Mapping the EORTC QLQ-C30 and QLQ H&N35 to the EQ-5D-5L and SF-6D for papillary thyroid carcinoma.

PURPOSE: Empirical evidence for the EORTC QLQ C30 scale in thyroid cancer mapping algorithms has not been found in China, which limits the cost-utility analysis of patients with papillary thyroid carcinoma (PTC) population. We developed mapping algorithms that use the EORTC QLQ-C30 and QLQ H&N35 to predict EQ-5D-5L and SF-6D health utility scores for PTC patients. METHODS: Data from 1050 Chinese PTC patients who completed the EORTC QLQ-C30, QLQ H&N35, EQ-5D-5L and SF-6D instruments were collected. Direct mapping (OLS, Tobit, Betamix) and indirect mapping functions (Order Probit) were used to estimate algorithms. The goodness-of-fit of mapping performance was assessed by MAE, RMSE, AIC, BIC, AE, and ICC. A fivefold cross-validation and random sample validation approach were used to test the stability of the models. RESULTS: The mean EQ-5D-5L and SF-6D utility scores were 0.8704 and 0.6368, respectively. We recommend the Betamix model for the EQ-5D-5L (MAE = 0.0363, RMSE = 0.0505, AIC = -3458.73, BIC = -3096.91, AE > 0.05(%) = 48.38, AE > 0.1(%) = 8.67, ICC = 0.8288 for the full sample dataset) and the Betamix model for the SF-6D (MAE = 0.0328, RMSE = 0.0417, AIC = -2788.91, BIC = -2605.51, AE > 0.05(%) = 42.76, AE > 0.1(%) = 3.62, ICC = 0.8657 for the full sample dataset), with EORTC QLQ-C30 all items, QLQ H&N35 all items, age and gender as the predicted variables showing the best performance. CONCLUSION: In the absence of preference-based quality of life tools, the mapping algorithms reported here are effective alternative for predicting the health utility of PTC patients, contributing to the cost-utility analysis studies.

Development of algorithms to estimate the EQ-5D-5L from the FACT-L in patients with lung cancer: a mapping study.

OBJECTIVE: This study aimed to develop a mapping algorithm to evaluate the EQ-5D-5L according to the FACT-L when the EQ-5D-5L is not available. METHODS: EQ-5D-5L and FACT-L data were collected from patients with lung cancer in Departments of Thoracic Surgery, Medical Oncology, Radiation Oncology, Sichuan Cancer Hospital. We used the ordinary least squares model (OLS), Tobit model (Tobit), two-part model (TPM), beta mixture regression (BM), and censored least absolute deviation model (CLAD) to map the results of the FACT-L according to EQ-5D-5L scores. To establish these models, the total score, dimension scores, squared items, and interaction items were introduced. Performance metrics including Adjusted R2, root mean square error (RMSE), and mean absolute error (MAE) were used to select the optimized model. RESULTS: The model with the best mapping performance was the BM model (BETAMIX4) with the PWB (physical well-being) dimension, FWB (functional well-being) dimension, the squared term of the PWB dimension, and the squared term of the FWB dimension as covariates. The final prediction metrics were Adjusted R2 = 0.695, RMSE = 0.206, and MAE = 0.109. Fivefold cross-validation (CV) results also demonstrated that the BM model had the best mapping power. CONCLUSIONS: This study developed an optimized mapping algorithm to predict the utility index from the FACT-L to the EQ-5D-5L, which provides an effective alternative reference for EQ-5D-5L estimation when the preference-based health utility values were unavailable.

Prediction of the SF-6D utility score from Lung cancer FACT-L: a mapping study in China.

OBJECTIVE: To develop a mapping algorithm for generating the Short Form Six-Dimension (SF-6D) utility score based on the Functional Assessment of Cancer Therapy-Lung (FACT-L) of lung cancer patients. METHODS: Data were collected from 625 lung cancer patients in mainland China. The Spearman rank correlation coefficient and principal component analysis were used to evaluate the conceptual overlap between the FACT-L and SF-6D. Five model specifications and four statistical techniques were used to derive mapping algorithms, including ordinary least squares (OLS), Tobit and beta-mixture regression models, which were used to directly estimate health utility, and ordered probit regression was used to predict the response level. The prediction performance was evaluated using the correlations between the root mean square error (RMSE), mean absolute error (MAE), concordance correlation coefficient (CCC), Akaike information criterion (AIC) and Bayesian information criterion (BIC) and the observed and predicted SF-6D scores. A five-fold cross-validation method was used to test the universality of each model and select the best model. RESULTS: The average FACT-L score was 103.024. The average SF-6D score was 0.774. A strong correlation was found between FACT-L and SF-6D scores (ρ = 0.797). The ordered probit regression model with the total score of each dimension and its square term, as well as age and sex as covariates, was most suitable for mapping FACT-L to SF-6D scores (5-fold cross-validation: RMSE = 0.0854; MAE = 0.0655; CCC = 0.8197; AEs > 0.1 (%) = 53.44; AEs > 0.05 (%) = 21.76), followed by beta-mixture regression for direct mapping. The Bland‒Altman plots showed that the ordered probit regression M5 had the lowest proportion of prediction scores outside the 95% agreement limit (-0.166, 0.163) at 4.96%. CONCLUSIONS: The algorithm reported in this paper enables lung cancer data from the FACT-L to be mapped to the utility of the SF-6D. The algorithm allows the calculation of quality-adjusted life years for cost-utility analyses of lung cancer.

Analysis of risk factors associated with fatal outcome among severe fever with thrombocytopenia syndrome patients from 2015 to 2019 in Shandong, China.

To better understand the progression of severe fever with thrombocytopenia syndrome (SFTS), identify early predictors of mortality, and improve the cure rate, the present study aimed to analyze the demographic feature, clinical characteristics, and laboratory parameters of patients with SFTS and to explore the risk factors associated with fatal outcome. We retrospectively analyzed demographic feature, clinical characteristics, and laboratory parameters of 216 laboratory-confirmed SFTS patients in Shandong province between January 2015 and December 2019. Univariate analysis was used to assess the relevance between these factors and fatal outcome. Factors with P < 0.05 in univariate analysis were further analyzed using multivariable logistic regression analysis to identify the independent risk factors for mortality of SFTS. Age, five complications (including CNS symptoms, pulmonary infection, heart failure, arrhythmia, and bleeding events), and ten abnormal laboratory parameters (including serum viral load, blood platelet, ALT, AST, LDH, CK, CK-MB, Cr, serum Ca2+, and APTT) were statistically significant by univariate analysis. These factors were further analyzed by multivariable logistic regression analysis, and the results indicated that coma, pulmonary infection, high viral load, and prolonged APTT were associated with fatal outcome in SFTS patients. Our study identified four independent risk factors associated with fatal outcome for SFTS patients. The results were hoped to provide help for active treatment of SFTS. However, the identification of risk factors is not absolutely associated with fatal outcome. Patients' risk should be assessed by dynamic observation of the changes in risk factor indicators.

Molecular and clinical epidemiological features of human astrovirus infections in children with acute gastroenteritis in Shandong province, China.

Human astrovirus (HAstV) is one of the most common causative agents of acute gastroenteritis in children with an infection rate estimated to range from 2% to 9% worldwide. This study was aimed at investigating the molecular and clinical epidemiological features of human astrovirus infections in children under 5 years old with acute gastroenteritis in Shandong province, China from July 2017 to June 2018. In total, 376 fecal samples and the corresponding clinical information were collected and analyzed. HAstV infections were detected in all age groups with an overall positive rate of 8.51%. In addition to acute diarrhea, the main clinical manifestations were fever, abdominal pain, vomiting, and dehydration, in which fever was the most common complication. Infections could be seen throughout the year with a peak in the colder season. Four genotypes were detected in which HAstV-1 was the most prevalent genotype with a prevalence of 78.12%, followed by HAstV-5 (9.38%), MLB-1 (9.38%), and MLB-2 (3.12%). HAstV-1 strains were classified as lineage 1a, 1b, and 1d, in which lineage 1a strains were the most prevalent followed by lineage 1b and lineage 1d strains. All HAstV-5 strains were classified as lineage 5b and no other lineages were detected. The results showed that HAstV infection was an important cause of acute gastroenteritis among children under 5 years old in Shandong province. Given that their disease spectrum had been broadened, HAstVs should be paid more attention, not only as a causative agent of acute gastroenteritis but also as a potential pathogen of unexpected diseases.

Molecular and epidemiological characterization of human adenoviruses infection among children with acute diarrhea in Shandong Province, China.

BACKGROUND: Human adenovirus (HAdV) had been recognized as one of the most common enteric viruses associated with acute diarrhea in children. The present study was carried out to demonstrate the molecular and epidemiological characterization of HAdV Infections among children in Shandong province in China between July 2017 and June 2018. METHODS: Fecal specimens were collected from children under 5 years old with acute diarrhea. DNA was extracted from the stool specimens and adenovirus DNA was detected by PCR amplification with specific primers. The amplification products were subjected to electrophoresis and visualized on a UV transilluminator. All positive RT-PCR amplification products were sequenced and the obtained sequences analyzed by MEGA (version 7.0). Demographic information and clinical manifestation data were also analyzed. RESULTS: In total, 656 fecal specimens were collected and the overall positive rate of HAdV was 7.47%. HAdV infections were detected in all age groups, in which children aged 13-24 months presented the highest positive rate. Seasonal pattern could be observed with a peak in December, January and February. Diarrhea, vomiting, dehydration and fever were the main clinical manifestations, in which vomiting was the most common accompanied symptom. By phylogenetic analysis, four species (A, B, C, and F) were detected and seven different serotypes were identified. HAdV-41 (48.98%, 24/49) was the most common serotype followed by HAdV-3 (18.37%, 9/49), HAdV-31 (14.29%, 7/49), HAdV-7 (8.16%, 4/49), HAdV-40 (4.08%, 2/49), HAdV-1 (4.08%, 2/49) and HAdV-2 (2.04%, 1/49). CONCLUSION: This study indicated that HAdV infection was an important cause of acute diarrhea among children under 5 years old in Shandong province. The results will contribute to (a) increase understanding of the role of HAdV in diarrheal children and enhance identification of the predominant diarrhea pathogen for diagnosis; (b) avoid abuse of antibiotics; (c) monitor the change of prevalent HAdV serotypes and promote vaccine development and vaccination.

Clinical and molecular epidemiological characterization of rotavirus infections in children under five years old in Shandong province, China.

Rotaviruses are important causative agents of acute gastroenteritis in children. In China, rotavirus infection has a prevalence rate of 30% and is therefore considered a serious public health problem. This study was carried out to investigate the clinical and molecular epidemiological characteristics of rotavirus infections in children under 5 years old with acute diarrhea in Shandong province, China. From July 2017 to June 2018, a total of 1211 fecal specimens were tested, and the prevalence of rotavirus infection was 32.12%. The mean age of the infected children was 12.2 ± 10.9 months, and the highest infection rate was observed in children aged 7-12 months, with a rate of 41.64%. G9P[8] (76.61%) was the most prevalent genotype combination, followed by G2P[4] (7.20%), G3P[8] (3.60%), and G9P[4] (2.06%). In addition to diarrhea, vomiting, fever, and dehydration were the most common clinical signs. In general, there was no significant difference in clinical manifestations among different age groups. However, the clinical manifestations differed significantly between vaccinated and unvaccinated children. Vaccinated children showed lower incidence and frequency of vomiting, lower incidence and degree of dehydration, and lower incidence of severe cases than unvaccinated children. These findings suggest that it is necessary to continuously monitor changes in the characteristics of rotavirus infections. Moreover, the introduction of vaccines into the national immunization program to prevent and control rotavirus infection is needed in China.

Molecular epidemiology of GII noroviruses in outpatients with acute gastroenteritis in Shandong Province, China.

Noroviruses have been recognized as the most important causative agents of acute gastroenteritis. The present study was carried out to investigate the molecular epidemiological features of genotype II (GII) norovirus in outpatients with acute gastroenteritis in Shandong province in China from July 2017 to June 2018. In total, 151 (10.30%) samples were positive for NoV GII strains by RT-PCR. Eight genotypes were detected: GII.2, GII.3, GII.4, GII.6, GII.7, GII.12, GII.13 and GII.17. GII.4 (43.71%) was the most prevalent genotype, and the dominant strains belonged to the group of Sydney-2012 strains. GII.17 (27.15%), which has become the main cause of outbreaks of acute gastroenteritis in China, also accounted for a high proportion. Meanwhile, three recombinant types (GII.P17-GII.7, GII.P3-GII.4 and GII.P12-GII.4) were observed and authenticated using Simplot software. The results showed that GII norovirus was the main cause of acute gastroenteritis in Shandong province. GII.4 and GII.17 were the dominant genotypes. Continuous observation and identification of emerging genotypes are necessary for understanding the evolution of the virus, control of infection, and development of vaccines.

Knockdown long non-coding RNA ANRIL inhibits proliferation, migration and invasion of HepG2 cells by down-regulation of miR-191.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with high fatality rate. Recent studies reported that up-regulation of long non-coding RNA antisense non-coding RNA in the INK4 locus (lncRNA ANRIL) was found in HCC tissues, and which could affect HCC cells biological processes. However, the potential molecular mechanism of ANRIL in HCC is still unclear. The study aimed to uncover the effect of ANRIL on HepG2 cells growth, migration and invasion. METHODS: The knockdown expression vectors of ANRIL were transfected into HepG2 cells, and qRT-PCR, CCK-8, flow cytometry, Transwell and western blot assays were performed to analyze the effect of ANRIL on cell proliferation, apoptosis, migration and invasion. The relative expression of miR-191 was then examined in ANRIL knockdown vector transfected cells. These experiments were repeated again for exploring the effect of miR-191 on HepG2 cells. NF-κB and Wnt/ß-catenin signaling pathways were examined by using western blot assay. RESULTS: Knockdown of ANRIL inhibited proliferation, induced apoptosis, meanwhile suppressed migration and invasion of HepG2 cells. Additionally, the results showed that the expression level of miR-191 was down-regulated by ANRIL knockdown in HepG2 cells. Importantly, overexpression of miR-191 reversed the anti-tumor effect of ANRIL on cell proliferation, apoptosis, migration and invasion in HepG2 cells. Besides, we found that ANRIL knockdown inactivated NF-κB and Wnt/ß-catenin pathways by regulating miR-191. CONCLUSIONS: These data demonstrated that ANRIL knockdown suppressed proliferation, migration, invasion, and promoted apoptosis in HepG2 cells by down-regulating miR-191 and inactivating NF-κB and Wnt/ß-catenin signaling pathways.

Spontaneous bacterial peritonitis caused by Aeromonas caviae in a patient with cirrhosis.

Spontaneous bacterial peritonitis (SBP) is a common complication of cirrhosis. Based on our current understanding of SBP, the most common etiologies for SBP in cirrhosis are Enterobacter and Streptococcal species. Th e Aeromonas species are ubiquitous in fresh or sea water. Aeromonas caviae is never identified as etiology in cases of SBP. A patient, who had a history of liver cirrhosis related to chronic hepatitis B virus infection for 1 year, presented with diarrhea. He had diarrhea 1 week later returned from coastal city. He was hospitalized and treated with norfloxacin after 7 days of severe symptoms, including fever, abdominal distention, and diarrhea. Analysis of the ascitic specimen revealed a white-cell count of 4.42 × 109 cells/L with 88% neutrophils. Analysis of stool specimen showed a white-cell count of 60 cells per high-power field. Th e patient started the injection of cefriaxone at a dose of 4 g/d. However, the situation was not improved. Th ree days later, stool and ascitic fluid culture showed positive for Aeromonas caviae. Antibiotic susceptibility testing revealed that imipenem, meropenem, amikacin, and cefoperazone-sulbactam were highly sensitive to the Aeromonas caviae. However, the bacilli resisted to ceftriaxone, ceftazidime, ampicillin-sulbactam, levofloxacin, and sulfamethoxazole. Ceftriaxone was then switched to imipenem. The patient was fully recovered 14 days later. Aeromonas caviae is a rare pathogen of SBP in cirrhosis. It resists to third-generation of cephalosporin and fluroquinolone, which are of frequently used dependent on clinical experience. It needs a special attention.

Adhesion GPCR ADGRE2 Maintains Proteostasis to Promote Progression in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematologic malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G protein-coupled receptors (GPCR) play integral roles in physiologic processes and human diseases. Particularly, one third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Here, we investigate the role of adhesion GPCRs in AML and whether they could be harnessed as antileukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells, which is associated with poor patient outcomes. Silencing ADGRE2 not only exerts antileukemic effects in AML cell lines and cells derived from patients with AML in vitro, but also delays AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activates phospholipase Cß/protein kinase C/MEK/ERK signaling to enhance the expression of AP1 and transcriptionally drive the expression of DUSP1, a protein phosphatase. DUSP1 dephosphorylates Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitates the DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP1, and DUSP1 exhibits robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML. Significance: Increased expression of the adhesion GPCR member ADGRE2 in AML supports leukemia stem cell self-renewal and leukemogenesis by modulating proteostasis via an MEK/AP1/DUSP1 axis, which can be targeted to suppress AML progression.

Pancreatic neuroendocrine tumor detected by technetium-99m methoxy-2-isobutylisonitrile single photon emission computed tomography/computed tomography: A case report.

BACKGROUND: Pancreatic neuroendocrine tumors (NETs) account for about 1%-2% of pancreatic tumors and about 8% of all NETs. Computed tomography (CT), magnetic resonance imaging, and endoscopic ultrasound are common imaging modalities for the diagnosis of pancreatic NETs. Furthermore, somatostatin receptor imaging is of great value for diagnosing pancreatic NETs. Herein, we report the efficacy of technetium-99m methoxy-2-isobutylisonitrile (99mTc-MIBI) single photon emission CT (SPECT)/CT for detecting pancreatic NETs. CASE SUMMARY: A 57-year-old woman presented to our hospital with a 1-d history of persistent upper abdominal distending pain. The distending pain in the upper abdomen was aggravated after eating, with nausea and retching. Routine blood test results showed a high neutrophil percentage, low leukomonocyte and monocyte percentages, and low leukomonocyte and eosinophil counts. Amylase, liver and kidney function, and tumor markers alpha-fetoprotein, carcinoembryonic antigen, and cancer antigen (CA) 125, CA72-4, CA19-9, and CA153 were normal. Abdominal CT showed a mass, with multiple calcifications between the pancreas and the spleen. The boundary between the mass and the pancreas and spleen was poorly defined. Contrast-enhanced CT revealed that the upper abdominal mass was unevenly and gradually enhanced. 99mTc-MIBI SPECT/CT revealed that a focal radioactive concentration, with mild radioactive concentration extending into the upper abdominal mass, was present at the pancreatic body and tail. The 99mTc-MIBI SPECT/CT manifestations were consistent with the final pathological diagnosis of pancreatic NET. CONCLUSION: 99mTc-MIBI SPECT/CT appears to be a valuable tool for detecting pancreatic NETs.

Obtaining SF-6D utilities from FACT-H&N in thyroid carcinoma patients: development and results from a mapping study.

Objective: There is limited evidence for mapping clinical tools to preference-based generic tools in the Chinese thyroid cancer patient population. The current study aims to map the FACT-H&N (Functional Assessment of Cancer Therapy-Head and Neck Cancer) to the SF-6D (Short Form Six-Dimension), which will inform future cost-utility analyses related to thyroid cancer treatment. Methods: A total of 1050 participants who completed the FACT-H&N and SF-6D questionnaires were included in the analysis. Four methods of direct and indirect mapping were estimated: OLS regression, Tobit regression, ordered probit regression, and beta mixture regression. We evaluated the predictive performance in terms of root mean square error (RMSE), mean absolute error (MAE), concordance correlation coefficient (CCC), Akaike information criterion (AIC) and Bayesian information criterion (BIC) and the correlation between the observed and predicted SF-6D scores. Results: The mean value of SF-6D was 0.690 (SD = 0.128). The RMSE values for the fivefold cross-validation as well as the 30% random sample validation for multiple models in this study were 0.0833-0.0909, MAE values were 0.0676-0.0782, and CCC values were 0.6940-0.7161. SF-6D utility scores were best predicted by a regression model consisting of the total score of each dimension of the FACT-H&N, the square of the total score of each dimension, and covariates including age and gender. We proposed to use direct mapping (OLS regression) and indirect mapping (ordered probit regression) to establish a mapping model of FACT-H&N to SF-6D. The mean SF-6D and cumulative distribution functions simulated from the recommended mapping algorithm generally matched the observed ones. Conclusions: In the absence of preference-based quality of life tools, obtaining the health status utility of thyroid cancer patients from directly mapped OLS regression and indirectly mapped ordered probit regression is an effective alternative.

Mapping study of papillary thyroid carcinoma in China: Predicting EQ-5D-5L utility values from FACT-H&N.

Objective: To develop a mapping algorithm that can be used to predict EQ-5D-5L health utility scores from FACT-H&N and obtain health utility parameters for Chinese patients with papillary thyroid carcinoma (PTC), which can be used for cost-utility analysis in health economic. Methods: A total of 1,050 patients with PTC from a tertiary hospital in China were included, and they completed FACT-H&N and EQ-5D-5L. Four mapping algorithms of direct mapping functions were used to derive the models: Ordinary least squares (OLS), Tobit model (Tobit), Two-part model (TPM), and Beta mixture regression model (Beta). The goodness-of-fit of models was assessed by the mean absolute error (MAE), root mean square error (RMSE), Akaike information criteria (AIC), Bayesian information criteria (BIC), and absolute error (AE). A fivefold cross-validation method was used to test the stability of the models. Results: The mean utility value of the EQ-5D-5L was 0.870 ± 0.094. The mean EQ-VAS score was 76.5 ± 13.0. The Beta mixture regression model mapping FACT-H&N to EQ-5D-5L achieved the best performance [fivefold cross-validation MAE = 0.04612, RMSE = 0.06829, AIC = -2480.538, BIC = -2381.137, AE > 0.05 (%) = 32.48, AE > 0.1 (%) = 8.95]. The independent variables in this model were Physical Well-Being (PWB), Emotional Well-Being (EWB), Head & Neck Cancer Subscale (HNCS) scores and its square term and interaction term scores. Conclusions: This study calculated the health utility score of Chinese patients with PTC. The reported algorithms can be used to map the FACT-H&N into the EQ-5D-5L, which can be applied in the cost-utility related study of patients with PTC.

NRF-2α and mitophagy underlie enhanced mitochondrial functions and biogenesis induced by T-2 toxin in GH3 cells.

T-2 toxin is a natural contaminant in grain cereals produced by species of Fusarium. Studies indicate that T-2 toxin can positively affect mitochondrial function, but the underlying mechanism is unclear. In this study, we examined the role of nuclear respiratory factor 2α (NRF-2α) in T-2 toxin-activated mitochondrial biogenesis and the direct target genes of NRF-2α. Furthermore, we investigated T-2 toxin-induced autophagy and mitophagy, and the role of mitophagy in changes in mitochondrial function and apoptosis. It was found that T-2 toxin significantly increased NRF-2α levels and nuclear localization of NRF-2α was induced. NRF-2α deletion significantly increased the production of reactive oxygen species (ROS), abrogated T-2 toxin-induced increases in ATP and mitochondrial complex I activity, and inhibited the mitochondrial DNA copy number. Meanwhile, With chromatin immunoprecipitation sequencing (ChIP-Seq), various novel NRF-2α target genes were identified, such as mitochondrial iron-sulphur subunits (Ndufs 3,7) and mitochondrial transcription factors (Tfam, Tfb1m, and Tfb2m). Some target genes were also involved in mitochondrial fusion and fission (Drp1), mitochondrial translation (Yars2) and splicing (Ddx55), and mitophagy. Further studies showed that T-2 toxin induced Atg5 dependent autophagy and Atg5/PINK1-dependent mitophagy. In addition, mitophagy defects increase ROS production, inhibit ATP levels and the expression of genes related to mitochondrial dynamics, and promote apoptosis in the presence of T-2 toxins. Altogether, these results suggest that NRF-2α plays a critical role in promoting mitochondrial function and biogenesis through regulation of mitochondrial genes, and, interestingly, mitophagy caused by T-2 toxin positively affected mitochondrial function and protected cell survival against T-2 toxin.

Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism.

BACKGROUND: Adult hematopoietic stem cells (HSCs) homeostasis is critically important in maintaining lifelong hematopoiesis. However, how adult HSCs orchestrate its homeostasis remains not fully understood. Imprinted gene Dlk1 has been shown to play critical role in mouse embryonic hematopoiesis and in regulation of stem cells, but its physiological roles in adult HSCs are unknown. METHODS: We performed gene expression analysis of Dlk1, and constructed conditional Dlk1 knockout (KO) mice by crossing Mx1 cre mice with Dlkflox/flox mice. Western blot and quantitative PCR were used to detect Dlk1 KO efficiency. Flow cytometry was performed to investigate the effects of Dlk1 KO on HSCs, progenitors and linage cells in primary mice. Competitive HSCs transplantation and secondary transplantation was used to examine the effects of Dlk1 KO on long-term hematopoietic repopulation potential of HSCs. RNA-Seq and cell metabolism assays was used to determine the underlying mechanisms. RESULTS: Dlk1 was highly expressed in adult mice long-term HSCs (LT-HSCs) relative to progenitors and mature lineage cells. Dlk1 KO in adult mice HSCs drove HSCs enter active cell cycle, and expanded phenotypical LT-HSCs, but undermined its long-term hematopoietic repopulation potential. Dlk1 KO resulted in an increase in HSCs' metabolic activity, including glucose uptake, ribosomal translation, mitochondrial metabolism and ROS production, which impaired HSCs function. Further, Dlk1 KO in adult mice HSCs attenuated Notch signaling, and re-activation of Notch signaling under Dlk1 KO decreased the mitochondrial activity and ROS production, and rescued the changes in frequency and absolute number of HSCs. Scavenging ROS by antioxidant N-acetylcysteine could inhibit mitochondrial metabolic activity, and rescue the changes in HSCs caused by Dlk1 KO. CONCLUSION: Our study showed that Dlk1 played an essential role in maintaining HSC homeostasis, which is realized by governing cell cycle and restricting mitochondrial metabolic activity.

Adipose-derived mesenchymal stem cell-secreted extracellular vesicles alleviate non-alcoholic fatty liver disease via delivering miR-223-3p.

Increasing studies have identified the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in non-alcoholic fatty liver disease (NAFLD) treatment. Hence, we further focused on the potential of adipose-derived MSC (ADSC)-EVs in NAFLD by delivering miR-223-3p. The uptake of isolated ADSC-EVs by hepatocytes was assessed, and the expression of miR-223-3p in ADSC-EVs and hepatocytes was characterized. It was established that miR-223-3p, enriched in ADSC-EVs, could be delivered by ADSC-EVs into hepatocytes. Using co-culture system and gain-of-function approach, we evaluated the effect of ADSC-EVs carrying miR-223-3p on lipid accumulation and liver fibrosis in pyrrolizidine alkaloids (PA)-induced hepatocytes and a high-fat diet-induced NAFLD mouse model. Bioinformatics websites and dual-luciferase reporter gene assay were performed to determine the interactions between miR-223-3p and E2F1, which was further validated by rescue experiments. ADSC-EVs containing miR-223-3p displayed suppressive effects on lipid accumulation and liver fibrosis through E2F1 inhibition, since E2F1 was demonstrated as a target gene of miR-223-3p. The protective role of ADSC-EVs by delivering miR-223-3p was then confirmed in the mouse model. Collectively, this study elucidated that ADSC-EVs delayed the progression NAFLD through the delivery of anti-fibrotic miR-223-3p and subsequent E2F1 suppression, which may suggest miR-223-3p-loaded ADSC-EVs to be a potential therapeutic approach for NAFLD.