Comprehensive Bioinformatic Analysis Reveals an Autophagy-related Gene Signature for Predicting Outcome, Immune Status, and Drug Sensitivity in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, but molecular complexity and tumor heterogeneity make predictive models for HCC prognosis ineffective. Many recent studies have suggested that autophagy is important in tumor progression. Using autophagy-related genes (ARGs), we attempted to create a novel signature for individual prognosis prediction in patients with HCC. METHODS: Differentially expressed ARGs (DE-ARGs) in HCC and normal samples were screened using TCGA datasets. Univariate Cox and multivariate Cox regression analyses were performed to determine ARGs related to survival in HCC. An autophagy-based signature was constructed using LASSO, and its correlation with the prognosis and the immune infiltration of HCC patients was explored. RESULTS: In this study, we screened 32 survival-related DE-ARGs by analyzing TCGA datasets. Functional enrichment indicated that the 32 DE-ARGs may play important functional and regulatory roles in cellular autophagy, the regulation of multiple signaling pathways, as well as in the context of cancer and neurological diseases. Based on PPI Network, we identified several hub genes. LASSO Cox regression analysis selected five genes (CASP8, FOXO1, PRKCD, SPHK1, and SQSTM1) for a novel prognostic model. AUCs of 0.752, 0.686, and 0.665 in the TCGA whole set indicated that the model accurately predicted 1-, 3-, and 5-year overall survival, respectively. Cox regression analysis showed that the five-gene signature is an independent and robust predictor in patients with HCC. The high-risk group demonstrated higher levels of immune cell infiltration and exhibited a strong correlation with the immune microenvironment and tumor stem cells. In addition, we further identified PRKCD and SQSTM1 as critical regulators involved in HCC progression. The expression levels of PRKCD and SQSTM1 genes play a crucial role in chemotherapy drug sensitivity and resistance. CONCLUSION: We introduce here a novel ARG-based predictive feature for HCC patients. Effective use of this signature will aid in determining a patient's prognosis and may lead to novel approaches to clinical decision-making and therapy.

Discovery of a novel lipid metabolism-related gene signature to predict outcomes and the tumor immune microenvironment in gastric cancer by integrated analysis of single-cell and bulk RNA sequencing.

Gastric cancer (GC) is a pressing global clinical issue, with few treatment options and a poor prognosis. The onset and spread of stomach cancer are significantly influenced by changes in lipid metabolism-related pathways. This study aimed to discover a predictive signature for GC using lipid metabolism-related genes (LMRGs) and examine its correlation with the tumor immune microenvironment (TIME). Transcriptome data and clinical information from patients with GC were collected from the TCGA and GEO databases. Data from GC samples were analyzed using both bulk RNA-seq and single-cell sequencing of RNA (scRNA-seq). To identify survival-related differentially expressed LMRGs (DE-LMRGs), differential expression and prognosis studies were carried out. We built a predictive signature using LASSO regression and tested it on the TCGA and GSE84437 datasets. In addition, the correlation of the prognostic signature with the TIME was comprehensively analyzed. In this study, we identified 258 DE-LMRGs in GC and further screened seven survival-related DE-LMRGs. The results of scRNA-seq identified 688 differentially expressed genes (DEGs) between the three branches. Two critical genes (GPX3 and NNMT) were identified using the above two gene groups. In addition, a predictive risk score that relies on GPX3 and NNMT was developed. Survival studies in both the TCGA and GEO datasets revealed that patients categorized to be at low danger had a significantly greater prognosis than those identified to be at high danger. Additionally, by employing calibration plots based on TCGA data, the study demonstrated the substantial predictive capacity of a prognostic nomogram, which incorporated a risk score along with various clinical factors. Within the high-risk group, there was a noticeable abundance of active natural killer (NK) cells, quiescent monocytes, macrophages, mast cells, and activated CD4 + T cells. In summary, a two-gene signature and a predictive nomogram have been developed, offering accurate prognostic predictions for general survival in GC patients. These findings have the potential to assist healthcare professionals in making informed medical decisions and providing personalized treatment approaches.

Aptasensors with palladium nanoparticle-modified hemin-containing metal-organic frameworks as the signal marker for detection of exosomes.

Zr-metal-organic frameworks (Zr-MOFs) have received increasing interest for their use as the signal marker in the development of sandwich-structured aptasensors for the detection of exosomes. However, Zr4+ ions of the Zr-MOFs can interact with not only the exosomes, but also the aptamers, leading to possible false positives and a large background response. In the present study, we report for the first time aptasensors with Pd nanoparticle (NP)-decorated and hemin-embedded UiO-66 MOFs serving as the signal amplification marker to eliminate false positives and decrease the background response of aptasensors. To construct aptasensors for detection of exosomes, CD63-specific aptamers were tethered onto magnetic Fe3O4 particles coated with polydopamine (PDA) and UiO-66-NH2 using glutaraldehyde crosslinking for capturing the exosomes. To prepare highly catalytic Zr-MOF-based signal markers, UiO-66 MOFs were modified with hemin followed by Pd NPs. The as-prepared Pd-decorated hemin-embedded MOFs showed high catalytic activity towards the chromogenic oxidation reaction of TMB by H2O2. Moreover, the decoration with Pd NPs led to the change of the surface charge state of the catalytic hemin-embedded UiO-66 MOFs from positive to negative, weakening the interaction between the signal marker and the negatively charged aptamers. Therefore, the as-prepared aptasensors showed an improved sensing performance towards exosomes with a linear concentration range from 4.28 × 102 to 4.28 × 105 and a limit of detection (LOD) of 86.2 particles per µL. The as-prepared aptasensors also showed high sensitivity and selectivity to the exosomes from different origins including the HeLa cell line and MCF-7 cell line.

TNFAIP6 defines the MSC subpopulation with enhanced immune suppression activities.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) have been intensively investigated in both pre-clinical and clinical studies. However, the therapeutic efficacy varies resulting from the heterogenicity of MSCs. Therefore, purifying the specific MSC subpopulation with specialized function is necessary for their therapeutic applications. METHODS: The large-scale RNA sequencing analysis was performed to identify potential cell markers for the mouse MSCs. Then, the immune suppression activities of the purified MSC subpopulation were assessed in vitro and in vivo. RESULTS: The TNFAIP6 (tumor necrosis factor alpha-induced protein 6) has been identified as a potential cell marker for mouse MSCs, irrespective of tissue origin and laboratory origin. The TNFAIP6+ mouse MSCs showed enhanced immune suppression activities and improved therapeutic effects on the mouse model of acute inflammation, resulting from faster response to immune stimulation. CONCLUSIONS: Therefore, we have demonstrated that the TNFAIP6+ MSC subpopulation has enhanced immune suppression capabilities.

The discovery of novel sanjuanolide derivatives as chemotherapeutic agents targeting castration-resistant prostate cancer.

There remains a critical need for more effective therapies for the treatment of castration-resistant prostate cancer (CRPC), which is the leading cause of death in patients with prostate cancer. In this study, a series of sanjuanolide derivatives were designed, synthesized and evaluated as potential anti-CRPC agents. Most of the compounds had excellent selectivity for CRPC cells with IC50 values < 20 µM. Moreover, minimal side effects on human normal hepatic MIHA cells and normal prostatic stromal myofibroblast WPMY-1 cells were observed, with IC50 > 100 µM. The representative compound S07 slowed down the proliferative rate of CRPC cells, promoted cell apoptosis and caused G2/M phase accumulation, as well as G1/G0 phase reduction. Further mechanistic studies showed that S07 treatment triggered intense DNA damage and provoked strong DNA damage response in a dose-dependent manner. These findings suggested that sanjuanolide derivatives, especially S07, selectively induced CRPC cell death by triggering intense DNA damage and DNA damage response.

Interleukin-1ß augments the angiogenesis of endothelial progenitor cells in an NF-κB/CXCR7-dependent manner.

Endothelial progenitor cells (EPCs) are able to trigger angiogenesis, and pro-inflammatory cytokines have beneficial effects on angiogenesis under physiological and pathological conditions. C-X-C chemokine receptor type 7 (CXCR-7), receptor for stromal cell-derived factor-1, plays a critical role in enhancing EPC angiogenic function. Here, we examined whether CXCR7 mediates the pro-angiogenic effects of the inflammatory cytokine interleukin-1ß (IL-1ß) in EPCs. EPCs were isolated by density gradient centrifugation and angiogenic capability was evaluated in vitro by Matrigel capillary formation assay and fibrin gel bead assay. IL-1ß elevated CXCR7 expression at both the transcriptional and translational levels in a dose- and time-dependent manner, and blockade of the nuclear translocation of NF-κB dramatically attenuated the IL-1ß-mediated up-regulation of CXCR7 expression. IL-1ß stimulation significantly promoted EPCs tube formation and this effect was largely impaired by CXCR7-siRNA transfection. IL-1ß treatment stimulated extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation, and inhibition of Erk1/2 phosphorylation partially impaired IL-1ß-induced tube formation of EPCs but without significant effects on CXCR7 expression. Moreover, blocking NF-κB had no significant effects on IL-1ß-stimulated Erk1/2 phosphorylation. These findings indicate that CXCR7 plays an important role in the IL-1ß-enhanced angiogenic capability of EPCs and antagonizing CXCR7 is a potential strategy for inhibiting angiogenesis under inflammatory conditions.

Baicalin alleviates hyperglycemia-induced endothelial impairment 1 via Nrf2.

Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine, which exhibits strong anti-inflammatory, anti-viral and anti-tumor activities. The present work was devoted to elucidate the molecular and cellular mechanisms underlying the protective effects of Baicalin against diabetes-induced oxidative damage, inflammation and endothelial dysfunction. Diabetic mice, induced by streptozotocin (STZ), were treated with intraperitoneal Baicalin injections. Human umbilical vein endothelial cells (HUVECs) were cultured either in normal glucose (NG, 5.5 mM) or high glucose (HG, 33 mM) medium in the presence or absence of Baicalin for 72 h. We observed an obvious inhibition of hyperglycemia-triggered oxidative damage and inflammation in HUVECs and diabetic aortal vasculature by Baicalin, along with restoration of hyperglycemia-impaired nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway activity. However, the protective effects of Baicalin almost completely abolished in HUVECs transduced with shRNA against Nrf2, but not with nonsense shRNA. Mechanistic studies demonstrated that HG decreased Akt and GSK3B phosphorylation, restrained nuclear export of Fyn and nuclear localization of Nrf2, blunted Nrf2 downstream target genes, and subsequently induced oxidative stress in HUVECs. However, those destructive cascade, were well prevented by Baicalin in HUVECs. Furthermore, LY294002 and ML385 (inhibitor of PI3K and Nrf2) attenuated Baicalin mediated Nrf2 activation and the ability of facilitates angiogenesis in vivo and ex vivo. Taken together, the endothelial protective effect of Baicalin under hyperglycemia condition could be partly attributed to its role in downregulating reactive oxygen species (ROS) and inflammation via the Akt/GSK3B/Fyn-mediated Nrf2 activation.

Normal Pregnancy and Birth Despite Ruptured Sinus of Valsalva Aneurysm: Another Case for the Record.

Sinus of Valsalva aneurysm is a rare cardiac abnormality. Ruptured sinus of Valsalva aneurysms in pregnancy are of course rarer still. We present a case in which an aneurysm ruptured into the right ventricular outflow tract during pregnancy. In 2012, a 26-year-old Chinese woman, in the 18th week of pregnancy and with no apparent evidence of cardiac problems, was diagnosed with atrioventricular septal defects and a sinus of Valsalva aneurysm that had ruptured into her right ventricular outflow tract. After an uncomplicated full-term pregnancy, she gave birth to a healthy baby boy by cesarean section. Fifty days postpartum, the patient underwent surgical repair of the ruptured aneurysm and other cardiac defects. Her surgical outcome was good. As of May 2013, the patient and her baby were healthy. Ruptured sinus of Valsalva aneurysm in pregnancy can be asymptomatic, and women with such a rupture can have a normal full-term pregnancy and give birth to healthy babies. Cesarean section is preferable for pregnant women with ruptured sinus of Valsalva aneurysm because the hemodynamic changes associated with labor can aggravate the aneurysm. Surgical repair should be performed as soon as the patient's condition allows.

The staining patterns of 53BP1 nuclear foci and 53BP1 mRNA level are associated with cervical cancer progression and metastasis.

p53-binding protein 1 (53BP1) plays a key role in DNA damage response mechanism, which protects genome integrity and guards against cancer. Although abnormal DNA damage response type of 53BP1 nuclear foci (NF) have been indicated to be associated with many types of malignancies, how the staining pattern of 53BP1 NF and the mRNA level of 53BP1 correlate with the clinicopathologic characteristics of cervical cancer is still unclear. In this study, we examined the staining pattern and mRNA level of 53BP1 in cervical premalignant and malignant lesions and normal cervical tissue by immunofluorescence staining and quantitative real-time polymerase chain reaction. We found that the level of 53BP1 NF increased in the following order: normal cervical tissues, cervical intraepithelial neoplasia (CIN) 1, CIN2/3, and cervical cancers, indicating that the level of 53BP1 NF increases as cervical cancer initiates and progresses. In addition, we also found that abnormal DNA damage response type of 53BP1 NF and low mRNA level of 53BP1 was significantly correlated with high histologic grade of cervical cancer, and low mRNA level of 53BP1 was also significantly associated with positive lymph node metastasis of cervical cancer.

Acute urticaria as a side effect of the Mirena® (levonorgestrel-releasing intrauterine system): a case report.

BACKGROUND: The levonorgestrel intrauterine system, Mirena®, is widely used for contraception and the treatment of idiopathic menorrhagia. Here, we reported one case of acute urticaria following Mirena® implantation to increase the awareness of possible adverse side effects associated with Mirena®. CASE PRESENTATION: The case presented is a 27-year-old Chinese woman who received Mirena® implantation for her adenomyosis and menorrhagia. The operation was successful and the patient did not experience any discomfort during the operation. However, she developed acute urticaria on her entire body accompanied with pruritic, slight left lower quadrant pain, and slight dizziness two hours after the operation. The patient was recommended to have the Mirena® removed immediately, and she took 10 mg oral methylprednisolone and 5 mg desloratadine tablet daily for five days. Her urticaria resolved and did not recur. CONCLUSION: The patient's acute urticaria seems to have been associated with the Mirena® levonorgestrel intrauterine system implantation, since she had no history of allergic reactions to materials used during the operation such as plastic, metal, alcohol, medications, and povidone-iodine.