabetes, hyperlipidemia, and hypertension. Regarding the mediating factors, psychological distress had the highest positive coefficient (Cr) on type 2 diabetes, hyperlipidemia, and hypertension (Cr: 0.4881-0.7084), followed by BMI (Cr: 0.1042-0.1617) and frequency of dining out (Cr: 0.0311-0.0478), and finally, sedentary time (Cr: 0.0103-0.0147). However, regression results on the follow-up survey reveal that trend in the impact of living in urban areas on chronic disease diminished as the level of the healthcare system improved. Additionally, urban living was more positively correlated with the incidence of metabolic disease than with the incidence of cardiovascular disease and cancer. Our findings provide empirical evidence that future urban health planning in LMICs should pay sustained attention to upgrading the level of public health infrastructure covering urban residents as well as rural-to-urban migrants, constructing a long-term dynamic system of chronic disease prevention and control, and regularly monitoring the mental health problems of residents in order to interrupt the process of urban chronic disease prevalence in an early stage.

3D Contour Printing of Anatomically Mimetic Cartilage Grafts with Microfiber-Reinforced Double-Network Bioink.

Bioprinting is an emerging technology for fabricating cell-laden scaffolds with custom shapes that resemble the complex architecture of human tissues, however, construction of mechanically competent tissue grafts which mimic irregular cartilage defect is still a big challenge. Here, 3D printing of short fiber-reinforced double-network bioink to generate anatomically accurate and mechanical tunable scaffold for cartilage regeneration is reported. Poly(lactic acid) (PLLA) short fibers are first prepared by electrospinning and then fragmented through aminolysis reaction. Composite inks are constructed with an incorporation of fragmented microfibers with varied amounts and lengths into oxidized alginate bioink. The results show that incorporation of PLLA short fibers not only improves the printing fidelity but also facilitates in generating mechanically strong constructs. By incorporating gelatin methacryloyl (GelMA) and optimizing the bioink composition, the fabricated constructs with a compressive stress of ≈150 kPa even after 100 cyclical compression loading (up to 40% of strain) are achieved. In addition, this mechanically reinforced alginate/GelMA double-network bioink displays good biocompatibility and supports bone marrow-derived stromal cell chondrogenesis in vitro. Collectively, these findings demonstrate this approach is capable of printing engineered grafts which resemble the irregular size and mechanical properties of cartilage and thus hold potential for functional tissue regeneration.

Evaluation of aroma characteristics in grass carp mince as affected by different washing processes using an E-nose, HS-SPME-GC-MS, HS-GC-IMS, and sensory analysis.

The aroma characteristics of grass carp mince washed in four processes were analyzed via electronic nose (E-nose), headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS), headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS), and sensory analysis techniques. Significant differences were revealed in the E-nose and sensory analysis results of the aroma characteristics of grass carp mince samples washed via different washing processes, while fifty-seven volatile compounds (thirteen aldehydes, eighteen alcohols, two ketones, eighteen hydrocarbons, two aromatic compounds, one furan, and two other compounds) and twenty volatile compounds (five aldehydes, four ketones, six alcohols, four esters, and one acid) were identified via HS-SPME-GC-MS and HS-GC-IMS of the Raw and washed grass carp mince samples, respectively. All these techniques revealed that the types and relative contents of volatile compounds in the grass carp mince decreased significantly and differently after each of the four washing processes. Moreover, compared with the water and saline solution washing processes, washing with weak alkaline solution processes exhibited the most significant removal effect on the volatile compounds of grass carp mince. Besides, the sensory analysis results also showed that weak alkaline solution washing processes (washing twice with pure water and once with 0.3% sodium bicarbonate solution) may be most effective in removing fishy off-odor compounds and contributing to a better overall aroma profile in grass carp mince. The findings of this study may provide some basic knowledge for the rational screening of washing methods in the production of high-quality grass carp surimi.

Methylation-mediated silencing of PTPRD induces pulmonary hypertension by promoting pulmonary arterial smooth muscle cell migration via the PDGFRB/PLCγ1 axis.

OBJECTIVE: Pulmonary hypertension is a lethal disease characterized by pulmonary vascular remodeling and is mediated by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Platelet-derived growth factor BB (PDGF-BB) is the most potent mitogen for PASMCs and is involved in vascular remodeling in pulmonary hypertension development. Therefore, the objective of our study is to identify novel mechanisms underlying vascular remodeling in pulmonary hypertension. METHODS: We explored the effects and mechanisms of PTPRD downregulation in PASMCs and PTPRD knockdown rats in pulmonary hypertension induced by hypoxia. RESULTS: We demonstrated that PTPRD is dramatically downregulated in PDGF-BB-treated PASMCs, pulmonary arteries from pulmonary hypertension rats, and blood and pulmonary arteries from lung specimens of patients with hypoxic pulmonary arterial hypertension (HPAH) and idiopathic PAH (iPAH). Subsequently, we found that PTPRD was downregulated by promoter methylation via DNMT1. Moreover, we found that PTPRD knockdown altered cell morphology and migration in PASMCs via modulating focal adhesion and cell cytoskeleton. We have demonstrated that the increase in cell migration is mediated by the PDGFRB/PLCγ1 pathway. Furthermore, under hypoxic condition, we observed significant pulmonary arterial remodeling and exacerbation of pulmonary hypertension in heterozygous PTPRD knock-out rats compared with the wild-type group. We also demonstrated that HET group treated with chronic hypoxia have higher expression and activity of PLCγ1 in the pulmonary arteries compared with wild-type group. CONCLUSION: We propose that PTPRD likely plays an important role in the process of pulmonary vascular remodeling and development of pulmonary hypertension in vivo .

Involvement of TRP Channels in Adipocyte Thermogenesis: An Update.

Obesity prevalence became a severe global health problem and it is caused by an imbalance between energy intake and expenditure. Brown adipose tissue (BAT) is a major site of mammalian non-shivering thermogenesis or energy dissipation. Thus, modulation of BAT thermogenesis might be a promising application for body weight control and obesity prevention. TRP channels are non-selective calcium-permeable cation channels mainly located on the plasma membrane. As a research focus, TRP channels have been reported to be involved in the thermogenesis of adipose tissue, energy metabolism and body weight regulation. In this review, we will summarize and update the recent progress of the pathological/physiological involvement of TRP channels in adipocyte thermogenesis. Moreover, we will discuss the potential of TRP channels as future therapeutic targets for preventing and combating human obesity and related-metabolic disorders.

Enhancing Stem Cell Therapy for Cartilage Repair in Osteoarthritis-A Hydrogel Focused Approach.

Stem cells hold tremendous promise for the treatment of cartilage repair in osteoarthritis. In addition to their multipotency, stem cells possess immunomodulatory effects that can alleviate inflammation and enhance cartilage repair. However, the widely clinical application of stem cell therapy to cartilage repair and osteoarthritis has proven difficult due to challenges in large-scale production, viability maintenance in pathological tissue site and limited therapeutic biological activity. This review aims to provide a perspective from hydrogel-focused approach to address few key challenges in stem cell-based therapy for cartilage repair and highlight recent progress in advanced hydrogels, particularly microgels and dynamic hydrogels systems for improving stem cell survival, retention and regulation of stem cell fate. Finally, progress in hydrogel-assisted gene delivery and genome editing approaches for the development of next generation of stem cell therapy for cartilage repair in osteoarthritis are highlighted.

Bioengineering Approaches to Accelerate Clinical Translation of Stem Cell Therapies Treating Osteochondral Diseases.

The osteochondral tissue is an interface between articular cartilage and bone. The diverse composition, mechanical properties, and cell phenotype in these two tissues pose a big challenge for the reconstruction of the defected interface. Due to the availability and inherent regenerative therapeutic properties, stem cells provide tremendous promise to repair osteochondral defect. This review is aimed at highlighting recent progress in utilizing bioengineering approaches to improve stem cell therapies for osteochondral diseases, which include microgel encapsulation, adhesive bioinks, and bioprinting to control the administration and distribution. We will also explore utilizing synthetic biology tools to control the differentiation fate and deliver therapeutic biomolecules to modulate the immune response. Finally, future directions and opportunities in the development of more potent and predictable stem cell therapies for osteochondral repair are discussed.

The effects of norethindrone on the ontogeny of gene expression along the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes in zebrafish (Danio rerio).

Little is known about the molecular effects of progestins on the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in fish prior to sexual differentiation. In this study, the effects of norethindrone (NET) on the ontogeny of HPG- and HPA-related genes in zebrafish embryo/early larvae prior to sexual differentiation were evaluated. Embryo/larvae were exposed to different concentrations (5, 50, 500 ng/L) of NET for 6 days. The levels of the transcripts of the genes closely related to the HPG and HPA axes were determined daily during 3 stages (embryo, embryo/larvae transition, and early larvae). The results showed that most genes were up-regulated and the ontogeny of genes in the HPA axis was earlier than that of HPG axis, especially for the upstream genes of both the HPG (gnrh2, gnrh3, fshb, lhb) and the HPA (crh, pomc, star) axes. In contrast, the transcriptional expressions of genes of the cortisol/stress pathway (cyp11b, mr) were inhibited and those of the progesterone pathway were not affected. More importantly, NET exposure induced the expressions of the genes (esr1, vtg1, hsd17b3, hsd11b2, ar) that are closely related to the steroid hormone pathways in the embryos/larvae stages, implying a precocious effects of NET in zebrafish. This study demonstrates that NET alters the expression of HPA- and HPG-axes related genes in zebrafish at early stages, pointing to the need for the same type of analysis during the zebrafish gonadal differentiation window.

Injectable ECM hydrogel for delivery of BMSCs enabled full-thickness meniscus repair in an orthotopic rat model.

Meniscal injuries have poor intrinsic healing capability and are associated with the development of osteoarthritis. Decellularized meniscus extracellular matrix (mECM) has been suggested to be efficacious for the repair of meniscus defect. However, main efforts to date have been focused on the concentration, crosslinking density and anatomical region dependence of the mECM hydrogels on regulation of proliferation and differentiation of adult mesenchymal stem cells (MSCs) in vitro 2D or 3D culture. A systematic investigation and understanding of the effect of mECM on encapsulated MSCs response and integrative meniscus repair by in vivo rat subcutaneous implantation and orthotopic meniscus injury model will be highly valuable to explore its potential for clinical translation. In this study, we investigated the in situ delivery of rat BMSCs in an injectable mECM hydrogel to a meniscal defect in a SD rat model. Decellularized mECM retained essential proteoglycans and collagens, and significantly upregulated expression of fibrochondrogenic markers by BMSCs versus collagen hydrogel alone in vitro 3D cell culture. When applied to an orthotopic model of meniscal injury in SD rat, mECM is superior than collagen I scaffold in reduction of osteophyte formation and prevention of joint space narrowing and osteoarthritis development as evidenced by histology and micro-CT analysis. Taken together, these results indicate mECM hydrogel is a highly promising carrier to deliver MSCs for long-term repair of meniscus tissue, while preventing the development of osteoarthritis.

Phosphatidylinositol 3-Kinase-DNA Methyltransferase 1-miR-1281-Histone Deacetylase 4 Regulatory Axis Mediates Platelet-Derived Growth Factor-Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells.

BACKGROUND: Platelet-derived growth factor BB, a potent mitogen of pulmonary artery smooth muscle cells (PASMCs), has been implicated in pulmonary arterial remodeling, which is a key pathogenic feature of pulmonary arterial hypertension. Previous microRNA profiling in platelet-derived growth factor BB-treated PASMCs found a significantly downregulated microRNA, miR-1281, but it has not been associated with any cellular function, and we investigated the possibility. METHODS AND RESULTS: Real-time quantitative reverse transcription-polymerase chain reaction assay proved that downregulation of miR-1281 was a conserved phenomenon in human and rat PASMCs. Overexpression and inhibition of miR-1281 in PASMCs promoted and suppressed, respectively, the cell proliferation and migration. Bioinformatic prediction and 3'-untranslated region reporter assay identified histone deacetylase 4 to be a direct target of miR-1281. Supporting this, proliferation and migration assay demonstrated the cellular function of histone deacetylase 4 is inversely correlated with that of miR-1281. Mechanistically, it is found that platelet-derived growth factor BB activates the phosphatidylinositol 3-kinase pathway, which then induces the expression of DNA methyltransferase 1, leading to enhanced methylation of a flanking CpG island and repressed miR-1281 expression. Finally, a reduced miR-1281 level was consistently identified in hypoxic PASMCs in vitro, in pulmonary arteries of rats with monocrotaline-induced pulmonary arterial hypertension, and in serum of patients with coronary heart disease-pulmonary arterial hypertension. These data suggest that there may be a diagnostic and therapeutic use for miR-1281. CONCLUSIONS: Herein, we report a novel regulatory axis, phosphatidylinositol 3-kinase-DNA methyltransferase 1-miR-1281-histone deacetylase 4, integrating multiple epigenetic regulators that participate in platelet-derived growth factor BB-stimulated PASMC proliferation and migration and pulmonary vascular remodeling.