Chromosome instability functions as a potential therapeutic reference by enhancing chemosensitivity to BCL-XL inhibitors in colorectal carcinoma.

Chromosome instability (CIN) and subsequent aneuploidy are prevalent in various human malignancies, influencing tumor progression such as metastases and relapses. Extensive studies demonstrate the development of chemoresistance in high-CIN tumors, which poses significant therapeutic challenges. Given the association of CIN with poorer prognosis and suppressed immune microenvironment observed in colorectal carcinoma (CRC), here we aimed to discover chemotherapeutic drugs exhibiting increased inhibition against high-CIN CRC cells. By using machine learning methods, we screened out two BCL-XL inhibitors Navitoclax and WEHI-539 as CIN-sensitive reagents in CRC. Subsequent analyses using a CIN-aneuploidy cell model confirmed the vulnerability of high-CIN CRC cells to these drugs. We further revealed the critical role of BCL-XL in the viability of high-CIN CRC cells. In addition, to ease the evaluation of CIN levels in clinic, we developed a three-gene signature as a CIN surrogate to predict prognosis, chemotherapeutic and immune responses in CRC samples. Our results demonstrate the potential value of CIN as a therapeutic target in CRC treatment and the importance of BCL-XL in regulating survival of high-CIN CRC cells, therefore representing a valuable attempt to translate a common trait of heterogeneous tumor cells into an effective therapeutic target.

Relationship between plasma TNF-α levels and agitation symptoms in first episode patients with schizophrenia.

BACKGROUND: Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS). METHODS: The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC). RESULTS: The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels. CONCLUSIONS: These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

Low expression of ACOT13 predicts poor prognosis and immunotherapy outcome in ovarian cancer.

OBJECTIVE: Acyl-CoA thioesterase 13 (ACOT13) is involved in lipid biosynthesis, gene transcription, and signal transduction. We explored the potential of ACOT13 to predict ovarian cancer (OC) prognosis and patient immunotherapy responses. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus databases were used to extract raw data. To investigate the potential of ACOT13 as a prognostic and immunotherapeutic marker for OC, bioinformatic analyses were performed using the TIMER website, LinkedOmics database, and R software. We also explored the effects on the invasive ability of OC cells in vitro using a ACOT13 knockdown. RESULTS: The expression of ACOT13 in OC was high and associated with a better prognosis. The expression of ACOT13 was also linked to immune cell invasion immunity-related gene expression. Additionally, immunotherapy was more effective in patients with high ACOT13 expression levels. Multiple critical signaling pathways were found to be involved in the role of ACOT13 in energy metabolism and cell mobility based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. OC cells invaded and migrated significantly more when ACOT13 was knocked down. CONCLUSION: High ACOT13 expression in OC is associated to a better OC outcome.

Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs.

Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant to therapy, and inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this heterogeneity and its effects. Here, we compile a cohort of 28 patient-derived glioblastoma stem cell-like lines (GSCs) known to reflect the properties of their tumor-of-origin; six of these were primary-relapse tumor pairs from the same patient. We generate and analyze 5 kbp-resolution chromosome conformation capture (Hi-C) data from all GSCs to systematically map thousands of standalone and complex structural variants (SVs) and the multitude of neoloops arising as a result. By combining Hi-C, histone modification, and gene expression data with chromatin folding simulations, we explain how the pervasive, uneven, and idiosyncratic occurrence of neoloops sustains tumor-specific transcriptional programs via the formation of new enhancer-promoter contacts. We also show how even moderately recurrent neoloops can relate to patient-specific vulnerabilities. Together, our data provide a resource for dissecting GBM biology and heterogeneity, as well as for informing therapeutic approaches.

[Impact of different angles of pulmonary surfactant administration on bronchopulmonaryplasia and intracranial hemorrhage in preterm infants: a prospective randomized controlled study]. / ä¸åŒè§’åº¦æ³¨å ¥è‚ºè¡¨é¢æ´»æ€§ç‰©è´¨å¯¹æ—©äº§å„¿æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯å’Œé¢ å† å‡ºè¡€çš„å½±å“ï¼šä¸€é¡¹å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To investigate the effects of different angles of pulmonary surfactant (PS) administration on the incidence of bronchopulmonary dysplasia and intracranial hemorrhage in preterm infants. METHODS: A prospective study was conducted on 146 preterm infants (gestational age <32 weeks) admitted to the Department of Neonatology, Provincial Hospital Affiliated to Anhui Medical University from January 2019 to May 2023. The infants were randomly assigned to different angles for injection of pulmonary surfactant groups: 0° group (34 cases), 30° group (36 cases), 45° group (38 cases), and 60° group (38 cases). Clinical indicators and outcomes were compared among the groups. RESULTS: The oxygenation index was lower in the 60° group compared with the other three groups, with shorter invasive ventilation time and oxygen use time, and a lower incidence of bronchopulmonary dysplasia than the other three groups (P<0.05). The incidence of intracranial hemorrhage was lower in the 60° group compared to the 0° group (P<0.05). The cure rate in the 60° group was higher than that in the 0° group and the 30° group (P<0.05). CONCLUSIONS: The clinical efficacy of injection of pulmonary surfactant at a 60° angle is higher than other angles, reducing the incidence of intracranial hemorrhage and bronchopulmonary dysplasia in preterm infants.

The development and the genetic diseases of the ciliary body.

The ciliary body, located at the junction of the choroid and iris, is crucial in the development of the embryonic eye. Notch2 signalling, Wnt signalling, transforming growth factor ß (TGF-ß) signalling, and Pax6 signalling are critical for coordinating the ciliary body formation. These signalling pathways are coordinated with each other and participate in the ciliary body development, ensuring the precise formation and optimal functioning of the eye structure. Although rare, ciliary body hypoplasia, ciliary tumours, and genetic-related iritis indicate the intricate nature of ciliary body development. Given the ciliary body's important biological significance and potential medical relevance, we aim to provide a comprehensive overview of the developmental molecular mechanisms governing ciliary body formation and function. Here, we focus on the intricate signalling pathways governing ciliary body development and corresponding genetic ciliary diseases.

An "All-In-One" Immunomodulator-Engineered Clinical Translatable Immunotherapy of Advanced Hepatocellular Carcinoma.

Clinical treatment of advanced hepatocellular carcinoma (HCC) remains a significant challenge. Utilizing 1-bromoacetyl-3,3-dinitroazetidine (RRx-001) to downregulate the expression of innate immune checkpoint molecule, cluster of differentiation 47 (CD47), provides a powerful means for treating advanced HCC containing abundant immunosuppressive macrophages. Herein engineering of a previously optimized Doxorubicin (DOX)-delivery nanoplatform based on sodium alginate is reported to further co-deliver RRx-001 (biotinylated aldehyde alginate-doxorubicin micelle prodrug nanoplatform, BEA-D@R) for efficient immunotherapy of advanced HCC. This groundbreaking  technique reveals the "all-in-one" immunotherapeutic functionalities of RRx-001. Besides the previously demonstrated functions of downregulating CD47 expression and increasing reactive nitrogen species (RNS) generation, another key function of RRx-001 for downregulating the expression of the adaptive immune checkpoint molecule programmed cell death 1 ligand 1 (PDL1) is first uncovered here. Combined with the reactive oxygen species (ROS) generation and an upregulated "eat me" signal level of DOX, BEA-D@R collectively increases RNS generation, enhances T-cell infiltration, and maximizes macrophage phagocytosis, leading to an average of 40% tumor elimination in a mice model bearing an initial tumor volume of ≈300 mm3 that mimics advanced HCC. Overall, the "all-in-one" immunotherapeutic functionalities of a clinical translatable nanoplatform are uncovered for enhanced immunotherapy of advanced HCC.

Arming Amorphous NiMoO4 on Nickel Phosphide Enables Highly Stable Alkaline Seawater Oxidation.

Seawater electrolysis holds tremendous promise for the generation of green hydrogen (H2). However, the system of seawater-to-H2 faces significant hurdles, primarily due to the corrosive effects of chlorine compounds, which can cause severe anodic deterioration. Here, a nickel phosphide nanosheet array with amorphous NiMoO4 layer on Ni foam (Ni2P@NiMoO4/NF) is reported as a highly efficient and stable electrocatalyst for oxygen evolution reaction (OER) in alkaline seawater. Such Ni2P@NiMoO4/NF requires overpotentials of just 343 and 370 mV to achieve industrial-level current densities of 500 and 1000 mA cm-2, respectively, surpassing that of Ni2P/NF (470 and 555 mV). Furthermore, it maintains consistent electrolysis for over 500 h, a significant improvement compared to that of Ni2P/NF (120 h) and Ni(OH)2/NF (65 h). Electrochemical in situ Raman spectroscopy, stability testing, and chloride extraction analysis reveal that is situ formed MoO4 2-/PO4 3- from Ni2P@NiMoO4 during the OER test to the electrode surface, thus effectively repelling Cl- and hindering the formation of harmful ClO-.

Benign thyroid nodules classified as ACR TI-RADS 4 or 5: Imaging and histological features.

BACKGROUND: American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) being most widely applied in clinical practice, there is an overlap in US imaging manifestations between benign and malignant thyroid nodules. OBJECTIVES: To analyze the imaging and histological characteristics of pathological benign thyroid nodules categorized as American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) 4 or 5, and to explore the correlation between the suspicious sonographic signs resulting in the misdiagnoses and the histopathological features. MATERIALS AND METHODS: Overall, 227 benign thyroid nodules (215 patients) in ACR TI-RADS 4 or 5 sampled through surgical excision were analyzed between December 2020 and August 2022. We retrospectively reread the ultrasound (US) images of the pathological discordant cases, after which we performed a systematic analysis focusing on the histopathological characteristics of thyroid lesions and recorded the findings. Qualitative US features and pathological significance of the thyroid nodules were analyzed using the chi-square and Fisher's exact tests. RESULTS: The pathological type of 227 thyroid nodules (n = 103 in ACR TI-RADS 4 and n = 124 in ACR TI-RADS 5) was nodular goiter together with other histopathological features, namely, fibrosis (n = 103, 45.4 %), calcification (n = 70, 30.8 %), adenomatous hyperplasia (n = 31, 13.7 %), follicular epithelial hyperplasia (n = 23, 10.1 %), Hashimoto's thyroiditis (n = 18, 7.9 %), and cystic degeneration (n = 16, 7.1 %). Fibrosis was the most common histopathological feature in both ACR TI-RADS 4 (n = 42, 40.8 %) and 5 (n = 61, 49.2 %) categories of benign thyroid nodules. Thyroid nodules with fibrosis demonstrated sonographic features of "taller than wide" (p < 0.05), while lesions with follicular epithelial hyperplasia were likely to be detected with irregular and/or lobulated margins and very hypoechoic on US (p < 0.05 for both). CONCLUSION: Benign thyroid nodules with histopathological findings such as fibrosis are associated with suspicious US features, which may give inappropriately higher TIRADS stratification.

Dynamic monitoring of circulating tumor DNA reveals outcomes and genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy.

BACKGROUND: Over 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse or progression remains a significant challenge. In this study, we prospectively investigate the prognostic value of dynamic circulating tumor DNA (ctDNA) and track genetic evolution non-invasively, for the first time in an Asian population of r/r patients undergoing CAR19 T-cell therapy. METHODS: Longitudinal plasma samples were prospectively collected both before lymphodepletion and at multiple timepoints after CAR19 T-cell infusion. ctDNA was detected using a capture-based next-generation sequencing which has been validated in untreated LBCL. RESULTS: The study enrolled 23 patients with r/r LBCL and collected a total of 101 ctDNA samples. Higher pretreatment ctDNA levels were associated with inferior progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.023). Patients with undetectable ctDNA negative (ctDNA-) at day 14 (D14) achieved an impressive 3-month complete response rate of 77.8% vs 22.2% (p=0.015) in patients with detectable ctDNA positive (ctDNA+), similar results observed for D28. CtDNA- at D28 predicted significantly longer 1-year PFS (90.9% vs 27.3%; p=0.004) and OS (90.9% vs 49.1%; p=0.003) compared with patients who remained ctDNA+. Notably, it is the first time to report that shorter ctDNA fragments (<170 base pairs) were significantly associated with poorer PFS (p=0.031 for D14; p=0.002 for D28) and OS (p=0.013 for D14; p=0.008 for D28) in patients with LBCL receiving CAR T-cell therapy. Multiple mutated genes exhibited an elevated prevalence among patients with progressive disease, including TP53, IGLL5, PIM1, BTG1, CD79B, GNA13, and P2RY8. Notably, we observed a significant correlation between IGLL5 mutation and inferior PFS (p=0.008) and OS (p=0.014). CONCLUSIONS: Our study highlights that dynamic ctDNA monitoring during CAR T-cell therapy can be a promising non-invasive method for early predicting treatment response and survival outcomes. Additionally, the ctDNA mutational profile provides novel insights into the mechanisms of tumor-intrinsic resistance to CAR19 T-cell therapy.

The relationship between atrial cardiopathy biomarkers and prognosis of patients with acute ischemic stroke after endovascular treatment.

Thromboembolism is a possible consequence of underlying atrial cardiopathy, which can occur even before the onset of atrial fibrillation. Our objective was to examine the association between biomarkers of atrial cardiopathy and outcomes of acute ischemic stroke (AIS) following endovascular treatment (EVT). We conducted a retrospective study that collected data from patients with AIS who underwent EVT and compared the outcomes between those with and without atrial cardiopathy. Neurological function was assessed using the modified Rankin Scale (mRS), with an mRS score >2 indicating poor function at day 90. Additionally, we evaluated secondary consequences, including symptomatic intracerebral hemorrhage (sICH), early neurological deterioration (END), and malignant cerebral edema (MCE). Our study included 87 patients (77.6 â€‹% male; mean age 60.93 â€‹± â€‹12.47 years). Among these patients, 29 (33.3 â€‹%) had atrial cardiopathy, while the remaining 58 (66.7 â€‹%) did not. In the atrial cardiopathy group, 12 patients (41.4 â€‹%) had poor functional outcomes (mRS>2), compared to 19 (32.8 â€‹%) in the non-atrial cardiopathy group. We observed sICH in 22 (25.3 â€‹%) patients, END in 14 (16.1 â€‹%) patients, MCE in 11 (12.6 â€‹%) patients, and two (2.3 â€‹%) patients who died in the hospital. We found that patients with PTFV1>5000 â€‹µV/ms (OR: 8.39, 95 â€‹% CI: 1.43-105.95, P â€‹= â€‹0.02) and NT-proBNP>250 â€‹pg/mL (OR: 5.09, 95 â€‹% CI: 1.20-27.63, P â€‹= â€‹0.03) had significantly higher risk of END. After adjusting for covariates in the Firth logistic regression, we further found that atrial cardiopathy was significantly associated with END, as revealed by both univariate (OR: 6.31, 95 â€‹% CI: 1.42-59.87, P â€‹= â€‹0.01) and multivariable firth regression models (Modle 1, OR: 7.10, 95 â€‹% CI: 1.57-67.38, P â€‹< â€‹0.01; Modle 2, OR: 7.82, 95 â€‹% CI: 1.69, 76.36, P â€‹< â€‹0.01; Modle 3, OR: 8.59, 95 â€‹% CI: 1.72-91.70, P â€‹< â€‹0.01). Moreover, we observed that atrial cardiopathy was associated with an increased risk of END in AIS patients with large artery atherosclerosis (LAA) receiving EVT. Therefore, clinicians should consider atrial cardiopathy as a possible underlying cause of AIS in their patients. Further investigation is warranted to elucidate the relationship between atrial cardiopathy and AIS's occurrence, progression, and prognosis.

Mitral valve leaflet blood cyst treated with minimally invasive approach: a case report and review of literature.

INTRODUCTION: Cardiac blood cyst is a very rare benign tumor of the heart in adults. Though it is very common in the first half year of life, it regresses with time and its occurrence is very rare in children older than six months and in adults. Until now less than 100 valvular blood cyst cases have been reported in adults. CASE PRESENTATION: We present a case of a 66-year-old male who presented to us with exertional chest tightness, shortness of breath, and right leg weakness for two weeks. He was diagnosed with a cardiac mass two months ago in another hospital. The physical examination was unremarkable. Abdominal ultrasound showed a cyst in the liver and left kidney. Echocardiography showed a mass-occupying lesion of a cystic nature in the mitral valve with moderate mitral regurgitation. Based on echocardiography findings and computed tomography report, the preliminary diagnosis of mitral valve cystic tumor was made. The patient underwent minimally invasive resection of the cyst. The posterior mitral cusp was repaired and a mitral annuloplasty ring was placed. The postoperative recovery was uneventful. The histopathology report confirmed the diagnosis of a cardiac blood cyst. The patient was followed up for six months without any complications. This case is presented to enrich the medical literature on the cardiac blood cyst. CONCLUSION: Although a cardiac blood cyst is a rare entity in adults, it still should be considered in the differential diagnosis of cardiac tumors. Because the natural history and hemodynamic effects are very diverse, large symptomatic cardiac blood cysts, especially in the left heart should be resected to avoid complications.

HDAC9 inhibition reduces skeletal muscle atrophy and enhances regeneration in mice with cigarette smoke-induced COPD.

Cigarette smoke (CS) is the major risk factor for chronic obstructive pulmonary disease (COPD), and sarcopenia is one of the significant comorbidities of COPD. However, the pathogenesis of CS-related deficient skeletal muscle regeneration has yet to be clarified. The impact of CS on myoblast differentiation was examined, and then we determined which HDAC influenced the myogenic process and muscle atrophy in vitro and in vivo. Finally, we further investigated the potential mechanisms via RNA sequencing. Long-term CS exposure activated skeletal muscle primary satellite cells (SCs) while inhibiting differentiation, and defective myogenesis was also observed in C2C12 cells treated with CS extract (CSE). The level of HDAC9 changed in vitro and in vivo in CS exposure models as well as COPD patients, as detected by bioinformatics analysis. Our data showed that CSE impaired myogenic capacity and myotube formation in C2C12 cells via HDAC9. Moreover, inhibition of HDAC9 in mice exposed to CS prevented skeletal muscle dysfunction and promoted SC differentiation. The results of RNA-Seq analysis and verification indicated that HDAC9 knockout improved muscle differentiation in CS-exposed mice, probably by acting on the AKT/mTOR pathway and inhibiting the P53/P21 pathway. More importantly, the serum of HDAC9 KO mice exposed to CS alleviated the differentiation impairment of C2C12 cells caused by serum intervention in CS-exposed mice, and this effect was inhibited by LY294002 (an AKT/mTOR pathway inhibitor). These results suggest that HDAC9 plays an essential role in the defective regeneration induced by chronic exposure to CS.

Resection of intracardiac leiomyoma originating from the inferior vena cava through a single median sternotomy incision using a silk suture snare technique: a case report.

BACKGROUND: Intracardiac leiomyoma is a rare benign right heart tumor that usually extends from the intravenous system. The patient often has a history of uterine leiomyoma. CASE PRESENTATION: We report a 46-year-old female patient who presented to us with exertional dyspnea, chest tightness, and shortness of breath for two weeks and had a history of uterine leiomyoma resection. Echocardiography showed a pedunculated solid mass in the right heart with the pedicle attached to the inferior vena cava. The surgery was performed under cardiopulmonary bypass established through the femoral artery and vein with a probable diagnosis of leiomyoma. The tumor was removed by ingenious surgical technique: a snare made of silk suture in which the tumor's pedicle was trapped, and the tumor with its pedicle was carefully removed with the help of a scalpel along the silk suture. The histopathology report confirmed the diagnosis of intravenous leiomyoma. The postoperative course was uneventful and the patient was discharged a week later. CONCLUSION: Intracardiac leiomyoma is a rare benign smooth muscle tumor. Surgery is the mainstay of treatment with different surgical approaches available. It is possible to completely remove cardiac leiomyomas through sternotomy without the need for an abdominal incision if the leiomyoma is originated in the inferior vena cava not far from the right atrium.

ZIP14 Affects the Proliferation, Apoptosis, and Migration of Cervical Cancer Cells by Regulating the P38 MAPK Pathway.

BACKGROUND: Cervical cancer (CC) remains a major public health concern and is a leading cause of female mortality worldwide. Understanding the molecular basis of its pathogenesis is essential for the development of novel therapeutic strategies. In this study, we aimed to dissect the role of a specific molecule, ZIP14, in the initiation and progression of CC. METHOD: We used Gene Expression Omnibus for target gene identification, while KEGG was used to delineate CC-related pathways. Proliferation, migration, and apoptosis levels in CC cells were assessed using CCK8, Transwell, and flow cytometry, respectively. The effect of the target genes on the in vivo tumorigenesis of CC cells was evaluated using the subcutaneous tumorigenesis assay. RESULTS: ZIP14 (SLC39A14) was found to be underexpressed in CC samples. Our KEGG pathway analysis revealed the potential involvement of the P38 mitogen-activated protein kinase (MAPK) pathway in CC pathogenesis. Overexpression of ZIP14 in HeLa and Caski cells increased p38 phosphorylation, inhibited cell growth and migration, and enhanced apoptosis. Conversely, ZIP14 knockdown produced the opposite effects. Importantly, the bioeffects induced by ZIP14 overexpression could be counteracted by the p38 MAPK pathway inhibitor SB203580. In vivo experiments further confirmed the influence of ZIP14 on CC cell migration. CONCLUSION: Our study is the first to elucidate the pivotal role of ZIP14 in the pathogenesis of CC, revealing its inhibitory effects through the activation of the p38 MAPK signaling pathway. The discovery not only provides a deeper understanding of CC's molecular underpinnings, but also highlights ZIP14 as a promising therapeutic target. As ZIP14 holds significant potential for therapeutic interventions, our findings lay a robust foundation for further studies and pave the way for the exploration of novel treatment modalities for cervical cancer.

[Platelet-rich Plasma Induces M2 Macrophage Polarization via Regulating AMPK Singling Pathway].

OBJECTIVE: To investigate the role of platelet-rich plasma (PRP) in inducing the M2 macrophage polarization via regulating AMPK singling pathway. METHODS: The expressions of M1 marker CD11c and M2 marker CD206 in macrophages of blank control group, LPS group, LPS+PRP group, and LPS+PRP+Compound C group were detected by flow cytometry. Western blot was used to observe the effects of PRP on the expression of AMPK-mTOR signaling pathway-related proteins at different times (12 h, 18 h and 24 h) after LPS treatment. RNA interference technology was used to silence the expression of AMPK in macrophages, and the expression of TGF-ß protein was subsequently examined by Western blot. RESULTS: LPS significantly reduced the expression of CD206 and increased the expression of CD11c (P <0.05). After the addition of PRP, the expression of CD206 was significantly increased (P <0.05), while the expression of CD11c was significantly decreased (P <0.05). Compared with LPS group, PRP treatment significantly increased the expressions of p-AMPK and p-ULK1 proteins at 12 h, 18 h and 24 h, while significantly decreased the expression of p-mTOR protein (P <0.05). After the addition of AMPK inhibitor Compound C, the expression of CD206 was significantly reduced (P <0.05) and the expression of CD11c was significantly increased compared with LPS+PRP group (P <0.05). After silencing the expression of AMPK in macrophages, the promotion effect of PRP on TGF-ß was significantly reduced (P <0.05). CONCLUSION: PRP can stimulate the transformation of macrophages to M2 type via AMPK signalling pathway.

SP1-Induced Upregulation of LncRNA AFAP1-AS1 Promotes Tumor Progression in Triple-Negative Breast Cancer by Regulating mTOR Pathway.

The long non-coding RNA (lncRNA) actin fiber-associated protein-1 antisense RNA 1 (AFAP1-AS1) exerted oncogenic activity in triple-negative breast cancer (TNBC). We designed this study and conducted it to investigate the upstream regulation mechanism of AFAP1-AS1 in TNBC tumorigenesis. In this work, we proved the localization of AFAP1-AS1 in the cytoplasm. We elucidated the mechanism by which the transcription factor specificity protein 1 (SP1) modulated AFAP1-AS1 in TNBC progression, which has yet to be thoroughly studied. Dual luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay revealed a strong affinity of SP1 toward the promoter regions P3 of AFAP1-AS1, proving the gene expression regulation of AFAP1-AS1 via SP1 in TNBC. Additionally, SP1 could facilitate the tumorigenesis of TNBC cells in vitro and in vivo by regulating the AFAP1-AS1 expression. Furthermore, silenced AFAP1-AS1 suppressed the expression of genes in the mTOR pathway, such as eukaryotic translation initiation factor 4B (EIF4B), mitogen-activated protein kinase-associated protein 1 (MAPKAP1), SEH1-like nucleoporin (SEH1L), serum/glucocorticoid regulated kinase 1 (SGK1), and its target NEDD4-like E3 ubiquitin protein ligase (NEDD4L), and promoted the gene expression of s-phase kinase-associated protein 2 (SKP2). Overall, this study emphasized the oncogenic role of SP1 and AFAP1-AS1 in TNBC and illustrated the AFAP1-AS1 upstream interaction with SP1 and the downstream modulatory of mTOR signaling, thus offering insights into the tumorigenesis mechanism in TNBC.

Gap junction-transported cAMP from the niche controls stem cell progeny differentiation.

The niche has been shown to control stem cell self-renewal in different tissue types and organisms. Recently, a separate niche has been proposed to control stem cell progeny differentiation, called the differentiation niche. However, it remains poorly understood whether and how the differentiation niche directly signals to stem cell progeny to control their differentiation. In the Drosophila ovary, inner germarial sheath (IGS) cells contribute to two separate niche compartments for controlling both germline stem cell (GSC) self-renewal and progeny differentiation. In this study, we show that IGS cells express Inx2 protein, which forms gap junctions (GJs) with germline-specific Zpg protein to control stepwise GSC lineage development, including GSC self-renewal, germline cyst formation, meiotic double-strand DNA break formation, and oocyte specification. Germline-specific Zpg and IGS-specific Inx2 knockdowns cause similar defects in stepwise GSC development. Additionally, secondary messenger cAMP is transported from IGS cells to GSCs and their progeny via GJs to activate PKA signaling for controlling stepwise GSC development. Therefore, this study demonstrates that the niche directly controls GSC progeny differentiation via the GJ-cAMP-PKA signaling axis, which provides important insights into niche control of stem cell differentiation and highlights the importance of GJ-transported cAMP in tissue regeneration. This may represent a general strategy for the niche to control adult stem cell development in various tissue types and organisms since GJs and cAMP are widely distributed.

The molecular link between obstructive sleep apnea and osteoarthritis: based on bioinformatics analysis and experimental validation.

BACKGROUND: Obstructive sleep apnea (OSA) and osteoarthritis (OA) are highly prevalent and seriously affect the patient's quality of life. Patients with OSA have a high incidence of OA, however, the underlying mechanism remains unclear. Here, we investigated the molecular link between OSA and OA via bioinformatics analysis and experimental validation. METHODS: We downloaded a peripheral blood monocyte microarray profile (GSE75097) for patients with OSA and two synovial microarray profiles (GSE55235 and GSE55457) for patients with OA from the Gene Expression Omnibus database. We identified OSA-associated differentially expressed genes (OSA-DEGs) in patients with OA. Additionally, we constructed protein-protein interaction networks to identify the key genes involved in OA. Immunohistochemistry was performed to verify the expression of key genes in OA rat models. RNA interference assay was performed to validate the effects of key genes on synovial cells. Gene-miRNA, gene-transcription factor, and gene-drug networks were constructed to predict the regulatory molecules and drugs for OA. RESULTS: Fifteen OSA-DEGs screened using the threshold criteria were enriched in the tumor necrosis factor (TNF) pathway. Combining the 12 algorithms of CytoHubba, we identified JUNB, JUN, dual specificity phosphatase 1 (DUSP1), and TNF-alpha-induced protein 3 (TNFAIP3) as the key OSA-DEGs involved in OA development. Immunohistochemistry and quantitative polymerase chain reaction revealed that these key genes were downregulated in the OA synovium, promoting TNF-α expression. Therefore, OSA-DEGs, JUN, JUNB, DUSP1, and TNFAIP3 function in OA by increasing TNF-α expression. Our findings provide insights on the mechanisms underlying the effects of OSA on OA.