The Role of Trait Emotional Intelligence in Quality of Life, Anxiety, and Depressive Symptoms After Radiotherapy in Lung Cancer Patients with Brain Metastases.

Objective: We aimed to investigate the association of trait emotional intelligence (TEI), anxiety, depression, and quality of life (QoL) in lung cancer individuals with brain metastases receiving radiotherapy. Methods: A total of 289 individuals with brain metastases from lung cancer after radiotherapy participated. Data were collected from October 2018 to December 2022. Data were collected on variables such as patient demographics, medical characteristics, TEI, anxiety, depression, and QoL. Pearson correlation analysis and structural equation modeling were used to analyze the data. Results: Correlation coefficients between TEI and anxiety, depression, and QoL scores were -0.451 (P = .007), -0.580 (P = .002), and 0.391 (P = .009). The correlation coefficient for depression and QoL was -0.433 (P = .008). Anxiety and depression mediate the positive correlation between trait EI and QoL. Conclusion: Individuals with high idiosyncrasies of emotional intelligence are able to more effectively regulate negative emotions associated with cancer symptoms and treatment, and thus better perceive QoL. Trait EI training can reduce anxiety and depression symptoms and further improve the QoL of lung cancer individuals.

Analyzing mitochondrial respiration of human induced pluripotent stem cell-derived myeloid progenitors using Seahorse technology.

Mitochondrial metabolism is critical in hematopoietic stem cell maintenance and differentiation. Here, we present a step-by-step protocol to efficiently differentiate human induced pluripotent stem cells into myeloid progenitors by a robust feeder- and serum-free system. Furthermore, we provide a protocol to subsequently assess mitochondrial function in iPSC-derived myeloid progenitors. We comprehensively describe a protocol to analyze and to quantify key parameters of mitochondrial respiration of iPSC-derived myeloid progenitors by the Seahorse XFe96 Analyzer. Additionally, our protocol includes extensive troubleshooting suggestions. For complete details on the use and execution of this protocol, please refer to Fan et al. (2022).1.

HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.

The relevance of molecular mechanisms governing mitochondrial proteostasis to the differentiation and function of hematopoietic and immune cells is largely elusive. Through dissection of the network of proteins related to HCLS1-associated protein X-1, we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB. As shown by stable isotope labeling by amino acids in cell culture (SILAC) proteomics, CLPB and HAX1 control the balance of mitochondrial protein synthesis and persistence crucial for proper mitochondrial function. Impaired mitochondrial protein dynamics are associated with decreased abundance of the serine-threonine kinase PRKD2 and HSP27 phosphorylated on serines 78 and 82. Cellular defects in HAX1-/- cells can be functionally reconstituted by HSP27. Thus, mitochondrial proteostasis emerges as a critical molecular and metabolic mechanism governing the differentiation and function of neutrophil granulocytes.

LncRNA EPB41L4A-AS2 represses Nasopharyngeal Carcinoma Metastasis by binding to YBX1 in the Nucleus and Sponging MiR-107 in the Cytoplasm.

Nasopharyngeal carcinoma (NPC) is known for its potential to progress to the lymph nodes and distant metastases at an early stage. As an important regulator in tumorigenesis biological processes, the functions of lncRNA in NPC tumor development remain largely unclear. In this research, the expression of EPB41L4A-AS2 in NPC tissues and cells was analyzed via real-time quantitative polymerase chain reaction (qRT-PCR). CCK8, colony formation, and EDU experiments were used to determine the viability of NPC cells. Transwell and wound healing assays were performed to test NPC cell migration and invasion. RNA pull-down and mass spectrometry analysis were used to identify potential binding proteins. Then, a popliteal lymph node metastasis model was established to test NPC metastasis. EPB41L4A-AS2 is repressed by transforming growth factor-beta, which is downregulated in NPC cells and tissue. It is associated with the presence of distant metastasis and adverse outcomes. The univariate and multivariate survival assays confirmed that EPB41L4A-AS2 expression was an independent predictor of progression-free survival (PFS) in patients with NPC. Biological analyses showed that overexpression of EPB41L4A-AS2 reduced the metastasis and invasion of NPC in vitro and in vivo, but had no significant effect on cell proliferation. Mechanistically, in the nucleus we identified that EPB41L4A-AS2 relies on binding to YBX1 to reduce the stability of Snail mRNA to enhance the expression of E-cadherin and reverse the progression of epithelial-to-mesenchymal transition (EMT). In the cytoplasm, we found that EPB41L4A-AS2 blocked the invasion and migration of NPC cells by promoting LATS2 expression via sponging miR-107. In a whole, the findings of this study help to further understand the metastasis mechanism of NPC and could help in the prevention and treatment of NPC metastasis.

Circ-ZDHHC5 Accelerates Esophageal Squamous Cell Carcinoma Progression in vitro via miR-217/ZEB1 Axis.

Circular RNA (circRNA) exhibits a covalently closed circular conformation and is structurally stable. Nevertheless, the precise effects exerted by circRNA in esophageal squamous cell carcinoma (ESCC) remains uncertain. circRNA was ascertained by a human circRNA array study and was confirmed by the quantification of reverse transcriptase polymerase reactions. A luciferase reporter, fluorescence in situ hybridization experiment was exploited to explore the interaction between circ-ZDHHC5 and miR-217. The function of circ-ZDHHC5 was determined by siRNA-mediated knockout of circ-ZDHHC5 in in vitro proliferation, migration, and invasion. circ-ZDHHC5, rather than linear ZDHHC5 mRNA, rose in the tissues of patients with ESCC, plasma, and ESCC cell lines in comparison with normal controls. Knockdown of circ-ZDHHC5 inhibited tumorigenesis in ESCC cells, and the co-transfection of si-circ-ZDHHC5 and miR-217 mimics further enhanced the above effect. Noticeably, the present study showed that circ-ZDHHC5 was an miR-217 sponge that modulated the expression of zinc finger E-box binding homeobox 1 (ZEB1), further facilitating ESCC tumorigenesis. As revealed by this study, circ-ZDHHC5 can act as a new potential circular biomarker for detecting ESCC. It provides a novel perceptivity for the treatment of ESCC suggesting that circ-ZDHHC5 could impact on ESCC progression by sponging miR-217 with ZEB1.

Long noncoding RNA PANDA promotes esophageal squamous carcinoma cell progress by dissociating from NF-YA but interact with SAFA.

Esophageal squamous cell carcinoma (ESCC) is one of the major global health problems, especially in Asia. Long non-coding RNAs (lncRNAs) have been increasingly identified and characterized in almost every aspect of biology, especially in cancer biology. This research desires to explore the regulatory mechanism of lncRNA PANDA (PANDA) on ESCC process. Quantitative real-time PCR (qRT-PCR) was carried out to detect the PANDA expression, which was up-regulated in matched cancerous tissues and adjacent noncancerous tissues from 134 patients and 9 ESCC cell lines. Higher expression of PANDA in ESCC tissues was associated with TNM stage, advanced clinical stage, and shorter overall survival of ESCC patients by MTT, EDU, colony formation assay and flow cytometry in KYSE180 and KYSE450 cells. Exogenous down-regulation of PANDA expression significantly suppressed ESCC cells proliferation and colony formation by arresting G1-S checkpoint transition in vitro, and retarded the development of tumors in vivo. Meanwhile, qRT-PCR and western blot assays showed that depletion of PANDA reduced E2F1, cyclinD1, cyclinD2, cyclinE1 and Bcl-2 expression. RIP showed the interaction between PANDA and NF-YA or SAFA. Our findings suggested that, PANDA drifted away from NF-YA to promote the expression of NF-YA-E2F1 co-regulated proliferation-promoting genes, and to limit the cell apoptosis. In addition, PANDA binds SAFA to switch on the tumor proliferation program through CyclinD1/2-Cyclin E1 and Bcl-2 pathways. PANDA could serve as a potential prognostic biomarker and therapeutic target for ESCC.

[Value of virtual reality technology in preoperative planning of transtrochanteric curved varus osteotomy for avascular necrosis of femoral head in adults].

OBJECTIVE: To research the value of virtual reality (VR) technology in the preoperative planning of transtrochanteric curved varus osteotomy for avascular necrosis of the femoral head (ANFH) in adults. METHODS: Between June 2018 and November 2018, 7 patients (11 hips) with ANFH, who were treated with transtrochanteric curved varus osteotomy, were enrolled in the study. There were 4 males (7 hips) and 3 females (4 hips) with an average age of 31.9 years (range, 14-46 years). Among them, 3 patients were unilateral ANFH and 4 patients were bilateral ANFH. There was 1 patient (1 hip) of traumatic ANFH, 2 patients (4 hips) of alcohol-induced ANFH, 2 patients (3 hips) of hormonal ANFH, and 2 patients (3 hips) of idiopathic ANFH. All hips were Association Research Circulation Osseous (ARCO) stage Ⅲ. There were 5 hips for Japanese Investigation Committee (JIC) type C1 and 6 hips for type C2. There were 5 hips for China-Japan Friendship Hospital (CJFH) type L1,1 for type L2, and 5 for type L3. The disease duration ranged from 5 to 12 months (mean, 8 months). Preoperative Harris score was 53.91±7.66. The neck-shaft angle ranged from 128 to 143° (mean, 133.9°). VR technology was adopted for the preoperative planning. CT data were imported into the software to construct the morphology of necrotic area, and the transrtrochanteric varus osteotomy was simulated. The varus angle was designed according to the integrity rate of femoral head. The planned varus angle was 6 to 16° (mean, 9.7°). The transtrochanteric curved varus osteotomy was performed according to the preoperative planning, and the varus angle and loading area were confirmed under fluoroscopy. If the planned varus angle was too small, it would continue to increase under the fluoroscopy until a satisfactory varus angle. Postoperative changes of the neck-shaft angle were calculated and compared with the preoperative planned varus angle (error). The hip function was assessed by using the Harris score. RESULTS: All incisions healed by first intention. All patients were followed up 6-11 months with an average of 8 months. The X-ray film at 2 days after operation showed that the neck-shaft angle was 112-135° (mean, 123.4°). The difference of the neck-shaft angle between pre- and post-operation was 6-16° (mean, 11.0°). Among them, the difference of the neck-shaft angle was consistent with planned varus angle in 5 hips, while the error of the remaining 6 hips was 1-4°. There was 1 patient (1 hip) of osteotomy nonunion at 4 months after operation, 1 patient (1 hip) of proximal femur fracture at 2 months after operation. The rest 5 patients (9 hips) obtained union at the osteotomy. At last follow-up, the Harris score was 82.18±16.35, showing significant difference when compared with preoperative score ( t=-5.195, P=0.000). CONCLUSION: VR technology is a brand-new preoperative planning method for transtrochanteric curved varus osteotomy in treating ANFH.

miRNA­30a­3p inhibits metastasis and enhances radiosensitivity in esophageal carcinoma by targeting insulin­like growth factor 1 receptor.

It has been demonstrated that microRNAs (miRNAs) serve important roles in various biological processes, such as tumorigenesis. In the present study, the role of miR­30a­3p in the pathogenesis of esophageal carcinoma (EC) was investigated. Reverse transcription­quantitative polymerase chain reaction was performed to determine the levels of miR­30a­3p expression in EC tissues and cell lines. Then, the effects of miR­30a­3p on the migration, invasion and radiosensitivity of EC cells were investigated using scratch­wound, Transwell and radiosensitivity assays, respectively. A dual­luciferase reporter assay was performed to determine potential interactions between miR­30a­3p and the 3'­untranslated region (3'­UTR) of insulin­like growth factor 1 receptor (IGF­1R). The results demonstrated that the levels of miR­30a­3p expression in EC tissues and cell lines were significantly decreased compared with those in paired healthy tissues and a human esophageal epithelial cell line. Upregulation of miR­30a­3p expression significantly suppressed migration, invasion and epithelial­mesenchymal transition (EMT), and enhanced radiosensitivity in EC cells. Analysis of luciferase activity demonstrated that miR­30a­3p interacted with the 3'­UTR of IGF­1R, and knockdown of IGF­1R induced similar effects on the migration, invasion, EMT and radiosensitivity of EC cells. The results indicated that miR­30a­3p suppressed metastasis and enhanced the radiosensitivity of EC cells via downregulation IGF­1R, suggesting that miR­30a­3p may be a potential therapeutic target in the treatment of EC.

Correction: HOTAIR regulates HK2 expression by binding endogenous miR-125 and miR-143 in oesophageal squamous cell carcinoma progression.

[This corrects the article DOI: 10.18632/oncotarget.21195.].

Long noncoding RNA UCA1 promotes the proliferation, invasion, and migration of nasopharyngeal carcinoma cells via modulation of miR-145.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common malignant tumor characterized by highly malignant local invasion and distant metastasis. Recently, increasing attention has been paid to long noncoding RNAs (lncRNAs), which play significant roles in tumorigenesis and progression. However, little is known about the potential role of the lncRNA urothelial carcinoma-associated 1 (UCA1) in NPC cell invasion and migration. METHODS: Real-time quantitative PCR was used to analyze the expression of lncRNA UCA1 in NPC cell lines and NP69. lncRNA UCA1 knock-down nasopharyngeal carcinoma cell line models were established through siRNA. Cell viability was evaluated by Cell counting kit-8 and Colony forming assay. The migration and invasion capacities were evaluated by wound healing and transwell migration and invasion assays. Western blot analysis were used to examine protein changes followed by UCA1 knock-down. RESULTS: Our study confirmed that UCA1 was upregulated in NPC cell lines and involved in NPC tumorigenesis according to our established UCA1-associated competing endogenous RNA network. Moreover, functional analyses indicated that the downregulation of UCA1 exerted inhibitory effects on cell proliferation, invasion, and migration. Mechanistic analyses revealed that UCA1 was the target of miR-145 and functioned as a sponge to repress miR-145 expression. Rescue experiments suggested that lncRNA UCA1 reversed the miR-145-mediated inhibition on oncogene ADAM17 expression, thus promoting the proliferation, invasion, and migration of NPC cells. CONCLUSION: LncRNA UCA1 functions as a tumor promoter in NPC. UCA1 promotes the proliferation and invasion of NPC cells by sponging miR-145, functionally altering ADAM17 expression targeted by miR-145. Our exploration of the underlying mechanism of UCA1 in NPC may provide novel therapeutic targets for NPC.

Protective properties of Huperzine A through activation Nrf2/ARE-mediated transcriptional response in X-rays radiation-induced NIH3T3 cells.

Huperzine A (HupA), derived from Huperzia Serrata, has exhibited a variety of biological actions, in particular neuroprotective effect. However, the protective activities of HupA on murine embryonic fibroblast NIH3T3 cells after X-rays radiation have not been fully elucidated. Herein, HupA treatment dramatically promoted cell viability, abated a G0/G1 peak accumulation, and ameliorated increase of cell apoptosis in NIH3T3 cells after X-rays radiation. Simultaneously, HupA notably enhanced activities of anti-oxidant enzymes, inhibited activity of lipid peroxide, and efficiently eliminated production of reactive oxygen species in NIH3T3 cells after X-rays radiation. Dose-dependent increase of antioxidant genes by HupA were associated with up-regulated Nrf2 and down-regulated Keap-1 expression, which was confirmed by increasing nuclear accumulation, and inhibiting of degradation of Nrf2. Notably, augmented luciferase activity of ARE may explained Nrf2/ARE-mediated signaling pathways behind HupA protective properties. Moreover, expression of Nrf2 HupA-mediated was significant attenuated by AKT inhibitor (LY294002), p38 MAPK inhibitor (SB202190) and ERK inhibitor (PD98059). Besides, HupA-mediated cell viability, and ROS production were dramatically bated by LY294002, SB202190, and PD98059. Taken together, HupA effectively ameliorated X-rays radiation-induced damage Nrf2-ARE-mediated transcriptional response via activation AKT, p38, and ERK signaling in NIH3T3 cells.

MicroRNA-125b inhibits cell proliferation and induces cell apoptosis in esophageal squamous cell carcinoma by targeting BMF.

MicroRNAs (miRNAs) have been reported to regulate the expression of genes by suppressing translation or facilitating mRNA decay. Their expression regulates a wide variety of cellular processes, including the development and progression of cancer. Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with high morbidity and recurrence in Asia. In the present study, the biological function of miR-125b and its underlying mechanism in ESCC were explored. The results revealed that miR-125b expression was significantly decreased in ESCC tissues and cell lines. A decrease in miR-125b was markedly related to lymphatic metastasis in patients. Functional analysis revealed that the overexpression of miR-125b using miR-125b mimics significantly inhibited cell growth and induced cell apoptosis, and increased the G1 phase of the cell cycle in EC109 and EC9706 cells. Notably, the miR-125b inhibitors revealed the opposite effect. Additionally, overexpression of miR-125b significantly inhibited tumor growth in vivo. Furthermore, BCL-2-modifying factor (BMF) was considered to be a potential candidate target of miR-125b based on miRNA target databases. miR-125b negatively regulated BMF expression by directly binding to its 3'-untranslated region. BMF was a functional target of miR-125b in the regulation of cell proliferation, cell apoptosis and the cell cycle in EC109 and EC9706 cells. In clinical ESCC specimens, BMF expression was upregulated, and negatively correlated with that of miR-125b. In conclusion, miR-125b had an antitumor role in ESCC cells mediated by targeting BMF, which can be potentially useful for tumorigenesis in ESCC.

Correction: HOTAIR regulates HK2 expression by binding endogenous miR-125 and miR-143 in oesophageal squamous cell carcinoma progression.

[This corrects the article DOI: 10.18632/oncotarget.21195.].

Downregulation of KLK13 promotes the invasiveness and metastasis of oesophageal squamous cell carcinoma.

KLK13 downregulation occurs in tumour tissues in comparison with adjacent normal tissues from patients with oesophageal squamous cell carcinoma (OSCC). KLK13 mRNA levels were tested in OSCC tumour tissues and adjacent noncancerous tissues from 138 patients. In addition, the correlation between KLK13 mRNA levels and OSCC clinicopathologic features was analysed. KLK13 mRNA levels decreased notably in tumour tissues compared with those in adjacent noncancerous tissues. And decreased KLK13 mRNA levels indicated significant correlations with higher tumour grade, elevated TNM (UICC, 2009) stage classification, deeper infiltration and more lymph node metastases. And thus KLK13 may be a promising diagnostic marker. Decreased KLK13 mRNA levels also correlate with poor survival, which indicates that KLK13 mRNA expression may be a potential prognostic marker, although it could not be an independent prognostic factor by multivariate analysis. In vitro experiments of the OSCC cell lines KYSE150 and KYSE450 demonstrated that overexpression of KLK13 inhibits cell invasion and migration. Thus, KLK13 is a unique novel molecule useful for monitoring OSCC progression. Full elucidation of the role of KLK13 in OSCC may reveal avenues for investigating the molecule's functional potential as a novel therapeutic drug for targeting OSCC.

Emerging roles of circular RNA hsa_circ_0000064 in the proliferation and metastasis of lung cancer.

Circular RNAs (circRNAs), a novel class of widespread and diverse endogenous RNAs, can regulate gene expression in mammals. CircRNAs have recently been identified as microRNA sponges and involved in the development of some human diseases. However, the role of circRNAs in the process of tumorigenesis and development of lung cancer remains vague. The purpose of this study is to investigate the role of circRNAs in the lung cancer. In this study, we chose hsa_circ_0000064 as a targeted circRNA to investigate its clinical significances in lung cancer patients. The result indicated that hsa_circ_0000064 was up-regulated in lung cancer tissues and lung cancer cell lines (A549 and H1229). Moreover, its aberrant expression was correlated with several clinical characteristics, including T stage, lymphatic metastasis, and TNM stage. Fluorescence in situ hybridization detected that hsa_circ_0000064 was mostly located in the cytoplasm in A549 and H1229 cells. In addition, knockdown of hsa_circ_0000064 with siRNA dramatically attenuated the proliferation, blocked cell cycle progression, and promoted cell apoptosis. Western blot analysis showed that the protein levels of caspase-3, caspase-9, bax, p21, CDK6 and cyclin D1 significantly restrained by si-hsa_circ_0000064, while the expression of bcl-2 notably increased in A549 and H1229 cells. Further, si-hsa_circ_0000064 also abated migration and invasion activities of A549 and H1229 cells, which may be associated with reduced expressions of MMP-2 and MMP-9. In general, our data suggest that hsa_circ_0000064 represents a novel potential biomarker and therapeutic target of lung cancer.

HOTAIR regulates HK2 expression by binding endogenous miR-125 and miR-143 in oesophageal squamous cell carcinoma progression.

Esophageal Squamous Cell Carcinoma (ESCC) is one of the most common malignant cancers worldwide with a high death rate worldwide. Long non-coding RNA (LncRNA) has been recently demonstrated to play a critical role in ESCC. LncRNA HOTAIR played important regulatory roles in ESCC. We highlight the molecular mechanisms by which HOTAIR could influence the expression of Hexokinase 2 (HK2) in ESCC through binding miR-125 and miR-143 directly. Taken together, this study identified a functional lncRNA HOTAIR involved with regulation of glycolysis via miRNA-125/miRNA-143-HK2 in ESCC cells. The "competitive endogenous RNA" (ceRNA) model of HOTAIR/miR-125 and miR143/HK2 interaction might serve as important targets for ESCC diagnosis and therapy.

Comparing the efficacy of induction-concurrent with concurrent-adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma: a propensity score matching analysis.

PURPOSE: This study aimed to compare the efficacy of induction-concurrent (IC-CCRT) with concurrent-adjuvant (CCRT-AC) chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated by intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Data on 834 patients with newly diagnosed, non-metastatic stage III-IVA (except T3N0) NPC receiving either IC-CCRT or CCRT-AC between July, 2004 and December, 2014 were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes of matched patients between IC-CCRT and CCRT-AC were compared. RESULTS: The median follow-up duration is 45.2 months (range, 1.07-145.4 months). Overall, 309 pairs were selected by PSM. Univariate analysis revealed the CCRT-AC group achieved significantly higher 3-year DFS (83.9% vs. 78.7 %; P = 0.014) and OS (87.6% vs. 87.0%; P = 0.031). Multivariate analysis also identified treatment group (IC-CCRT vs. CCRT-AC) as an independent prognostic factor for 3-year DFS (HR, 1.546; 95% CI, 1.113-2.149; P = 0.009) and OS (HR, 1.487; 95% CI, 1.035-2.136; P = 0.032). Subgroup analysis revealed IC-CCRT was a protective factor for DMFS (HR, 0.145; 95% CI, 0.043-0.488; P = 0.002) in stage III disease; however, it could adversely affected DFS (HR, 2.009; 95% CI, 1.316-3.065; P = 0.001), OS (HR, 1.671; 95% CI, 1.060-2.636; P = 0.027) and DMFS (HR, 1.986; 95% CI, 1.155-3.416; P = 0.013) in stage IVA disease. CONCLUSIONS: CCRT-AC may be a more effective treatment modality in patients with stage IVA NPC disease, while IC-CCRT was superior in stage III disease.

Ten-year survival outcomes for patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: An analysis of 614 patients from a single center.

OBJECTIVES: Intensity-modulated radiotherapy (IMRT) has been applied in nasopharyngeal carcinoma (NPC) for nearly twenty years, while little is known about the ten-year survival outcomes. This study aimed at evaluating the 10-year survival outcomes for patients with NPC receiving IMRT. MATERIALS AND METHODS: Data on 614 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2004 and 2008 were retrospectively reviewed. Survival outcomes stratified by tumor stage were compared. RESULTS: The median follow-up duration was 112.7months (range, 7.6-156.8months) for the entire cohort. The 10-year local relapse-free survival rates for T1, T2 and T3 were 94.2%, 92.5% and 91.4% (P>0.05), respectively, and significantly higher than that of T4 disease (79.3%, P<0.05 for all rates). As N category increased from N0 to N3, the 10-year distant metastasis-free survival rates significantly decreased accordingly (P<0.01 for all rates). Furthermore, the 10-year overall survival rates were 100%, 87.1%, 75.5% and 55.6% for stage I, II, III and IV, respectively (P<0.05 except stage I and II). Multivariate analysis established tumor stage and age as independent prognostic factors. Late toxicities were assessable for 495 (80.6%) patients and most were Grade I/II damages. Xerostomia (387 of 489, 79.1%) and hearing impairment (212 of 495, 42.8%) remained the most troublesome. CONCLUSION: IMRT could achieve satisfactory survival outcomes for NPC patients with acceptable late toxicities. However, distant control still remains poor, especially for patients with N3 disease.

Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes.

We identify SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2), also known as BAF60b (BRG1/Brahma-associated factor 60b), as a critical regulator of myeloid differentiation in humans, mice, and zebrafish. Studying patients from three unrelated pedigrees characterized by neutropenia, specific granule deficiency, myelodysplasia with excess of blast cells, and various developmental aberrations, we identified three homozygous loss-of-function mutations in SMARCD2. Using mice and zebrafish as model systems, we showed that SMARCD2 controls early steps in the differentiation of myeloid-erythroid progenitor cells. In vitro, SMARCD2 interacts with the transcription factor CEBPɛ and controls expression of neutrophil proteins stored in specific granules. Defective expression of SMARCD2 leads to transcriptional and chromatin changes in acute myeloid leukemia (AML) human promyelocytic cells. In summary, SMARCD2 is a key factor controlling myelopoiesis and is a potential tumor suppressor in leukemia.

Autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition.

Mitoribosome in mammalian cells is responsible for synthesis of 13 mtDNA-encoded proteins, which are integral parts of four mitochondrial respiratory chain complexes (I, III, IV and V). ERAL1 is a nuclear-encoded GTPase important for the formation of the 28S small mitoribosomal subunit. Here, we demonstrate that knockdown of ERAL1 by RNA interference inhibits mitochondrial protein synthesis and promotes reactive oxygen species (ROS) generation, leading to autophagic vacuolization in HeLa cells. Cells that lack ERAL1 expression showed a significant conversion of LC3-I to LC3-II and an enhanced accumulation of autophagic vacuoles carrying the LC3 marker, all of which were blocked by the autophagy inhibitor 3-MA as well as by the ROS scavenger NAC. Inhibition of mitochondrial protein synthesis either by ERAL1 siRNA or chloramphenicol (CAP), a specific inhibitor of mitoribosomes, induced autophagy in HTC-116 TP53 (+/+) cells, but not in HTC-116 TP53 (-/-) cells, indicating that tumor protein 53 (TP53) is essential for the autophagy induction. The ROS elevation resulting from mitochondrial protein synthesis inhibition induced TP53 expression at transcriptional levels by enhancing TP53 promoter activity, and increased TP53 protein stability by suppressing TP53 ubiquitination through MAPK14/p38 MAPK-mediated TP53 phosphorylation. Upregulation of TP53 and its downstream target gene DRAM1, but not CDKN1A/p21, was required for the autophagy induction in ERAL1 siRNA or CAP-treated cells. Altogether, these data indicate that autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition.