A deep learning-based 3D Prompt-nnUnet model for automatic segmentation in brachytherapy of postoperative endometrial carcinoma.

PURPOSE: To create and evaluate a three-dimensional (3D) Prompt-nnUnet module that utilizes the prompts-based model combined with 3D nnUnet for producing the rapid and consistent autosegmentation of high-risk clinical target volume (HR CTV) and organ at risk (OAR) in high-dose-rate brachytherapy (HDR BT) for patients with postoperative endometrial carcinoma (EC). METHODS AND MATERIALS: On two experimental batches, a total of 321 computed tomography (CT) scans were obtained for HR CTV segmentation from 321 patients with EC, and 125 CT scans for OARs segmentation from 125 patients. The numbers of training/validation/test were 257/32/32 and 87/13/25 for HR CTV and OARs respectively. A novel comparison of the deep learning neural network 3D Prompt-nnUnet and 3D nnUnet was applied for HR CTV and OARs segmentation. Three-fold cross validation and several quantitative metrics were employed, including Dice similarity coefficient (DSC), Hausdorff distance (HD), 95th percentile of Hausdorff distance (HD95%), and intersection over union (IoU). RESULTS: The Prompt-nnUnet included two forms of parameters Predict-Prompt (PP) and Label-Prompt (LP), with the LP performing most similarly to the experienced radiation oncologist and outperforming the less experienced ones. During the testing phase, the mean DSC values for the LP were 0.96 ± 0.02, 0.91 ± 0.02, and 0.83 ± 0.07 for HR CTV, rectum and urethra, respectively. The mean HD values (mm) were 2.73 ± 0.95, 8.18 ± 4.84, and 2.11 ± 0.50, respectively. The mean HD95% values (mm) were 1.66 ± 1.11, 3.07 ± 0.94, and 1.35 ± 0.55, respectively. The mean IoUs were 0.92 ± 0.04, 0.84 ± 0.03, and 0.71 ± 0.09, respectively. A delineation time < 2.35 s per structure in the new model was observed, which was available to save clinician time. CONCLUSION: The Prompt-nnUnet architecture, particularly the LP, was highly consistent with ground truth (GT) in HR CTV or OAR autosegmentation, reducing interobserver variability and shortening treatment time.

Epidemiology and risk factors of oral frailty among older people: an observational study from China.

OBJECTIVES: This study aimed to compare the prevalence of oral frailty among community-dwelling older people in Nanjing, China with the usage of different measurements, and to investigate the potential risk factors of oral frailty. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: A total of 338 community-dwelling older people in Nanjing, China were recruited. METHODS: Oral frailty was measured based on the Oral Frailty Index-8 (OFI-8) scale and other measurement methods including the number of natural teeth (TN), repetitive saliva-swallowing test (RSST), and oral diadochokinesis (ODK). The chi-square test and the binary logistic regression analysis were performed to identify potential risk factors for oral frailty. RESULTS: There were 310 participants included in the analysis. Prevalence of oral frailty by using the OFI-8, OFI-8 + TN, OFI-8 + ODK, OFI-8 + TN + ODK and RSST measurement methods were 69.0%, 27.4%, 51.9%, 21.0% and 2.9%, respectively. Passive smoking (OR = 2.04; 95%CI 1.03-4.03), being widowed/unmarried (OR1 = 2.53; 95%CI 1.25-5.10; OR2 = 2.94; 95%CI 1.12-7.77), pre-frailty (OR = 1.76; 95%CI 1.03-3.01), frailty (OR = 3.01; 95%CI 1.39-6.54), and aged 80 years and above (OR = 3.99; 95%CI 1.35-11.81) were found to be risk factors of oral frailty by the usage of the four kinds of measurement methods. CONCLUSIONS AND IMPLICATIONS: The definition and diagnostic criteria of oral frailty are strongly needed to be unified in future research. Only subjective assessment is not enough for assessing oral frailty. Among objective indicators, RSST is not suitable as a screening method for oral frailty. In addition, objective indicators including TN and ODK should be valued for early screening and preventive interventions. The risk factors of oral frailty include physical frailty, passive smoking, and being widowed.

Semaphorin 7A interacts with nuclear factor NF-kappa-B p105 via integrin ß1 and mediates inflammation.

Semaphorin7a (SEMA7A), a membrane-anchored member of the semaphorin protein family, could be involved in a diverse range of immune responses via its receptor integrin ß1. Recently, we reported that the SEMA7AR148W mutation (a gain-of-function mutation, Sema7aR145W in mice) is a risk factor for progressive familial intrahepatic cholestasis and nonalcoholic fatty liver disease via upregulated membrane localization. In this study, we demonstrated that integrin ß1 is a membrane receptor for nuclear factor NF-kappa-B p105 (NF-κB p105) and a critical mediator of inflammation. Integrin ß1 could interact with the C-terminal domain of NF-κB p105 to promote p50 generation and stimulate the NF-κB p50/p65 signalling pathway, upregulate TNF-α and IL-1ß levels, and subsequently render hepatocytes more susceptible to inflammation. The induction of integrin ß1 depends on elevated Sema7a membrane localization. Moreover, we revealed elevated levels of Sema7aWT (SEMA7AWT) in hepatocellular carcinoma (HCC) patients and an HCC mouse model. In line with our findings, the NF-κB p50/p65 pathway could also be activated by high Sema7a expression and repressed by integrin ß1 silencing. In conclusion, our findings suggest that the Sema7aR145W (SEMA7AR148W) mutation and high Sema7aWT (SEMA7AWT) expression both activate the NF-κB p50/p65 pathway via integrin ß1 and play a crucial role in inflammatory responses. Video Abstract.

N6-methyladenosine methylation mediates non-coding RNAs modification in microplastic-induced cardiac injury.

Owing to their potential adverse health effects, global contamination by microplastics (MPs) has attracted increased scientific and societal concerns. However, in vivo studies on MP toxicity, along with its effects and underlying mechanisms, remain limited. We recently found that non-coding RNA (ncRNAs) contribute to MP-mediated vascular toxicity. Moreover, previous studies have identified N6-methyladenosine (m6A) modifications in ncRNAs as influencing factors in cardiovascular disease. However, whether and how m6A modifications in ncRNAs are affected by MP-induced cardiotoxicity remain unknown. Herein, we profiled differentially expressed ncRNAs and their related m6A modification profiles in MP-exposed myocardial tissue using RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq). First, we observed that MPs accumulated in different organs and upregulated apoptosis in the heart, liver, spleen, and kidney cells. Furthermore, total m6A and METTL3 levels increased in the myocardium after exposure to MPs. RNA-seq results revealed that 392 lncRNAs and 302 circRNAs were differentially expressed in MP-treated mouse myocardium compared to the control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that these altered lncRNAs and circRNAs were closely associated with endocytosis, cellular senescence, and cell cycle signaling pathways, which may cause cardiotoxicity. Furthermore, MeRIP-seq data showed different distributions and abundances of m6A modifications in lncRNAs and circRNAs. Additionally, we identified differentially m6A methylated lncRNAs and circRNAs through conjoint analysis of the two high-throughput sequencing datasets and found that both m6A modifications and the expression of circ-Arfgef2 and lncG3bp2 were upregulated after exposure to MPs. This suggests that MP-induced m6A modifications in ncRNAs are involved in cardiotoxicity. Our findings contribute to a better understanding of MP-induced cardiotoxicity and new molecular targets for treating cardiac injury.

Systematic analysis of the prognostic and immunological role of DHX33 in pan-cancer.

DEAH-box helicase 33 (DHX33) is a potent oncogenic agent on patients with hepatocellular carcinoma and colon cancer. Nevertheless, the prognostic significance of DHX33 in human pan-cancers remains unclear. Various bioinformatics tools have been used to clarify the oncogenic effects of DHX33 in pan-cancers. The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) were used to evaluate DHX33 at the mRNA and protein levels, respectively. The pan-cancer prognostic prediction value of DHX33 was evaluated using the Kaplan-Meier plotter. The association between DHX33 levels and clinicopathological features was then determined using the UALCAN database. In addition, gene set enrichment analysis and nomogram prediction models were constructed. The association between DHX33 levels and immune cell infiltration was then assessed using TISIDB. We determined that DHX33 is aberrantly overexpressed in pan-cancers and related to lung adenocarcinoma (LUAD) clinical stage (p < .001). Moreover, DHX33 overexpression was indicative of poor overall survival, disease-free survival, and progression-free interval in patients with LUAD (p < .05). Furthermore, DHX33 levels were associated with age, N stage, T stage, and pathologic stage in patients with LUAD (p < .001). Additionally, multivariate Cox analysis revealed that DHX33 was an independent risk factor for OS in patients with LUAD. A nomogram model between DHX33 levels and characteristic clinical parameters was developed. Additionally, DHX33 levels correlated with immunomodulators and chemokines. Finally, gene set enrichment analysis revealed that the amyloid fiber formation pathway and the WICH complex positively regulates RNA expression pathway, which was the most enriched in LUAD. Our data revealed oncogenic effects of DHX33 in various cancers. We suggest that DHX33 may serve as a biomarker for poor prognosis in LUAD.

Psychometric evaluation of the student nurse stressor-14 scale for undergraduate nursing interns.

BACKGROUND: Currently, there are few scales used to assess the stressors experienced by undergraduate nursing interns during clinical practice, and the assessment of stressors during clinical practice is not comprehensive; the scale includes some unique stressors during training that is not available in the existing instruments used to assess nursing student practice stress in China. AIM: The study aimed to explore the structure of the Chinese revision of the Student Nurse Stressor-14 Scale(SNS-14-CHI)and investigate the psychometric properties it among Chinese undergraduate nursing interns. METHODS: The original scale was culturally adjusted and revised after expert correspondence on the entries, and 414 undergraduate nursing interns were recruited from three cities in China to administer the questionnaire. Reliability was measured by internal consistency, fold-half reliability, and stability. Content validity was evaluated using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) to assess the validity of the SNS-14-CHI. RESULTS: The SNS-14-CHI retained 14 items, the EFA supported a 2-factor structure, and the items' factor attribution differed from the original scale. The CFA results showed a good model fit. The Cronbach coefficient of the scale was 0.934, and the coefficient values of the two factors were 0.890 and 0.898. The content validity index of the scale was 0.964.The cumulative variance contribution of the 2-factor structure was 60.445%. The split-half reliability and stability were 0.869,0.762, respectively. CONCLUSION: The SNS-14-CHI has excellent reliability and validity among undergraduate nursing trainees. The evaluation results of the scale can provide a reference for nursing managers to develop educational programs and interventions to quantify nursing student stress.

Anti-Ro52 antibodies are associated with the prognosis of adult idiopathic inflammatory myopathy-associated interstitial lung disease.

OBJECTIVES: In the present study, we aimed to assess the prevalence and clinical significance of anti-Ro52 antibodies in a cohort of patients with idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) with different myositis-specific autoantibodies (MSAs). METHODS: A cohort of 267 IIM-ILD patients, including 62 patients with PM, 126 patients with DM and 79 patients with clinically amyopathic DM (CADM) were retrospectively analysed in this study. Clinical and laboratory findings, pulmonary function tests (PFTs), HRCT patterns and treatment information were compared between patients with and without anti-Ro52 antibodies. The association between prognosis and anti-Ro52 antibodies was also evaluated based on different MSA subgroups. RESULTS: Anti-Ro52 antibodies were more frequent in patients with anti-MDA5 (62.1%, P < 0.01) and anti-Jo1 (64.9%, P < 0.01) antibodies than in those with other MSAs. The proportion of patients with anti-Jo1 antibodies was higher in the anti-Ro52 antibody-positive group than in the anti-Ro52 antibody-negative group. Patients with anti-Ro52 antibodies were more likely to exhibit the Gottron sign than the anti-Ro52 antibody-negative group (P < 0.001). Furthermore, it was a predictive factor for rapid progression interstitial lung disease (RP-ILD) (P = 0.001) and was also associated with a higher mortality rate (log-rank test, P = 0.001). Furthermore, RP-ILD was more frequently exhibited in anti-MDA5- and anti-Ro52-positive patients. Moreover, anti-Ro52 antibody positivity was closely associated with a higher mortality rate in anti-MDA5-ILD patients (log-rank test, P < 0.05). CONCLUSIONS: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5 and anti-Jo1 antibodies. Within all patients with IIM-ILD, those with anti-Ro52 autoantibodies had a higher frequency of RP-ILD and a poorer prognosis, especially in the anti-MDA5 antibody subgroup.

YTHDF1 Regulates Pulmonary Hypertension through Translational Control of MAGED1.

Rationale: Posttranscriptional modifications are implicated in vascular remodeling of pulmonary hypertension (PH). m6A (N6-methyladenosine) is an abundant RNA modification that is involved in various biological processes. Whether m6A RNA modification and m6A effector proteins play a role in pulmonary vascular remodeling and PH has not been demonstrated.Objectives: To determine whether m6A modification and m6A effectors contribute to the pathogenesis of PH.Methods: m6A modification and YTHDF1 expression were measured in human and experimental PH samples. RNA immunoprecipitation analysis and m6A sequencing were employed to screen m6A-marked transcripts. Genetic approaches were employed to assess the respective roles of YTHDF1 and MAGED1 in PH. Primary cell isolation and cultivation were used for function analysis of pulmonary artery smooth muscle cells (PASMCs).Measurements and Main Results: Elevated m6A levels and increased YTHDF1 protein expression were found in human and rodent PH samples as well as in hypoxic PASMCs. The deletion of YTHDF1 ameliorated PASMC proliferation, phenotype switch, and PH development both in vivo and in vitro. m6A RNA immunoprecipitation analysis identified MAGED1 as an m6A-regulated gene in PH, and genetic ablation of MAGED1 improved vascular remodeling and hemodynamic parameters in SU5416/hypoxia mice. YTHDF1 recognized and promoted translation of MAGED1 in an m6A-dependent manner that was absent in METTL3-deficient PASMCs. In addition, MAGED1 silencing inhibited hypoxia-induced proliferation of PASMCs through downregulating PCNA.Conclusions: YTHDF1 promotes PASMC proliferation and PH by enhancing MAGED1 translation. This study identifies the m6A RNA modification as a novel mediator of pathological changes in PASMCs and PH.

Exercise-induced peptide EIP-22 protect myocardial from ischaemia/reperfusion injury via activating JAK2/STAT3 signalling pathway.

Recent studies have revealed that exercise has myocardial protective effects, but the exact mechanism remains unclear. Studies have increasingly found that peptides play a protective role in myocardial ischaemia-reperfusion (I/R) injury. However, little is known about the role of exercise-induced peptides in myocardial I/R injury. To elucidate the effect of exercise-induced peptide EIP-22 in myocardial I/R injury, we first determined the effect of EIP-22 on hypoxia/reperfusion (H/R)- or H2 O2 -induced injury via assessing cell viability and lactate dehydrogenase (LDH) level. In addition, reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) was assessed by fluorescence microscope. Meanwhile, Western blot and TUNEL methods were used to detect apoptosis level. Then, we conducted mice I/R injury model and verified the effect of EIP-22 by measuring cardiac function, evaluating heart pathology and detecting serum LDH, CK-MB and cTnI level. Finally, the main signalling pathway was analysed by RNA-seq. In vitro, EIP-22 treatment significantly improved cells viabilities and MMP and attenuated the LDH, ROS and apoptosis level. In vivo, EIP-22 distinctly improved cardiac function, ameliorated myocardial infarction area and fibrosis and decreased serum LDH, CK-MB and cTnI level. Mechanistically, JAK/STAT signalling pathway was focussed by RNA-seq and we confirmed that EIP-22 up-regulated the expression of p-JAK2 and p-STAT3. Moreover, AG490, a selective inhibitor of JAK2/STAT3, eliminated the protective roles of EIP-22. The results uncovered that exercise-induced peptide EIP-22 protected cardiomyocytes from myocardial I/R injury via activating JAK2/STAT3 signalling pathway and might be a new candidate molecule for the treatment of myocardial I/R injury.

Cytokeratin 19 fragment is associated with severity and poor prognosis of interstitial lung disease in anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: In the present study, we aimed to assess the clinical significance of cytokeratin 19 fragment (CYFRA21-1) in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-interstitial lung disease (MDA5-DM-ILD). METHODS: A total of 73 MDA5-DM-ILD patients were retrospectively analysed in this work. Their clinical characteristics, including clinical manifestations, laboratory findings, peripheral blood lymphocyte subsets and lung function, were compared between patients with acute/subacute interstitial pneumonia (A/SIP) and chronic interstitial pneumonia (CIP). The level of serum CYFRA21-1 was also compared between the above-mentioned two groups of patients, and its association with the clinical features and mortality of MDA5-DM-ILD was also evaluated. RESULTS: Of the 73 MDA5-DM-ILD patients, 26 patients exhibited the A/SIP pattern. The level of serum CYFRA21-1 was higher in MDA5-DM patients with A/SIP compared with the CIP group (P = 0.009). Lower oxygenation index (OI), CD3+CD4+ T cell counts and percentage of CD3+CD4+ cells were also observed in MDA5-DM patients with A/SIP compared with the CIP group. Higher serum CYFRA21-1, lower OI, and lower zone consolidation were associated with a higher risk of A/SIP in MDA5-DM-ILD. In addition, 38 decedents with MDA5-DM-ILD exhibited a greater level of CYFRA21-1 compared with 35 survivors (P < 0.001). Furthermore, it was a prognostic factor and also associated with a higher mortality rate (log-rank test, P < 0.001). CONCLUSIONS: CYFRA21-1 could be a useful serum indicator associated with occurrence of A/SIP in MDA5-DM-ILD. Moreover, it was associated with a poor survival in MDA5-DM-ILD patients.

Novel insight from the first lung transplant of a COVID-19 patient.

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.

Bmi-1 alleviates adventitial fibroblast senescence by eliminating ROS in pulmonary hypertension.

OBJECTIVES: Pulmonary hypertension (PH) is a life-threatening progressive disease with high mortality in the elderly. However, the pathogenesis of PH has not been fully understood and there is no effective therapy to reverse the disease process. This study aims to determine whether cellular senescence is involved in the development of PH. METHODS: The rat PH model was established by intraperitoneal injection of monocrotaline and evaluated by pulmonary arteriole wall thickness and right ventricular hypertrophy index. Human lung fibroblasts (HLFs) were treated with CoCl2 or hypoxia to induce cellular senescence in vitro. SA-ß-gal staining and the changes of senescent markers were used to examine cellular senescence. The molecular mechanism of cellular senescence was further explored by detecting reactive oxygen species (ROS) levels and culturing cells with a conditioned medium. RESULTS: We revealed the cellular senescence of pulmonary adventitial fibroblasts in vivo in the rat PH model. The expression of Bmi-1, an important regulator of senescence, was decreased in the lungs of PH rats and localized in adventitial fibroblasts. The in vitro experiments showed that p16 expression was increased while Bmi-1 expression was decreased after CoCl2 treatment in HLFs. Mechanistically, Bmi-1 could alleviate CoCl2-induced HLFs senescence by eliminating ROS which further promoted the proliferation of pulmonary artery smooth muscle cells by paracrine mode of action of HLFs. CONCLUSION: Bmi-1 alleviates the cellular senescence of pulmonary fibroblasts in PH, which expands the pathogenesis of PH and provides a theoretical basis for targeting senescent cells in the treatment of PH.

Muscle death participates in myofibrillar abnormalities in FHL1 knockout mice.

BACKGROUND: Mutations in the four and-a-half LIM domain protein 1 (FHL1) gene or FHL1 protein deletion have been identified as the cause of rare hereditary myopathies or cardiomyopathies. In our previous study, autophagy activation was associated with myofibrillar abnormalities in FHL1 knockout (KO) mice. P2RX7 induces cell death, such as autophagy, pyroptosis or apoptosis via cell-specific downstream signaling; however, the roles of P2RX7 in pyroptosis or apoptosis in myofibrillar abnormalities in FHL1 KO mice have not been well elucidated. METHODS: In this study, skeletal muscle and heart of 2.5 months old WT and FHL1 KO male mice histomorphology were examined by hematoxylin and eosin staining. The indicators for pyroptosis (NLRP3; ASC; cleaved-caspase1; IL-1ß), apoptosis (Apaf-1; Bcl-2; caspase9; cleaved-caspase3), and P2RX7 were detected in the triceps (Tri), tibialis anterior muscles (TA), and heart by western blot and/or immunohistochemistry in WT and FHL1 KO male mice. RESULTS: Indicators for pyroptosis (ASC; cleaved-caspase1; IL-1ß) and apoptosis (Apaf-1 and cleaved-caspase3), as well as P2RX7 were upregulated in Tri, tibialis TA, and heart in FHL1 KO mice, indicating pyroptosis and apoptosis play important roles in myofibrillar abnormalities in FHL1 KO mice. CONCLUSIONS: P2RX7 may participate in myofibrillar abnormalities by activating pyroptosis and apoptosis in FHL1 KO mice. These findings have basic implications for the understanding of myopathies induced by FHL1 deficiency and provide new avenues for the treatment of these hereditary myopathies by modulating P2RX7.

Lung carcinoma with diffuse cystic lesions misdiagnosed as pulmonary langerhans cell histocytosis: a case report.

BACKGROUND: Cystic airspace is an uncommon imaging manifestation involved in non-small lung cancer (NSCLC). Diffuse cystic lesion is even rarer as pulmonary manifestation of NSCLC. In the present study, we reported a rare case of NSCLC associated with progressive diffusion of cystic lesions misdiagnosed as Pulmonary langerhans cell histocytosis (PLCH), finally diagnosed by transbronchial cryobiopsy (TBCB). CASE PRESENTATION: A 52-year-old woman was admitted to our hospital due to cough and dyspnea. High-resolution computed tomography (HRCT) presented diffuse cystic shadow mostly, concomitantly with nodular densities in bilateral lungs. A lung biopsy revealed poorly differentiated adenocarcinoma with vascular tumor emboli. The epidermal growth factor receptor (EGFR) mutation on exon 18 (G719X, G719) was detected by mutation test. The patient received treatment of tyrosine kinase inhibitor (afatinib). CONCLUSIONS: Diffuse cystic lesion can be a rare manifestation of lung cancer. It was important to improve the recognition of diffuse cystic lung diseases to avoid misdiagnosis.

Swietenine extracted from Swietenia relieves myocardial hypertrophy induced by isoprenaline in mice.

As a traditional plant medicine in tropical areas, Swietenia macrophylla seeds are usually applied for some chronic diseases, including hypertension, diabetes, and so on. Few studies have been carried out to identify the effective elements in seed extract and their indications. In this study, we first investigated the functions of the swietenine, an extract from S. macrophylla seeds, using a model of myocardial hypertrophy induced by isoprenaline (ISO). At cellular level, H9c2 cell hypertrophy was also established through the treatment with ISO. The cardiac pathological remodeling was evaluated by echocardiography and histological analysis. Western blot and RT-qPCR were used to detect the expression of possible hypertrophy-promoting genes. Here, our results indicated that swietenine remarkably attenuated ISO-induced myocardial hypertrophy in vivo and in vitro. Moreover, Akt phosphorylation, ANP and BNP mRNA expression were efficiently decreased. Based on these findings, we concluded that swietenine might be a promising anti-hypertrophic agent against cardiac hypertrophy.

Molecularly Engineered Macrophage-Derived Exosomes with Inflammation Tropism and Intrinsic Heme Biosynthesis for Atherosclerosis Treatment.

Atherosclerosis (AS) is a major contributor to cardiovascular diseases worldwide, and alleviating inflammation is a promising strategy for AS treatment. Here, we report molecularly engineered M2 macrophage-derived exosomes (M2 Exo) with inflammation-tropism and anti-inflammatory capabilities for AS imaging and therapy. M2 Exo are derived from M2 macrophages and further electroporated with FDA-approved hexyl 5-aminolevulinate hydrochloride (HAL). After systematic administration, the engineered M2 Exo exhibit excellent inflammation-tropism and anti-inflammation effects via the surface-bonded chemokine receptors and the anti-inflammatory cytokines released from the anti-inflammatory M2 macrophages. Moreover, the encapsulated HAL can undergo intrinsic biosynthesis and metabolism of heme to generate anti-inflammatory carbon monoxide and bilirubin, which further enhance the anti-inflammation effects and finally alleviate AS. Meanwhile, the intermediate protoporphyrin IX (PpIX) of the heme biosynthesis pathway permits the fluorescence imaging and tracking of AS.

Responsive Exosome Nano-bioconjugates for Synergistic Cancer Therapy.

Exosomes hold great potential in therapeutic development. However, native exosomes usually induce insufficient effects in vivo and simply act as drug delivery vehicles. Herein, we synthesize responsive exosome nano-bioconjugates for cancer therapy. Azide-modified exosomes derived from M1 macrophages are conjugated with dibenzocyclooctyne-modified antibodies of CD47 and SIRPα (aCD47 and aSIRPα) through pH-sensitive linkers. After systemic administration, the nano-bioconjugates can actively target tumors through the specific recognition between aCD47 and CD47 on the tumor cell surface. In the acidic tumor microenvironment, the benzoic-imine bonds of the nano-bioconjugates are cleaved to release aSIRPα and aCD47 that can, respectively, block SIRPα on macrophages and CD47, leading to abolished "don't eat me" signaling and improved phagocytosis of macrophages. Meanwhile, the native M1 exosomes effectively reprogram the macrophages from pro-tumoral M2 to anti-tumoral M1.

Phosphoinositide 3-kinase/protein kinase B inhibition restores regulatory T cell's function in pulmonary sarcoidosis.

Sarcoidosis is a systemic granulomatous disease associated with Th1/ regulatory T cells (Treg) paradigm. PI3K/Akt signaling, critical for maintaining Treg's homeostasis, is aberrantly activated in sarcoidosis patients. Here we tested the role of the PI3K inhibitors, LY294002 and BKM120, in immune modulation in experimental pulmonary sarcoidosis, concerning Th1/Th17/Treg immune profile detected by fluorescence-activated cell sorting analysis or quantitative polymerase chain reaction, as well as the effect on Treg's suppressive functions. Our investigation showed abnormal activation of PI3K/Akt signaling both in lung and Treg in pulmonary sarcoidosis, along with decreased frequency and damaged function of Treg. Blockage of PI3K suppressed this signaling in Treg, rebalanced Th1/Treg, inhibited the production of inflammatory cytokines, and enhanced Treg's function. These results demonstrate the key role of the PI3K/Akt signaling in regulating Th1/Th2 rebalances and indicates that PI3K/Akt signaling is critical for the optimal Treg responses in pulmonary sarcoidosis. Thus, PI3K inhibitors have potential for therapeutic translation, and can be candidate for add-on drugs to treat pulmonary sarcoidosis.

A long-term retrospective study of patients with biopsy-proven cryptogenic organizing pneumonia.

Cryptogenic organizing pneumonia (COP) is characterized by good response to corticosteroids, but frequent relapses after reduction or cessation of treatment are noted. The incidence, risk factors of relapse, and long-term outcomes of patients with COP remain undetermined. Patients with COP from September 2010 to December 2017 were enrolled. Hospital and office records were used as data sources. Clinical information, lab examinations, chest radiographs, treatment courses, and follow-up data were collected. Relapse group was defined as worsening of clinical manifestations in combination with progression of radiographic abnormalities in the absence of identified causes. Eighty-seven patients with COP were enrolled. Of them, 73 patients were treated with corticosteroids with relapse rate yielding 31.5% (23 of 73). Eleven patients were treated with macrolides and none of them relapsed. Fever was more common (65.2% vs. 32.0%, p = 0.004), C-reactive protein (CRP) was higher (31.5 ± 39.4 mg/L vs. 17.5 ± 32.2 mg/L, p = 0.038), and diffusion capacity for carbon monoxide (DLCO) % predicted was lower (45.9 ± 14.2% vs. 57.6 ± 18.5%, p = 0.050) in relapse group compared to nonrelapse group. Four patients who presented with organizing pneumonia (OP) as the first manifestation were ultimately diagnosed with OP secondary to autoimmune disease in follow-up. We showed relapse was common in COP patients treated with corticosteroids, but the prognosis was favorable. Fever, elevated CRP, and a reduced DLCO were related to relapse. As OP may not always be cryptogenic, a careful follow-up should be programmed to diagnose the underlying systemic disease.

Bone marrow-derived mononuclear cell therapy for nonischaemic dilated cardiomyopathy-A meta-analysis.

OBJECTIVE: The therapeutic effects of bone marrow-derived mononuclear cells (BMMNCs) transplantation in patients with nonischaemic dilated cardiomyopathy (DCM) are still under debate. Current randomized controlled trials (RCTs) reported conflicting results. The aim of this study was to assess the effects of BMMNCs transplantation on left ventricular ejection fraction (LVEF) in patients with nonischaemic DCM. METHODS: A comprehensive search of PubMed, EMBASE and Cochrane Controlled Trials Register was performed. We included RCTs reporting data on LVEF in patients with nonischaemic DCM after BMMNCs transplantation. RESULTS: Seven RCTs including 463 patients were included. BMMNCs transplantation significantly improved LVEF by 3.79% (95% CI: 0.56%-7.03%; P = .007) and LVESV by -24.36 mL (95% CI: -46.36 to -2.36 mL; P = .03), while had no impact on the risk of all-cause death (OR 0.92; 95% CI: 0.41 to 2.08%; P = .84). Subgroup analysis demonstrated a more significant improvement of LVEF in patients with longer follow-up (~15 months to 5 years) than shorter ones (12 months). Moreover, using bone marrow mononuclear cells was more effective than using G-CSF-stimulated bone marrow/peripheral blood stem cells in the improvement of LVEF in patients with nonischaemic DCM. CONCLUSIONS: Bone marrow-derived mononuclear cells transplantation is associated with a moderate, but significant, improvement in LVEF in patients with nonischaemic DCM. This meta-analysis supports further RCT conductions using BMMNCs transplantation with larger patient's population and longer term follow-up.