Vascular smooth muscle cell-specific miRNA-214 deficiency alleviates simulated microgravity-induced vascular remodeling.

The human cardiovascular system has evolved to accommodate the gravity of Earth. Microgravity during spaceflight has been shown to induce vascular remodeling, leading to a decline in vascular function. The underlying mechanisms are not yet fully understood. Our previous study demonstrated that miR-214 plays a critical role in angiotensin II-induced vascular remodeling by reducing the levels of Smad7 and increasing the phosphorylation of Smad3. However, its role in vascular remodeling evoked by microgravity is not yet known. This study aimed to determine the contribution of miR-214 to the regulation of microgravity-induced vascular remodeling. The results of our study revealed that miR-214 expression was increased in the forebody arteries of both mice and monkeys after simulated microgravity treatment. In vitro, rotation-simulated microgravity-induced VSMC migration, hypertrophy, fibrosis, and inflammation were repressed by miR-214 knockout (KO) in VSMCs. Additionally, miR-214 KO increased the level of Smad7 and decreased the phosphorylation of Smad3, leading to a decrease in downstream gene expression. Furthermore, miR-214 cKO protected against simulated microgravity induced the decline in aorta function and the increase in stiffness. Histological analysis showed that miR-214 cKO inhibited the increases in vascular medial thickness that occurred after simulated microgravity treatment. Altogether, these results demonstrate that miR-214 has potential as a therapeutic target for the treatment of vascular remodeling caused by simulated microgravity.

Atomically-Thin Holey 2D Nanosheets of Defect-Engineered MoN-Mo5 N6 Composites as Effective Hybridization Matrices.

The defect engineering of inorganic solids has received significant attention because of its high efficacy in optimizing energy-related functionalities. Consequently, this approach is effectively leveraged in the present study to synthesize atomically-thin holey 2D nanosheets of a MoN-Mo5 N6 composite. This is achieved by controlled nitridation of assembled MoS2 monolayers, which induced sequential cation/anion migration and a gradual decrease in the Mo valency. Precise control of the interlayer distance of the MoS2 monolayers via assembly with various tetraalkylammonium ions is found to be crucial for synthesizing sub-nanometer-thick holey MoN-Mo5 N6 nanosheets with a tunable anion/cation vacancy content. The holey MoN-Mo5 N6 nanosheets are employed as efficient immobilization matrices for Pt single atoms to achieve high electrocatalytic mass activity, decent durability, and low overpotential for the hydrogen evolution reaction (HER). In situ/ex situ spectroscopy and density functional theory (DFT) calculations reveal that the presence of cation-deficient Mo5 N6 domain is crucial for enhancing the interfacial interactions between the conductive molybdenum nitride substrate and Pt single atoms, leading to enhanced electron injection efficiency and electrochemical stability. The beneficial effects of the Pt-immobilizing holey MoN-Mo5 N6 nanosheets are associated with enhanced electronic coupling, resulting in improvements in HER kinetics and interfacial charge transfer.

Photo-Driven Ion Directional Transport across Artificial Ion Channels: Band Engineering of WS2 via Peptide Modification.

Biological photo-responsive ion channels play important roles in the important metabolic processes of living beings. To mimic the unique functions of biological prototypes, the transition metal dichalcogenides, owing to their excellent mechanical, electrical, and optical properties, are already used for artificial intelligent channel constructions. However, there remain challenges to building artificial bio-semiconductor nanochannels with finely tuned band gaps for accurately simulating or regulating ion transport. Here, two well-designed peptides are employed for the WS2 nanosheets functionalization with the sequences of PFPFPFPFC and DFDFDFDFC (PFC and DFC; P: proline, D: aspartate, and F: phenylalanine) through cysteine (Cys, C) linker, and an asymmetric peptide-WS2 membrane (AP-WS2M) could be obtained via self-assembly of peptide-WS2 nanosheets. The AP-WS2M could realize the photo-driven anti-gradient ion transport and vis-light enhanced osmotic energy conversion by well-designed working patterns. The photo-driven ion transport mechanism stems from a built-in photovoltaic motive force with the help of formed type II band alignment between the PFC-WS2 and DFC-WS2. As a result, the ions would be driven across the channels of the membrane for different applications. The proposed system provides an effective solution for building photo-driven biomimetic 2D bio-semiconductor ion channels, which could be extensively applied in the fields of drug delivery, desalination, and energy conversion.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Clinical prediction models for knee pain in patients with knee osteoarthritis: a systematic review.

OBJECTIVE: To identify and describe existing models for predicting knee pain in patients with knee osteoarthritis. METHODS: The electronic databases PubMed, EMBASE, CINAHL, Web of Science, and Cochrane Library were searched from their inception to May 2023 for any studies to develop and validate a prediction model for predicting knee pain in patients with knee osteoarthritis. Two reviewers independently screened titles, abstracts, and full-text qualifications, and extracted data. Risk of bias was assessed using the PROBAST. Data extraction of eligible articles was extracted by a data extraction form based on CHARMS. The quality of evidence was graded according to GRADE. The results were summarized with descriptive statistics. RESULTS: The search identified 2693 records. Sixteen articles reporting on 26 prediction models were included targeting occurrence (n = 9), others (n = 7), progression (n = 5), persistent (n = 2), incident (n = 1), frequent (n = 1), and flares (n = 1) of knee pain. Most of the studies (94%) were at high risk of bias. Model discrimination was assessed by the AUROC ranging from 0.62 to 0.81. The most common predictors were age, BMI, gender, baseline pain, and joint space width. Only frequent knee pain had a moderate quality of evidence; all other types of knee pain had a low quality of evidence. CONCLUSION: There are many prediction models for knee pain in patients with knee osteoarthritis that do show promise. However, the clinical extensibility, applicability, and interpretability of predictive tools should be considered during model development.

Impact of Shenmai Injection Combined with Chemotherapy on T-cell Subsets and Cytokine Profiles in Patients with Advanced Non-Small Cell Lung Cancer.

Background: Non-small cell lung cancer (NSCLC) represents a significant portion of lung cancer cases, with a poor prognosis and limited treatment options for advanced stages. Enhancing the effectiveness of chemotherapy through adjunctive therapies is a critical area of research. Objective: To evaluate the effect of Shenmai injection combined with chemotherapy on T-cell subsets and cytokine expression in patients with advanced NSCLC. Methods: A comparative prospective study was conducted, and a total of 96 patients with advanced NSCLC were selected. Patients were divided into two groups based on different chemotherapy regimens: an observation group (48 patients) receiving Shenmai injection combined with chemotherapy and a control group (48 patients) receiving chemotherapy alone. The study measures and compares the levels of T-cell subsets (CD3+, CD4+, CD4+/CD8+) and cytokines (IL-2, IL-4, IL-5, IL-6, TNF-α, IFN-γ, VEGF, bFGF, CA125, and CEA) before and after treatment in both groups. Statistical analysis was performed on the collected data. Results: Significant changes were observed in the levels of T-cell subsets and cytokines before and after chemotherapy in both groups (P < .05). Compared with the control group, the observation group exhibited significant improvement in T-cell subsets CD3+, CD4+, and CD4+/CD8+ (P < .05). Furthermore, the levels of cytokines IL-2, IL-4, IL-5, IL-6, TNF-α, IFN-γ, VEGF, bFGF, CA125, and CEA were significantly lower in the observation group compared to the control group (all P < .05). Conclusions: Shenmai injection combined with chemotherapy enhances the cellular immune function in patients with advanced NSCLC. This combination therapy not only reverses tumor progression but also improves the overall therapeutic effect, suggesting a promising adjunctive treatment strategy for advanced NSCLC.

Single Idiosyncratic Ionic Generator Working in Iso-Osmotic Solutions Via Ligand Confined Assembled in Gaps Between Nanosheets.

Numerous reported bioinspired osmotic energy conversion systems employing cation-/anion-selective membranes and solutions with different salinity are actually far from the biological counterpart. The iso-osmotic power generator with the specific ionic permselective channels (e.g., K+ or Na+ channels) which just allow specific ions to get across and iso-osmotic solutions still remain challenges. Inspired by nature, we report a bioinspired K+ -channel by employing a K+ selective ligand, 1,1,1-tris{[(2'-benzylaminoformyl)phenoxy]methyl}ethane (BMP) and graphene oxide membrane. Specifically, the K+ and Na+ selectivity of the prepared system could reach up to ≈17.8, and the molecular dynamics simulation revealed that the excellent permselectivity of K+ mainly stemmed from the formed suitable channel size. Thus, we assembled the K+ -selective iso-osmotic power generator (KSIPG) with the power density up to ≈15.1 mW/m2 between equal concentration solutions, which is higher than traditional charge-selective osmotic power generator (CSOPG). The proposed strategy has well shown the realizable approach to construct single-ion selective channels-based highly efficient iso-osmotic energy conversion systems and would surely inspire new applications in other fields, including self-powered systems and medical materials, etc.

Bioinspired Light-Driven Proton Pump: Engineering Band Alignment of WS2 with PEDOT:PSS and PDINN.

Bioinspired two-dimensional (2D) nanofluidic systems for photo-induced ion transport have attracted great attention, as they open a new pathway to enabling light-to-ionic energy conversion. However, there is still a great challenge in achieving a satisfactory performance. It is noticed that organic solar cells (OSCs, light-harvesting device based on photovoltaic effect) commonly require hole/electron transport layer materials (TLMs), PEDOT:PSS (PE) and PDINN (PD), respectively, to promote the energy conversion. Inspired by such a strategy, an artificial proton pump by coupling a nanofluidic system with TLMs is proposed, in which the PE- and PD-functionalized tungsten disulfide (WS2 ) multilayers construct a heterogeneous membrane, realizing an excellent output power of ≈1.13 nW. The proton transport is fine-regulated due to the TLMs-engineered band structure of WS2 . Clearly, the incorporating TLMs of OSCs into 2D nanofluidic systems offers a feasible and promising approach for band edge engineering and promoting the light-to-ionic energy conversion.

Lycorine suppresses the malignancy of breast carcinoma by modulating epithelial mesenchymal transition and ß-catenin signaling.

Lycorine, an isoquinoline alkaloid can exhibit significant anti-cancer effects. The present study was conducted to illustrate the underlying mechanisms of action of lycorine on breast carcinoma under in vitro and in vivo settings Tandem Mass Tag assay and Kyoto Encyclopedia of Genes and Genomes analysis revealed that 20 signaling pathways were closely related to tumorigenesis, especially Wnt signaling pathway and tight junctions. The results demonstrated that lycorine evidently inhibited the proliferation of MDA-MB-231 and MCF-7 cells with IC50 values of 1.84 ± 0.21 µM and 7.76 ± 1.16 µM, respectively. It also blocked cell cycle in G2/M phase, caused a decrease in mitochondrial membrane potential, and induced apoptosis pathways through regulating caspase-3, caspase-8, caspase-9, and PARP expression. Moreover, lycorine effectively repressed the ß-catenin signaling and reversed epithelial-mesenchymal transition (EMT) process. Furthermore, 4T1/Luc homograft tumor model was used to further demonstrate that lycorine significantly inhibited the growth and metastasis of breast tumor. These findings highlight the significance of lycorine as potential anti-neoplastic agent to combat breast cancer.

Berberine inhibits breast carcinoma proliferation and metastasis under hypoxic microenvironment involving gut microbiota and endogenous metabolites.

A potential role of berberine, a benzyl isoquinoline alkaloid, in cancer therapy is apparent. Its underlying mechanisms of berberine against breast carcinoma under hypoxia have not been elucidated. We focused on the doubt how berberine restrains breast carcinoma under hypoxia in vitro and in vivo. A molecular analysis of the microbiome via 16 S rDNA gene sequencing of DNA from mouse faeces confirmed that the abundances and diversity of gut microbiota were significantly altered in 4T1/Luc mice with higher survival rate following berberine treatment. A metabolome analysis liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS) revealed that berberine regulated various endogenous metabolites, especially L-palmitoylcarnitine. Furthermore, the cytotoxicity of berberine was investigated in MDA-MB-231, MCF-7, and 4T1 cells. In vitro to simulate under hypoxic environment, MTT assay showed that berberine inhibited the proliferation of MDA-MB-231, MCF-7, and 4T1 cells with IC50 values of 4.14 ± 0.35 µM, 26.53 ± 3.12 µM and 11.62 ± 1.44 µM, respectively. Wound healing and trans-well invasion studies revealed that berberine inhibited the invasion and migration of breast cancer cells. RT-qPCR analysis shed light that berberine reduced the expression of hypoxia-inducible factor-1α (HIF-1α) gene. Immunofluorescence and western blot demonstrated that berberine decreased the expression of E-cadherin and HIF-1α protein. Taken together, these results provide evidence that berberine efficiently suppresses breast carcinoma growth and metastasis in a hypoxic microenvironment, highlighting the potential of berberine as a promising anti-neoplastic agent to combat breast carcinoma.

IL8 of Takifugu rubripes is a chemokine that interacts with peripheral blood leukocytes and promotes antibacterial defense.

Interleukin 8 (IL8) is a CXC chemokine that plays a crucial role on promoting inflammatory response and immune regulation. In teleost, IL8 can induce the migration and activation of immune cells. However, the biological functions of IL8 are still unknown in Takifugu rubripes. In this study, we examined the biological characteristics of TrIL8 in T. rubripes. TrIL8 is composed of 98 residues and contained a chemokine CXC domain. We found that the TrIL8 expression was detected in diverse organs and significantly increased by Vibrio harveyi or Edwardsiella tarda challenge. The recombinant TrIL8 (rTrIL8) exhibited significantly the binding capacities to 8 tested bacteria. In addition, rTrIL8 could bind to peripheral blood leukocytes (PBL), and increased the expression of immune gene, resistance to bacterial infection, respiratory burst, acid phosphatase activity, chemotactic activity, and phagocytic activity of PBL. In the presence of rTrIL8, T. rubripes was enhanced the resistance to V. harveyi infection. These results indicated that TrIL8 is a chemokine and involved in the activation of immune cells against bacterial infection in teleost.

Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination.

BACKGROUND: Without adequate treatment, pathological cardiac hypertrophy induced by sustained pressure overload eventually leads to heart failure. WWP1 (WW domain-containing E3 ubiquitin protein ligase 1) is an important regulator of aging-related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload-induced cardiac remodeling and heart failure is yet to be determined. METHODS: To examine the correlation of WWP1 with hypertrophy, we analyzed WWP1 expression in patients with heart failure and mice subjected to transverse aortic constriction (TAC) by Western blotting and immunohistochemical staining. TAC surgery was performed on WWP1 knockout mice to assess the role of WWP1 in cardiac hypertrophy, heart function was examined by echocardiography, and related cellular and molecular markers were examined. Mass spectrometry and coimmunoprecipitation assays were conducted to identify the proteins that interacted with WWP1. Pulse-chase assay, ubiquitination assay, reporter gene assay, and an in vivo mouse model via AAV9 (adeno-associated virus serotype 9) were used to explore the mechanisms by which WWP1 regulates cardiac remodeling. AAV9 carrying cardiac troponin T (cTnT) promoter-driven small hairpin RNA targeting WWP1 (AAV9-cTnT-shWWP1) was administered to investigate its rescue role in TAC-induced cardiac dysfunction. RESULTS: The WWP1 level was significantly increased in the hypertrophic hearts from patients with heart failure and mice subjected to TAC. The results of echocardiography and histology demonstrated that WWP1 knockout protected the heart from TAC-induced hypertrophy. There was a direct interaction between WWP1 and DVL2 (disheveled segment polarity protein 2). DVL2 was stabilized by WWP1-mediated K27-linked polyubiquitination. The role of WWP1 in pressure overload-induced cardiac hypertrophy was mediated by the DVL2/CaMKII/HDAC4/MEF2C signaling pathway. Therapeutic targeting WWP1 almost abolished TAC induced heart dysfunction, suggesting WWP1 as a potential target for treating cardiac hypertrophy and failure. CONCLUSIONS: We identified WWP1 as a key therapeutic target for pressure overload induced cardiac remodeling. We also found a novel mechanism regulated by WWP1. WWP1 promotes atypical K27-linked ubiquitin multichain assembly on DVL2 and exacerbates cardiac hypertrophy by the DVL2/CaMKII/HDAC4/MEF2C pathway.

Vascular smooth muscle cell-specific miRNA-214 knockout inhibits angiotensin II-induced hypertension through upregulation of Smad7.

Vascular remodeling is a prominent trait during the development of hypertension, attributable to the phenotypic transition of vascular smooth muscle cells (VSMCs). Increasing studies demonstrate that microRNA plays an important role in this process. Here, we surprisingly found that smooth muscle cell-specific miR-214 knockout (miR-214 cKO) significantly alleviates angiotensin II (Ang II)-induced hypertension, which has the same effect as that of miR-214 global knockout mice in response to Ang II stimulation. Under the treatment of Ang II, miR-214 cKO mice exhibit substantially reduced systolic blood pressure. The vascular medial thickness and area in miR-214 cKO blood vessels were obviously reduced, the expression of collagen I and proinflammatory factors were also inhibited. VSMC-specific deletion of miR-214 blunts the response of blood vessels to the stimulation of endothelium-dependent and -independent vasorelaxation and phenylephrine and 5-HT induced vasocontraction. In vitro, Ang II-induced VSMC proliferation, migration, contraction, hypertrophy, and stiffness were all repressed with miR-214 KO in VSMC. To further explore the mechanism of miR-214 in the regulation of the VSMC function, it is very interesting to find that the TGF-ß signaling pathway is mostly enriched in miR-214 KO VSMC. Smad7, the potent negative regulator of the TGF-ß/Smad pathway, is identified to be the target of miR-214 in VSMC. By which, miR-214 KO sharply enhances Smad7 levels and decreases the phosphorylation of Smad3, and accordingly alleviates the downstream gene expression. Further, Ang II-induced hypertension and vascular dysfunction were reversed by antagomir-214. These results indicate that miR-214 in VSMC established a crosstalk between Ang II-induced AT1R signaling and TGF-ß induced TßRI /Smad signaling, by which it exerts a pivotal role in vascular remodeling and hypertension and imply that miR-214 has the potential as a therapeutic target for the treatment of hypertension.

Antidepressant-like effects of cinnamamide derivative M2 via D2 receptors in the mouse medial prefrontal cortex.

Major depressive disorder is a global mental illness associated with severe mortality and disability. The dopaminergic system is involved in both the etiology and therapeutics of depression. Distinct functions of dopamine D1 and D2 receptor subtypes have attracted considerable research interest, and their roles in the pathogenesis of depression and interaction with antidepressants need to be comprehensively elucidated. Herein, we investigated the antidepressant effects of a candidate antidepressant from a cinnamamide derivative, M2, and examined underlying neural mechanisms. We observed that a single dose of M2 (30 mg/kg, ip) produced rapid antidepressant-like effects in mice subjected to the forced swim and tail suspension tests. Using whole-cell recordings in mouse coronal brain slices, we found that application of M2 (10-150 µM) concentration-dependently increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) of the pyramidal neurons in the medial prefrontal cortex (mPFC). Furthermore, M2-induced enhancement of sEPSC frequency was abolished by sulpiride (10 µM), a dopamine D2 receptor antagonist, but not by the dopamine receptor D1 antagonist, SCH23390 (10 µM). In addition, M2 administration significantly increased expression levels of synaptogenesis-related proteins, including p-mTOR and p-TrkB, in the mPFC at 30 min, and increased postsynaptic protein PSD-95 at 24 h. Our results demonstrated that M2 produces rapid antidepressant actions through a novel mechanism via dopamine D2 receptor-mediated enhancement of mPFC neurotransmission.

Factors influencing depression in community-dwelling elderly patients with osteoarthritis of the knee in China: a cross-sectional study.

BACKGROUND: Knee osteoarthritis (OA) and depression are both major health issues influencing the quality of elderly life. The aim of the present study was to explore the prevalence of depression and the factors influencing depression in community-dwelling elderly patients with OA of the knee in China. METHODS: We conducted a cross-sectional descriptive study. The study included 214 participants aged 60 and older diagnosed with OA of the knee. The depression of the elderly was measured by using the Geriatric Depression Scale (GDS). Participants were asked to complete a demographic questionnaire, the GDS, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the society dimension of Arthritis Impact Measurement Scales 2 (AIMS2). In addition, the participants performed a timed up and go test (TUG) and the stair-climb test (SCT). RESULTS: The average age of the participants was 69.2 ± 7.63 years old, their body mass index (BMI) was 25.2 ± 3.85, and their disease duration was 5.9 ± 7.72 years. The mean total score of the GDS was 4.43 ± 2.89, and the GDS scores correlated positively with pain (r = 0.45, P < 0.001), stiffness (r = 0.40, P < 0.001), physical function (r = 0.52, P < 0.001),TUG (r = 0.35, P < 0.001), and SCT (r = 0.47, P < 0.001) and negatively with social support (r = - 0.35, P < 0.001).Analysis using multiple regression demonstrated that physical function, social support, and SCT explained 36.8% of the variance in depression. CONCLUSIONS: Our findings suggested that physical function, social support, and lower extremity strength were predictors of depressive symptoms in community-dwelling elderly people with OA of the knee. Focusing on this elderly group with increasing functional exercise, positive social interaction and support, and lower limb muscle strength training should help in the prevention of depression.

High serum exosomal long non-coding RNA DANCR expression confers poor prognosis in patients with breast cancer.

BACKGROUND: Exosomal long non-coding RNAs (lncRNAs) serve as excellent candidate biomarkers for clinical applications. The expression of differentiation antagonizing non-protein coding RNA (DANCR) has been shown to be decreased in breast cancer (BC) tissues and cell lines. However, the clinical value of circulating exosomal DANCR in BC has not been explored. METHODS: A total of 120 BC patients, 70 benign breast disease (BBD) patients, and 105 healthy women were recruited in this study. Total RNA was extracted from serum samples, and the level of serum exosomal lncRNA DANCR was evaluated by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: Serum exosomal lncRNA DANCR levels were significantly higher in BC patients than in BBD patients and normal controls. The diagnostic performance of serum exosomal lncRNA DANCR was good, and the combination of serum exosomal lncRNA DANCR, CA153, and CEA greatly improved the diagnostic accuracy for BC. High serum exosomal lncRNA DANCR level was associated with various clinicopathological variables including lymph node metastasis, ER status, HER2 status, and TNM stage. In addition, the BC patients in the high serum exosomal lncRNA DANCR expression group had significantly shorter 5-year overall survival time. Multivariate analysis demonstrated that serum exosomal lncRNA DANCR was an independent risk factor for BC. CONCLUSION: Serum exosomal lncRNA DANCR may be a useful non-invasive biomarker for the clinical diagnosis and prognosis of BC.

Establishment and Validation of Coagulation Factor-Based Nomogram for Predicting the Recurrence-Free Survival of Prostate Cancer.

INTRODUCTION: We aimed to establish and validate a coagulation feature-based nomogram to predict recurrence-free survival in prostate cancer patients. METHODS: The study included 168 prostate cancer patients who had received radical prostatectomy between 2012 and 2018. Kaplan-Meier plot and log-rank analysis were used to screen recurrence-free survival-related features. The nomogram was established by combining the significant coagulation features with clinicopathological characteristics by using Cox regression analysis. The accuracy and clinical significance of the nomogram model were assessed by the receiver operating characteristic curve, Kaplan-Meier plot, and calibration plot. We explored the correlation between coagulation pathway activity and patient prognosis in public datasets by using gene set variation analysis (GSVA). RESULTS: The results suggested that patients classified by the nomogram into the high-risk subgroup showed unfavorable prognoses compared with those in the low-risk subgroup in both the training (log-rank p < 0.0001) and validation (log-rank p = 0.0004) cohorts. The nomogram model exhibited high discriminative accuracy in the training cohort (1-year area under the curve [AUC] of 0.74 and 3-year AUC of 0.69), which was confirmed in the internal validation cohort (C-index = 0.651). The calibration plots confirmed good concordance for the prediction of recurrence-free survival at 1 and 3 years. Subgroup analyses confirmed the utility of this model in different clinicopathological subgroups. Finally, GSVA suggested that patients with higher coagulation pathway scores mostly had unfavorable prognoses compared to those with lower scores, a result consistent with the findings above. CONCLUSIONS: We developed a practical nomogram model for predicting recurrence-free survival in prostate cancer patients. This model may offer clinicians prognostic assessments and facilitate personalized treatment.

LncRNA IGF2-AS promotes endometriosis progression through targeting miR-370-3p/IGF2 axis and activating PI3K/AKT/mTOR signaling pathway.

PURPOSE: Endometriosis, a gynecological disease, is difficult to be cured. Currently, to identify more potential biomarkers for the early diagnosis of endometriosis is urgently needed. Insulin like growth factor 2 (IGF2) has been revealed to correlate with endometriosis. This research aimed to further explore the role of IGF2 and its up-stream mechanism in endometriosis. METHODS: Primary ectopic endometrial stromal cells (EESCs) were extracted from ectopic endometrial tissues which were pathological endometrial tissues resected from three patients with II-III endometriosis. Primary normal endometrial stromal cells (NESCs) were extracted from normal endometrial tissues of two patients with grade III cervical dysplasia and one patient with uterine leiomyoma III. Four endometriotic cell lines (EEC145T, hEM15A, hEM5B2, and 12Z) and normal human endometrial epithelial cells (hEECs) were purchased. Cell proliferation, migration, and invasion were evaluated through functional assays. The molecular interaction between RNAs was investigated through mechanistic analyses. RESULTS: We discovered that IGF2 was upregulated in purchased endometriotic cells and primary EESC. Suppression of IGF2 hampered cell proliferation, migration, and invasion. Furthermore, insulin-like growth factor 2 antisense RNA (IGF2-AS) was uncovered to positively regulate IGF2 expression and enhanced proliferative, migratory, and invasive abilities of endometriotic cells. Mechanistically, miR-370-3p was found to bind with IGF2-AS and IGF2. IGF2-AS competitively bind with miR-370-3p to upregulate IGF2. Furthermore, IGF2-AS was revealed to activate the PI3K/AKT/mTOR signaling pathway through targeting miR-370-3p/IGF2 axis. CONCLUSION: IGF2-AS promotes endometriotic cell growth via regulating IGF2/miR-370-3p axis and further activating PI3K/AKT/mTOR signaling pathway.

3' untranslated region of Ckip-1 inhibits cardiac hypertrophy independently of its cognate protein.

AIMS: 3' untranslated region (3' UTR) of mRNA is more conserved than other non-coding sequences in vertebrate genomes, and its sequence space has substantially expanded during the evolution of higher organisms, which substantiates their significance in biological regulation. However, the independent role of 3' UTR in cardiovascular disease was largely unknown. METHODS AND RESULTS: Using bioinformatics, RNA fluorescent in situ hybridization and quantitative real-time polymerase chain reaction, we found that 3' UTR and coding sequence regions of Ckip-1 mRNA exhibited diverse expression and localization in cardiomyocytes. We generated cardiac-specific Ckip-1 3' UTR overexpression mice under wild type and casein kinase 2 interacting protein-1 (CKIP-1) knockout background. Cardiac remodelling was assessed by histological, echocardiography, and molecular analyses at 4 weeks after transverse aortic constriction (TAC) surgery. The results showed that cardiac Ckip-1 3' UTR significantly inhibited TAC-induced cardiac hypertrophy independent of CKIP-1 protein. To determine the mechanism of Ckip-1 3' UTR in cardiac hypertrophy, we performed transcriptome and metabolomics analyses, RNA immunoprecipitation, biotin-based RNA pull-down, and reporter gene assays. We found that Ckip-1 3' UTR promoted fatty acid metabolism through AMPK-PPARα-CPT1b axis, leading to its protection against pathological cardiac hypertrophy. Moreover, Ckip-1 3' UTR RNA therapy using adeno-associated virus obviously alleviates cardiac hypertrophy and improves heart function. CONCLUSIONS: These findings disclose that Ckip-1 3' UTR inhibits cardiac hypertrophy independently of its cognate protein. Ckip-1 3' UTR is an effective RNA-based therapy tool for treating cardiac hypertrophy and heart failure.

The role of postmastectomy radiation in patients with ypN0 breast cancer after neoadjuvant chemotherapy: a meta-analysis.

BACKGROUND: It has been demonstrated that postmastectomy radiation therapy (PMRT) was beneficial for breast cancer patients who are axillary lymph node-positive. However, the effectiveness of radiotherapy in pathological negative nodes (ypN0) after neoadjuvant chemotherapy (NAC) remains open to considerable debate. Here, we aim to evaluate whether PMRT improves loco-regional control and survival for such patients. METHODS: The literature from January 2004 to June 2019 was searched. The effects of PMRT on local-regional recurrence (LRR) and survival was evaluated in a meta-analysis. Pooled relative risk (RR) values with 95% confidence intervals (CIs) were computed using random and fixed-effect model. Subgroup and heterogeneity analyses were also conducted. RESULTS: Twelve studies that included 17,747 patients met the inclusion criteria. Pooled results showed that PMRT was associated with reduced LRR (RR, 0.38; 95% CI, 0.19-0.77, P = 0.007), particularly in patients with stage III breast cancer (RR, 0.16; 95% CI, 0.07-0.37, P < 0.001). However, no significant difference in disease-free survival were observed with the addition of PMRT for ypN0 patients (RR, 0.70; 95% CI, 0.21-2.27, P = 0.55). Also, there was no statistically significant association between radiotherapy with overall survival (RR, 0.81; 95% CI, 0.64-1.04, P = 0.10). CONCLUSIONS: Our meta-analysis indicated that PMRT might reduce local-regional recurrence for ypN0 patients after NAC, but lack of benefit for survival outcomes. Prospective randomized clinical trial data will be needed to confirm our results.