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Maintenance of an appropriate oxygen concentration is essential for the function of the liver. However, in many pathological conditions, and particularly in the tumor microenvironment, cells and tissues are frequently in a hypoxic state. In the presence of hypoxia, the cells adapt to the low oxygen levels through the hypoxia‑inducible factor (HIF) pathway. Overgrowth of tumor cells restricts the diffusion of oxygen in tumors, leading to insufficient blood supply and the creation of a hypoxic microenvironment, and, as a consequence, activation of the expression of HIFs. HIFs possess a wide range of target genes, which function to control a variety of signaling pathways; thus, HIFs modulate cellular metabolism, immune escape, angiogenesis, metastasis, extracellular matrix remodeling, cancer stem cells and other properties of the tumor. Given their crucial role in the occurrence and development of tumors, HIFs are expected to become new targets of precise treatment of hepatocellular carcinoma.

INTRODUCTION: Erdheim–Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis. The clinical spectrum of ECD is diverse, varying from asymptomatic focal lesion to life-threatening multisystem infiltration. Neurological manifestations of ECD are common, mostly due to the involvement of the central nerve system. However, spinal nerve or peripheral nerve involvement has rarely been mentioned. CASE PRESENTATION: Herein, we present a case of a 32-year-old female patient complaining about radiating pain on the front and lateral side of her left thigh for 2 months. Spinal MRI with contrast enhancement showed a space-occupying lesion on the left L3/L4 intervertebral foramen, indicating an initial diagnosis of lumbar nerve schwannoma. The patient underwent surgery to remove the mass and decompress the lumbar nerve. Postoperative histological examination revealed the diffuse infiltration of foamy histiocytes that were CD68(+), CD163(+), and CD1a(−) on immunostaining, which confirmed the diagnosis of Erdheim–Chester disease. The radiating pain was gradually alleviated and PET-CT was performed but showed no further involvement of ECD. DISCUSSION: To the best of our knowledge, this is the first case of ECD demonstrated as an infiltrative mass on the spinal nerve, with imaging manifestations and compression symptoms similar to those of peripheral nerve schwannoma.

AIMS To analyze the factors affecting the prognosis of hepatoblastoma (HB) with lung metastasis in children. METHODS The HB patients with lung metastases admitted to Beijing Tongren Hospital, Capital Medical University were collected. The clinical data, overall results, and prognostic factors were analyzed. Multivariate analysis was done by the Cox proportional hazards model for patients' prognosis. RESULTS Finally, 98 HB patients (64 boys and 34 girls) with lung metastasis met the inclusion criteria, in which 64 patients had lung metastases at diagnosis (median age, 22.3 months) and 34 patients developed lung metastases while on treatment (median time, 6.5 months). The survival time and 5-year survival rate of patients with standard treatment were significantly longer than that of without standard treatment (P

Background The protective effect of melatonin against bone metabolism imbalance in osteoporosis (OP) induced by drugs such as retinoic acid (RA) is unclear. The aim of this study was to explore the role of melatonin in bone destruction based on a mouse model. Methods RA-induced OP model mice were established. To assess the effect of melatonin on these mice, micro-CT was used to characterize the trabecular structure of normal mice and those treated with RA (model), RA + low-dose melatonin (Mlt-L), RA + high-dose melatonin (Mlt-H), and RA + alendronate sodium (positive control). The shape of the trabecular bone, the length and diameter of the femoral head and the height and diameter of vertebra(L1) of each group were also measured and the number of osteoclasts was determined by Tartrate-resistant acid phosphatase (TRACP) staining. Meanwhile, the expression of alkaline phosphatase (ALP) was evaluated by immunohistochemistry assays. The differences between groups in terms of liver and kidney oxidation–related indexes and serum and urinary indicators related to bone metabolism were also analyzed. Furthermore, qRT-PCR and western blotting were used to evaluate the effect of melatonin on osteogenic and osteoclastic differentiation in MC3T3-E1 and RAW264.7 cells, respectively. Results RA induction led to a decrease in the amount and density of trabecular bone, a decrease in the length and diameter of the femur and height, diameter of the vertebra (L1), a decrease in bone mass and density and the expression of ALP, and an increase in the number of osteoclasts. Melatonin treatment alleviated these effects induced by RA, increasing the amount of trabecular bone in OP mice, improving the microstructure of the femur and vertebra(L1) and increasing bone mass bone density and the expression of ALP, as well as decreasing the number of osteoclasts. Additionally, blood and urinary bone metabolism-related indicators showed that melatonin promoted bone formation and inhibited bone resorption. Determination of oxidant and antioxidant biomarkers in the livers and kidneys of the mice revealed that melatonin promoted the antioxidant level and suppressed the level of oxidant molecules in these organs. In vitro, RA promoted osteoclasts and inhibit osteogenesis by increasing oxidative stress levels in the RAW264.7 and MC3T3-E1 cells, but melatonin reversed this effect. Melatonin may, therefore, play a role in the ERK/SMAD and NF-κB pathways. Conclusions Melatonin can alleviate bone loss in RA-induced OP model mice, repair the trabecular microstructure, and promote bone formation. These effects may be related to reducing oxidation levels in vivo and vitro through the ERK/SMAD and NF-κB pathways.

Chordoma is an extremely rare malignant bone tumor with a high rate of relapse. While cancer stem cells (CSCs) are closely associated with tumor recurrence, which depend on its capacity to self-renew and induce chemo-/radioresistance, whether and how CSCs participate in chordoma recurrence remains unclear. The current study found that tumor cells in recurrent chordoma displayed more dedifferentiated CSC-like properties than those in corresponding primary tumor tissues. Meanwhile, MTNR1B deletion along with melatonin receptor 1B (MTNR1B) down-regulation was observed in recurrent chordoma. Further investigation revealed that activation of Gαi2 by MTNR1B upon melatonin stimulation could inhibit SRC kinase activity via recruiting CSK and SRC, increasing SRC Y530 phosphorylation, and decreasing SRC Y419 phosphorylation. This subsequently suppressed β-catenin signaling and stemness via decreasing β-catenin p-Y86/Y333/Y654. However, MTNR1B loss in chordoma mediated increased CSC properties, chemoresistance, and tumor progression by releasing melatonin's repression of β-catenin signaling. Clinically, MTNR1B deletion was found to correlate with patients' survival. Together, our study establishes a novel convergence between melatonin and β-catenin signaling pathways and reveals the significance of this cross talk in chordoma recurrence. Besides, we propose that MTNR1B is a potential biomarker for prediction of chordoma prognosis and selection of treatment options, and chordoma patients might benefit from targeting MTNR1B/Gαi2/SRC/β-catenin axis.

Lnc-BMP1-1 is a lncRNA transcribed from SFTPC (surfactant associated protein C), a lung tissue specific gene encoding pulmonary-associated surfactant protein C (SPC) that is solely secreted by alveolar typeⅡ epithelial cells, among which the ones with SFTPC+ might be transformed into lung adenocarcinoma cells. Caveolin-1 (Cav-1) is a candidate tumor suppressor gene and is vital for coping with oxidative stress induced by cigarette smoke. When comparing lung cancer tissues with their adjacent normal tissues, the expression of lnc-BMP1-1 were decreased, especially in patients with cigarette smoking history (P=0.027), and positively associated with the expression of Cav-1 (P

Hypertrophic differentiation is not only the terminal process of endochondral ossification in the growth plate but is also an important pathological change in osteoarthritic cartilage. Collagen type II (COL2A1) was previously considered to be only a structural component of the cartilage matrix, but recently, it has been revealed to be an extracellular signaling molecule that can significantly suppress chondrocyte hypertrophy. However, the mechanisms by which COL2A1 regulates hypertrophic differentiation remain unclear. In our study, a Col2a1 p.Gly1170Ser mutant mouse model was constructed, and Col2a1 loss was demonstrated in homozygotes. Loss of Col2a1 was found to accelerate chondrocyte hypertrophy through the bone morphogenetic protein (BMP)-SMAD1 pathway. Upon interacting with COL2A1, integrin β1 (ITGB1), the major receptor for COL2A1, competed with BMP receptors for binding to SMAD1 and then inhibited SMAD1 activation and nuclear import. COL2A1 could also activate ITGB1-induced ERK1/2 phosphorylation and, through ERK1/2-SMAD1 interaction, it further repressed SMAD1 activation, thus inhibiting BMP-SMAD1-mediated chondrocyte hypertrophy. Moreover, COL2A1 expression was downregulated, while chondrocyte hypertrophic markers and BMP-SMAD1 signaling activity were upregulated in degenerative human articular cartilage. Our study reveals novel mechanisms for the inhibition of chondrocyte hypertrophy by COL2A1 and suggests that the degradation and decrease in COL2A1 might initiate and promote osteoarthritis progression., Breaking a destructive cycle A signaling feedback loop that contributes to cartilage degeneration may offer a fruitful target for the treatment of osteoarthritis. During the early stages of this disorder, cartilage-forming chondrocytes undergo a process of expansion known as hypertrophy, after which they die and are replaced by calcium. Researchers led by Peiqiang Su and Dongsheng Huang of Sun Yat-sen University have demonstrated that COL2A1, an important structural protein, represents an important safeguard against hypertrophy. COL2A1 helps maintain chondrocytes in their normal, healthy state, but Su and Huang showed that signaling factors produced during cartilage repair can reduce COL2A1 levels. This in turn accelerates hypertrophy, promoting further depletion of COL2A1 and ultimately leading to full-blown osteoarthritis. Drugs that break this cycle and preserve COL2A1 could thus help protect endangered joints before the damage becomes severe.

Arthrogryposis is a group of phenotypically and genetically heterogeneous disorders characterized by congenital contractures of two or more parts of the body; the pathogenesis and the causative genes of arthrogryposis remain undetermined. We examined a four‐generation arthrogryposis pedigree characterized by camptodactyly, limited forearm supination, and loss of myofibers in the forearms and hands. By using whole‐exome sequencing, we confirmed MET p.Y1234C mutation to be responsible for arthrogryposis in this pedigree. MET p.Y1234C mutation caused the failure of activation of MET tyrosine kinase. A Met p.Y1232C mutant mouse model was established. The phenotypes of homozygous mice included embryonic lethality and complete loss of muscles that originated from migratory precursors. Heterozygous mice were born alive and showed reduction of the number of myofibers in both appendicular and axial muscles. Defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were proven to be responsible for the skeletal muscle dysplasia of mutant mice. Overall, our study shows MET to be a causative gene of arthrogryposis and MET mutation could cause skeletal muscle dysplasia in human beings.

Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro culture results in loss of MSC stemness. The inflammation that occurs at stem cell transplant sites (such as that resulting from TNF-α) is a contributing factor for stem cell treatment failure. Currently, there is little evidence regarding the protective role of melatonin with regard to the negative effects of TNF-α on the stemness of MSCs. In this study, we report a melatonin-based method to reduce the inflammatory effects on the stemness of bone marrow mesenchymal stem cells (BMMSCs). The results of colony formation assays, Alizarin red staining, western blotting, and reverse transcription-polymerase chain reactions suggest that melatonin can reverse the inflammatory damage caused by TNF-α treatment in the third, seventh, and tenth generations of primary BMMSCs (vs. control and the TNF-α-treated group). Meanwhile, a detailed analysis of the molecular mechanisms showed that the melatonin receptor and YAP signaling pathway are closely related to the role that melatonin plays in negative inflammatory effects against BMMSCs. In addition, in vivo experiments showed that melatonin could reverse the damage caused by TNF-α on bone regeneration by BMMSCs in nude mice. Overall, our results suggest that melatonin can reverse the loss of stemness caused by inflammatory factor TNF-α in BMMSCs. Our results also provide a practical strategy for the application of BMMSCs in tissue engineering and cell therapy.

Background: Gallbladder neuroendocrine carcinoma (GB-NEC) is rare and there are few reports at present. We sought to review the current knowledge of GB-NEC and provide recommendations for clinical management. Methods: A systemic literature research was conducted in the websites of Pubmed, Medline, Web of Science, CNKI, Wanfang Data using the keywords including gallbladder combined with neuroendocrine carcinoma or neuroendocrine tumor or neuroendocrine neoplasm. Two reviewers independently screened the articles by reading the title, abstract and full-text. Results: In computed tomography (CT) and magnetic resonance imaging (MRI) examination, a well-defined margin, gallbladder replacing type with larger hepatic and lymphatic metastases could be helpful for differential diagnosis of GB-NEC and gallbladder adenocarcinoma (GB-ADC). Older age, unmarried status, large tumor size (>5 cm), positive margins, and distant Surveillance, Epidemiology and End result (SEER) stage are independently associated with poor survival. Surgical resection remains as the preferred and primary treatment. The potential survival benefit of lymphadenectomy for patients remains controversial. Platinum-based postoperative adjuvant chemotherapy may improve the survival. The efficacy of other treatments including immunotherapy, targeted therapy and somatostatin analogue needs further investigation. Conclusion: Typical imaging features could be helpful for preoperative diagnosis. Age, margin status, tumor size, marital status, histopathologic subtype and SEER stage may be independent predictors for the survival. Remarkable advances regarding the treatment for GB-NEC have been achieved in recent years. Further studies are needed to investigate the survival benefit of lymphadenectomy for patients with GB-NEC.

The high-quality reutilization of recycled concrete aggregate, particularly the valorization of recycled fine aggregate (RFA) that exhibits inherent defects, is of great importance to mitigate environmental concerns associated with aggregate depletion and waste concrete disposition. In this study, RFA and industrial wastes were successfully used to develop high performance green lightweight engineered cementitious composites (HPGLW-ECC) through proper tailoring of the components. The designed eco-friendly material exhibiting a density of 1733 kg/m3, tensile strength up to 6.42 MPa and tensile strain capacity to 7.46% features impressive mechanical properties. It is remarked that the incorporation of 0–1 mm RFA contributes to the continuous grading of HPGLW-ECC and minimizes the gaps between the particles, which improves the overall compactness of the material. The high roughness of RFA favors the interlocking effect between fiber and matrix and contributes to the development of fiber bridging capacity. Moreover, the self-cementing of RFA further densifies the microstructure of HPGLW-ECC. The enhancement effects of 0–1 mm RFA on the mechanical performance of HPGLW-ECC were characterized by the refinement of microstructural pores as well as by the failure morphology features of fiber and matrix.

Neuroblastoma (NB) is the most common malignant solid tumor in the peripheral nervous system in infants and young children, with a high degree of malignancy. The clinical characteristics and prognosis of NB in infants are unique. The present study retrospectively analyzed the prognosis of infant NB cases that underwent different treatments. In total, 16 infant NB cases (10 male and 6 female) who were treated between February 2007 and August 2013 in Beijing Tongren Hospital (Beijing, China), were enrolled in the study. They were diagnosed by pathology, medical imaging and serology methods. These 16 patients were subjected to comprehensive treatment, including chemotherapy, surgery, autologous peripheral blood stem cell transplantation (APBSCT) and radiation therapy. The age distribution and clinical stages were: 5 cases (31.25%) at ≤3 months (4 cases at stage 4s and 1 case at stage 4); 2 cases (12.5%) at 3-6 months (both at stage 4s); and 9 cases (56.25%) at 6-12 months (2 cases at stage 4s, 6 cases at stage 4 and 1 case at stage 3). Subsequent to treatment, nicotinic acid esterase (NSE) levels in the patient's serum significantly decreased. The NSE levels in 12 cases (75%) dropped to the reference value (0-15.2 ng/dl). All the NB infants at stages 4s and 3 were treated by surgery and chemotherapy (100%; 9/9). The 5 NB infants at stage 4 were treated by chemotherapy and surgery. For the 2 NB infants who experienced recurrence or whose condition was partially relieved after conventional therapy, APBSCT therapy was applied. At the last follow-up in September 2014, 13 cases (81.25%) presented with a complete response, 2 cases (12.50%) with a partial response and 1 case (6.25%) with recurrence after transplantation (progressive disease). In conclusion, infant NB cases are sensitive to chemotherapy, particularly the cases at stage 4s, which occur with a higher incidence, but with a better clinical response and prognosis after treatment.

Hepatoblastoma is a malignant liver tumor generally diagnosed in infants and children

Abnormalities of membranous and endochondral ossification in patients with adolescent idiopathic scoliosis (AIS) remain incompletely understood. To investigate abnormalities in the melatonin signaling pathway and cellular response to melatonin in AIS, a case‑control study of osteogenic and chondrogenic differentiation was performed using human mesenchymal stem cells (hMSCs). AIS was diagnosed by physical and radiographic examination. hMSCs were isolated from the bone marrow of patients with AIS and control subjects (n=12 each), and purified by density gradient centrifugation. The expression levels of melatonin receptors (MTs) 1 and 2 were detected by western blotting. Osteogenic and chondrogenic differentiation was induced by culturing hMSCs in osteogenic and chondrogenic media containing vehicle or 50 nM melatonin. Alkaline phosphatase (ALP) activity assays, quantitative glycosaminoglycan (GAG) analysis, and reverse transcription‑quantitative polymerase chain reaction analysis were performed. Compared with controls, MT2 demonstrated low expression in the AIS group. Melatonin increased ALP activity, GAG synthesis and upregulated the expression of genes involved in osteogenic and chondrogenic differentiation including, ALP, osteopontin, osteocalcin, runt-related transcription factor 2, collagen type II, collagen type X, aggrecan and sex‑determining region Y-box 9 in the normal control hMSCs, but did not affect the AIS groups. Thus, AIS hMSCs exhibit abnormal cellular responses to melatonin during osteogenic and chondrogenic differentiation, which may be associated with abnormal membranous and endochondral ossification, and skeletal growth. These results indicate a potential modulating role of melatonin via the MT2 receptor on abnormal osteogenic and chondrogenic differentiaation in patients with AIS.

Hypoxia and a marked increase in inflammatory cytokines are common hallmarks of intervertebral disc degeneration; these events disrupt the normal balance between extracellular matrix (ECM) degradation and synthesis in degenerative intervertebral discs. SIRT1, one of the NAD+-dependent class III histone deacetylases, controls cellular processes and is regulated by hypoxia and inflammatory cytokines in a cell-type-dependent manner. SIRT1 protects degenerative human nucleus pulposus cells against apoptosis. However, the role of SIRT1 in inflammation in intervertebral discs is still unclear. The current study showed that in rat NP cells, as in other cells, SIRT1 suppressed the induction of the mRNA expression of proteases that degrade ECM induced by TNF-α. Moreover, real-time PCR, transfection, and loss- and gain-of-function experiments revealed that SIRT1 mRNA and protein expression were refractory to hypoxia and HIF-1α. Additionally, SIRT1 mRNA and protein expression and the activity of the SIRT1 promoter were not affected by inflammatory cytokines but were sustained by NF-κB signaling in the presence or absence of TNF-α. In summary, the present study suggested that SIRT1 is not affected by hypoxia and inflammatory cytokines in rat intervertebral discs. Moreover, not HIF-1α but NF-κB signaling is critical for the maintenance of SIRT1 expression in NP cells under physiologic and pathophysiologic conditions.

Overexpression of lysyl oxidase (LOX) is often observed in estrogen receptor negative (ER-) breast cancer patients with bone metastasis. In the present bioinformatics study, we observed that LOX is a prognostic factor for poor progression free survival in patients with ER- breast cancer. LOX overexpression was positively correlated with resistance to radiation, doxorubin and mitoxantrone, but negatively correlated with resistance to bisphosphonate, PARP1 inhibitors, cisplatin, trabectedin and gemcitabine. LOX overexpression was also associated with EMT and stemness of cancer cells, which leads to chemotherapeutic resistance and poor outcome in ER- patients. Although we suggest several therapeutic interventions that may help in the management of LOX+ ER- breast cancer patients, experiments to validate the function of LOX in ER- breast cancer are still needed.

Hydroquinone (HQ), one of the main metabolites of benzene, is a well-known human leukemogen. However, the specific mechanism of how benzene or HQ contributes to the development of leukemia is unknown. In a previous study, we demonstrated the upregulation of DNA methyltransferase (DNMT) expression in HQ-induced malignant transformed TK6 (HQ-TK6) cells. Here, we investigated whether a regulatory loop between the long noncoding RNA FAS-AS1 and DNMT3b exists in HQ-TK6 cells and benzene-exposed workers. We found that the expression of FAS-AS1 was downregulated in HQ-TK6 cells and workers exposed to benzene longer than 1.5 years via histone acetylation, and FAS-AS1 expression was negatively correlated with the time of benzene exposure. Restoration of FAS-AS1 in HQ-TK6 cells promoted apoptosis and inhibited tumorigenicity in female nude mice. Interestingly, treatment with a DNMT inhibitor (5-aza-2-deoxycytidine), histone deacetylase inhibitor (trichostatin A), or DNMT3b knockout led to increased FAS-AS1 through increased H3K27ac protein expression in HQ-TK6 cells, and DNMT3b knockout decreased H3K27ac and DNMT3b enrichment to the FAS-AS1 promoter region, which suggested that DNMT3b and/or histone acetylation involve FAS-AS1 expression. Importantly, restoration of FAS-AS1 resulted in reduced expression of DNMT3b and SIRT1 and increased expression of FAS in both HQ-TK6 cells and xenograft tissues. Moreover, the average DNMT3b expression in 17 paired workers exposed to benzene within 1.5 years was decreased, but that of the remaining 103 paired workers with longer exposure times was increased. Conversely, DNMT3b was negatively correlated with FAS-AS1 expression. Both FAS-AS1 and DNMT3b influenced the enrichment of H3K27ac in the FAS promoter region by regulating the expression of SIRT1, consequently upregulating FAS expression. Taken together, these observations demonstrate crosstalk between FAS-AS1 and DNMT3b via a mutual inhibition loop and indicate a new mechanism by which FAS-AS1 regulates the expression of FAS in benzene-related carcinogenesis.

Long non-coding RNAs (lncRNAs) usually refer to non-coding RNA transcripts >200 nucleotides in length. In terms of the full genomic transcript, the proportion of lncRNAs far exceeds that of coding RNA. Initially, lncRNAs were considered to be the transcriptional noise of genes, but it has since been demonstrated that lncRNAs serve an important role in the regulation of cellular activities through interaction with DNA, RNA and protein. Numerous studies have demonstrated that various intricate signaling pathways are closely related to lncRNAs. Here, we focus on a large number of studies regarding the interaction of lncRNAs with important signaling pathways. It is comprehensively illustrated that lncRNAs regulate key metabolic components and regulatory factors of signaling pathways to affect the biological activities of tumor cells. Evidence suggests that the abnormal expression or mutation of lncRNAs in human tumor cells, and their interaction with signaling pathways, may provide a basis and potential target for the diagnosis and treatment of human cancers.

INTRODUCTION: Vertebroplasty (VP) is a well-known and effective therapeutic method for relieving the pain and improving the quality of life of patients with vertebral compression fractures. Major complications of VP are infrequent, occurring in no more than 1% of such procedures, whereas spinal subdural and epidural hematomas are extremely rare complications. CASE PRESENTATION: We present a unique case of a spinal subdural hematoma (sSDH) (from T4 to T12) occurring immediately after VP to treat a traumatic vertebral compression fracture, followed by a spinal epidural hematoma (SEH) (from T3 to T12) after the decompressive laminectomy, occurring in a 64-year-old patient. After removing of the big spinal epidural hematoma, the patient’s symptoms improved progressively and she recovered after 2 months. DISCUSSION: This is a rare case of sSDH and SEH occurring continuously after VP. The pathogenesis may be that the puncture damaged the abnormal blood vessel of spinal dura mater. A small-probability event is not an impossible event. We hope to bring more attention to the rare complications of VP by sharing this unusual case.

Adolescent idiopathic scoliosis (AIS) is the most common type of spinal deformity and has a significant genetic background. Genome-wide association studies (GWASs) identified several susceptibility loci associated with AIS. Among them is a locus on chromosome 6q24.1 that we identified by a GWAS in a Japanese cohort. The locus is represented by rs6570507 located within GPR126. To ensure the association of rs6570507 with AIS, we conducted a meta-analysis using eight cohorts from East Asia, Northern Europe and USA. The analysis included a total of 6,873 cases and 38,916 controls and yielded significant association (combined P = 2.95 × 10−20; odds ratio = 1.22), providing convincing evidence of the worldwide association between rs6570507 and AIS susceptibility. In silico analyses strongly suggested that GPR126 is a susceptibility gene at this locus.

Docetaxel is an effective and commonly used chemotherapeutic drug for cancer. Autophagy has been reported to be involved in the anticancer mechanism of docetaxel. However, the effect of docetaxel on lysosomal function remains elusive. In the present study, we first found that docetaxel treatment enhances autophagic flux in different cancer cells. Moreover, docetaxel treatment activates lysosomal function and promotes its fusion with autophagosome. Second, doctaxel treatment activates TFEB (transcription factor EB), a key nuclear transcription factor in control of lysosome biogenesis and function. We found that docetaxel promotes TFEB nuclear translocation and increases its transcriptional activity while knockdown of TFEB impairs lysosomal activation by docetaxel. Thirdly, TFEB activation by docetaxel is mediated by ROS (reactive oxygen species) generation and scavenging of ROS suppresses TFEB activity and lysosomal function in docetaxel-treated cells. Finally, inhibition of lysosomal function leads to increased docetaxel-induced cell death, suggesting that lysosomal activation protects against docetaxel-mediated apoptosis. Taken together, our results provide novel insights into the regulatory mechanisms of docetaxel on lysosomes, which could facilitate the development of novel potential cancer therapeutic agents via lysosomal inhibition.

To investigate the cardiotoxicity indexes in children with malignant tumors after the administration of anthracycline (ANT) chemotherapy.Data from 131 children with malignant tumors who were treated using ANT chemotherapy at our hospital from January 2011 to December 2015 were collected to analyze the serologic indexes (such as N-terminal pro-brain natriuretic peptide [NT-proBNP] and isoenzyme of creatine kinase [CK-MB]) and changes in corrected QT interval(QT-c) and left ventricular ejection fraction (LVEF) before and after treatment with different ANT cumulative doses.General clinical data revealed that 2 of the 131 children developed clinical cardiotoxicity. The ANT cumulative dose range was 12-697 mg/mNT-proBNP showed significant changes when the ANT dose was200 mg/m

Infection is a fatal complication in cancer patients that sometimes is not distinguished from tumour progression. We compared the diagnostic value of procalcitonin (PCT), C-reactive protein (CRP) and lactate dehydrogenase (LDH) in paediatric malignant solid tumour concurrent with infection and tumour progression. The 152 children enrolled were divided into infection and control groups. Each group was divided further into stable and progression groups. An intergroup comparison was made in terms of serum PCT, CRP and LDH in all children. PCT, CRP and LDH levels were significantly higher in the infection than in the control groups (P P r = 0.684; CRP, r = 0.570; PCT, r = 0.322). Thus, PCT has the highest value in diagnosing infection and is less susceptible to tumour progression than CRP. LDH has obvious advantages in judging tumour progression.

Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with the prevalence of approximately 3%. We previously conducted a genome-wide association study (GWAS) using a Japanese cohort and identified a novel locus on chromosome 9p22.2. However, a replication study using multi-population cohorts has not been conducted. To confirm the association of 9p22.2 locus with AIS in multi-ethnic populations, we conducted international meta-analysis using eight cohorts. In total, we analyzed 8,756 cases and 27,822 controls. The analysis showed a convincing evidence of association between rs3904778 and AIS. Seven out of eight cohorts had significant P value, and remaining one cohort also had the same trend as the seven. The combined P was 3.28 × 10−18 (odds ratio = 1.19, 95% confidence interval = 1.14–1.24). In silico analyses suggested that BNC2 is the AIS susceptibility gene in this locus.

Hepatocellular carcinoma (HCC) has the second highest mortality rate worldwide among all cancers. Previous studies have revealed the significant involvement of long noncoding RNAs (lncRNAs) in numerous human cancers including HCC. Both oncogenic and tumor repressive lncRNAs have been identified and implicated in the complex process of hepatocarcinogenesis. They can be further explored as prospective diagnostic, prognostic, and therapeutic markers for HCC. An in-depth understanding of lncRNAs’ mechanism in HCC is therefore required to fully explore their potential role. In the current review, we will concentrate on the underlying function, molecular mechanisms, and potential clinical implications of lncRNA in HCC.

MicroRNAs (miRNAs) have been recognized as key regulators of tumorigenesis and progression. Serum miR-302c-3p expression is prominently deregulated in HCV-related hepatocellular carcinoma (HCC). However, the expression of miR-302c-3p and its functional role in HBV-related HCC are rarely investigated. In this study, we found that the expression levels of miR-302c-3p were prominently down-regulated in HCC tissues compared to matched tumor-adjacent tissues. Moreover, miR-302c-3p under-expression was detected in HCC cell lines compared to a normal hepatic cell line LO2. Low miR-302c-3p expression was positively correlated with multiple tumor nodes, venous infiltration and advanced TNM tumor stage of HCC patients. Notably, our follow up data and TCGA data demonstrated that low miR-302c-3p expression predicted a poor survival of HCC patients. Functionally, miR-302c-3p overexpression inhibited migration and invasion of MHCC97H cells in vitro. Additionally, miR-302c-3p knockdown showed an opposite effect on these metastatic behaviors of HepG2 cells. MiR-302c-3p negatively regulated tumor necrosis factor receptor associated factor 4 (TRAF4) abundance by directly targeting 3'-UTR of TRAF4 mRNA. The expression of TRAF4 was up-regulated in HCC tissues. The level of TRAF4 mRNA was inversely correlated with miR-302c-3p expression in HCC specimens. Mechanistically, miR-302c-3p restrained AKT-mediated epithelial-mesenchymal transition (EMT) in HCC cells. Importantly, TRAF4 restoration reversed the inhibitory effect of miR-302c-3p on AKT-induced EMT and HCC cell metastasis. MK2206, an AKT inhibitor, inhibited miR-302c-3p knockdown-induced EMT in HepG2 cells. In summary, these results indicate that miR-302c-3p exhibits a tumor suppressive role in HCC by targeting TRAF4. Inhibition of miR-302c-3p/TRAF4 axis may serve as a therapeutic target for HCC.

Hepatocellular carcinoma (HCC) is a global health problem and one of the most common malignant tumors. Recent studies have shown that noncoding RNAs (ncRNAs) contribute to the pathogenesis of hepatocellular carcinoma (HCC). These RNAs may be involved in a variety of pathological processes such as cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. In addition, abnormal expression of ncRNAs in HCC may provide potential prognostic or diagnostic biomarkers. This review provides an overview of the role and potential applications of ncRNAs, miRNAs, lncRNAs, circRNAs, and snoRNAs in liver cancer.

Table S1. AJCC TNM Staging System. (DOCX 18 kb)

Proteoglycan degradation contributing to the pathogenesis of intervertebral disc (IVD) degeneration is induced by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Cell autophagy exists in degenerative diseases, including osteoarthritis and inter-vertebral disc degeneration. However, the autophagy induced by TNF-α and IL-1β and the corresponding molecular mechanism appear to be cell-type dependent. The effect and mechanism of autophagy regulated by TNF-α and IL-1β in IVDs remains unclear. Additionally, the impact of autophagy on the catabolic effect in inflammatory conditions also remains elusive. In the present study, autophagy activator and inhibitor were used to demonstrate the impact of autophagy on the catabolic effect induced by TNF-α. A critical role of autophagy was identified in rat nucleus pulposus (NP) cells: Inhibition of autophagy suppresses, while activation of autophagy enhances, the catabolic effect of cytokines. Subsequently, the autophagy-related gene expression in rat NP cells following TNF-α and IL-1β treatment was observed using immunofluorescence, quantitative polymerase chain reaction and western blot analysis; however, no association was present. In addition, nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases and p38 mitogen-activated protein kinase inhibitors and TNF-α were used to determine the molecular mechanism of autophagy during the inflammatory conditions, and only the NF-κB and JNK inhibitor were found to enhance the autophagy of rat NP cells. Finally, IKKβ knockdown was used to further confirm the effect of the NF-κB signal on human NP cells autophagy, and the data showed that IKKβ knockdown upregulated the autophagy of NP cells during inflammatory conditions.

The additional mutational complexity associated with copy number variation (CNV) can provide important clues as to the underlying mechanisms of CNV formation. Correct annotation of the additional mutational complexity is, however, a prerequisite for establishing the mutational mechanism. We illustrate this point through the characterization of a novel ∼230 kb EXT1 duplication CNV causing autosomal dominant hereditary multiple osteochondromas. Whole-genome sequencing initially identified the CNV as having a 22-bp insertion at the breakpoint junction and, unprecedentedly, multiple breakpoint-flanking micromutations on both sides of the duplication. Further investigation revealed that this genomic rearrangement had a duplication-inverted triplication-duplication structure, the inverted triplication being a 41-bp sequence synthesized from a nearby template. This permitted the identification of the sequence determinants of both the initiation (an inverted Alu repeat) and termination (a triplex-forming sequence) of break-induced replication and suggested a possible model for the repair of replication-associated double-strand breaks.

The success of treating a wide variety of pediatric diseases with HSCT, hematologic malignancies in particular, has resulted in an increased number of long-term survivors. This study is the first large-scale, multicentre report that describes the evolution of pediatric HSCTs in China during the period of 1998-2012. Of all 1052 patients, 266 cases were treated with autologous HSCs and 786 used allogeneic HSCs. The disease indications for HSCTs mainly included leukemias, lymphoma, solid tumors, and non-malignant disorders. The total number of HSCTs, especially unrelated donor transplants, appeared to be increasing year by year. For patients with neuroblastoma, the therapeutic efficacy seemed to be poor, with a five-yr OS and DFS rate of 34.5 ± 14.3% and 20.7 ± 9.6%, respectively. In contrast, the survival of patients with SAA was prominently improved, and their five-yr OS and DFS rates were 82.8 ± 4% and 80.7 ± 4.1%, respectively. Patients who received cord blood transplants had a lower incidence of acute GVHD than that of PB and/or BM transplants from unrelated donors. This report offers us a valuable resource for evaluating the changes in HSCTs in China over the past 14 yr.

Purpose: This study was implemented to investigate the associations between SNP in mature microRNA (miRNA) sequence and lung cancer prognosis and to verify the function of those SNP. Experimental Design: Eight SNPs (rs3746444T>C in hsa-mir-499, rs4919510C>G in hsa-mir-608, rs13299349G>A in hsa-mir-3152, rs12220909G>C in hsa-mir-4293, rs2168518G>A in hsa-mir-4513, rs8078913T>C in hsa-mir-4520a, rs11237828T>C in hsa-mir-5579, and rs9295535T>C in hsa-mir-5689) were analyzed in a southern Chinese population with 576 patients with lung cancer, and the significant results were validated in two additional cohorts of 346 and 368 patients, respectively. A series of experiments were performed to evaluate the relevancies of those potentially functional SNPs. Results: We found that the microRNA-499 rs3746444T>C polymorphism exhibited a consistently poor prognosis for patients with lung cancer in the discovery set [HR, 1.24; 95% confidence interval (CI), 1.02–1.49; P = 0.028], in the validation set I (HR, 1.31; 95% CI, 1.01–1.71; P = 0.048) and in the validation set II (HR, 1.45; 95% CI, 1.12–1.86; P = 0.004). The adverse effect of CT/CC variants was more remarkable in patients receiving platinum-based chemotherapy. Further functional assays demonstrated that the rs3746444C variant allele influences the expression of several cancer-related genes and affects lung cancer cells' proliferation and tumor growth in vivo and in vitro via the cisplatinum resistance. Conclusion: Our findings suggested that the rs3746444T>C polymorphism in mature miR-499 sequence could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy, which may be a useful biomarker to predict lung cancer patients' prognosis. Clin Cancer Res; 21(7); 1602–13. ©2015 AACR.

Recent studies have recognized the genetic variants in the WW domain-containing oxidoreductase (WWOX) gene as genetic determinants of lung function, reflecting that the WWOX gene may be a susceptible factor of chronic obstructive pulmonary disease (COPD), which characters as poor lung function. We have previously showed that the copy number variation-67048 (CNV-67048) of WWOX was associated with lung cancer risk. Here, we hypothesized that the CNV-67048 affects COPD susceptibility. Based on a two-stage case-control study with a total of 1791 COPD patients and 1940 controls of southern and eastern Chinese, we found that the loss genotypes (0-copy and 1-copy) of CNV-67048 harbored a significantly increased risk of COPD, with an odds ratio (OR) as 1.29 (1.11-1.49) when compared with the common 2-copy genotype. The pre-forced expiratory volume in one second (pre-FEV1) to pre-forced vital capacity (pre-FVC) of carriers with loss genotypes (0.729 ± 0.130) was significantly lower than carriers with 2-copy genotype (0.747 ± 0.124; p = 7.93 × 10(-5)). However, no significant difference was observed on pre-FEV1, pre-FVC and the annual decline of pre-FEV1 between the loss genotypes and 2-copy genotype carriers. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to COPD, which might be a genetic biomarker to predict risk of COPD in Chinese.

The prognostic significance of microRNA (miR)-210 and the caspase 8-associated protein 2 (CASP8AP2) gene in children with acute lymphoblastic leukemia (ALL) has been validated and CASP8AP2 has been demonstrated as a target of miR-210. In the present study, the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine miR-210 and CASP8AP2 expression in 91 children with ALL. Associations between gene expression levels and the prognostic value of combined detection of the two indicators were analyzed. Results from a receiver operating characteristic curve demonstrated that threshold values of miR-210 and CASP8AP2 were 3.8243 and 0.4760, respectively. Although the expression of miR-210 and CASP8AP2 were not associated at the mRNA level in pediatric ALL, combined detection of the two predicted ALL prognosis with an increased accuracy. Furthermore, an equation was devised including minimal residual disease at day 33 and expression of miR-210 and CASP8AP2, which may enable bone marrow relapse to be predicted more precisely compared with the current risk stratification.

Describing the morphologic features of the thoracic pedicle in patients with adolescent idiopathic scoliosis is necessary for placement of pedicle screws. Previous studies showed inadequate reliability owing to small sample size and heterogeneity of the patients surveyed. To use CT scans (1) to describe the morphologic features of 2718 thoracic pedicles from 60 female patients with Lenke Type 1 adolescent idiopathic scoliosis and 60 age-, sex-, and height-matched controls; and (2) to classify the pedicles in three types based on pedicle width and analyze the distribution of each type. A total of 2718 pedicles from 60 female patients with Lenke Type 1 adolescent idiopathic scoliosis and 60 matched female controls were analyzed via CT. All patients surveyed were diagnosed with adolescent idiopathic scoliosis, Lenke Type 1, at the First Affiliated Hospital of Sun Yat-sen University, and all underwent pedicle screw fixation between January 2008 and December 2013 with preoperative radiographs and CT images on file. We routinely obtained CT scans before these procedures; all patients who underwent surgery during that period had CT scans, and all were available for analysis here. Control subjects had CT scans for other clinical indications and had no abnormal findings of the spine. The control subjects were chosen to match patients in terms of age (15 ± 2.6 years versus 15 ± 2.6 years) and sex. Height of the two groups also was matched (154 ± 9 cm versus 155 ± 10 cm; mean difference, −1.06 cm; 95% CI, −1.24 to −0.81 cm; p < 0.001). Pedicle width and length were measured from T1 to T12. The thoracic spine was classified in four regions: apical vertebra in the structural curve (AV-SC), nonapical vertebra in the structural curve (NAV-SC), apical vertebra in the nonstructural curve (AV-NSC), and nonapical vertebra in the nonstructural curve (NAV-NSC). Pedicles were classified in three types: pedicle width less than 2 mm as Type I, 2 mm to 4 mm as Type II, and greater than 4 mm as Type III. Types I and II were defined as dysplastic pedicles. Paired t test, independent samples t test, one-way ANOVA, followed by Bonferroni’s post hoc test and chi-square or Fisher’s exact tests were used for statistical comparisons between patients and controls, as appropriate. No difference was found between pedicle width on the convex side (PWv) and in controls (PWn), but pedicle width on the concave side (PWc) (4.99 ± 1.87 mm) was found to be narrower than PWv (6 ± 1.66 mm) and PWn (6 ± 1.45 mm). The variation degree of pedicle width (VDPW) was greatest in the AV-SC region (34% ± 37%), in comparison to AV-NSC (20% ± 25%) (mean difference, 14%; 95% CI, 1.15%–27%; p = 0.025), NAV-SC (17% ± 30%) (mean difference, 17%; 95% CI, 7%–27%; p < 0.001), and NAV-NSC (11% ± 24%) (mean difference, 24%; 95% CI, 13%–34%; p < 0.001). Dysplastic pedicles appeared more in patients with adolescent idiopathic scoliosis (22%; 293 of 1322) compared with controls (13%; 178 of 1396) (odds ratio [OR] = 0.51; 95% CI, 0.42–0.63; p < 0.001). In patients with adolescent idiopathic scoliosis, they commonly occurred on the concave side 34% (228 of 661) and on the AV-SC region (32%; 43 of 136). Pedicle width on the concave side was narrower than pedicle width on the convex side and pedicle width in healthy control subjects. The apical vertebra in the structural curve was the most variegated region of the curve with the highest prevalence of dysplastic pedicles. Our study can help surgeons perform preoperative assessments in females with adolescent idiopathic scoliosis, and with preoperative and intraoperative management for difficult pedicle screw placement. In particular, our results suggest that surgeons should exercise increased vigilance when selecting pedicle screw dimensions, especially in the concave aspect of the mid-thoracic curve, to avoid cortical breeches. Future studies should evaluate other Lenke types of adolescent idiopathic scoliosis, and males with adolescent idiopathic scoliosis.

Background Spinal osteochondroma is a rare but recognized cause of myelopathy. Brown-Sequard syndrome is a form of severe myelopathy characterized by a clinical picture of hemisection of the spinal cord. Brown-Sequard syndrome caused by osteochondroma is extremely rare, calling for individualized surgical procedures. Case Description We report a 16-year-old girl with hereditary multiple exostoses and a rare case of thoracic osteochondroma causing partial Brown-Sequard syndrome. Customized surgical procedures were designed to avoid iatrogenic spinal cord injury. The patient underwent neural decompression and tumor excision through a transpedicular approach. The surgical procedure consisted of 4 consecutive steps: 1) laminectomy, 2) costotransversectomy and pediculectomy, 3) extracavitary removal of the mass, and 4) pedicular fixation with fusion. Total resection of the tumor was achieved macroscopically without intraoperative spinal cord injury. The postoperative recovery was uneventful, and the patient returned to a normal life without evidence of recurrence at 24-month follow-up. Conclusions For patients with hereditary multiple exostosis and new onset of neurologic symptoms, the possibility of a spinal osteochondroma should be considered. In the situation of an intraspinal exostosis protruding from the lateral side, customized surgical procedures with a transpedicular approach may be a valid way to minimize intraoperative neural injury and achieve a satisfactory outcome.

Scientific Reports 5: Article number: 8087; published online: 28 January 2015; updated: 24 August 2017. In the original version of this Article, an additional affiliation for Ying Shi was omitted. The correct affiliations are listed below: Pancreatic Disease Institute, Union Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430022, China.

Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder characterized by three-dimensional spinal curvatures, affecting 2–3% of school age children, yet the causes underlying AIS are not well understood. Here, we firstly conducted a whole-exome sequencing and linkage analysis on a three-generation Chinese family with autosomal dominant (AD) AIS, then performed targeted sequencing in a discovery cohort comprising 20 AD-AIS families and 86 simplex patients, and finally identified three disease-associated missense variants (c.886G> A, c.1943C> T and c.1760C> T) in the MAPK7 gene (encoding mitogen-activated protein kinase 7). Genotyping of the three rare variants in a Chinese replication cohort comprising 1,038 simplex patients and 1,841 controls showed that their combined allele frequency was significantly over-represented in patients as compared with controls (2.0% (41/2076) vs. 0.7% (27/3,682); odds ratio = 2.7; P = 2.8 × 10−5). In vitro, we demonstrated that the three MAPK7 mutants disrupted nuclear translocation in cellular models, which is necessary for the normal function of MAPK7. In vivo, we also conducted CRISPR/Cas9-mediated deletion of mapk7 in zebrafish recapitulating the characteristic phenotype of idiopathic scoliosis. Taken together, our findings suggest that rare coding variants in MAPK7 predispose to AIS, providing clues to understanding the mechanisms of AIS. This article is protected by copyright. All rights reserved

It is highly possible that copy number variations (CNVs) in susceptible regions have effects on chronic obstructive pulmonary disease (COPD) development, while long noncoding RNA (lncRNAs) have been shown to cause COPD. We hypothesized that the common CNV, named nsv823469 located on 6p22.1, and covering lncRNAs (major histocompatibility complex, class I, A (HLA-A) and HLA complex group 4B (HCG4B)) has an effect on COPD risk. This association was assessed through a two-stage case-control study, and was further confirmed with COPD and pulmonary function-based family analyses, respectively. The copy number loss (0-copy/1-copy) of nsv823469 significantly decreased risk of COPD compared with normal (2-copy) (OR = 0.77, 95% CI = 0.69–0.85). The loss allele, inducing copy number loss of nsv823469, has a tendency to transmit to offspring or siblings (P = 0.010) and is associated with forced expiratory volume in 1 second (FEV1) (P = 0.030). Furthermore, the copy number loss of nsv823469 in normal pulmonary tissue decreases the expression levels of HCG4B (r = 0.315, P = 0.031) and HLA-A (r = 0.296, P = 0.044). Our data demonstrates that nsv823469 plays a role in COPD and pulmonary function inheritance by potentially altering expression of HCG4B.

Recent genome-wide association studies implicated that the nicotinic acetylcholine receptors (nAChRs) are common susceptible genes of two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. We aimed to test whether the copy number variations (CNVs) in nAChRs have hereditary contributions to development of the two diseases. In two, two-stage, case–control studies of southern and eastern Chinese, a common CNV-3956 that duplicates the cholinergic receptor, nicotinic, α7 (CHRNA7) gene was genotyped in a total of 7880 subjects and its biological phenotype was assessed. The ≥4-copy of CNV-3956 increased COPD risk (≥4-copy vs 2/3-copy: OR=1.44, 95% CI=1.23–1.68) and caused poor lung function, and it similarly augmented risk (OR=1.49, 95% CI=1.29–1.73) and worsened prognosis (hazard ratio (HR)=1.25, 95% CI=1.07–1.45) of lung cancer. The ≥4-copy was estimated to account for 1.56% of COPD heritability and 1.87% of lung cancer heritability, respectively. Phenotypic analysis further showed that the ≥4-copy of CNV-3956 improved CHRNA7 expression in vivo and increased the carriers' smoking amount. The CNV-3956 of CHRNA7 contributed to increased risks and poor prognoses of both COPD and lung cancer, and this may be a genetic biomarker of the two diseases.

Epithelial-mesenchymal transition (EMT) plays a key role in the development of chronic obstructive pulmonary disease (COPD) and lung cancer.There are five major EMT regulatory genes (Snai1, Slug, Zeb1, Zeb2, and Twist1) involved in EMT. We hypothesized that germline variants in these genes may influence the development of both diseases.Seven genetic variants were genotyped in two two-stage case-control studies with 2,072 lung cancer cases and 2,077 control subjects, and 1,791 patients with COPD and 1,940 control subjects to show their associations with development of both diseases.An exon variant c.353TC(p.Val118Ala) of Snai1 harbored decreased risks of lung cancer (CT/CC vs. TT: odds ratio [OR], 0.76; 95% confidence interval [CI], 0.65-0.90) and COPD (CC vs. CT vs. TT: OR, 0.75; 95% CI, 0.63-0.89), and c.353TC affected lung cancer risk indirectly through COPD (COPD accounted for 6.78% of effect that the variant had on lung cancer). Moreover, c.353TC was correlated with lung cancer stages in smoking patients (P = 0.013), and those with the c.353C genotypes were less likely to have metastasis at diagnosis than those with the c.353TT genotype (OR, 0.60; 95% CI, 0.41-0.88). The c.353C allele encoding p.118Ala attenuated Snai1's ability to up-regulate mesenchymal biomarkers (i.e., fibronectin and vimentin) expression, and to promote EMT-like changes, including morphologic changes, cell migration, and invasion. However, these effects were not observed for the other variants.The functional germline variant c.353TC (p.Val118Ala) of Snai1 confers consistently decreased risks of lung cancer and COPD, and this variant affects lung cancer risk through a mediation effect of COPD.

Here we investigated the establishment of multicenter cooperative treatment groups in China, as well as radiotherapy compliance and effectiveness among children with renal tumors. Medical records were reviewed for 316 children with renal tumors diagnosed by a multicenter cooperative group from 14 hospitals in China from 1998 to 2012. Median patient age was 29.5 months (range, 2–173 months old), and male-to-female ratio was 1.4 : 1. After a median follow-up of 22 months (range, 1–177 months), five-year event-free survival rates were 72% overall; 76.1% for favorable histology (251 cases); 59% for unfavorable histology (27 cases); and 91%, 75%, 71%, 53%, and 48.5%, respectively for Stages I, II, III, IV, and V. Following standardized criteria, radiation therapy was indicated for 153 patients, among whom five-year event-free survival was 72.8% for the 95 who received radiation and 24% for the 58 patients who did not. Our results are reasonable but can be further improved and show the feasibility of a multicenter cooperative group model for childhood renal tumor treatment in China. Radiation therapy is important for stage III and IV patients but remains difficult to implement in some parts of China. Government management departments and medical professionals must pay attention to this situation. This clinical trial is registered with ChiCTR-PRCH-14004372.

Objective Neuroblastoma (NB) is the most common extracranial solid malignancy in children. Metastatic involvement of brain is rare in NB. This study was established to evaluate the clinical characteristics, treatment and prognosis of NB patients with brain metastases. Patients and methods From September 2005 to December 2016, the clinical data of 15 cases with brain metastases among 264 NB patients admitted to Beijing Tongren Hospital, Capital Medical University were collected and retrospectively analysed. The clinical features of the 15 patients were summarised, and the patients were grouped according to different treatment methods and followed up for a median time of 41 months. The survival curves were plotted, and the Log-rank test was performed to compare the effect of different treatment methods on the prognosis. Results The proportion of brain metastases in NB patients in our hospital is 5.68% (15/264). For the prognosis of 15 NB cases, the survival time of combined radiotherapy and/or autologous peripheral blood stem cell transplantation group was longer than that of simple operation and chemotherapy group (61.79 ± 9.59 vs. 30.00 ± 5.99 months, P = 0.03). Among the 15 patients, 4 cases underwent intracranial tumor resection, 4 cases received craniospinal irradiation, and the rest received maintenance chemotherapy. The 2-year survival rate was 82.2%, and the 5-year survival rate was 19.9%. The survival time of combined intracranial surgery and/or radiotherapy group was significantly longer than that of the chemotherapy group (46.67 ± 6.69 vs. 16.42 ± 1.42 months, P = 0.003). Conclusions The incidence of brain metastases NB in children is relatively small, but the prognosis is very poor. Active chemotherapy, radiotherapy and surgery-based comprehensive treatment can prolong the survival time.

e15077 Background: With the increase of treatment course, acquired resistance of epidermal growth factor receptor (EGFR) blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this acquired resistance; however, the potential function of other genes has not been extensively investigated. Methods: This study included 17 mCRC patients with acquired cetuximab resistance, and mutations in circulating tumor DNA (ctDNA) from plasma samples were identified using target-capture deep sequencing. Analysis of mutational prevalence in ctDNA, three CRC tissue-based datasets and one ctDNA dataset was performed. Mutation predicted with significant effect on acquired resistance was selected and the functional analysis was validated in CRC cells. Results: The prevalence of mutations identified in ctDNA was consistent with CRC tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclonal. Multiply resistance mechanisms of cetuximab were co-existed in individual patient, with one of them even harbored nine distinct mutations. In particularly, function analysis of Krüppel-like factor 4 (KLF4) mutation p.A472D revealed increased cetuximab resistance in CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. Conclusions: The KLF4 mutation p.A472D contributes to acquired cetuximab resistance in patients with mCRC and it may serve as a new biomarker useful in clinical application. Monitoring somatic mutations related to acquired cetuximab resistance in mCRC patients through ctDNA is an appropriate means of providing real-time insights useful for clinical reference and treatment planning.

Intramembranous ossification and endochondral ossification are two ways through which bone formation and fracture healing occur. Accumulating amounts of evidence suggests that melatonin affects osteoblast differentiation, but little is known about the effects of melatonin on the process of chondrogenic differentiation. In this study, the effects of melatonin on human mesenchymal stem cells (MSCs) undergoing chondrogenic differentiation were investigated. Cells were induced along chondrogenic differentiation via high-density micromass culture in chondrogenic medium containing vehicle or 50 nm melatonin. Histological study and quantitative analysis of glycosaminoglycan (GAG) showed induced cartilage tissues to be larger and richer in GAG, collagen type II and collagen type X in the melatonin group than in the untreated controls. Real-time RT-PCR analysis demonstrated that melatonin treatment significantly up-regulated the expression of the genes involved in chondrogenic differentiation, including aggrecan (ACAN), collagen type II (COL2A1), collagen type X (COL10A1), SRY (sex-determining region Y)-box 9 (SOX9), runt-related transcription factor 2 (RUNX2) and the potent inducer of chondrogenic differentiation, bone morphogenetic protein 2 (BMP2). And the expression of melatonin membrane receptors (MT) MT1 and MT2 were detected in the chondrogenic-induced-MSCs by immunofluorescence staining. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to increase the size and GAG synthesis of the induced cartilage tissues, as well as to completely reverse the effect of melatonin on the gene expression of ACAN, COL2A1, COL10A1, SOX9 and BMP2 after 7 days of differentiation. These findings demonstrate that melatonin enhances chondrogenic differentiation of human MSCs at least partially through melatonin receptors.

UNLABELLED Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) is recognized as oncogenic and simulative role on tumorigenesis by virtue of abnormal expression in cancer including nasopharyngeal carcinoma (NPC). We hypothesized that the copy number variation (CNV)-30450, which duplicates the MAPKAPK2 promoter, may affect MAPKAPK2 expression and be associated with NPC risk. In two independent case-control panels of southern and eastern Chinese with a total of 1590 NPC patients and 1979 cancer-free controls, we investigated the association between CNV-30450 and NPC risk by genotyping the CNV-30450 with the TaqMan assay, and tested its biological effect. Consistent findings were observed in the two populations, that the increased copy number of CNV-30450 was associated with increased risk of NPC (3/4-copy versus 2-copy: odds ratio = 1.28, 95% confidence interval = 1.10-1.49), in which lies a biological mechanism that the adverse genotypes enhanced the promoter activity of MAPKAPK2 and elevated MAPKAPK2 expression. Moreover, the CNV-30450 adverse genotypes significantly interacted with Epstein-Barr virus (EBV) infection on increasing NPC risk (P = 0.035), and the genotype-phenotype correlation was only significant in EBV-positive cases (P = 0.037) but not in EBV-negative ones (P = 0.366). These data suggest that the functional CNV-30450 in the MAPKAPK2 promoter elevates the NPC risk with a modulation by EBV infection, which may be an indicator of susceptibility to NPC. SUMMARY This case-control study suggests that the functional CNV-30450 in the MAPKAPK2 promoter elevates the NPC risk with a modulation by EBV infection, which may be an indicator of susceptibility to NPC.

Objective: To explore clinical experience and propose new ideas for treating children diagnosed with orbital rhabdomyosarcoma (RMS). Methods: We retrospectively analyzed the clinical data for30 patients (16 males and 14 females, with a median age of 6.2 years) with primary orbital RMS who were enrolled in the Department of Eye Oncology and Pediatrics of our hospital from November 2004 to December 2012. International Rhabdomyosarcoma Organization Staging Standards indicated that among the 30 patients, 4 cases were in phase II, 20 were in phase III, and 6 were in phase IV. All patients underwent a multidisciplinary collaborative model of comprehensive treatment (surgery, chemotherapy, external radiotherapy, 125 I radioactive particle implantation, and autologous peripheral blood stem-cell transplantation). Results: Follow-up was conducted until March 2013, with a median follow-up time of 47.2 months (5 to 95 months), and 7 deaths occurred. The 2-year estimated survival rate reached 86.1%, the ≥3-year estimated survival rate was 77%, and the 5-year estimated survival rate was 70.6%. Conclusions: The multidisciplinary collaborative model can be a safe and effective approach to the comprehensive treatment of children with orbital RMS. It has clinical significance in improving the tumor remission rate.