An analysis of the relationship of triglyceride glucose index with gastric cancer prognosis: A retrospective study.

AIMS/INTRODUCTION: Gastric cancer, one of the most common malignant tumors worldwide, is affected by insulin resistance. The triglyceride glucose (TYG) index is considered a surrogate indicator of insulin resistance; however, its prognostic value in patients with gastric cancer remains obscure. This study aimed to determine whether the TYG index could predict the long-term prognosis of patients with gastric cancer after radical resection gastrectomy. MATERIALS AND METHODS: We retrospectively analyzed patients with gastric cancer who underwent radical resection gastrectomy. The preoperative TYG index was calculated using the patients' laboratory data. Patients were divided into two groups based on a high or low TYG index. We observed overall survival and evaluated the clinical application value of the index using Cox proportional hazards regression to calculate independent parameters. A prediction model was also established. RESULTS: In total, 822 patients with gastric cancer were included. The high and low TYG index groups comprised 353 and 469 patients, respectively. The overall survival time was significantly longer in the high-index group than in the low-index group. In the multivariate analysis, TYG index, preoperative age, surgical procedure, tumor node metastasis (TNM) stage, N stage, and postoperative complications (all p < 0.01) were considered independent prognostic predictors. Based on the multivariate analysis, the riglyceride glucose (TYG) index hazard ratio was 0.70 (95% confidence interval, 0.54-0.89, p = 0.004). CONCLUSIONS: We established a model with a high clinical application value and clinical practice relevance to predict the prognosis of gastric cancer. In this model, TYG was an independent protective factor for gastric cancer prognosis.

Mutual communication between radiosensitive and radioresistant esophageal cancer cells modulates their radiosensitivity.

Radiotherapy is an important treatment modality for patients with esophageal cancer; however, the response to radiation varies among different tumor subpopulations due to tumor heterogeneity. Cancer cells that survive radiotherapy (i.e., radioresistant) may proliferate, ultimately resulting in cancer relapse. However, the interaction between radiosensitive and radioresistant cancer cells remains to be elucidated. In this study, we found that the mutual communication between radiosensitive and radioresistant esophageal cancer cells modulated their radiosensitivity. Radiosensitive cells secreted more exosomal let-7a and less interleukin-6 (IL-6) than radioresistant cells. Exosomal let-7a secreted by radiosensitive cells increased the radiosensitivity of radioresistant cells, whereas IL-6 secreted by radioresistant cells decreased the radiosensitivity of radiosensitive cells. Although the serum levels of let-7a and IL-6 before radiotherapy did not vary significantly between patients with radioresistant and radiosensitive diseases, radiotherapy induced a more pronounced decrease in serum let-7a levels and a greater increase in serum IL-6 levels in patients with radioresistant cancer compared to those with radiosensitive cancer. The percentage decrease in serum let-7a and the percentage increase in serum IL-6 levels at the early stage of radiotherapy were inversely associated with tumor regression after radiotherapy. Our findings suggest that early changes in serum let-7a and IL-6 levels may be used as a biomarker to predict the response to radiotherapy in patients with esophageal cancer and provide new insights into subsequent treatments.

Breastfeeding is associated with reduced risks of central obesity and hypertension in young school-aged children: a large, population-based study.

BACKGROUND: Previous studies examined the effects of breastfeeding on measured values of body circumferences or blood pressure during childhood. However, limited data are available for the association between child feeding and a specific disease diagnosed as central obesity or hypertension. Hence, we aimed to examine whether the type and duration of breastfeeding are associated with obesity/central obesity or hypertension in young school-aged children. METHODS: We matched the data obtained from a cross-sectional survey in 2019 with retrospective breastfeeding information recorded in the database. Heights, weights, waist circumferences, and blood pressures of 8480 children in first grade of primary schools in Shanghai, China were measured to diagnose obesity, central obesity, and hypertension. Data on child feeding was collected retrospectively from clinical records. Associations between the type/duration of breastfeeding and children's measured values of body mass index, waist circumference, and blood pressure were analysed by linear regression. Associations between the type/duration of breastfeeding and risks of obesity, central obesity, and hypertension were analysed by generalised linear models. RESULTS: Breastfeeding duration was inversely associated with blood pressure values in children in the first grade. Each month's increase in the duration of any breastfeeding was associated with a 0.07 mmHg decrease in systolic blood pressure (P < 0.01) and a 0.05 mmHg decrease in diastolic blood pressure (P < 0.01). Any breastfeeding > one month was associated with a reduced risk of hypertension (adjusted risk ratio 0.84; 95% CI 0.73, 0.96, P = 0.01). Exclusive breastfeeding > one month was associated with a reduced risk of central obesity (adjusted risk ratio 0.76; 95% CI: 0.60, 0.96, P = 0.02). Any breastfeeding > 12 months was linked with a lower risk of hypertension (adjusted risk ratio 0.83; 95% CI 0.70, 0.98, P = 0.03). CONCLUSIONS: Lack of breastfeeding is associated with higher risks of central obesity and hypertension during middle childhood. As a potential component of the public health strategy to reduce population levels of metabolic and cardiovascular diseases, breastfeeding could be a vital prevention strategy.

LiOtBu-Promoted trans-Stereoselective and ß-Regioselective Hydroboration of Propargyl Alcohols.

A convenient and efficient trans-stereoselective and ß-regioselective hydroboration of propargyl alcohols was achieved simply with LiOtBu as the base and (Bpin)2 as the boron reagent in dimethyl sulfoxide at room temperature. Both terminal and internal propargyl alcohols with diverse structures and functional groups underwent the transformation smoothly to produce ß-Bpin-substituted (E)-allylic alcohols, of which the synthetic potentials were demonstrated by the downstream conversions of boronate, alkenyl, and hydroxyl groups.

Evaluation the benefits of additional radiotherapy for gastric cancer patients after D2 resection using CT based radiomics.

OBJECTIVES: The value of adding radiotherapy (RT) is still unclear for patients with gastric cancer (GC) after D2 lymphadenectomy. The purpose of this study is to predict and compare the overall survival (OS) and disease-free survival (DFS) of GC patients treated by chemotherapy and chemoradiation based on contrast-enhanced CT (CECT) radiomics. METHODS: A total of 154 patients treated by chemotherapy and chemoradiation in authors' hospital were retrospectively reviewed and randomly divided into the training and testing cohorts (7:3). Radiomics features were extracted from contoured tumor volumes in CECT using the pyradiomics software. Radiomics score and nomogram with integrated clinical factors were developed to predict the OS and DFS and evaluated with Harrell's Consistency Index (C-index). RESULTS: Radiomics score achieved a C index of 0.721(95%CI: 0.681-0.761) and 0.774 (95%CI: 0.738-0.810) in the prediction of DFS and OS for GC patients treated by chemotherapy and chemoradiation, respectively. The benefits of additional RT only demonstrated in subgroup of GC patients with Lauren intestinal type and perineural invasion (PNI). Integrating clinical factors further improved the prediction ability of radiomics models with a C-index of 0.773 (95%CI: 0.736-0.810) and 0.802 (95%CI: 0.765-0.839) for DFS and OS, respectively. CONCLUSIONS: CECT based radiomics is feasible to predict the OS and DFS for GC patients underwent chemotherapy and chemoradiation after D2 resection. The benefits of additional RT only observed in GC patients with intestinal cancer and PNI.

Longitudinal association between the timing of adiposity peak and rebound and overweight at seven years of age.

BACKGROUND: The timing of adiposity peak (AP) or adiposity rebound (AR) is a determinant of overweight or obesity in adolescence and adulthood. However, limited studies have reported the association in young school-age children. We aimed to evaluate this association and explore the role of health behaviours in it. METHODS: Routinely collected, sequential, anthropometric data from the 1st to 80th months of age were used to estimate AP and AR timings in 2330 children born in Shanghai between 2010 and 2013. Multivariate regression analyses were applied to identify the associations between the AP or AR timings and the risk of developing overweight or obesity in first-grade school children. The roles of health behaviours, including dietary patterns, physical activity level, sleep and snacking habits, and screen time, were also evaluated. RESULTS: Children with a late AP or an early AR were at higher risk of overweight but not obesity or central obesity in their first grade. A high physical activity level was associated with a lower risk of having overweight in children with a late AP, and limited screen time was associated with a decreased risk of having overweight or obesity in children with an early AR. The absence of a late-night snacking habit in children with a non-early AR indicated a decreased risk of having overweight. However, this association was not observed among children with an early AR. CONCLUSION: The timings of AP and AR are tied to overweight in middle childhood. Prevention strategies are suggested to move forward to control late AP and early AR.

Secure predictor-based neural dynamic surface control of nonlinear cyber-physical systems against sensor and actuator attacks.

This paper addresses a secure predictor-based neural dynamic surface control (SPNDSC) issue for a cyber-physical system in a nontriangular form suffering from both sensor and actuator deception attacks. To avoid the algebraic loop problem, only partial states are employed as input vectors of neural networks (NNs) for approximating unknown dynamics, and compensation terms are further developed to offset approximation errors from NNs. With introduction of nonlinear gain functions and attack compensators, adverse effects of an intelligent adversary are alleviated effectively. Furthermore, we present stability analysis and prove the ultimate boundedness of all signals in the closed-loop system. The effectiveness of the proposed control strategy is illustrated by two examples.

ADAP1 promotes latent HIV-1 reactivation by selectively tuning KRAS-ERK-AP-1 T cell signaling-transcriptional axis.

Immune stimulation fuels cell signaling-transcriptional programs inducing biological responses to eliminate virus-infected cells. Yet, retroviruses that integrate into host cell chromatin, such as HIV-1, co-opt these programs to switch between latent and reactivated states; however, the regulatory mechanisms are still unfolding. Here, we implemented a functional screen leveraging HIV-1's dependence on CD4+ T cell signaling-transcriptional programs and discovered ADAP1 is an undescribed modulator of HIV-1 proviral fate. Specifically, we report ADAP1 (ArfGAP with dual PH domain-containing protein 1), a previously thought neuronal-restricted factor, is an amplifier of select T cell signaling programs. Using complementary biochemical and cellular assays, we demonstrate ADAP1 inducibly interacts with the immune signalosome to directly stimulate KRAS GTPase activity thereby augmenting T cell signaling through targeted activation of the ERK-AP-1 axis. Single cell transcriptomics analysis revealed loss of ADAP1 function blunts gene programs upon T cell stimulation consequently dampening latent HIV-1 reactivation. Our combined experimental approach defines ADAP1 as an unexpected tuner of T cell programs facilitating HIV-1 latency escape.

Dihydroartemisinin enhances the anti-tumor activity of oxaliplatin in colorectal cancer cells by altering PRDX2-reactive oxygen species-mediated multiple signaling pathways.

BACKGROUND: Globally, colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Oxaliplatin based treatments are frequently used as chemotherapeutic methods for CRC, however, associated side effects and drug resistance often limit their clinical application. Dihydroartemisinin (DHA) induces apoptosis in various cancer cells by increasing reactive oxygen species (ROS) production. However, the direct target of DHA and underlying molecular mechanisms in oxaliplatin-mediated anti-tumor activities against CRC are unclear. METHODS: We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), flow cytometry, and colony formation assays to investigate cell phenotype alterations and ROS generation. We also used quantitative Real-Time PCR (qRT-PCR) and western blotting to measure relative gene and protein expression. Finally, an in vivo mouse xenograft model was used to assess the anti-tumor activity of oxaliplatin and DHA alone, and combinations. RESULTS: DHA synergistically enhanced the anti-tumor activity of oxaliplatin in colon cancer cells by regulating ROS-mediated ER stress, signal transducer and activator of transcription 3 (STAT3), C-Jun-amino-terminal kinase (JNK), and p38 signaling pathways. Mechanistically, DHA increased ROS levels by inhibiting peroxiredoxin 2 (PRDX2) expression, and PRDX2 knockdown sensitized DHA-mediated cell growth inhibition and ROS production in CRC cells. A mouse xenograft model showed strong anti-tumor effects from combination treatments when compared with single agents. CONCLUSIONS: We demonstrated an improved therapeutic strategy for CRC patients by combining DHA and oxaliplatin treatments.

Clinical analysis of myelin oligodendrocyte glycoprotein antibody-associated demyelination in children: A single-center cohort study in China.

BACKGROUND AND PURPOSE: Myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) are detected at a high rate in childhood of acquired demyelinating syndrome (ADS), but the spectrum and characteristics of MOG-Abs-associated disorders (MOGAD) in children are to be determined. This study aimed to identify clinical features in Chinese children with MOGAD. METHODS: Of 48 children in whom MOGAD were diagnosed in our hospital, we analyzed the manifestations, laboratory test results, imaging characteristics, autoimmune antibodies in cerebrospinal fluid and serum, and response to treatment. We used a cell transfection immunofluorescence assay to test for MOG-Abs in serum. RESULTS: Of the 48 children, the most common phenotypes were acute disseminated encephalomyelitis (ADEM) (20/48, 41.7%) and optic neuritis (ON) (13/48, 27.1%). The onset ages of ON were significantly higher than those of ADEM (8.68±2.86 & 4.80±2.77, P<0.01). Cerebral lesions manifested as ADEM-like, leukodystrophy-like and other patterns. All children received first-line immunomodulatory therapy and some of them received second-line drugs, whose acute clinical symptoms were alleviated to some extent. 34 patients (34/48,70.8%) experienced one episode, the main phenotypes were ADEM (19/34,55.9%) and encephalitis (9/34,26.5%), and 14 children (14/48,29.2%) had two or more episodes, the primary expressions were ADEM-ON (8/14,57.1%) and recurrent ON (3/14,21.4%). During our follow-up, 8 patients suffered relapsed, but the MOG-Ab titers were not increase during acute stages. 4 patients (4/9,44.4%) of ADEM with ON were developed cognitive impairment, epilepsy and other sequelae, and 2 patients (2/3, 66.7%) of repeated ON suffered visual impairment. CONCLUSION: The clinical phenotypes of MOGAD are age-dependent, the onset ages of ADEM are significantly younger than those of the ON children, and leukodystrophy-like pattern could occur in infancy. Cerebral lesions of MRI were extensive and various, manifested as ADEM-like, leukodystrophy-like, ON and other patterns. The titers of MOG-Ab should not be used as the only basis for recurrence and long-term immunoregulatory treatment. Most children had a good prognosis, however, the phenotype of ADEM-ON at onset was tend to relapse, sometimes with cognitive impairment, epilepsy, and other sequelae. Repeated ON could cause visual impairment.

Systematic reconstruction of an effector-gene network reveals determinants of Salmonella cellular and tissue tropism.

The minimal genetic requirements for microbes to survive within multiorganism communities, including host-pathogen interactions, remain poorly understood. Here, we combined targeted gene mutagenesis with phenotype-guided genetic reassembly to identify a cooperative network of SPI-2 T3SS effector genes that are sufficient for Salmonella Typhimurium (STm) to cause disease in a natural host organism. Five SPI-2 effector genes support pathogen survival within the host cell cytoplasm by coordinating bacterial replication with Salmonella-containing vacuole (SCV) division. Unexpectedly, this minimal genetic repertoire does not support STm systemic infection of mice. In vivo screening revealed a second effector-gene network, encoded by the spv operon, that expands the life cycle of STm from growth in cells to deep-tissue colonization in a murine model of typhoid fever. Comparison between Salmonella infection models suggests how cooperation between effector genes drives tissue tropism in a pathogen group.

Nivolumab for Metastatic Urothelial Cancer in a Renal Allograft Recipient With Subsequent Graft Rejection and Treatment Complete Remission: A Case Report.

Immune checkpoint inhibitors (ICIs) expanded the therapeutic options for several cancers. However, whether some special groups of patients including those with organ transplantation can receive ICIs remains unclear. In this report we presented an interesting case. A 54-year-old woman underwent kidney transplantation, developed metastasis 7 years after operation of the bladder tumor. Her disease progressed after chemotherapy and radiotherapy. Anti-PD-1 immunotherapy was then considered. After two cycles of nivolumab immunotherapy, the patient's renal function declined rapidly. Acute allograft rejection was considered. There was no significant decrease in creatinine after glucocorticoid pulse therapy. Third course of nivolumab was given, and regularly hemodialysis was simultaneously conducted. Two weeks later, the patient showed left abdominal pain. CT scan revealed a reduction in tumor burden, while enlarged volume of kidney graft. Immunotherapy stopped. Two months after the third course, CT demonstrated a complete remission to immunotherapy. 23 months after the third course, CT showed that the swelling transplanted kidney was smaller than previous, and no recurrence was observed.

miR-20b and miR-125a promote tumorigenesis in radioresistant esophageal carcinoma cells.

Radiation therapy is an effective method in the management of esophageal cancer. MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. However, the roles of specific miRNAs in radioresistant esophageal cancer remain to be investigated. In present study, the relative expression level of miR-20b-5p and miR-125a-5p were evaluated by quantitative Real-time polymerase chain reaction. Cell counting Kit-8 assay, wound-healing assay, transwell assay were used to assess cell proliferation, cell migration and cell invasion. TUNEL and Annexin V-FITC assays were applied to evaluate cell apoptosis. Dual-luciferase reporter gene assay was conducted to identify direct targets of miRNAs. The protein expression level was assessed by Western blot. The results indicated that miR-20b-5p was increased in radioresistant KYSE-150R cells compared with KYSE-150 cells, whereas miR-125a-5p was downregulated. MiR-20b-5p upregulation promoted cell proliferation, migration, invasion, and the EMT process, and decreased apoptosis by negatively regulating PTEN. MiR-125a-5p inhibited cell proliferation, migration, invasion, the EMT process and it induced apoptosis by negatively regulating IL6R. These data indicate that miR-20b-5p and miR-125a-5p promote tumorigenesis in radioresistant KYSE-150R cells and have the potential to be used as novel therapeutic targets for the treatment of esophageal cancer.

Immunological Classification of Pancreatic Carcinomas to Identify Immune Index and Provide a Strategy for Patient Stratification.

Background: Cancer immunotherapy has produced significant positive clinical effects in a variety of tumor types. However, pancreatic ductal adenocarcinoma (PDAC) is widely considered to be a "cold" cancer with poor immunogenicity. Our aim is to determine the detailed immune features of PDAC to seek new treatment strategies. Methods: The immune cell abundance of PDAC patients was evaluated with the single-sample gene set enrichment analysis (ssGSEA) using 119 immune gene signatures. Based on these data, patients were classified into different immune subtypes (ISs) according to immune gene signatures. We analyzed their response patterns to immunotherapy in the datasets, then established an immune index to reflect the different degrees of immune infiltration through linear discriminant analysis (LDA). Finally, potential prognostic markers associated with the immune index were identified based on weighted correlation network analysis (WGCNA) that was functionally validated in vitro. Results: Three ISs were identified in PDAC, of which IS3 had the best prognosis across all three cohorts. The different expressions of immune profiles among the three ISs indicated a distinct responsiveness to immunotherapies in PDAC subtypes. By calculating the immune index, we found that the IS3 represented higher immune infiltration, while IS1 represented lower immune infiltration. Among the investigated signatures, we identified ZNF185, FANCG, and CSTF2 as risk factors associated with immune index that could potentially facilitate diagnosis and could be therapeutic target markers in PDAC patients. Conclusions: Our findings identified immunologic subtypes of PDAC with distinct prognostic implications, which allowed us to establish an immune index to represent the immune infiltration in each subtype. These results show the importance of continuing investigation of immunotherapy and will allow clinical workers to personalized treatment more effectively in PDAC patients.

Pre-Birth and Early-Life Factors Associated With the Timing of Adiposity Peak and Rebound: A Large Population-Based Longitudinal Study.

Background: The late occurrence of adiposity peak (AP) and the early occurrence of adiposity rebound (AR) are considered the earliest indicators for obesity and its related health conditions later in life. However, there is still limited information for their upstream factors. Therefore, in this study, we aimed to identify the parental and child factors associated with the timing of AP and AR in the early stage of life. Methods: This is a population-based longitudinal study conducted in Shanghai, China. The BMI data of children born between September 2010 and October 2013 were followed from birth to 80 months. Subject-specific body mass index trajectories were fitted by non-linear mixed-effect models with natural cubic spline functions, and the individual's age at AP and AR was estimated. The generalized linear regression models were applied to identify the upstream factors of late occurrence of AP and early occurrence AR. Results: For 7,292 children with estimated AP, boys were less likely to have a late AP [adjusted risk ratio (RR) = 0.83, 95% confidence interval (CI): 0.77-0.90, p < 0.001], but preterm born children had a higher risk of a late AP (adjusted RR = 1.25, 95% CI: 1.07-1.47, p < 0.01). For 10,985 children with estimated AR, children with breastfeeding longer than 4 months were less likely to have an early AR (adjusted RR = 0.80, 95% CI: 0.73-0.87, p < 0.001), but children who were born to advanced-age mothers and who were born small for gestational age had a higher risk of having an early AR (adjusted RR = 1.21, 95% CI: 1.07-1.36, p < 0.01; adjusted RR = 1.20, 95% CI: 1.04-1.39, p = 0.01). Conclusions: Modifiable pre-birth or early-life factors associated with the timing of AP or AR were found. Our findings may help develop prevention and intervention strategies at the earliest stage of life to control later obesity and the health conditions and diseases linked to it.

Identification and Mechanism of the PD-1/PD-L1 Genomic Signature SORL1 as Protective Factor in Bladder Cancer.

Background: Immunotherapy has recently shown remarkable efficacy for advanced bladder cancer patients. Accordingly, identifying a biomarker associated with the programmed cell death protein 1 (PD-1)/its ligand (PD-L1) genomic signature to predict patient prognosis is necessary. Methods: In this study, we used mutation data and RNA-seq data of bladder cancer samples acquired from The Cancer Genome Atlas (TCGA) database to combine PD-1/PD-L1-associated mutational signatures with PD-1/PD-L1-associated differentially expressed genes (DEGs). Then, we performed a Kaplan-Meier analysis on the corresponding clinical data of the TCGA bladder urothelial carcinoma (BLCA) cohort to identify prognostic genes, and the results were validated using the GSE48075 cohort. The online platform UCSC Xena was used to analyze the relationship between the candidate genes and clinical parameters. We utilized the Human Protein Atlas (HPA) database to validate the protein expression levels. Then, correlation analysis, cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) analysis, and gene set enrichment analysis (GSEA) were used to clarify the mechanism. Results: We identified one prognostic gene, sortilin related receptor 1 (SORL1), whose downregulation was associated with a comparatively advanced BLCA stage. While further exploring this finding, we found that SORL1 expression was negatively correlated with PD-1/PD-L1 expression and M2 macrophage levels. Furthermore, we found that the downregulation of SORL1 expression was significantly associated with a higher epithelial-mesenchymal transition (EMT) score. Conclusion: We described a novel PD-1/PD-L1-associated signature, SORL1, that predicts favorable outcomes in bladder cancer. SORL1 might reduce immune suppression and inhibit the M2 macrophage-induced EMT phenotype of tumor cells.

Indoor volatile organic compounds exposures and risk of childhood acute leukemia: a case-control study in shanghai.

A case-control study was conducted to investigate the relationship between indoor air pollution and childhood acute leukemia (AL) in Shanghai. 97 cases and 148 gender-, age-, and residence-matched controls were included. Indoor air pollution was evaluated by questionnaires and quantitative measurement including 14 volatile organic compounds (VOCs) and nitrogen dioxide (NO2) in the homes of the two groups. The levels of individual VOCs, VOC families, TVOC (sum of the concentrations of the individual VOCs) and NO2 were compared between the two groups. Exposure to styrene and butyl alcohol were associated with an increased risk of childhood AL (styrene: odds ratio (OR)=2.33, 95% confidence interval (CI): 1.07-5.07; butyl alcohol: OR = 2.51, 95%CI: 1.19-5.28); 4th quartile of chlorinated hydrocarbons (OR = 2.52, 95%CI: 1.02-6.26) and 3rd quartile of TVOC (OR = 4.03, 95%CI: 1.06-6.81) had significant higher ORs for childhood AL compared with that in the lowest quartiles. Elevated levels of individual VOCs, VOC families and TVOC were also associated with self-reported risk factors. Our findings suggest that VOCs exposure was associated with an elevated risk of childhood AL, underscore that more attention should be paid to indoor air pollution as a risk factor of childhood AL.

Exosomal LncRNA-NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p.

BACKGROUND: The chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers. However, its high cardiotoxicity hampered its clinical use. Exosomes derived from stem cells showed a therapeutic effect against Dox-induced cardiomyopathy (DIC). Previous studies reported that exosomes derived from mesenchymal stem cells (MSCs) pretreated with macrophage migration inhibitory factor (MIF) (exosomeMIF) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). This study aimed to investigate the role of exosomeMIF in the treatment of DIC. RESULTS: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF). Regulatory lncRNAs activated by MIF pretreatment were explored using genomics approaches. Fluorescence-labeled exosomes were tracked in vitro by fluorescence imaging. In vivo and in vitro, miR-221-3p mimic transfection enforced miR-221-3p overexpression, and senescence-associated ß-galactosidase assay was applied to test cellular senescence. Exosomal delivering LncRNA-NEAT1 induced therapeutic effect in vivo was confirmed by echocardiography. It demonstrated that exosomesMIF recovered the cardiac function and exerted the anti-senescent effect through LncRNA-NEAT1 transfer against Dox. TargetScan and luciferase assay showed that miR-221-3p targeted the Sirt2 3'-untranslated region. Silencing LncRNA-NEAT1 in MSCs, miR-221-3p overexpression or Sirt2 silencing in cardiomyocytes decreased the exosomeMIF-induced anti-senescent effect against Dox. CONCLUSIONS: The results indicated exosomeMIF serving as a promising anti-senescent effector against Dox-induced cardiotoxicity through LncRNA-NEAT1 transfer, thus inhibiting miR-221-3p and leading to Sirt2 activation. The study proposed that exosomeMIF might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy.

PD-1 inhibitor inducing exosomal miR-34a-5p expression mediates the cross talk between cardiomyocyte and macrophage in immune checkpoint inhibitor-related cardiac dysfunction.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been an important therapeutic advancement in the field of cancer medicine. Recent reports provided greater insights into the cardiovascular adverse events, which prohibited the use of ICIs. Cardiovascular adverse events occur in different forms, such as myocarditis and cardiomyopathy, myocardial fibrosis, heart failure and pericardial disease. Cardiac aging overlapped with the occurrence of some cardiac diseases. Exosomes mediate cell-cell cross talk in cardiac diseases by transferring a variety of biomolecules, including microRNAs (miRs). miR-34a-5p is a well-known miR associated with the cardiac senescence. This study aimed to investigate whether cardiovascular adverse effects of the programmed cell death 1 (PD-1) inhibitor, a widely used ICI, were related to exosomal-transferred miR-34a-5p in cardiac senescence in a mouse model. METHODS AND RESULTS: The upregulation of miR-34a-5p in cardiomyocytes induced by exosomes derived from PD-1 inhibitor-treated macrophages, accompanied by cardiac senescence, caused cardiac injury in mouse hearts. miR-34a-5p was identified as an exosomal transfer RNA to induce cardiac senescence-related injury. Inhibiting miR-34a-5p in macrophages attenuated the exosomePD-1 inhibitor-induced pro-senescent effect in cardiomyocytes. TargetScan and luciferase assay showed that miR-34a-5p targeted the serine/threonine-protein phosphatase 1 regulatory subunit 10 (PNUTS) 3'-untranslated region. CONCLUSIONS: Exosomes derived from PD-1 inhibitor-treated macrophages exerted a pro-senescent effect by modulating the miR-34a-5p/PNUTS signaling pathway. The findings might supply new targets to ameliorate cardiac injury in patients with cancer receiving PD-1 inhibitor treatment.

Safety and outcomes of volumetric modulated arc therapy in the treatment of patients with inoperable lung cancer.

Background: Published data on the effects and toxicities of volumetric modulated arc therapy (VMAT) in the management of inoperable lung cancer are scarce. Materials and methods: The clinical outcomes and pulmonary toxicities of 134 patients with consecutive inoperable lung cancer who underwent VMAT from March 2011 to September 2016 were retrospectively reviewed. The dosimetric and characteristic factors associated with acute radiation pneumonitis (RP) and pulmonary fibrosis were evaluated with univariate and multivariate analysis. Results: The average prescription doses to these 134 patients were 57.07±6.27 Gy (range 52-64 Gy). The overall median follow-up time was 18.6 months (range, 2-45 mo), with a median follow-up time for the surviving patients of 20 months (range, 7-45 mo). The 2-year progression-free survival (PFS) and overall survival (OS) for all patients were 18.2% and 38.4%, with a median PFS and OS of 7.6 months and 18.6 months, respectively. The percent of patients with grade III/higher RP and pulmonary fibrosis were 10.5% and 9.0%, respectively. V13 (p=0.02) and age (p=0.02) were independently associated with acute RP according to multivariate analysis. The constraints for lung dosimetric metrics V10,V13,V20 and V30 were approximately 49%,41%,26% and 17% in VMAT treatment of lung cancer to limit the RP rate < 10%. Conclusion: VMAT can be delivered safely with acceptable acute and late toxicities for lung cancer patients. Lung dosimetric metrics were valuable in predicting acute RP. A lung V13 constraint of 40% was helpful to limit the RP rate < 10% in VMAT treatment of lung cancer patients.