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Background Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. Methods shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. Results We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. Conclusion In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.

Background Cancer‐associated fibroblasts (CAFs) with different gene profiles from normal fibroblasts (NFs) have been implicated in tumor progression. Angiopoietin‐like protein 4 (ANGPTL4) has been shown to regulate tumor angiogenesis and metastasis, and predict poor prognosis. However, the ANGPTL4 expression in CAFs, especially in gallbladder CAFs (GCAFs) and its relationship with patient prognosis is unclear. Methods Affymetrix gene profile chip analysis in vitro was performed to detect the different gene expression profiles between GCAFs and NFs. RT‐qPCR, immunohistochemistry, and western blotting were performed to investigate the different expression levels of ANGPTL4 in GCAFs/NFs in vitro and in an in vivo nude mouse model of xenograft tumors. Finally, the ANGPTL4 expression was investigated in the stroma of different lesion tissues of the human gallbladder by immunohistochemistry, especially the expression in GCAFs in vivo by co‐immunofluorescence, and their prognostic significance in patients with gallbladder cancer (GBC) was assessed. Results ANGPTL4 was upregulated in both GCAFs in vitro and in the xenograft stroma of nude mice in vivo, and its expression was also significantly upregulated in human GBC stroma co‐localized with the interstitial markers fibroblast secreted protein‐1 and α‐smooth muscle actin. In addition, the elevated ANGPTL4 expression in GCAFs was correlated with tumor differentiation, liver metastasis, venous invasion and Nevin staging, and GBC patients with an elevated ANGPTL4 expression in GACFs were found to have a lower survival rate. Conclusions Increased ANGPTL4 expression in GCAFs correlates with poor patient prognosis, which indicates a potential therapeutic target for human GBCs., ANGPTL4 expression was upregulated in GCAF, which was significantly related to the degree of clinical GBC differentiation, liver metastasis, venous invasion, and Nevin staging, and GBC patients with elevated ANGPTL4 expression in GCAF had lower survival rate.

BACKGROUND: Population aging is now a universal trend. Many elderly persons can only conduct limited and short time walking because of age-related skeletal muscle decline of the lower limbs. The wearable device for walking assistance is beneficial to improve the life quality of the elderly. OBJECTIVE: This study aimed to propose a soft exosuit for walking assistance of the elderly and verify its feasibility. METHODS: The wearable structure and control strategy were presented. The performance of the soft exosuit was tested by force tracking evaluation and metabolic cost test. RESULTS: The mean error of the measured and target peak force was 1.1%. The metabolic cost with assistance on while wearing the exosuit was reduced by 9.2% compared with that in locomotion assistance off. The reduction of assistance on was 7.1% compared with no exosuit. CONCLUSIONS: The proposed soft exosuit has the potential to improve the walking efficiency of the elderly.

All-trans retinoic acid (ATRA) and pre-upfront arsenic trioxide (ATO) have revolutionized the therapy of acute promyelocytic leukemia (APL). However, internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations is associated with increased risk of relapse. The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA, idarubicin (IDA) and/or ATO, followed by ATRA plus ATO along with anthracycline, as consolidation therapy. A total of 72 patients newly diagnosed with APL were included in this study. 83.3% of the patients achieved complete remission (CR) after induction therapy. FLT3-ITD mutations were detected in 16 (22.2%) patients and closely related to bcr-3 PML-RARa transcript (P

Background Hepatocellular carcinoma (HCC) associated with macroscopic vascular invasion and distant metastasis is an advanced-stage disease with an extremely poor prognosis and low survival rate. Therefore, there is an urgent need to develop novel therapeutic strategies to extend the lives of patients with advanced HCC. Case presentation We represent a case of HCC with macroscopic vascular invasion and pulmonary metastasis responding dramatically to the combination treatment with drug-eluting beads transarterial chemoembolization (DEB-TACE) and Huaier granule. A 64-year-old man with hepatitis B virus (HBV)-induced liver cirrhosis was diagnosed with advanced HCC involved renal vein and inferior vena cava accompanied by pulmonary metastasis. The patient received three cycles of on-demand DEB-TACE from 9th September 2016 to 22nd August 2017 and combined with Huaier granule 20 g three times a day orally. Eight months following the treatment, complete response occurred with regression of HCC and vascular thrombus and disappearance of pulmonary metastasis. The levels of AFP had decreased from 8165.8ng/mL to within the normal range (1.7 ng/mL). This is the first case report of complete response of HCC to the combination treatment with DEB-TACE and Huaier granule. At the most recent follow-up, he remained in remission 36 months after cessation of treatment without clinical or imaging evidence of disease recurrence. The current overall survival is 54 months since the initial treatment. Conclusion Data from this clinical case report suggest that the combination treatment with DEB-TACE and Huaier granule is a promising therapeutic option for advanced HCC with macroscopic vascular invasion and distant metastasis.

Long non‑coding RNA (lncRNA) forkhead box P4 antisense RNA 1 (FOXP4‑AS1) has been determined to function as an oncogene in various types of cancer. However, the biological function and the underlying mechanisms of FOXP4‑AS1 in mantle cell lymphoma (MCL) remain to be uncovered. The expression and the associated clinicopathological characteristics and prognostic significance of FOXP4‑AS1 were explored in MCL clinical samples. The effects of FOXP4‑AS1 on MCL cellular behaviors, including proliferation, migration and invasion were analyzed using CCK‑8, crystal violet and Transwell assays. The downstream molecules of FOXP4‑AS1 were explored using bioinformatics analysis and dual luciferase assay. Our results showed that FOXP4‑AS1 expression was upregulated in MCL patients, and that the high expression of FOXP4‑AS1 was correlated with the unfavorable prognosis of patients. Functionally, while FOXP4‑AS1 downregulation inhibited proliferation, migration and invasion of MCL cells, FOXP4‑AS1 overexpression had promotive effects on these cellular processes. Mechanistically, FOXP4‑AS1 was found to act as a competing endogenous (ce)RNA for miR‑423‑5p to regulate the expression of nucleus accumbens‑associated 1 (NACC1). The negative regulation of FOXP4‑AS1 on miR‑423‑5p compared to that of miR‑423‑5p on NACC1 was determined at the mRNA or protein levels in MCL cells. Moreover, an inverse expression correlation between FOXP4‑AS1 and miR‑423‑5p, and that between miR‑423‑5p and NACC1 was confirmed in MCL clinical samples. In addition, rescue assay showed that miR‑423‑5p upregulation or NACC1 knockdown abolished the promoting effects of FOXP4‑AS1 on MCL cell proliferation, migration and invasion. In conclusion, FOXP4‑AS1 promotes MCL progression through the upregulation of NACC1 expression by inhibiting miR‑423‑5p. FOXP4‑AS1 may serve as a novel therapeutic target for patients with MCL.

Children with kidney insufficiency are susceptible to vancomycin-induced acute kidney injury (VIAKI), but there is a lack of compelling clinical data. We conducted a nested case-control study to evaluate the relationship between kidney insufficiency and incidence of VIAKI in children. Patients were considered to have VIAKI if they met the criteria for eGFR change according to pRIFLE-I or p-RIFLE-F. Case group comprised patients who developed VIAKI. Case-control ratio was 1:3; patients were matched for age, severity, and nature of illness and initial vancomycin dose. Primary endpoint was incidence of VIAKI at three levels of kidney function, calculated using Kaplan-Meier curve and log-rank test. Secondary endpoint was treatment-related in-hospital mortality amongst case and control groups. Amongst 386 children who fit study criteria, 31 developed VIAKI (8.03%). Thirty-one cases and 93 controls were selected from the observed cohort. Three risk factors were identified for VIAKI: moderate kidney insufficiency (OR 8.8, 2.4–32.8), vancomycin trough concentration ≥ 15 μg/mL (OR 7.7, 1.7–34.4), and furosemide use (OR 24.8, 6.4–98.2). A significant difference in time to VIAKI was noted between patients with moderate kidney insufficiency and patients with mild kidney insufficiency or normal kidney function (p < 0.001). In-hospital mortality rate in case group was 45.2%, compared to 18.3% in control group (p < 0.01). Children with moderate kidney insufficiency are more likely to develop VIAKI than those with normal and mild kidney insufficiency. Patients who develop VIAKI have higher in-hospital mortality than those who do not develop VIAKI.

Summary Mouse embryonic stem cells (ESCs) cultured in defined medium resemble the pre-implantation epiblast in the ground state, with full developmental capacity including the germline. β-Catenin is required to maintain ground state pluripotency in mouse ESCs, but its exact role is controversial. Here, we reveal a Tcf3-independent role of β-catenin in restraining germline and somatic lineage differentiation genes. We show that β-catenin binds target genes with E2F6 and forms a complex with E2F6 and HMGA2 or E2F6 and HP1γ. Our data indicate that these complexes help β-catenin restrain and fine-tune germ cell and neural developmental potential. Overall, our data reveal a previously unappreciated role of β-catenin in preserving lineage differentiation integrity in ground state ESCs., Highlights • β-Catenin depletion irreversibly compromised lineage development of ground state ESCs • TCF3-independent role of β-catenin in determining lineage differentiation potential • E2F6, HP1γ, and HMGA2 are β-catenin interaction partners and co-bound to target genes • β-Catenin and protein partners fine-tune germline and neural development potential, In this article, Tao and colleagues show that β-catenin functions beyond derepressing TCF3 targeted pluripotency network in ESCs. β-Catenin physically interacts with protein partners, including transcription factor and chromatin modulators. Together, they preserve the integrity of lineage differentiation of ground state ESCs by restraining and fine-tuning their germline and neural development potential.

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-β-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.

Neuroblastoma (NB) is the most common extra-cranial solid tumor in childhood with the overall 5 years' survival less than 40%. Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and over expressed in multiple cancers, including neuroblastoma. We found that higher PLK1 expression related to poor outcome of NB patients. BI2536, a small molecule inhibitor against PLK1, significantly reduced cell viability in a panel of NB cell lines, with IC50 less than 100 nM. PLK1 inhibition by BI 2536 treatment induced cell cycle arrest at G2/M phase and cell apoptosis in NB cells. Realtime PCR array revealed the PLK1 inhibition related genes, such as BIRC7, TNFSF10, LGALS1 and DAD1 et al. Moreover, autophagy activity was investigated in the NB cells treated with BI 2536. BI 2536 treatment in NB cells increased LC3-II puncta formation and LC3-II expression. Formation of autophagosome induced by BI 2536 was observed by transmission electron microscopy. However, BI2536 abrogated the autophagic flux in NB cells by reducing SQSTM1/p62 expression and AMPKαT172 phosphorylation. These results provide new clues for the molecular mechanism of cell death induced by BI 2536 and suggest that BI 2536 may act as new candidate drug for neuroblastoma.

Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G(2)/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.

BACKGROUND The occurrence of nonalcoholic fatty liver disease (NAFLD) is closely related to type 2 diabetes, especially in patients with insulin resistance. The purpose of this research was to elucidate the major genes and transcriptional regulation of insulin resistance in the progression of NAFLD. MATERIAL AND METHODS We downloaded the gene expression matrix of GSE89632 from Gene Expression Omnibus. Then the principal component analysis was used to identify whether the samples were clustered. Differentially expressed genes were identified by limma R package. Enrichment analysis and protein‑protein interaction network was used to find potential function and screening hub genes. We further used ChIP-seq data from ENCODE to predict the transcriptional regulation of hub genes. Finally, we verified the functions of hub genes with clinical information. RESULTS These hub genes were significantly enriched in "response to insulin", "response to glucose", and "fat cell differentiation". ChIP-seq data showed that EGR1 (early growth response gene-1) may play an important role in the transcriptional regulation of SOCS1 (suppressor of cytokine signaling 1), SOCS3 (suppressor of cytokine signaling 3), and Fos gene family in the liver, as the low expression of EGR1 in patients with insulin resistance may promote the occurrence and development of NAFLD. Similarly, correlation analysis showed that EGR1 was positively correlated with the expression of SOCS1, SOCS3, and the genes of Fos gene family, and EGR1 was negatively correlated with the degree of steatosis. CONCLUSIONS Newly identified hub genes and their transcriptional regulation may promote understanding of the molecular mechanisms underlying insulin resistance related to the progression of NAFLD and provide a new therapy target and biomarkers.

A wide range of organohalogenated flame retardants (HFRs) and organophosphate esters (OPEs) were measured in air and floor dust from 10 offices in Stockholm, Sweden. Concentrations of ∑18 emerging HFRs, ∑21 legacy HFRs and ∑11 OPEs from the offices were found to be 420, 510, and 1600000 ng/g, respectively, in floor dust and 400, 15, and 160 000 pg/m

Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

// Peng-Liang Wang 1 , Fang-Tao Xiao 1 , Bao-Cheng Gong 1 and Fu-Nan Liu 1 1 Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China Correspondence to: Fu-Nan Liu, email: lfn540@126.com Keywords: dietary habit, gastric cancer, cancer prevention, epidemiology Received: February 28, 2017 Accepted: August 28, 2017 Published: September 15, 2017 ABSTRACT Background: Many studies investigated the association between alcohol drinking and gastric cancer risk, but the results were controversial. We performed a meta-analysis of observational studies to explore the association. Materials and Methods: We searched PubMed to identify the relevant studies that reported the association between alcohol drinking and gastric cancer risk up to December 31, 2016. We pooled relative risks (RRs) in random effects model and performed dose-response analysis to quantify the association. Cochran Q test and I 2 analyses were used to evaluate the heterogeneity. Meta-regression, subgroup, sensitivity and publication bias analyses were also performed. Results: 75 studies were included in our study. The pooled RR of high vs low total alcohol drinking was 1.25 (95% CI, 1.15–1.37, P < 0.001), and a nonlinear association was further observed. Subgroup analysis showed that alcohol drinking significantly associated with the risk of gastric noncardia cancer (RR, 1.19; 95% CI, 1.01–1.40, P = 0.033), but not with the risk of gastric cardia cancer (RR, 1.16; 95% CI, 0.98–1.39, P = 0.087). Notably, the pooled RRs of high vs low analyses were 1.13 (95% CI, 1.03–1.24, P = 0.012) for beer drinking, 1.22 (95% CI, 1.06–1.40, P = 0.005) for liquor drinking, and 0.99 (95% CI, 0.84–1.16, P = 0.857) for wine drinking. Conclusions: Our meta-analysis found a nonlinear association between alcohol drinking and gastric cancer risk, and heavy drinking level was strongly related to gastric cancer risk. Beer and liquor had significant positive associations with gastric cancer risk, while wine drinking would not increase gastric cancer risk. These results need to be verified in future research.

// Zhong-Yan Liu 1, * , Jin Cao 1, * , Jing-Tao Zhang 1, * , Guo-Li Xu 1 , Xin-Ping Li 1 , Fang-Tao Wang 1 , Kamar Hasan Ansari 1 , Hassan Mohamed 1 and Yue-Zu Fan 1 1 Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200065, P.R. China * These authors have contributed equally to this work Correspondence to: Yue-Zu Fan, email: fanyuezu@hotmail.com Keywords: gallbladder neoplasm, ring finger protein 125, metastasis, prognosis, signaling pathway Received: December 10, 2016 Accepted: April 19, 2017 Published: May 25, 2017 ABSTRACT Human gallbladder cancer (GBC) is a lethal aggressive malignant neoplasm. Identification of potential molecular biomarkers and development of targeted therapeutics for GBC patients is very necessary. In this study, we firstly investigated the correlation between ring finger protein 125 (RNF125) expression and the metastasis and prognosis of GBC, and the underlying molecular mechanism. RNF125 expression in a cohort of GBC tissues was examined; its correlation with clinicopathological and prognostic factors of GBC patients was analyzed. Moreover, the metastasis-related difference expressed genes in highly and lowly aggressive GBC cell lines were identified; and the influence of RNF125 knockdown on the metastatic phenotypes and characteristic EMT markers in highly aggressive GBC NOZ cells was detected. Furthermore, the underlying molecular mechanism of RNF125 effect was explored. The results showed that RNF125 was highly expressed in GBC tissues and related with aggressive characteristics such as Nevin stage ( P = 0.041) etc. and unfavorable prognosis of GBC patients ( P = 0.023, log-rank test). And, RNF125 was proved to a positive metastasis-related gene in vitro . RNF125 knockdown inhibited the invasion and migration, enhanced the adhesion, upregulated E-cadherin and β-catenin expression, and downregulated vimentin and N-cadherin expression (all P < 0.001) of NOZ cells in vitro . RNF125 promoting effect on GBC tumor progression was identified to relate with the activation of TGF-β1-SMAD3-ID1 signaling pathway. These findings firstly confirm that high RNF125 expression is related with aggressive characteristics and unfavorable prognosis of GBC patients; RNF125 promotes the invasion and metastasis of human GBCs via activating the TGF-β1-SMAD3-ID1 signaling pathway.

Summary The SARS-CoV-2 infection status of hospitalized children was surveyed in the department of pediatric hematology and oncology in three different hospitals of epidemic areas in Hubei, China. A cross-sectional study was performed to investigate the clinical characteristics, lung CT scan, SARS-CoV-2 nucleic acid test and serum antibodies of hospitalized children with hemato-oncological diseases from January 23 to April 24, 2020. 299 children were enrolled in this study, including 176 males (58.9%) and 123 females (41.1%), aged from 2 months to 16 years. 255 cases (85.3%) received chemotherapy or other immunosuppressive therapies, and there were 44 cases (14.7%) of other benign diseases. Nucleic acid test was performed on 258 children (86.3%) and one case was positive. 163 cases (54.5%) were tested for serum antibodies, and all of them were negative. Lung CT scan was performed on 247 children (82.6%), and 107 of them showed infectious changes. Only one case (0.33%) of COVID-19 was diagnosed in the group. The prevalence rate of COVID-19 in enrolled children with hemato-oncological diseases in Hubei was 0.33%. Immunosuppressed patients are not prone to produce related antibodies. Comprehensive protective measures and ward management can reduce the risk of SARS-CoV-2 infection in the group patients.

Background: In this retrospective analysis, we investigate the clinical features and prognosis of 23 infant patients ( 100 × 109/L at initial diagnosis as a risk factor for poor OS and EFS. Conclusion: Treatment of infant ALL with the standard childhood ALL regimen achieved an OS rate similar to patients with high-risk ALL, and WBC at initial diagnosis may be an important prognostic indicator.

Gemcitabine (GEM), as an anti-metabolic nucleoside analog, has been shown to have anticancer effects in various tumors, but its chemotherapy resistance is still an important factor leading to poor prognosis of cancer patient. A large number of studies in recent years have shown that autophagy plays an important role in the chemotherapy sensitivity of many tumors, including pancreatic, non-small cell lung, and bladder cancer. However, whether GEM causes autophagy in gallbladder cancer (GBC) and whether it is related to chemotherapy resistance is unknown. In the present study, we demonstrated that GEM induced apoptosis and protective autophagy in GBC cells, which may be related to the AKT/mTOR signaling pathway, and GEM in combination with autophagy inhibitor chloroquine can strengthen the cytotoxic effect of GEM on GBC in vitro and in vivo. These findings showed that both autophagy and AKT/mTOR signals were engaged in GBC cell death evoked by GEM, GBC patients might benefit from this new treatment strategy, and molecular targeted treatment in combination with autophagy inhibitors shows promise as a treatment improvement.

Qi Guo,1,2,* Chao Zhang,1,* Xu Guo,1,3,* Fang Tao,1 Yao Xu,1 Guowei Feng,4 Xiuxin Han,1 Zhiwu Ren,1 Hui Zhang,2 Pingfang Zhang,2 Xin Wang,5 Guowen Wang1 1Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China; 2Department of Orthopedics, General Hospital of North China Petroleum Administration, Renqiu, China; 3Department of Orthopedics, Cangzhou Central Hospital, Cangzhou, China; 4Department of Urology, Tianjin Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; 5Department of Epidemiology and Biostatistics, First Affiliated Hospital, Army Medical University, Chongqing 400038, China * These authors contributed equally to this work Purpose: The purpose of this study was to assess the incidence of and the risk factors and prognostic factors for bone metastasis (BM) in initial metastatic renal cell carcinoma (RCC) based on a large population analysis.Patients and methods: Data were obtained for a total of 45,824 RCC patients recorded in the database of the Surveillance, Epidemiology, and End Results program of the National Cancer Institute between 2010 and 2014. Multivariate logistic and Cox regression analyses were used to identify the risk factors and prognostic factors associated with BM in RCC patients. Kaplan–Meier analysis was used to estimate the overall survival of RCC patients, and the difference between the survival curves was tested by log-rank tests.Results: A total of 1,509 (3.29%) patients were diagnosed with bone metastases at initial diagnosis. Male gender, higher T stage, lymph node involvement, poor tumor grade, presence of lung, liver, and brain metastases, and the collecting duct type of RCC were positively associated with BM occurrence. The median survival time for RCC patients with bone metastases was 12.0 (95% confidence interval [CI]: 10.69–13.31) months, and the survival time for those with collecting duct, clear-cell, papillary, and chromophobe subtypes of RCC were 3 (95% CI: 0.23–5.77), 13 (95% CI: 11.60–14.40), 8 (95% CI: 5.09–10.91), and 11 (95% CI: 5.02–16.98) months; these differences were significantly different (P

Transplantation of hematopoietic stem cells (HSCs) from human umbilical cord blood (hUCB) holds great promise for treating a broad spectrum of hematological disorders including cancer. However, the limited number of HSCs in a single hUCB unit restricts its widespread use. Although extensive efforts have led to multiple methods for ex vivo expansion of human HSCs by targeting single molecules or pathways, it remains unknown whether it is possible to simultaneously manipulate the large number of targets essential for stem cell self-renewal. Recent studies indicate that N6-methyladenosine (m6A) modulates the expression of a group of mRNAs critical for stem cell-fate determination by influencing their stability. Among several m6A readers, YTHDF2 is recognized as promoting targeted mRNA decay. However, the physiological functions of YTHDF2 in adult stem cells are unknown. Here we show that following the conditional knockout (KO) of mouse Ythdf2 the numbers of functional HSC were increased without skewing lineage differentiation or leading to hematopoietic malignancies. Furthermore, knockdown (KD) of human YTHDF2 led to more than a 10-fold increase in the ex vivo expansion of hUCB HSCs, a fivefold increase in colony-forming units (CFUs), and more than an eightfold increase in functional hUCB HSCs in the secondary serial of a limiting dilution transplantation assay. Mapping of m6A in RNAs from mouse hematopoietic stem and progenitor cells (HSPCs) as well as from hUCB HSCs revealed its enrichment in mRNAs encoding transcription factors critical for stem cell self-renewal. These m6A-marked mRNAs were recognized by Ythdf2 and underwent decay. In Ythdf2 KO HSPCs and YTHDF2 KD hUCB HSCs, these mRNAs were stabilized, facilitating HSC expansion. Knocking down one of YTHDF2′s key targets, Tal1 mRNA, partially rescued the phenotype. Our study provides the first demonstration of the function of YTHDF2 in adult stem cell maintenance and identifies its important role in regulating HSC ex vivo expansion by regulating the stability of multiple mRNAs critical for HSC self-renewal, thus identifying potential for future clinical applications.

To confirm the association between baseline blood pressure (BP) levels and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in patients with essential hypertension.A total of 347 patients were enrolled from the Dongzhi community in Anhui Province, China. The C677T polymorphism of the MTHFR gene was detected using high-throughput TaqMan allelic discrimination assay. Baseline BP was measured using a standardized mercury-gravity monometer.In the whole sample, the frequency of the MTHFR C677T genotypes CC, CT, and TT were 38.6%, 48.1%, and 13.3%, respectively. In a recessive model (CC+CT versus TT genotypes), baseline diastolic blood pressure (DBP) was significantly higher in patients with the TT genotype compared to those with the CT or CC genotypes (P= 0.013). We also divided all patients into three groups based on the tertiles of the baseline BP distribution. Compared to subjects in the lowest tertile of DBP, the adjusted odds of having the TT genotype among subjects in the highest tertile was 2.6 (95% CI: 1.1 to 6.2). However, no significant associations were observed between baseline systolic blood pressure (SBP) and the MTHFR C677T polymorphism.The MTHFR gene polymorphism could be an important genetic determinant of baseline DBP levels in Chinese essential hypertensive patients.

Purpose: Based on a large-population analysis, we aimed to estimate the incidence and survival of bone metastases (BM) in initial bladder cancer (BC) patients and to identify the risk and prognostic factors of BC patients with BM. Patients and methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, bladder cancer patients diagnosed between 2010 and 2014 were retrieved. Multivariate logistic and Cox regression analyses were employed to identify risk factors and prognostic factors for BM in BC patients. A Kaplan-Meier analysis with log-rank test was used to estimate the overall survival for BC and the difference between the survival curves. Results: A total of 1,223 (1.39%) BC patients were diagnosed with de novo BM. Variables such as age between 41 to 60 years, black race, unmarried status, higher T stage, higher N stage, poor tumour differentiation grade, lung metastases, liver metastases, and brain metastases were positively associated with BM occurrence. The median survival for BC patients with BM was dramatically decreased to 4.0 months. Factors including advanced age, absence of surgery, and presence of lung, liver, or brain metastases all predicted worse survival. Conclusion: BM can dramatically decrease the survival of bladder cancer patients. The findings of the present study can provide population-based identification of risk and prognostic factors for BC patients with BM at initial diagnosis, which can be used for BM occurrence prediction and individualized treatment plan-making.

SUMMARY Tumor-initiating stem cells (TSCs) are critical for drug resistance and immune escape. However, the mutual regulations between TSC and tumor microenvironment (TME) remain unclear. Using DNA-label retaining, single-cell RNA sequencing (scRNA-seq), and other approaches, we investigated intestinal adenoma in response to chemoradiotherapy (CRT), thus identifying therapy-resistant TSCs (TrTSCs). We find bidirectional crosstalk between TSCs and TME using CellPhoneDB analysis. An intriguing finding is that TSCs shape TME into a landscape that favors TSCs for immunosuppression and propagation. Using adenoma-organoid co-cultures, niche-cell depletion, and lineaging tracing, we characterize a functional role of cyclooxygenase-2 (Cox-2)-dependent signaling, predominantly occurring between tumor-associated monocytes and macrophages (TAMMs) and TrTSCs. We show that TAMMs promote TrTSC proliferation through prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, which enhances β-catenin activity via AKT phosphorylation. Thus, our study shows that the bidirectional crosstalk between TrTSC and TME results in a pro-tumorigenic and immunosuppressive contexture., Graphical Abstract, In brief He et al. examined the nature of therapy-resistant tumor-initiating stem cells (TSCs) in murine intestinal adenoma using single-cell RNA sequencing (scRNA-seq) analysis and revealed a bidirectional crosstalk between TSC and its microenvironment, TME, in which TSC shapes TME, especially tumor-associated monocyte and macrophage (TAMM), into an immunosuppressive barrier and pro-tumorigenic niche.

Neuroblastoma is the most common extracranial solid childhood tumor. Despite the availability of advanced multimodal therapy, high-risk patients still have low survival rates. p21-activated kinase 4 (PAK4) has been shown to regulate many cellular processes in cancer cells, including migration, polarization and proliferation. However, the role of PAK4 in neuroblastoma remains unclear. In the present study, we demonstrated that PAK4 was overexpressed in neuroblastoma tissues and was correlated with tumor malignance and prognosis. To investigate the function of PAK4 in neuroblastoma, we used a small-molecule inhibitor that targets PAK4, that is, PF-3758309. Our results showed that PF-3758309 significantly induced cell cycle arrest at the G1 phase and apoptosis in neuroblastoma cell lines. Meanwhile, the inhibition of PAK4 by PF-3758309 increased the expression of CDKN1A, BAD and BAK1 and decreased the expression of Bcl-2 and Bax. In addition, we screened the target genes of PAK4 by PCR array and found that 23 genes were upregulated (including TP53I3, TBX3, EEF1A2, CDKN1A, IFNB1 and MAPK8IP2) and 20 genes were downregulated (including TNFSF8, Bcl2-A1, Bcl2L1, SOCS3, BIRC3 and NFKB1) after PAK4 inhibition by PF-3758309. Moreover, PAK4 was found to regulate the cell cycle and apoptosis via the ERK signaling pathway. In conclusion, the present study demonstrated, for the first time, the expression and function of PAK4 in neuroblastomas and the inhibitory effect of PF-3758309, which deserves further investigation as an alternative strategy for neuroblastoma treatment.

We conducted a cross-sectional study to investigate the effects of the adenosine triphosphate-binding cassette transporter 1 (ABCA1) I883M and lipoprotein lipase (LPL) HindIII polymorphisms on lipid levels in patients with hyperlipidemia. A total of 533 patients were enrolled. Serum lipid parameters were determined by an automatic biochemistry analyzer. Genotyping of the ABCA1 I883M and LPL HindIII was carried out using the polymerase chain reaction-restriction fragment length polymorphism technique. Multiple linear regression analysis was used to estimate the associations between serum lipid levels and the genetic polymorphisms. The frequency distribution of the ABCA1 I883M and LPL HindIII polymorphisms did not deviate from Hardy-Weinberg equilibrium. The major finding of our regression analysis showed that neither the ABCA1 I883M nor the LPL HindIII polymorphism was associated with baseline serum lipid levels in the total population. However, among patients with elevated alanine aminotransferase (ALT) levels (ALT ≥ 40 U/L), carriers of the M allele of the ABCA1 gene had lower levels of high-density lipoprotein cholesterol (HDL-C) and higher levels of low-density lipoprotein cholesterol (LDL-C) after adjusting for age, sex, smoking status, alcohol consumption, education level, occupation, and work intensity ( P < .05 for both). A test on interaction terms between the ABCA1 I833M polymorphism and ALT on HDL-C and LDL-C levels also remained significant ( P = .001 and P = .014, respectively). Our data suggest that there are significant interactive effects between ABCA1 I883M and ALT levels on HDL-C and LDL-C levels. However, the LPL HindIII polymorphism did not influence lipid levels.

A recent algicidal mode indicates that fungal mycelia can wrap and eliminate almost all co-cultivated algal cells within a short time span. However, the underlying molecular mechanism is rarely understood. We applied proteomic analysis to investigate the algicidal process of Trametes versicolor F21a and identified 3,754 fungal proteins. Of these, 30 fungal enzymes with endo- or exoglycosidase activities such as β-1,3-glucanase, α-galactosidase, α-glucosidase, alginate lyase and chondroitin lyase were significantly up-regulated. These proteins belong to Glycoside Hydrolases, Auxiliary Activities, Carbohydrate Esterases and Polysaccharide Lyases, suggesting that these enzymes may degrade lipopolysaccharides, peptidoglycans and alginic acid of algal cells. Additionally, peptidase, exonuclease, manganese peroxidase and cytochrome c peroxidase, which decompose proteins and DNA or convert other small molecules of algal cells, could be other major decomposition enzymes. Gene Ontology and KEGG pathway enrichment analysis demonstrated that pyruvate metabolism and tricarboxylic acid cycle pathways play a critical role in response to adverse environment via increasing energy production to synthesize lytic enzymes or uptake molecules. Carbon metabolism, selenocompound metabolism, sulfur assimilation and metabolism, as well as several amino acid biosynthesis pathways could play vital roles in the synthesis of nutrients required by fungal mycelia.

Insufficient number of examined lymph nodes (eLNs) was considered to increase significantly the risk of stage migration in gastric cancer patients. The aim of our study is to establish a nomogram predicting the overall survival (OS) for patients with an insufficient number of eLNs. A total of 872 gastric cancer patients with extended lymphadenectomies were assigned randomly (2:1) to the development cohort and the validation cohort. The nomogram was established based on the Cox regression model using the development cohort. The concordance index (C-index) was used to evaluate the discriminative ability. We also compared our model with two other staging systems. Using multivariate analysis, age, sex, tumor location, depth of invasion, macroscopic type, lymphovascular invasion, the number of eLNs, and metastatic lymph nodes were selected and incorporated into the nomogram. The C-index of the nomogram was 0.742 and 0.743 in development and validation cohorts, respectively, which were significantly superior to the C-indices (range 0.705–0.712, all P

The present study investigates the effects of age and mating status on the circadian variations of gland sex pheromone titre in female Spodoptera litura Fabricius. Similar to other nocturnal moths, S. litura females exhibit circadian variations of gland sex pheromone contents, with higher levels during scotophase and lower levels during photophase. The sex pheromone titre in the glands peaks during the first scotophase after eclosion and sharply declines afterwards. Higher pheromone contents during scotophase may facilitate female reproductive activities, and the negative relationship between pheromone titre and female calling is likely the result of pheromone release during female calling. Interestingly, the present study demonstrates that mated S. litura females have significantly higher sex pheromone titre in their pheromone glands (PGs) than virgin females. This finding contrasts with all previous studies of other insect species, in which mating generally reduces the sex pheromone titre in female PGs. In S. litura, mating and male accessory gland fluids can suppress female calling behaviours and re-matings. These results suggest that the suppression of female calling behaviours by mating and male accessory gland fluids may significantly reduce the release of sex pheromones and thus result in higher sex pheromone titre in the PGs of mated females.

Purpose: The aim of this study was to identify influencing factors for sleep quality among shift-working nurses based on a three-factor scoring model that included sleep efficacy, sleep quality and daily dysfunction. Methods: A cross-sectional survey of 513 nurses in a hospital in Shanghai, China, was conducted using a self-reported questionnaire. Sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI). Data were analyzed based on the three-factor PSQI model: Factor 1, sleep efficacy; Factor 2, sleep quality; Factor 3, daily disturbances. Results: After adjusting for age, marital status, and having children, multivariate logistic regression analysis showed that participants who had previous shift work experience which was at least 6 months ago, or were currently performing shift work were significantly more likely to have poor sleep quality (PSQI > 5) than those who had never done shift work (adjusted odds ratios of 3.943 and 3.975, respectively, both p

Gallbladder cancer (GBC) is a lethal aggressive malignant neoplasm of the biliary tract. Potential prognostic markers and therapeutic targets for this disease are urgently required. Cancer‑associated fibroblasts (CAFs) play a key role in tumorigenesis and the development of cancer. Nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) expression has been reported to be involved in tumorigenesis and useful for tumor prognosis. However, NOX1 expression in the stroma of GBCs, particularly gallbladder cancer‑associated fibroblasts (GCAFs), and its prognostic significance in GBC patients remains unclear. In the present study, NOX1 expression in the stroma of human gallbladder lesions in vivo was investigated, as well as in GCAFs and co‑cultures of GBC‑SD+GCAFs in vitro, and their correlation with clinicopathological parameters and the prognosis of GBC patients were evaluated. The results revealed that NOX1 expression was significantly upregulated in the stroma of GBCs compared with precancerous and benign lesions of the gallbladder; NOX1 expression was localized to gallbladder stromal fibroblasts expressing α‑smooth muscle actin and fibroblast secreted protein‑1. Furthermore, these observations were confirmed by the fact that NOX1 expression was upregulated in GCAFs as determined by Affymetrix gene profile chip analysis and reverse transcription‑quantitative PCR. In addition, overexpression was observed in formed spheroids of GBC‑SD+GCAF co‑cultures by immunohistochemistry and western blotting in vitro. Thus, it was verified that NOX1 expression was upregulated in GCAFs. Furthermore, upregulated stromal NOX1 expression was correlated with aggressive characteristics such as differentiation degree (P=0.042), venous invasion (P=0.041), resection methods (P=0.002), and a lower survival rate (P=0.025, log‑rank test) of patients with GBC. Stromal NOX1 expression (P=0.047) was an independent prognostic factor for the overall survival rate of patients with GBC. GBC patients with upregulated NOX1 expression in GCAFs had a poorer prognosis. These results revealed that stromal NOX1 may be a novel biomarker and/or target, and may contribute to the discovery of new tumor markers and potential targeted therapeutics for human GBCs.

Adequate blood supply is essential for tumor survival, growth and metastasis. The tumor microenvironment (TME) is dynamic and complex, comprising cancer cells, cancer-associated stromal cells and their extracellular products. The TME serves an important role in tumor progression. Cancer-associated fibroblasts (CAFs) are the principal component of stromal cells within the TME, and contribute to tumor neo-angiogenesis by altering the proteome and degradome. The present paper reviews previous studies of the molecular signaling pathways by which CAFs promote tumor neo-angiogenesis and highlights therapeutic response targets. Also discussed are potential strategies for antitumor neo-angiogenesis to improve tumor treatment efficacy.

Objectives: Identify the efficacy of multidisciplinary treatment including palliative spinal surgery on patients with Tomita type 7 spinal metastases. Patients and methods: A retrospective analysis of surgery treated spinal metastatic patients from January 2013 to December 2016 in Tianjin Medical University Cancer Institute and Hospital were performed. Surgical procedures and intraoperative parameters and postoperative adjuvent treatments were studied. Patients’ demographic characteristics and medical conditions including paralysis statues, quality of life and pain levels and postoperative survival time were identified. Results: 50 patients were identified with mean age at the time of surgery of 57.68 years old (range 27–78 years). The mean Tokuhashi score was 8.48 and the spinal instability neoplastic score (SINS) averaged at 10.52 points. 48 patients (96%) encountered epidural spinal cord compression. Kaplan-Meier method determined median postoperative survival time was 12.00 months (95% CI: 7.05–16.95 months). The mean score of visual analogue scale (VAS) decreased from 7.66 preoperatively to 1.96 postoperatively. The Frankel scale was improved by at least one grade in 47 patients. Patient’s quality of life showed significant improvements. Conclusion: Multidisciplinary treatment including palliative spinal surgery was associated with alleviating pain, improving neurologic function and quality of life in patients with Tomita type 7 spinal metastases.

Background Relaxin is a peptide hormone which has been demonstrated to be safe and has a therapeutic effect on acute heart failure in clinic trials. However, its effect on diastolic function is still unknown. The aims of the study were to determine whether relaxin could improve the diastolic function in pressure-overloaded rat model and to analyze potential mechanisms. Methods and results In the present study, a pressure-overloaded rat model induced by transaortic constriction (TAC) was established. Four weeks after TAC, echocardiography was performed and then all the rat models were randomly divided into 3 groups: models without intramyocardial injection (TAC), with intramyocardial injection of empty adenoviral vector (TAC+GFP) and adenoviral vector overexpression relaxin-2 gene (TAC+RLN2). A sham group was also included. Twelve days after intramyocardial injection, echocardiography and hemodynamics were carried out to evaluate diastolic function in sham, TAC, TAC+GFP and TAC+RLN2 groups. Then hearts were harvested for subsequent examinations. The results indicated that relaxin-2 had ameliorated diastolic function in the pressure-overloaded rats. Compared with the TAC and TAC+GFP groups, the relaxin-2 gene transfer increased phosphorylation of Akt at both the Ser473 and Thr308 sites. Meanwhile, it increased the Ser16 and Thr17- phosphorylation levels of phospholamban (PLB). Furthermore, SERCA2 activity was enhanced in the TAC+RLN2 group more than in the TAC and TAC+GFP groups. Conclusions These results demonstrated that relaxin-2 gene therapy improved diastolic function in pressure-overloaded rats. The potential mechanism may be that relaxin-2 gene transfer enhances SERCA2 activity in hearts by increasing phospholamban phosphorylation through nuclear-targeted Akt phosphorylation.

Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor, however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35, p &lt, 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy, however, the underlying mechanisms remain to be determined.

Background Asthma is one of the most significant diseases worldwide and causes overwhelming costs physically and economically. The study of asthma has revealed various groups of asthma patients who share phenotypic characteristics that naturally elicit the need for personalized asthma therapy. An increasing amount of pharmacogenetics research, genotype-based trials and precision medicine trials have been conducted to investigate this problem. Methods A systematic bibliography retrieval was performed in MEDLINE (Ovid) and PubMed for our topic and all relative records were exported and screened. Results We identified 377 publications and added 4 articles related to this topic artificially to reach a bigger scope, of which 36 met the inclusion criteria. Our review focuses on the three most widely used treatments for asthma management, which are β-adrenergic receptor agonists, inhaled corticosteroids (ICS) and anti-leukotriene modifiers. We summarize the existing loci reported in the literature that are potentially associated with drug responses to typically used medications. Conclusion Our results suggest that a genetic test with high predictive accuracy could predict therapeutic responses, and proper management can be achieved in asthma patients. This personalized approach to curative medicine should make way for the realization of personalized preventive and predictive medicine in the coming years.

Background Overexpression of cyclin D1 dependent kinases 4 and 6 (CDK4/6) is a common feature of many human cancers including leukemia. LEE011 is a novel inhibitor of both CDK4 and 6. To date, the molecular function of LEE011 in leukemia remains unclear. Methods Leukemia cell growth and apoptosis following LEE011 treatment was assessed through CCK-8 and annexin V/propidium iodide staining assays. Cell senescence was assessed by β-galactosidase staining and p16INK4a expression analysis. Gene expression profiles of LEE011 treated HL-60 cells were investigated using an Arraystar Human LncRNA array. Gene ontology and KEGG pathway analysis were then used to analyze the differentially expressed genes from the cluster analysis. Results Our studies demonstrated that LEE011 inhibited proliferation of leukemia cells and could induce apoptosis. Hoechst 33,342 staining analysis showed DNA fragmentation and distortion of nuclear structures following LEE011 treatment. Cell cycle analysis showed LEE011 significantly induced cell cycle G1 arrest in seven of eight acute leukemia cells lines, the exception being THP-1 cells. β-Galactosidase staining analysis and p16INK4a expression analysis showed that LEE011 treatment can induce cell senescence of leukemia cells. LncRNA microarray analysis showed 2083 differentially expressed mRNAs and 3224 differentially expressed lncRNAs in LEE011-treated HL-60 cells compared with controls. Molecular function analysis showed that LEE011 induced senescence in leukemia cells partially through downregulation of the transcriptional expression of MYBL2. Conclusions We demonstrate for the first time that LEE011 treatment results in inhibition of cell proliferation and induction of G1 arrest and cellular senescence in leukemia cells. LncRNA microarray analysis showed differentially expressed mRNAs and lncRNAs in LEE011-treated HL-60 cells and we demonstrated that LEE011 induces cellular senescence partially through downregulation of the expression of MYBL2. These results may open new lines of investigation regarding the molecular mechanism of LEE011 induced cellular senescence. Electronic supplementary material The online version of this article (doi:10.1186/s12935-017-0405-y) contains supplementary material, which is available to authorized users.

Survivors of hypoxic-ischemic brain damage (HIBD), besides impairment of psychomotor development, often develop circadian rhythm disorders, although the underlying mechanisms are largely unknown. Here, we first verified that mRNA and protein expression of pineal aralkylamine N-acetyltransferase (Aanat), a key regulator for melatonin (MT) synthesis, along with MT, were severely impaired after HIBD. In addition, we demonstrated that neonatal HIBD disrupted the circadian rhythmicity of locomotor activities in juvenile rats. Based on bioinformatics analysis of a high throughput screening of miRNA expression changes after HIBD (Ding et al., 2015), we identified one microRNA, miR-325-3p, as a potential candidate responsible for the down regulation of Aanat after HIBD. Luciferase reporter assays demonstrated a specific interaction between miR-325-3p and Aanat mRNA 3'-UTR. miR-325-3p blocked norepinephrine (NE) induced Aanat activation in cultured pinealocytes. In addition, miR-325-3p inhibition partially rescued Aanat induction by NE, which was significantly reduced under oxygen glucose deprivation. By elucidating the role of pineal miR-325-3p on Aanat expression upon injury, our study provides new insights into the pathophysiological mechanisms of circadian dysfunction and potential therapeutic targets after HIBD.

Kidney-replenishing herb is a traditional medicine formula in China which has been widely used for clinical treatment of recurrent miscarriage. Our previous study showed that Kidney-replenishing herb could promote proliferation and inhibit apoptosis of the human first-trimester trophoblasts. In the present study, we further explored the potential mechanism and signal pathway of Kidney-replenishing herb on human trophoblast cells. Our research showed that Kidney-replenishing herb stimulated proliferation and reduced apoptosis of human trophoblast cells in vitro, and this appeared to be positive correlation with SOCS-3 transcription, suggesting that Kidney-replenishing herb regulated biological functions of human trophoblast cells by inducing SCOS-3 expression. Furthermore, the Kidney-replenishing herb treatment stimulated the phosphorylation of ERK1/2, and blocking the signaling pathway by mitogen-activated protein MAPK (MEK) inhibitor, U0126, inhibited Kidney-replenishing herb-induced SOCS-3 transcription, depressed proliferation, and promoted apoptosis of human trophoblasts. Kidney-replenishing herbs still induced ERK1/2 phosphorylation after SOCS-3 siRNA silence. Overexpression of SOCS-3 stimulated the proliferation of trophoblast. These findings suggest that SOCS-3 expression is induced by Kidney-replenishing herbs via activation of MAPK pathways, and this may possibly be involved in promoting human trophoblast cells growth which is contributed to embryo development.

This study aimed to assess the predictive effect of soluble ST2 (sST2) and depressive symptoms in patients with heart failure (HF) and to determine whether the prognosis of HF patients with preserved ejection fraction (HFpEF) differs from those with reduced ejection fraction (HFrEF). A cohort of 233 HF patients was followed for 1 year. Depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale. The primary endpoint was all-cause mortality and HF-related hospitalization. For the analysis of survival, the left ventricular ejection fraction (LVEF) cut-offs for defining HFpEF were set at 50%, 45%, and 40%, respectively. With increasing LVEF, levels of sST2 were gradually decreased (45.2 ng/mL, 35.8 ng/mL, and 32.1 ng/mL in patients with LVEF ≤ 40%, 41% to 49%, and ≥ 50%, respectively, P for trend0.001), as well as the prevalence of depressive symptoms (35.4%, 33.3%, and 20.4%, respectively, P for trend = 0.022). After 1-year follow-up, 128 patients (54.9%) achieved the primary endpoint and 47 patients (20.2%) died. Depressive symptoms were independent risk factors of all-cause mortality and HF-related hospitalization. The combined presence of elevated sST2 (36.0 ng/mL) and depressive symptoms was associated with a 4.9-fold increased risk of the primary endpoint. Regardless of LVEF cut-offs, the associated risk of adverse outcomes in HFpEF was as high as in HFrEF after adjustment for significant risk factors including sST2 and N-terminal pro-brain natriuretic peptide. In conclusion, depressive symptoms provided additional prognostic information to that of sST2 in HF patients. The prognosis of HFpEF patients was similar to that of HFrEF patients.

Regulation of hematopoietic stem cells (HSCs) by bone marrow (BM) niches has been extensively studied; however, whether and how HSC subpopulations are distinctively regulated by BM niches remain unclear. Here, we functionally distinguished reserve HSCs (rHSCs) from primed HSCs (pHSCs) based on their response to chemotherapy and examined how they are dichotomously regulated by BM niches. Both pHSCs and rHSCs supported long-term hematopoiesis in homeostasis; however, pHSCs were sensitive but rHSCs were resistant to chemotherapy. Surviving rHSCs restored the HSC pool and supported hematopoietic regeneration after chemotherapy. The rHSCs were preferentially maintained in the endosteal region that enriches N-cadherin+ (N-cad+) bone-lining cells in homeostasis and post-chemotherapy. N-cad+ cells were functional bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes in vitro and in vivo. Finally, ablation of N-cad+ niche cells or deletion of SCF from N-cad+ niche cells impaired rHSC maintenance during homeostasis and regeneration.

To assess associations of the serum level of 25-hydroxyvitamin D with insulin resistance and β-cell function in a healthy Chinese female population. This cross-sectional study included 1382 female participants free of type 2 diabetes who were recruited in Shanghai. Blood samples were collected within a winter season and the serum levels of 25-hydroxyvitamin D, fasting plasma glucose and insulin, and other biochemical parameters were determined. Insulin resistance and β-cell function were assessed using the homeostasis model assessments of insulin resistance (HOMA-IR) and β-cell function (HOMA-B), respectively. Multiple linear regression analyses adjusted for age, parathyroid hormone, Ca2+ and BMI revealed that independent inverse associations existed between the serum level of 25-hydroxyvitamin D and HOMA-IR (P