Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its ...cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3β/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5 mg/kg, i.p., once a week for three times, the total cumulative dose is 15 mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.
While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game ...changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP). The porous MSNP interior allows contemporaneous delivery of the ICD-inducing chemotherapeutic agent, oxaliplatin (OX). The nanovesicles plus free OX or OX/IND-MSNP induce effective innate and adaptive anti-PDAC immunity when used in a vaccination approach, direct tumor injection or intravenous biodistribution to an orthotopic PDAC site. Significant tumor reduction or eradication is accomplishable by recruiting cytotoxic T lymphocytes, concomitant with downregulation of Foxp3
T cells.
Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be ...delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.
Astrocytes express a complex repertoire of intracellular Ca2+ transients (events) that represent a major form of signaling within individual cells and in astrocytic syncytium. These events have ...different spatiotemporal profiles, which are modulated by neuronal activity. Spontaneous Ca2+ events appear more frequently in distal astrocytic processes and independently from each other. However, little is known about the mechanisms underlying such subcellular distribution of the Ca2+ events. Here, we identify the initiation points of the Ca2+ events within the territory of single astrocytes expressing genetically encoded Ca2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca2+ events start in an optimal range of thin distal processes. Our mathematical model demonstrated that a high surface‐to‐volume of the thin processes leads to increased amplitude of baseline Ca2+ fluctuations caused by a stochastic opening of Ca2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca2+‐induced Ca2+ release from the Ca2+ stores by activating inositol 1,4,5‐trisphosphate (IP3) receptors. In agreement with the model prediction, the spontaneous Ca2+ events frequency depended on the extracellular Ca2+ concentration. Astrocytic depolarization by high extracellular K+ increased the frequency of the Ca2+ events through activation of voltage‐gated Ca2+ channels in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca2+ events frequency. Therefore, structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.
Majority of spontaneous Ca2+ events start in thin astrocytic processes.
Higher surface‐to‐volume ratio of the process is responsible for larger intracellular Ca2+ fluctuations.
Larger intracellular Ca2+ fluctuations trigger Ca2+‐dependent Ca2+ release.
Upregulated expression of immune checkpoint molecules correlates with exhausted phenotype and impaired function of cytotoxic T cells to evade host immunity. By disrupting the interaction of PD-L1 and ...PD1, immune checkpoint inhibitors can restore immune system function against cancer cells. Growing evidence have demonstrated apigenin and luteolin, which are flavonoids abundant in common fruits and vegetables, can suppress growth and induce apoptosis of multiple types of cancer cells with their potent anti-inflammatory, antioxidant and anticancer properties. In this study, the effects and underlying mechanisms of luteolin, apigenin, and anti-PD-1 antibody combined with luteolin or apigenin on the PD-L1 expression and anti-tumorigenesis in KRAS-mutant lung cancer were investigated. Luteolin and apigenin significantly inhibited lung cancer cell growth, induced cell apoptosis, and down-regulated the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3. Both luteolin and apigenin showed potent anti-cancer activities in the H358 xenograft and Lewis lung carcinoma model in vivo, and the treatment with monoclonal PD1 antibody enhanced the infiltration of T cells into tumor tissues. Apigenin exhibited anti-tumor activity in Genetically engineered KRASLA2 mice. In conclusion, both apigenin and luteolin significantly suppressed lung cancer with KRAS mutant proliferation, and down-regulated the IFN-γ induced PD-L1 expression. Treatment with the combination of PD-1 blockade and apigenin/luteolin has a synergistic effect and might be a prospective therapeutic strategy for NSCLC with KRAS-mutant.
•Luteolin and apigenin can downregulate the PD-L1 expression in NSCLC with KRAS mutation.•The combination of apigenin or luteolin with PD-1 mAb enhanced tumor growth control and improved survival.•Apigenin but not luteolin exhibited anti-tumor activity in KRASLA2 mice.
Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving ...standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options.
This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18–65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III–IVA, excluding T3–4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12–16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111.
Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33–42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% 95% CI 80·4–90·6) than in the standard therapy group (75·7% 69·9–81·9), with a stratified hazard ratio of 0·50 (95% CI 0·32–0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 9% patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group.
The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma.
The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation.
For the Chinese translation of the abstract see Supplementary Materials section.
The triglyceride–glucose (TyG) index has been correlated with insulin resistance. We aim to investigate the role of the TyG index on cardiovascular (CV) events in type 2 diabetes mellitus and compare ...the roles of fasting glucose, hemoglobin A1c, and the TyG index in predicting CV events. This retrospective study enrolled 3524 patients with type 2 diabetes from the Kaohsiung Medical University Research Database in 2009 in this longitudinal study and followed them until 2015. The TyG index was calculated as log (fasting triglyceride level (mg/dL) × fasting glucose level (mg/dL)/2). CV events included myocardial infarction, unstable angina, stroke, hospitalization for coronary artery disease, peripheral artery disease, and CV-related death. The association between variables and CV events was assessed using a multivariable stepwise Cox proportional hazard analysis. Two hundred and fifteen CV events (6.1%) were recorded during a follow-up period of 5.93 years. The multivariable stepwise analysis showed that high fasting glucose (HR, 1.007; p < 0.001) and a high TyG index (HR, 1.521; p = 0.004) but not hemoglobin A1c or triglycerides were associated with a higher rate of CV events. Adding fasting glucose and the TyG index to the basic model improved the predictive ability of progression to a CV event (p < 0.001 and p = 0.018, respectively), over that of hemoglobin A1c (p = 0.084) and triglyceride (p = 0.221). Fasting glucose and the TyG index are useful parameters and stronger predictive factors than hemoglobin A1c and triglyceride for CV events and may offer an additional prognostic benefit in patients with type 2 diabetes.
Background
This meta-analysis aimed to investigate the value of preoperative sarcopenia in predicting complications after esophagectomy. Clinicopathologic characteristics of sarcopenia patients, ...which may support sarcopenia management, also were studied.
Methods
This study searched for articles describing an association between sarcopenia and short-term outcomes after esophagectomy using PubMed, EMBASE, and the Cochrane Library. Mantel–Haenszel and inverse variance models were used for the meta-analyses of end points.
Results
The meta-analysis included 14 studies comprising a total of 2387 patients. Sarcopenia was significantly associated with advanced age (weighted mean difference WMD, 3.48; 95% confidence interval CI, 2.22–4.74), lower body mass index (WMD − 2.22; 95% CI − 2.65 to − 1.79), squamous cell carcinoma (odds ratio OR, 2.78; 95% CI 1.72–4.47), advanced clinical tumor stage (OR 1.65; 95% CI 1.28–2.15), and neoadjuvant therapy (OR 1.87; 95% CI 1.38–2.53). The sarcopenia patients showed lower preoperative albumin levels (WMD − 0.11; 95% CI − 0.19 to − 0.04) than the nonsarcopenia patients. Sarcopenia was significantly predictive of pneumonia (OR 2.58; 95% CI 1.75–3.81) and overall complications (OR 1.52; 95% CI 1.07–2.15) after esophagectomy. The sarcopenia patients also showed nonsignificant increases in the risks of anastomotic leakage (OR 1.29; 95% CI 0.99–1.67), vocal cord palsy (OR 2.03; 95% CI 0.89–4.64), and major complications (≥ Clavien-Dindo grade III; OR 1.30; 95% CI 0.95–1.79) but not increased operation time, blood loss, or mortality.
Conclusions
Preoperative sarcopenia assessment showed considerable potential for predicting postoperative complications for esophageal cancer patients. To realize this potential, more effective diagnostic criteria and severity classifications for sarcopenia are warranted.
Contests have long existed to source ideas and solutions. The emergence of crowdsourcing contest platforms greatly reduces the costs and broadens the reach of running contests by facilitating access ...to a large pool of labor, making contests a cost‐efficient approach to procure ideas/solutions even for employers of limited resources. As a result, the use of contests surges and there is a flux of small‐to‐medium size contests to these platforms. This study focuses on these new waves of small‐to‐medium‐size contests on crowdsourcing contest platforms and extends the literature in several ways: First, prior literature focuses extensively on contest prize, we also consider the effect of contest duration, which plays salient role on contest platforms. Our findings provide evidence that contest duration affects both the number and the quality of contestants attracted to a contest. Second, prior literature assumes contests exist independently and that the quality distribution of contestants is exogenous; accordingly, the number of contestants can be regarded as a proxy of contest performance. We show that contest design parameters have direct effects on the quality distribution of contestants. Specifically, increasing contest duration, while attracting more contestants, results in a downward shift on the quality distribution of the contestants attracted to the contest. Third, recognizing that each contest does not exist independently on crowdsourcing contest platforms, we also incorporate the number of competing contests in our model. Our results provide practical recommendations on how to set up successful contests and attract high‐quality contestants to a contest on a crowdsourcing contest platform.
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