Multi-omics characterization and validation of invasiveness-related molecular features across multiple cancer types.

BACKGROUND: Tumor invasiveness reflects many biological changes associated with tumorigenesis, progression, metastasis, and drug resistance. Therefore, we performed a systematic assessment of invasiveness-related molecular features across multiple human cancers. MATERIALS AND METHODS: Multi-omics data, including gene expression, miRNA, DNA methylation, and somatic mutation, in approximately 10,000 patients across 30 cancer types from The Cancer Genome Atlas, Gene Expression Omnibus, PRECOG, and our institution were enrolled in this study. RESULTS: Based on a robust gene signature, we established an invasiveness score and found that the score was significantly associated with worse prognosis in almost all cancers. Then, we identified common invasiveness-associated dysregulated molecular features between high- and low-invasiveness score group across multiple cancers, as well as investigated their mutual interfering relationships thus determining whether the dysregulation of invasiveness-related genes was caused by abnormal promoter methylation or miRNA expression. We also analyzed the correlations between the drug sensitivity data from cancer cell lines and the expression level of 685 invasiveness-related genes differentially expressed in at least ten cancer types. An integrated analysis of the correlations among invasiveness-related genetic features and drug response were conducted in esophageal carcinoma patients to outline the complicated regulatory mechanism of tumor invasiveness status in multiple dimensions. Moreover, functional enrichment suggests the invasiveness score might serve as a predictive biomarker for cancer patients receiving immunotherapy. CONCLUSION: Our pan-cancer study provides a comprehensive atlas of tumor invasiveness and may guide more precise therapeutic strategies for tumor patients.

Pan-cancer characterization of metabolism-related biomarkers identifies potential therapeutic targets.

BACKGROUND: Generally, cancer cells undergo metabolic reprogramming to adapt to energetic and biosynthetic requirements that support their uncontrolled proliferation. However, the mutual relationship between two critical metabolic pathways, glycolysis and oxidative phosphorylation (OXPHOS), remains poorly defined. METHODS: We developed a "double-score" system to quantify glycolysis and OXPHOS in 9668 patients across 33 tumor types from The Cancer Genome Atlas and classified them into four metabolic subtypes. Multi-omics bioinformatical analyses was conducted to detect metabolism-related molecular features. RESULTS: Compared with patients with low glycolysis and high OXPHOS (LGHO), those with high glycolysis and low OXPHOS (HGLO) were consistently associated with worse prognosis. We identified common dysregulated molecular features between different metabolic subgroups across multiple cancers, including gene, miRNA, transcription factor, methylation, and somatic alteration, as well as investigated their mutual interfering relationships. CONCLUSION: Overall, this work provides a comprehensive atlas of metabolic heterogeneity on a pan-cancer scale and identified several potential drivers of metabolic rewiring, suggesting corresponding prognostic and therapeutic utility.

Identification and validation of tumor environment phenotypes in lung adenocarcinoma by integrative genome-scale analysis.

PURPOSE: To comprehensively elucidate the landscape of the tumor environment (TME) of lung adenocarcinoma (LUAD), which has a profound impact on prognosis and response to immunotherapy. METHODS AND MATERIALS: Using a large dataset of LUAD patients from The Cancer Genome Atlas, Gene Expression Omnibus database (GEO), and our institution (n = 1411), we estimated the infiltration pattern of 24 immune cell populations in each sample and systematically correlated the TME phenotypes with genomic traits and clinicopathologic characteristics. RESULTS: The LUAD microenvironment was classified into two distinct TME clusters (A and B), and a random forest classifier model was constructed. TMEcluster A was characterized by sparse distribution of immune cell infiltration, relatively low levels of immunomodulators and slightly higher mutation load. By contrast, enrichment of both cytotoxic T cells and immunosuppressor cells was observed in TMEcluster B. Moreover, several immune-related cytokines or markers including IFN-γ, TNF-ß, and several immune checkpoint molecules such as PD-L1 were also upregulated in TMEcluster B. Multivariable Cox analysis revealed that the TMEcluster was an independent prognostic factor (TMEcluster B vs. A, hazard ratio = 0.68, 95% confidence interval = 0.50-0.91, p = 0.010). These findings were all externally validated in the data from the GEO database and our institution. CONCLUSIONS: Our findings describe a comprehensive landscape of LUAD immune infiltration pattern and integrate several previously proposed biomarkers associated with distinct immunophenotypes, thus shedding light on how tumors interact with immune microenvironment. Our results may guide a more precise immune therapeutic strategy for LUAD patients.

Primary hepatic angiosarcoma and potential treatment options.

Angiosarcomas account for a mere 2-3% of adult soft tissue sarcomas, with an overall poor outcome. Depending on the primary site, angiosarcomas have distinct prognosis. Primary hepatic angiosarcomas (PHAs) are much rare tumors, with worse prognosis compared with other angiosarcomas. PHA is reported to be associated with vinyl chloride, but the majority of patients were still with unknown etiology. As PHA lacks specific symptoms, signs, or images, pathological diagnosis is necessary. The review summarizes 25 articles published from January 2000 to December 2012, including 64 cases of PHA with detailed information. Survival curves are estimated using the Kaplan-Meier method by SPSS 21.0. We find that the median survival time is 5 months; local excision alone or combination with adjuvant therapy is the optimal choice, with median survival time of 17 months. In addition, liver transplant is abandoned for high recurrence rate; emergent transcatheter arterial embolization is thought to be an efficient method for controlling intra-abdominal bleeding; and transcatheter arterial chemoembolization and chemotherapy may be helpful in improving survival.

Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome.

Non-small cell lung cancer (NSCLC) is found worldwide with high incidence and poor prognoses. Nowadays, insights in the interaction between tumors and immune system have led to the development of immunotherapy as a fundamentally new concept for the treatment of NSCLC. Adoptive cell transfer represents an important advancement in cancer immunotherapy such as cytokine-induced killer and γδ T-cells. Recent clinical research studies provide evidence for the positive effects of adoptive immunotherapy, which is probably associated with levels of cytokines, cell doses, and immune microenvironment. This review summarizes the current condition of adoptive immunotherapy in NSCLC and the long-standing confusion in this field.

Therapeutic effect of haploidentical peripheral blood stem cell treatment on relapsed/refractory ovarian cancer.

The traditional immunotherapy is limited on relapsed/refractory metastatic ovarian cancer because tumors cause immunosuppression. Since new therapeutic strategies to improve clinical outcomes for patients with relapsed/refractory metastatic ovarian carcinoma are needed, the aim of this study was to evaluate the therapeutic effect of haploidentical peripheral blood stem cells (haplo-PBSCs) adoptive treatment on relapsed/refractory ovarian cancer. Thirteen patients with advanced stage of ovarian cancer and refractory history after surgery and chemotherapy were treated with interleukin-2 activated haplo-PBSCs donated by their parents or children. Clinical outcomes including therapeutic response by measuring tumor size changes using CT scanning, CA-125 levels and survival times were evaluated. T and NK cell population in patients before and after treatment was detected by flow cytometry analysis. The median follow-up time after haplo-PBSCs adoptive treatment was 14 months. At the time of the last follow-up, the median overall survival after haplo-PBSCs adoptive treatment was 9.1 months. Ten patients (76.9%) achieved a relief of symptoms, including abdominal distention, ache, fatigue, and poor appetite. During the first 2 months after treatment, CA125 levels decreased in 10 patients (76.9%). Five patients (38.5%) had a stable disease and 1 patient (8%) had partial response. T cell population (CD3+CD4+ and CD3+CD8+) and CD3-CD16+CD56+ NK cells were increased in patients after haplo-PBSCs adoptive treatment. Our study reveals that haplo-PBSCs adoptive treatment is associated with an anti-tumor effect and increasing immune responses in patients with relapsed/refractory ovarian cancer.

How do tumor stem cells actively escape from host immunosurveillance?

Tumor stem cells (TSCs) are considered as the "seeds" in tumor development, metastasis and recurrence. Despite the various immunosurveillance mechanisms in the host, TSCs may possess the phenotypic and functional properties to evade host immunosurveillance and immune-mediated rejection in immunologically intact individuals. The mechanisms of TSC recognition and their consequent destruction are actively disturbed by various processes, including altered immunogenicity of TSCs, production of TSC-derived regulatory molecules, and interaction of TSCs with tumor-infiltrating immune cells. In addition to these TSC-mediated mechanisms, the diverse mesenchymal cells and cytokines in the tumor microenvironment are contribute to TSC immune escape. Recent mechanistic studies provide a more comprehensive understanding of TSCs in the biology, prevention, and therapy of solid tumors. This review will focus on the latest findings for mechanisms underlying TSCs' escape from the attack of immune system.

Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study.

OBJECTIVE: Cytokine-induced killer (CIK) cells have the ability to kill tumor in vitro and in vivo. This study was designed to evaluate the clinical efficacy of CIK cell immunotherapy following regular chemotherapy in patients with non-small cell lung cancer (NSCLC) after surgery. METHODS: A paired study, with 87 stage I-IV NSCLC patients in each group, was performed. Patients received either chemotherapy (arm 2) or chemotherapy in combination with autologous CIK cell immunotherapy (arm 1). Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Of the 87 paired patients, 50 had early-stage disease (stage I-IIIA) and 37 had advanced-stage disease (stage IIIB-IV). Among early-stage patients, the distribution of 3-year PFS rate and median PFS time showed no statistical difference between the two groups (p = 0.259 and 0.093, respectively); however, the 3-year OS rate and median OS time in arm 1 were significantly higher than those in arm 2 (82 vs. 66 %; p = 0.049 and 73 vs. 53 months; p = 0.006, respectively). Among the advanced-stage patients, the 3-year PFS and OS rates of arm 1 were significantly higher than those of arm 2 (6 vs. 3 %; p < 0.001 and 31 vs. 3 %; p < 0.001, respectively); the median PFS and OS times in arm 1 were also significantly longer than those in arm 2 (13 vs. 6 months; p = 0.001 and 24 vs. 10 months; p < 0.001, respectively). Multivariate analyses indicated that the frequency of CIK cell immunotherapy was significantly associated with prolonged PFS (HR = 0.91; 95 % CI 0.85-0.98; p = 0.012) and OS (HR = 0.83; 95 % CI, 0.74-0.93; p = 0.001) in the arm 1. CONCLUSIONS: The data suggested that CIK cell immunotherapy could improve the efficacy of conventional chemotherapy in NSCLC patients, and increased frequency of CIK cell treatment could further enhance the beneficial effects. A multi-center randomized trial is being carried out in our hospital to further validate these findings.

PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway.

Phosphoglycerate mutase 1 (PGAM1) is a crucial glycolytic enzyme, and its expression status has been confirmed to be associated with tumor progression and metastasis. However, the precise role and other biological functions of PGAM1 remain unclear. Here, we report that PGAM1 expression is upregulated and related to poor prognosis in patients with breast cancer (BC). Functional experiments showed that knockdown of PGAM1 could suppress the proliferation, invasion, migration, and epithelial-mesenchymal transition of BC cells. Through RNA sequencing, we found that argininosuccinate synthase 1 (ASS1) expression was markedly upregulated in BC cells following PGAM1 knockdown, and it is required to suppress the malignant biological behavior of BC cells. Importantly, we demonstrated that PGAM1 negatively regulates ASS1 expression through the cAMP/AMPK/CEBPB axis. In vivo experiments further validated that PGAM1 promoted tumor growth in BC by altering ASS1 expression. Finally, immunohistochemical analysis showed that downregulated ASS1 levels were associated with PGAM1 expression and poor prognosis in patients with BC. Our study provides new insight into the regulatory mechanism of PGAM1-mediated BC progression that might shed new light on potential targets and combination therapeutic strategies for BC treatment.

Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage III) esophageal squamous cell carcinoma: a study protocol for a prospective, single-arm, single-center, open-label, phase-II trial (Keystone-001).

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most refractory malignant tumors. Esophageal cancer (EC) is a malignant tumor with a high incidence worldwide, and over 50% of EC cases occur in China. Under the National Comprehensive Cancer Network (NCCN) guidelines, concurrent chemoradiotherapy is the only standard neoadjuvant treatment for locally advanced ESCC. In the first-line treatment of advanced ESCC, the efficacy of immune checkpoint inhibitors (ICIs) combined with systemic chemotherapy is significantly better than that of chemotherapy alone. Paclitaxel and cisplatin (TP), as one of the neoadjuvant chemotherapy regimens for locally advanced ESCC, have been widely used in China in recent years. ICIs combined with TP as neoadjuvant therapy seems promising. Methods: This is an open-label, single-arm, single-center, phase-II trial. Locally advanced resectable (stage III) ESCC patients who have not undergone previous systemic treatments will be enrolled in this study. All the subjects will intravenously receive 3 cycles of pembrolizumab (200 mg) on day 1, paclitaxel (135 mg/m2) on day 2, and cisplatin (20 mg/m2) on days 2-4, every 3 weeks. After an efficacy evaluation, the subjects will undergo Da Vinci robot-assisted radical resection. If the postoperative pathologic results do not reveal a complete response, pembrolizumab will be administrated for at least 6 cycles as an adjuvant therapy with the same usage as before. The primary endpoints are the major pathological response and safety. The secondary endpoints include the objective response rate (ORR), overall survival (OS), disease-free survival (DFS), the R0 resection rate, and perioperative complications. The exploratory endpoint is to examine the correlation between related biomarkers and tumor responses to this neoadjuvant treatment regimen. Discussion: This trial is the first enrolled study to evaluate the safety and efficacy of pembrolizumab combined with TP as neoadjuvant therapy for locally advanced ESCC. Currently, under the NCCN guidelines, neoadjuvant chemoradiotherapy (nCRT) is the only recommended treatment for locally advanced ESCC. This phase-II study will provide preliminary evidence of the efficacy of pembrolizumab combined with TP as novel neoadjuvant therapy for patients with locally advanced ESCC. Trial Registration: Clinicaltrials.gov (Identifier: NCT04389177).

Erchen Decoction Ameliorates the Metabolic Abnormalities of High-Fat Diet-Fed Rats.

Objective: Brown adipose tissue (BAT) dissipates chemical energy to protect against obesity. In the present study, we aimed to determine the effects of Erchen decoction on the lipolysis and thermogenesis function of BAT in high-fat diet-fed rats. Methods: Sprague-Dawley rats were randomly divided into four groups, which were fed a control diet (C) or a high-fat diet (HF), and the latter was administered with high and low doses of Erchen decoction by gavage once a day, for 12 weeks. Body weight, the serum lipid profile, serum glucose, and insulin levels of the rats were evaluated. In addition, the phosphorylation and protein and mRNA expression of AMP-activated protein kinase (AMPK), adipose triglyceride lipase (ATGL), peroxisome proliferator-activated receptor γ coactivator- (PGC-) 1α, and uncoupling protein 1 (UCP-1) in BAT were measured by immunoblotting and RT-PCR. Results: Erchen decoction administration decreased body weight gain and ameliorated the abnormal lipid profile and insulin resistance index of the high-fat diet-fed rats. In addition, the expression of p-AMPK and ATGL in the BAT was significantly increased by Erchen decoction. Erchen decoction also increased the protein and mRNA expression of PGC-1α and UCP-1 in BAT. Conclusion: Erchen decoction ameliorates the metabolic abnormalities of high-fat diet-fed rats, at least in part via activation of lipolysis and thermogenesis in BAT.

A Phase IB Trial of Autologous Cytokine-Induced Killer Cells in Combination with Sintilimab, Monoclonal Antibody Against Programmed Cell Death-1, plus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: Can the Cytokine-induced killer (CIK) cells in combination with immune checkpoint inhibitor further improve the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients? What are the adverse reactions of this combination therapy? But these problems are not clear. Therefore, we conducted a phase 1b trial to evaluate the safety and efficacy of autologous CIK cells therapy combined with Sintilimab, antibody against programmed cell death-1, plus chemotherapy in untreated, advanced NSCLC patients. PATIENTS AND METHODS: Patients with stage IIIB/IIIC/IV NSCLC received Sintilimab, platinum-based doublet chemotherapy, and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or 2 years. The primary endpoints were safety and objective response rate (ORR). RESULTS: Thirty-four patients received the treatment. 94.1% of patients experienced treatment-related adverse events (TRAEs). Grade 3 or greater TRAEs occurred in 64.7% of patients. One (2.9%) patient died of grade 5 immune-related pneumonia. The ORR and DCR were 82.4% (95% CI, 65.5%-93.2%) and 100.0% (95% CI, 89.7%-100.0%), respectively. Objective responses were evaluated in 14 of 15 non-squamous patients (93.3%; 95% CI, 68.1%-99.8%) and in 14 of 19 squamous patients (73.7%; 95% CI, 48.8%-90.9%). Median PFS was 19.3 months (95% CI, 8.3 months to not available). CONCLUSION: Autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy was well tolerable and showed encouraging efficacy in patients with previously untreated, advanced NSCLC (ClinicalTrials.gov number, NCT03987867).

[Expression of indoleamine 2, 3-dioxygenase and its correlation with prognosis in breast cancer patients].

OBJECTIVE: To investigate the expression of indoleamine 2, 3-dioxygenase (IDO) in breast cancer and its correlation with clinicopathologic factors and prognosis. METHODS: The expression of IDO, CD31, CD105 proteins in 40 specimens of breast cancer were assessed by immunohistochemistry. RESULTS: The overexpression rate of IDO in breast cancer was 67.5% (27/40), and expression of IDO was closely associated with clinical stage and lymph nodes metastasis. The disease-free survival rate in patients with IDO overexpression was not significantly lower than that in patients with negative or low expression of IDO (P > 0.05). Moreover, the expression of IDO was positively correlated with CD105-labeled microvessel density (r = 0.659, P < 0.05). CONCLUSIONS: Expression of IDO is associated with clinical stage and lymph nodes metastasis, and microvessel densitty. IDO expression may promote the growth and metastasis of breast cancer, probably via the increased agiogenesis. A larger sample study is needed to verify whether the prognosis of beast cancer is significantly correlated with IDO expression.

Study on the Mechanism of the Reversible Color Change of Polyacrylic Acid Modified Gold Nanoparticles Responding to pH.

In view of various explanations regarding the pH response of the nanocomposite of gold nanoparticles (AuNPs) modified with polyacrylic acid (PAA) molecules in reported literature, in this work, AuNPs with a size of 20 nm saturatedly loaded with PAA molecules (AuNPs-PAAs) were used to investigate the following aspects of this issue. We investigated the effects of pH on the stability of AuNPs-PAAs in the presence of salt, CTAB, poly (sodium styrenesulfonate) (PSS), ethanol, and free PAA, respectively. Common techniques were undertaken to evaluate the stability, including UV-Vis spectroscopy, Zeta potential analysis, and TEM. The results show that AuNPs-PAAs could respond to pH variations, having a reversible aggregation-to-disaggregation, accompanying their Zeta potential change. The proposed corresponding mechanism was that this reversible change was attributes to the net charge variation of AuNPs-PAAs induced by a reversible protonation-to-deprotonation of PAA rather than the conformational change. It was found that salt, CTAB, PSS, and free PAA could strengthen the dispersity of AuNPs-PAAs, even though their absolute Zeta potential values were decreased to small values or dropped to nearly zero. This abnormal phenomenon was explained by solvation. It was also found that AuNPs-PAAs have an opposite pH response in aqueous and ethanol solutions, justifying the solvation effect. All these results revealed the conformational stability of PAAs immobilized on AuNPs. The methods and the findings of this investigation give some new insights to understand the pH-response of AuNPs-PAAs composites and the design of AuNPs-PAAs-based functional sensors.

Survival analysis of second primary malignancies after cervical cancer using a competing risk model: implications for prevention and surveillance.

BACKGROUND: Previous studies have reported an increased risk for second primary malignancies (SPMs) after cervical cancer (CC). This study aims to quantify and assess the risk of developing SPMs in long-term survivors of CC. METHODS: A population-based cohort of CC patients aged 20-79 years was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. A competing risk model and corresponding nomogram were constructed to predict the 3-, 5-, and 10-year cumulative risks of SPMs. A Fine-Gray plot was created to validate the model. Finally, we performed decision curve analysis (DCA) to evaluate the clinical usefulness of the model by calculating the net benefit. RESULTS: A total of 34,295 patients were identified, and approximately 6.3% of the study participants developed SPMs. According to the multivariable competing-risk model, older black CC survivors with localized disease who were treated with radiation therapy were more susceptible to SPMs. The 3-, 5-, and 10-year cumulative incidences of SPMs were 2.5%, 3.6%, and 6.2%, respectively. Calibration curves showed good agreement between the predicted and observed models. The DCA yielded a wide range of risk thresholds at which the net benefits could be obtained from our proposed model. CONCLUSIONS: This study provides physicians with a practical, individualized prognostic estimate to assess the risk of SPMs among CC survivors. CC survivors remain at a high risk of developing SPMs, and further surveillance should focus especially on the patients with black race, older age, localized disease, or those having received radiation therapy.

Conformational Stability of Poly (N-Isopropylacrylamide) Anchored on the Surface of Gold Nanoparticles.

To verify the temperature sensitive failure of poly (N-isopropylacrylamide) (PNIPAM) anchored on the surface of gold nanoparticles (AuNPs), the UV-Vis spectra with temperature variations of the following aqueous solutions respectively containing AuNPs-PNIPAM, Au-PNIPAM/PNIPAM, PNIPAM, in different media (including salt, ethanol, HCl and cetyltrimethylammoniumbromide (CTAB)), were systematically determined. The results indicated that the UV-Vis spectrum of AuNPs-PNIPAM suspension hardly changed even above the Lower Critical Solution Temperature (LCST) of PNIPAM, but that of Au-PNIPAM/PNIPAM sharply increased only in absorbance intensity. A possible mechanism of the failed temperature sensitivity of PNIPAM anchored on the surface of AuNPs was proposed. Being different from free PNIPAM molecules, a strong interaction exists among PNIPAM molecules anchored on the surface of AuNPs, restraining the change in conformation of PNIPAM. The temperature sensitivity of Au-PNIPAM/PNIPAM originates from the free PNIPAM molecules rather than the anchored PNIPAM one. The changing electrostatic interaction could effectively regulate the aggregation behavior of AuNPs-PNIPAM and enhance its sensitivity to temperature.

PP2 Ameliorates Renal Fibrosis by Regulating the NF-κB/COX-2 and PPARγ/UCP2 Pathway in Diabetic Mice.

Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy (DN). We aimed to evaluate the effects of PP2 on renal fibrosis of DN. GSE33744 and GSE86300 were downloaded from the GEO database. Firstly, 839 DEGs were identified between nondiabetic and diabetic mice renal glomerular samples. COX-2 was selected to assess the effects of PP2 on renal glomerulosclerosis. In db/db mice, PP2 decreased the expression of COX-2, phosphorylated p65, and fibrotic proteins, accompanied with attenuated renal glomerulosclerosis. In cultured glomerular mesangial cells, high glucose- (HG-) induced p65 phosphorylation and COX-2 expression were attenuated by PP2 or NF-κB inhibitor PDTC. PP2, PDTC, or COX-2 inhibitor NS-398 ameliorated abnormal proliferation and expression of fibrotic proteins induced by HG. Secondly, 238 DEGs were identified between nondiabetic and diabetic mice renal cortex samples. UCP2 was selected to assess the effects of PP2 on renal tubulointerstitial fibrosis. In db/db mice, PP2 decreased the expression of PPARγ and UCP2, accompanied with attenuated renal tubulointerstitial fibrosis and EMT. In cultured proximal tubular cells, HG-induced PPARγ and UCP2 expression was inhibited by PP2 or PPARγ antagonist GW9662. PP2, GW9662, or UCP2 shRNA ameliorated HG-induced EMT. These results indicated that PP2 ameliorated renal fibrosis in diabetic mice.

The ß3 Adrenergic Receptor Agonist CL316243 Ameliorates the Metabolic Abnormalities of High-Fat Diet-Fed Rats by Activating AMPK/PGC-1α Signaling in Skeletal Muscle.

PURPOSE: Skeletal muscle has a major influence on whole-body metabolic homeostasis. In the present study, we aimed to determine the metabolic effects of the ß3 adrenergic receptor agonist CL316243 (CL) in the skeletal muscle of high-fat diet-fed rats. METHODS: Sprague-Dawley rats were randomly allocated to three groups, which were fed a control diet (C) or a high-fat diet (HF), and half of the latter were administered 1 mg/kg CL by gavage once weekly (HF+CL), for 12 weeks. At the end of this period, the serum lipid profile and glucose tolerance of the rats were evaluated. In addition, the phosphorylation and protein and mRNA expression of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, and carnitine palmitoyl transferase (CPT)-1b in skeletal muscle were measured by Western blot analysis and qPCR. The direct effects of CL on the phosphorylation (p-) and expression of AMPK, PGC-1α, and CPT-1b were also evaluated by Western blotting and immunofluorescence in L6 myotubes. RESULTS: CL administration ameliorated the abnormal lipid profile and glucose tolerance of the high-fat diet-fed rats. In addition, the expression of p-AMPK, PGC-1α, and CPT-1b in the soleus muscle was significantly increased by CL. CL (1 µM) also increased the protein expression of p-AMPK, PGC-1α, and CPT-1b in L6 myotubes. However, the effect of CL on PGC-1α protein expression was blocked by the AMPK antagonist compound C, which suggests that CL increases PGC-1α protein expression via AMPK. CONCLUSION: Activation of the ß3 adrenergic receptor in skeletal muscle ameliorates the metabolic abnormalities of high-fat diet-fed rats, at least in part via activation of the AMPK/PGC-1α pathway.

Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events.

OBJECTIVE: Distinguishing immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) from the AEs caused by chemotherapy, targeted therapy, or infection is highly difficult. This study offers new insights into evaluating the diagnosis, differential diagnostic, and prognostic value of ferritin for irAEs induced by ICIs. METHODS: From December 1, 2018, to April 1, 2019, we examined 318 patients with malignant tumors who received serum ferritin monitoring. The cohort comprised 231 patients treated with PD-1 inhibitor or combination with chemotherapy, and 87 patients treated with chemotherapy. Of the 231 patients, 90 had irAEs (irAE group), 70 had non-irAEs (non-irAE group), 67 had no AEs (no irAE-non irAE group), and 4 had unclassified AEs. In the 87 patients, 60 had AEs (AE group), and 27 had no AEs (no AE group). Statistical analyses were conducted with nonparametric Mann-Whitney tests. RESULTS: At the onset of AEs in the irAE group, ferritin (normal range, 35-150 µg/L) rose to a median of 927 µg/L (range, 117-17,825 µg/L) from 86 µg/L at baseline (range, 29-421 µg/L) (P < 0.001). Ferritin levels at the onset of AEs in the irAE group were significantly higher than those in the non-irAE group (median, 81 µg/L; range, 32-478 µg/L) (P < 0.001) and the AE group (median, 103 µg/L; range, 23-712 µg/L) (P < 0.001). After treatment in the irAE group, ferritin continuously decreased to a normal range in recovered patients, showed no significant changes in stable patients, and continued to rise in patients who died. CONCLUSIONS: Ferritin can be used as a diagnostic, differential diagnostic, and prognostic marker for irAEs in patients treated with ICIs.

Study on the Assembly Structure Variation of Cetyltrimethylammonium Bromide on the Surface of Gold Nanoparticles.

In this work, the self-assembly behavior of cetyltrimethylammonium bromide (CTAB) on the surface of citrate-capped gold nanoparticles (AuNPs) in solution has been studied by UV-vis absorption spectroscopy, fluorescence probe techniques, ζ potentiometric methods, transmission electron microscopy, etc. The UV-vis spectra show that the color with the increase of CTAB for the mixture containing CTAB and a given amount of AuNPs changes from red to blue and then to red. The absolute value of ζ potential corresponding to this color change decreases initially and then increases. Specially, the reversible color change, from red to blue and then to red, could be observed only in the case of a gradual addition of a AuNP solution to a CTAB solution; however, this reversible change is not suitable for the mixture formed in a reverse order of mixing. The results from pyrene used as the fluorescence probe indicate that the features in the fluorescence spectrum (including fluorescence quenching, I 1/I 3, and the excimer) well correspond to those from the UV-vis spectrum mentioned above. Based on the experimental results, the mechanism of the assembly structure variation of CTAB on the surface of negatively charged AuNPs was proposed. For a given amount of AuNPs, the assembly structure of CTAB on the surface of AuNPs undergoes the transformation from a monolayer to a bilayer with the increase of CTAB. In the case of the concentration of CTAB far beyond its critical micelle concentration (CMC) and the higher ratio of CTAB and AuNPs, there is a possibility of the formation of an extra micellar structure only after the formation of a double-layer structure.