Novel SERCA2 inhibitor Diphyllin displays anti-tumor effect in non-small cell lung cancer by promoting endoplasmic reticulum stress and mitochondrial dysfunction.

Abnormal calcium signaling is associated with non-small cell lung cancer (NSCLC) malignant progression, poor survival and chemotherapy resistance. Targeting endoplasmic reticulum (ER) Ca2+ channels or pumps to block calcium uptake in the ER induces ER stress and concomitantly promotes mitochondrial calcium uptake, leading to mitochondrial dysfunction and ultimately inducing cell death. Here, we identified Diphyllin was a potential specific inhibitor of endoplasmic reticulum (ER) calcium-importing protein sarco/endoplasmic-reticulum Ca2+ ATPase 2 (SERCA2). In vitro and in vivo studies showed that Diphyllin increased NSCLC cell apoptosis, along with inhibition of cell proliferation and migration. Mechanistically, Diphyllin promoted ER stress by directly inhibiting SERCA2 activity and decreasing ER Ca2+ levels. At the same time, the accumulated Ca2+ in cytoplasm flowed into mitochondria to increase reactive oxygen species (ROS) and decrease mitochondrial membrane potential (MMP), leading to cytochrome C (Cyto C) release and mitochondrial dysfunction. In addition, we found that Diphyllin combined with cisplatin could have a synergistic anti-tumor effect in vitro and in vivo. Taken together, our results suggested that Diphyllin, as a potential novel inhibitor of SERCA2, exerts anti-tumor effects by blocking ER Ca2+ uptake and thereby promoting ER stress and mitochondrial dysfunction.

PDZ and LIM Domain-Encoding Genes: Their Role in Cancer Development.

PDZ-LIM family proteins (PDLIMs) are a kind of scaffolding proteins that contain PDZ and LIM interaction domains. As protein-protein interacting molecules, PDZ and LIM domains function as scaffolds to bind to a variety of proteins. The PDLIMs are composed of evolutionarily conserved proteins found throughout different species. They can participate in cell signal transduction by mediating the interaction of signal molecules. They are involved in many important physiological processes, such as cell differentiation, proliferation, migration, and the maintenance of cellular structural integrity. Studies have shown that dysregulation of the PDLIMs leads to tumor formation and development. In this paper, we review and integrate the current knowledge on PDLIMs. The structure and function of the PDZ and LIM structural domains and the role of the PDLIMs in tumor development are described.

Aqueous extract of Cordyceps cicadae (Miq.) promotes hyaluronan synthesis in human skin fibroblasts: A potential moisturizing and anti-aging ingredient.

Cordyceps cicadae (Miq.) is an edible fungus with unique and valuable medicinal properties that is commonly used in traditional Chinese medicine, but its anti-aging effects on the skin fibroblast are not well studied. The aim of the present study was to analyze the active components of aqueous C. cicadae extract (CCE), determine the effects of CCE on hyaluronan synthesis in human skin fibroblasts, and explore the underlying mechanisms. The results of this study indicate that CCE was rich in polysaccharides, five alditols (mainly mannitol), eight nucleosides, protein, and polyphenols, which were present at concentrations of 62.7, 110, 8.26, 35.7, and 3.8 mg/g, respectively. The concentration of extract required to inhibit 50% of 2,2-azino-bis (3-ethylbenzothiazo-line-6-sulphonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazil (DPPH) radical scavenging capacities were 0.36 ± 0.03 and 4.54 ± 0.10 mg/mL, respectively, indicating that CCE exhibits excellent antioxidant activities. CCE showed no cytotoxicity to skin fibroblasts at concentrations ≤ 100 µg/mL, and promoted HA synthesis in fibroblasts. Treatment of fibroblast cells with 100 µg/mL CCE enhances the HA content to 1293 ± 142 ng/mL, which is significantly more than that in the non-treatment (NT) group (p = 0.0067). Further, RNA sequencing detected 1,192 differentially expressed genes (DEGs) in CCE-treated fibroblasts, among which 417 were upregulated and 775 were downregulated. Kyoto Encyclopedia of Genes (KEGG) and Genomes pathway (GO) analysis based on RNA sequencing revealed that CCE mainly affected cytokine-cytokine receptor interaction regulated by HA synthesis-related genes. CCE upregulated HA synthase 2 (HAS2), epidermal growth factor (EGF)-related genes, heparin-binding EGF-like growth factor, C-C motif chemokine ligand 2, interleukin 1 receptor-associated kinase 2, and other genes related to fibroblast differentiation and proliferation. CCE downregulated the gene of matrix metallopeptidase 12 (MMP12), which leads to cell matrix loss. RT-qPCR further verified CCE significantly upregulated HAS2 expression and significantly downregulated MMP12 expression, thus promoting hyaluronan synthesis. CCE shows potential as a moisturizer and anti-aging agent in functional foods and cosmetics.

Identification of m7G-Related miRNA Signatures Associated with Prognosis, Oxidative Stress, and Immune Landscape in Lung Adenocarcinoma.

The role of N7-methylguanosine(m7G)-related miRNAs in lung adenocarcinoma (LUAD) remains unclear. We used LUAD data from The Cancer Genome Atlas (TCGA) to establish a risk model based on the m7G-related miRNAs, and divided patients into high-risk or low-risk subgroups. A nomogram for predicting overall survival (OS) was then constructed based on the independent risk factors. In addition, we performed a functional enrichment analysis and defined the oxidative stress-related genes, immune landscape as well as a drug response profile in the high-risk and low-risk subgroups. This study incorporated 28 m7G-related miRNAs into the risk model. The data showed a significant difference in the OS between the high-risk and low-risk subgroups. The receiver operating characteristic curve (ROC) predicted that the area under the curve (AUC) of one-year, three-year and five-year OS was 0.781, 0.804 and 0.853, respectively. The C-index of the prognostic nomogram for predicting OS was 0.739. We then analyzed the oxidative stress-related genes and immune landscape in the high-risk and low-risk subgroups. The data demonstrated significant differences in the expression of albumin (ALB), estimated score, immune score, stromal score, immune cell infiltration and functions between the high-risk and low-risk subgroups. In addition, the drug response analysis showed that low-risk subgroups may be more sensitive to tyrosine kinase inhibitor (TKI) and histone deacetylase (HDAC) inhibitors. We successfully developed a novel risk model based on m7G-related miRNAs in this study. The model can predict clinical prognosis and guide therapeutic regimens in patients with LUAD. Our data also provided new insights into the molecular mechanisms of m7G in LUAD.

Circulating insulin-like growth factor-1 and risk of lung diseases: A Mendelian randomization analysis.

Background: Insulin-like growth factor-1 (IGF-1) display a vital role in in the pathogenesis of lung diseases, however, the relationship between circulating IGF-1 and lung disease remains unclear. Methods: Single nucleotide polymorphisms (SNPs) associated with the serum levels of IGF-1 and the outcomes data of lung diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer and idiopathic pulmonary fibrosis (IPF) were screened from the public genome-wide association studies (GWAS). Two-sample Mendelian randomization (MR) analysis was then performed to assess the independent impact of IGF-1 exposure on these lung diseases. Results: Totally, 416 SNPs related to circulating IGF-1 levels among 358,072 participants in UK Biobank. According to a primary casual effects model with MR analyses by the inverse variance weighted (IVW) method, the circulating IGF-1 was demonstrated a significantly related with the risk of asthma (OR, 0.992; 95% CI, 0.985-0.999, P=0.0324), while circulating IGF-1 showed no significant correlation with CODP (OR, 1.000; 95% CI, 0.999-1.001, P=0.758), lung cancer (OR, 0.979, 95% CI, 0.849-1.129, P=0.773), as well as IPIGFF (OR, 1.100, 95% CI, 0.794-1.525, P=0.568). Conclusion: The present study demonstrated that circulating IGF-1 may be causally related to lower risk of asthma.

Recent advances of nanomaterial-based anti-angiogenic therapy in tumor vascular normalization and immunotherapy.

Anti-angiogenesis therapy and immunotherapy are the first-line therapeutic strategies for various tumor treatments in the clinic, bringing significant advantages for tumor patients. Recent studies have shown that anti-angiogenic therapy can potentiate immunotherapy, with many clinical trials conducted based on the combination of anti-angiogenic agents and immune checkpoint inhibitors (ICIs). However, currently available clinical dosing strategies and tools are limited, emphasizing the need for more improvements. Although significant progress has been achieved, several big questions remained, such as how to achieve cell-specific targeting in the tumor microenvironment? How to improve drug delivery efficiency in tumors? Can nanotechnology be used to potentiate existing clinical drugs and achieve synergistic sensitization effects? Over the recent few years, nanomedicines have shown unique advantages in antitumor research, including cell-specific targeting, improved delivery potentiation, and photothermal effects. Given that the applications of nanomaterials in tumor immunotherapy have been widely reported, this review provides a comprehensive overview of research advances on nanomaterials in anti-angiogenesis therapy, mainly focusing on the immunosuppressive effects of abnormal tumor vessels in the tumor immune microenvironment, the targets and strategies of anti-angiogenesis nanomedicines, and the potential synergistic effects and molecular mechanisms of anti-angiogenic nanomedicines in combination with immunotherapy, ultimately providing new perspectives on the nanomedicine-based synergy between anti-angiogenic and immunotherapy.

Regular Late Bedtime Significantly Affects the Skin Physiological Characteristics and Skin Bacterial Microbiome.

Background: Late bedtime is a common form of unhealthy sleep pattern in adulthood, which influences circadian rhythm, and negatively affects health. However, little is known about the effect of regular late bedtime on skin characteristics, particularly on skin microbiome. Objective: To investigate the changes and effects of the regular late bedtime on skin physiological parameters and facial bacterial microbiome of 219 cases of Chinese women aged 18-38 years living in Shanghai. Methods: Based on the Self-Evaluation Questionnaire, bedtime was categorized as 11:00 PM; thus, the volunteers were divided into early bedtime group (S0) and late bedtime group (S1). The physiological parameters of facial skin were measured by non-invasive instrumental methods, and the skin microbiome was analyzed by 16S rRNA high-throughput sequencing. Results: The skin physiological parameters of the late bedtime group exhibited significant decrease in skin hydration content, skin firmness (F4) and elasticity (R2), while TEWL, sebum and wrinkle significantly increased. The result indicated that late bedtime significantly impaired the integrity of skin barrier, damaged skin structure, and disrupted water-oil balance. Furthermore, the analysis of α-diversity, Sobs, Ace and Chao index were found to significantly decrease (P < 0.05) in the late bedtime group, suggesting that late bedtime reduced both the abundance and the diversity of facial bacterial microbiota. Moreover, the abundance of Pseudomonas increased significantly, while Streptococcus, Stenotrophomonas, Acinetobacter, Haemophilus, Actinomyces and Neisseria decreased significantly. In addition, Spearman correlation analysis revealed strong correlations between the microbiota and the physiological parameters. Notably, the abundance of Pseudomonas significantly positively correlated with skin firmness and elasticity, but significantly negatively correlated with skin hemoglobin content, melanin content and skin hydration. Conclusion: Bedtime is an important factor in maintaining skin health. Regular late bedtime not only damages the skin barrier and skin structure but also reduces the diversity and composition of facial bacterial microbiome.

Molecular profiling and identification of prognostic factors in Chinese patients with small bowel adenocarcinoma.

Small bowel adenocarcinoma (SBA) is a rare malignancy with a poor prognosis and limited treatment options. Despite prior studies, molecular characterization of this disease is not well defined, and little is known regarding Chinese SBA patients. In this study, we conducted multigene next-generation sequencing and 16S ribosomal RNA gene sequencing on samples from 76 Chinese patients with surgically resected primary SBA. Compared with colorectal cancer and Western SBA cohorts, a distinctive genomic profile was revealed in Chinese SBA cohorts. According to the levels of clinical actionability to targetable alterations stratified by OncoKB system, 75% of patients harbored targetable alterations, of which ERBB2, BRCA1/2, and C-KIT mutations were the most common targets of highest-level actionable alterations. In DNA mismatch repair-proficient (pMMR) patients, significant associations between high tumor mutational burden and specific genetic alterations were identified. Moreover, KRAS mutations/TP53 wild-type/nondisruptive mutations (KRASmut /TP53wt/non-dis ) were independently associated with an inferior recurrence-free survival (hazard ratio [HR] = 4.21, 95% confidence interval [CI] = 1.94-9.14, P < .001). The bacterial profile revealed Proteobacteia, Actinobacteria, Firmicutes, Bacteroidetes, Fusobacteria, and Cyanobacteria were the most common phyla in SBA. Furthermore, patients were clustered into three subgroups based on the relative abundance of bacterial phyla, and the distributions of the subgroups were significantly associated with the risk of recurrence stratified by TP53 and KRAS mutations. In conclusion, these findings provided a comprehensive molecular basis for understanding SBA, which will be of great significance in improving the treatment strategies and clinical management of this population.

Prognostic Performance of Different Lymph Node Staging Systems in Patients With Small Bowel Neuroendocrine Tumors.

Background: The prognostic significance of the lymph node (LN) classification for small bowel neuroendocrine tumors (SBNETs) remains unknown. The aim of the present study was to evaluate and compare the prognostic assessment of different LN staging systems. Methods: Patients with SBNETs were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The X-tile program was used to determine the cutoff value of the resected lymph nodes (RLNs), negative lymph nodes (NLNs), lymph node ratio (LNR), and the log odds of positive lymph nodes (LODDS). Survival analyses were performed using Kaplan-Meier curves with log-rank test. Logistic regression analysis was used to evaluate the differences between different periods. Univariate and multivariate Cox proportional hazards models were used to assess the prognostic value of different LN staging systems on cause-specific survival (CSS). The relative discriminative abilities of the different LN staging systems were assessed using the Akaike information criterion (AIC) and the Harrell consistency index (HCI). Result: A total of 3,680 patients were diagnosed with SBNETs between 1988 and 2014 from the SEER database. A significant difference over time (1988-1999 vs. 2000-2014) was seen in age (P <0.001), tumor differentiation (P <0.001), T stage (P <0.001), and RLN (P <0.001) subgroups. Multivariate Cox survival analysis identified that LN status stratified by the number of RLNs, NLNs, LNR, and LODDS all predicted CSS in patients with SBNETs (all P <0.05), whereas the number of positive lymph nodes (PLNs) failed (P = 0.452). When assessed using categorical variables, LODDS staging systems showed the best prognostic performance (HCI: 0.766, AIC: 7,575.154) in the whole population. Further analysis based on different RLNs after eliminating the missing data showed that when the RLNs are <12, the LODDS (HCI: 0.769, AIC: 1,088.731) maintained the best prognostic performance as well when the RLNs are ≥12 (HCI: 0.835, AIC: 825.692). Among patients with LNR scores of 0 or 1, there was a residual heterogeneity of outcomes that were better stratified and characterized by the LODDS. Conclusion: LODDS was a better predicator of survival when LN status was stratified as a categorical variable and should be considered when assessing the prognosis of patients with SBNETs to allow a more reliable means to stratify patient survival.

MicroRNA-30a targets BECLIN-1 to inactivate autophagy and sensitizes gastrointestinal stromal tumor cells to imatinib.

Gastrointestinal stromal tumors (GISTs), the most widespread type of sarcoma, contain driver gene mutations predominantly of receptor tyrosine kinase and platelet-derived growth factor receptor alpha. However, the inevitable development of resistance to imatinib (IM) cannot be fully attributed to secondary driver gene mutations. In this study, we investigated the role of microRNA-30a in sensitization of GIST cells to IM in vivo and in vitro. Higher levels of miR-30a were detected in GIST-T1 cells, which were more sensitive to IM than GIST-882 cells. IM treatment also reduced miR-30a levels, indicating the possible role of miR-30a in GIST IM resistance. Subsequently, miR-30a was confirmed to be an IM sensitizer via a mechanism that was attributed to its involvement in the regulation of cell autophagy. The interaction of miR-30a and autophagy in IM treated GIST cells was found to be linked by beclin-1. Beclin-1 knockdown increased IM sensitivity in GIST cell lines. Finally, miR-30a was confirmed to enhance IM sensitivity of GIST cells in mouse tumor models. Our study provides evidence for the possible role of miR-30a in the emergence of secondary IM resistance in GIST patients, indicating a promising target for overcoming this chemoresistance.

Denosumab and Sunitinib in the treatment of giant-cell tumor of bone with pulmonary and bone metastases in an adolescent: A case report.

INTRODUCTION: Giant cell tumor of bone with pulmonary and bone metastases is exceedingly rare in adolescents. Furthermore, Denosumab and Sunitinib in the treatment of giant cell tumor of bone has never been reported. PATIENT CONCERNS: A 16-year-old boy complained of fever, chest tightness, and shortness of breath and back pain for 5 days. DIAGNOSIS: Giant cell tumor of bone with pulmonary and bone metastases. INTERVENTIONS: The patient underwent 2 surgeries for giant cell tumor of bone located in the spine and received Denosumab to reduce local recurrence and control the metastases. Then Sunitinib was added into treatment strategies after the progressing of metastases. OUTCOMES: Within 5 months of Denosumab and Sunitinib, lung metastases were shrinking (stable disease, response evaluation criteria in solid tumors version 1.1). Until now about 4 years into treatment the patient is still survival. Pulmonary and bone metastases are stable. CONCLUSIONS: This is a case of multi-center giant cell tumor of bone, it does not only provide a reference to the treatment of similar cases of the clinic but also reflects the limitations of the application of Denosumab in the real world.

CircUBAP2-mediated competing endogenous RNA network modulates tumorigenesis in pancreatic adenocarcinoma.

We investigated the role of the competing endogenous RNA (ceRNA) network in the development and progression of pancreatic adenocarcinoma (PAAD). We analyzed the expression profiles of PAAD and normal pancreatic tissues from multiple GEO databases and identified 457 differentially expressed circular RNAs (DEcircRNAs), 19 microRNAs (DEmiRNAs) and 1993 mRNAs (DEmRNAs). We constructed a ceRNA network consisting of 4 DEcircRNAs, 3 DEmiRNAs and 149 DEmRNAs that regulates the NF-kappa B, PI3K-Akt, and Wnt signaling pathways. We then identified and validated five hub genes, CXCR4, HIF1A, ZEB1, SDC1 and TWIST1, which are overexpressed in PAAD tissues. The expression of CXCR4, HIF1A, ZEB1, and SDC1 in PAAD was regulated by circ-UBAP2 and hsa-miR-494. The expression of CXCR4 and ZEB1 correlated with the levels of M2 macrophages, T-regulatory cells (Tregs) and exhausted T cells in the PAAD tissues. The expression of CXCR4 and ZEB1 positively correlated with the expression of CTLA-4 and PD-1. This suggests that CXCR4 and ZEB1 proteins inhibit antigen presentation and promote immune escape mechanisms in PAAD cells. In summary, our data suggest that the circUBAP2-mediated ceRNA network modulates PAAD by regulating the infiltration and function of immune cells.

Comparison of clinical features and outcomes in patients with extraskeletal vs skeletal Ewing sarcoma: an SEER database analysis of 3,178 cases.

BACKGROUND: The clinicopathological characteristics, outcomes and prognostic factors of primary extraskeletal Ewing sarcoma (EES) remained insufficiently explored. We aimed to examine these aspects and compared the same with skeletal Ewing sarcoma (SES). PATIENTS AND METHODS: We identified Ewing sarcoma, peripheral primitive neuroectodermal tumors or Askin tumor patients who were registered in the Surveillance, Epidemiology, and End Results database from 1973 to 2014. Clinicopathological features were assessed by using Fisher's exact tests. Cancer-specific survival (CSS) and overall survival (OS) were estimated by using the Kaplan-Meier method and the Cox proportional hazards model. Prognostic factors were identified by multivariate Cox regression analysis. RESULTS: The age of patients with EES was diagnosed to be higher and they were more likely to be female (46.1% vs 36.2%; P<0.001), have tumor <10 cm (49.8% vs 35.4%; P<0.001), have regional node involvement (5.4% vs 1.0%; P<0.001) and receive surgery (69.1% vs 53.8%; P<0.001) compared to patients with skeletal tumors. Metastatic status did not differ by origin. Kaplan-Meier analysis showed that the origin had significant difference in CSS and OS among patients aged 0-19 years and with metastatic stage at presentation, but not in patients aged 20-39, ≥40 years and with no-metastatic stage. A Cox multivariable model controlling for differences between groups confirmed inferior survival for patients with EES. Age, tumor size, tumor stage and surgery were the most important factors significantly influencing both CSS and OS in the EES and SES patients. Race, year of diagnosis and tumor site were associated with CSS and OS among patients with SES, but failed in EES. CONCLUSION: The clinicopathological characteristics, outcomes and prognostic factors differed among patients with EES compared to patients with SES. Extraskeletal origin was an unfavorable prognostic factor.

Prognosis and nomogram for predicting postoperative survival of duodenal adenocarcinoma: A retrospective study in China and the SEER database.

As primary duodenal adenocarcinoma is rare, the prognostic factors of this disease remain insufficiently explored, especially in China. We identified postoperative duodenal adenocarcinoma patients at a Chinese double-center (from 2006 to 2016) or who were registered with the Surveillance, Epidemiology, and End Results (SEER) database (from 2004 to 2014). Clinicopathological features and significant prognostic factors for cancer-specific survival (CSS) were reviewed and analyzed by using univariate and multivariate Cox proportional hazards regression. Then, a nomogram predicting CSS was constructed based on the SEER database and validated externally by using the separate Chinese cohort. Totally, 137 patients from the Chinese double-center and 698 patients from the SEER database were included for analysis. The multivariate analyses showed that age, tumor grade and TNM stage were independent prognostic factors. The nomogram constructed using these factors showed a clear prognostic superiority to the AJCC-TNM classification, 7th ed. (C-index: SEER cohort, 0.693 vs 0.625, P < 0.001; Chinese cohort, 0.677 vs 0.659, P < 0.001, respectively). In summary, the valuable prognostic factors in patients with duodenal adenocarcinoma were age, tumor grade and TNM stage. This study developed a nomogram that can precisely predict the CSS for postoperative duodenal adenocarcinoma patients.

Endostar combined with chemotherapy in a pediatric osteosarcoma with pulmonary metastasis and malignant pleural effusion: A case report.

RATIONALE: Angiogenesis is a key factor for tumor growth and metastasis both in cancer and sarcoma. Endostar, a novel safe and well-tolerated recombinant human endostatin, can suppress the expression of VEGF and the activation of ERK, MAPK, and AKT, and then inhibit tumor progression. PATIENT CONCERNS: A pediatric osteosarcoma with pulmonary metastasis and malignant pleural effusion. DIAGNOSES: Osteosarcoma with pulmonary metastasis and malignant pleural effusion. INTERVENTIONS: Considering the physical condition of patient, the patient underwent surgical resection of the right lung lesion after receiving endostar combined with chemotherapy and maintained endostar alone for 47 cycles. OUTCOMES: The patient obtained pathologic complete remission and had been in progression-free survival up to now. LESSONS: Our experience could provide a treatment strategy for pediatric osteosarcoma patients with pulmonary metastasis and malignant pleural effusion.