Targeting cancer stemness mediated by BMI1 and MCL1 for non-small cell lung cancer treatment.

Lung cancer is the leading cause of cancer-associated death, with a global 5-year survival rate <20%. Early metastasis and recurrence remain major challenges for lung cancer treatment. The stemness property of cancer cells has been suggested to play a key role in cancer plasticity, metastasis and drug-resistance, and is a potential target for drug development. In this study, we found that in non-small cell lung cancer (NSCLC), BMI1 and MCL1 play crucial roles of cancer stemness including invasion, chemo-resistance and tumour initiation. JNK signalling serves as a link between oncogenic pathway or genotoxicity to cancer stemness. The activation of JNK, either by mutant EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule, BI-44, was developed, which effectively suppressed BMI1/MCL1 expressions and inhibited tumour formation and progression in preclinical models. Targeting cancer stemness mediated by BMI1/MCL1 with BI-44 provides the basis for a new therapeutic approach in NSCLC treatment.

Electroencephalogram valid rate in simple reaction time task as an easy index of children's attention functions.

BACKGROUND: Electroencephalogram (EEG) signal artifacts occur often in children, but an EEG valid rate (VR), constructed by excluding the artifacts, might be meaningful to evaluate children's neuropsychological functions. The aim of this study was to develop an easy screening index, the EEGVR, and to investigate attention function in children using this index. METHODS: The EEG was carried out during a 4 min simple reaction time (SRT) task as standard procedure in 50 children, consisting of 26 with attention-deficit-hyperactivity disorder (ADHD; mean age, 9.8 years; range, 8-11.3 years) and 24 without (mean age, 10.1 years; range, 7.8-12 years). An easy index was derived from the valid rate (VR) of EEG using area under the receiver operating characteristic curve. The index was applied to regroup the 50 children into high VR (HVR) and low VR (LVR) groups, while the Comprehensive Non-verbal Attention Test (CNAT) and four behavioral questionnaires were compared between the two groups in order to investigate the validity of this index. RESULTS: The EEGVR at 75% was optimal to identify HVR and LVR (sensitivity, 0.769; specificity, 0.792). The LVR group had significantly lower scores on both CNAT and the behavioral questionnaires, although the demographic variables and full-scale intelligence quotient (FSIQ) were similar between the two groups. CONCLUSIONS: The EEGVR in an SRT task might be an easy and effective index to screen the attention function of children, and could consequently contribute to the early diagnosis of ADHD.

Factors Related to Frailty in Older Cancer Patients Undergoing Colorectal Surgery: A Longitudinal Study.

BACKGROUND: Frailty is common in older cancer patients undergoing colorectal surgery, but few studies have focused on frailty and its associations in this population. OBJECTIVE: The aim of this study was to investigate the prevalence of frailty and its associations in older cancer patients undergoing colorectal surgery. METHODS: A convenience sample of 88 cancer patients 60 years or older undergoing colorectal surgery was recruited from 1 medical center. Frailty, physical activity, functional status, anxiety, depression, and social support of the patients were assessed before surgery, at discharge post surgery, and at 1 month post surgery. RESULTS: The prevalence of frailty in cancer patients undergoing colorectal surgery was 22.7% before surgery, decreased to 19.3% before discharge, and was 12.7% at 1 month after surgery. The proportion of prefrail patients significantly increased from 47.7% before surgery to 71.1% before discharge and was 64.6% at 1 month after surgery. Frail patients were more likely to be older and unmarried, have a lower albumin level, have lower physical activity, and be more dependent on others than nonfrail patients. CONCLUSION: Older cancer patients undergoing colorectal surgery were more likely to be prefrail after surgery than before surgery. Assessment of frailty and its associated factors is necessary for older cancer patients undergoing colorectal surgery before and after surgery. IMPLICATIONS FOR PRACTICE: Frailty may occur in cancer patients after colorectal surgery and is related to malnutrition and low physical activity. Appropriate discharge planning with physical activity tracking and an appropriate diet is encouraged to prevent frailty in cancer patients after colorectal surgery.

Effects of Twenty Hours of Neurofeedback-Based Neuropsychotherapy on the Executive Functions and Achievements among ADHD Children.

Objective. Neurofeedback can reduce ADHD symptoms; however, current programs are relatively long, with fewer concerns about executive function (EF). The present study aimed to investigate a 20-hour combined computerized training neurofeedback program. Methods. Fifty ADHD children were randomly assigned to either the experimental group (EXP) or the wait-list control group (CON), who took training after the post-tests. The EF measures were the Tower of London (ToL), Wisconsin Card Sorting Test (WCST), and Comprehensive Nonverbal Attention Test (CNAT). SNAP-IV and questionnaires reported by parents constituted the behavioral measures. Two-way repeated-measures ANOVA and bootstrapping dependent t-tests were also used. Results. The F-tests revealed the interaction effects on ADHD symptoms and math scores. The EXP had increased the ToL scores, decreased the error and perseverative error rates on WCST, as well as the dysexecutive index on CNAT in the t-test. Conclusions. The training effects were related to behavioral symptoms and functions, EFs, and generalized achievement performances. We suggest that future studies could apply to different patients and examine the maintenance of the program.

The aberrant cancer metabolic gene carbohydrate sulfotransferase 11 promotes non-small cell lung cancer cell metastasis via dysregulation of ceruloplasmin and intracellular iron balance.

Aberrant metabolism has been proposed as one of the emerging hallmarks of cancer. However, the interplay between metabolic disorders and cancer metastasis remains to be defined. To explore the sophisticated metabolic processes during metastatic progression, we analyzed differentially expressed metabolic genes during the epithelial-mesenchymal transition (EMT) of lung cancer cells and defined the EMT-associated metabolic gene signature in lung adenocarcinoma patients. We found that the glycosaminoglycan (GAG)-chondroitin sulfate (CS) biosynthesis pathway was upregulated in the mesenchymal state of lung cancer and associated with poor prognosis. Notably, carbohydrate sulfotransferase 11 (CHST11), a crucial CS biosynthetic enzyme, was confirmed as a poor prognosis marker in non-small cell lung cancer (NSCLC) by immunohistochemical analysis. Moreover, forced CHST11 expression promoted invasion and metastasis, which was abolished by depleting the final product of CS biosynthesis by chondroitinase ABC treatment or active-domain negative CHST11. In vivo metastasis mouse models showed that CHST11 increased lung colonies number and sulfated mucosubstance expression. Furthermore, microarray analysis revealed ceruloplasmin (CP), which facilitated iron metabolism, was the downstream effector of CHST11. CP was upregulated by CHST11 through interferon-γ signaling pathway stimulation and related to unfavorable prognosis. Both forced CP expression and long-term iron treatment increased invasion and lung colony formation. Furthermore, we found 3-AP, an iron chelator, hampered the CHST11-induced metastasis. Our findings implicate that the novel CHST11-CP-iron axis enhances EMT and may serve as a new therapeutic target to treat NSCLC patients.

Development of the Subjective Cognitive Decline Scale for Mandarin-Speaking Population.

Subjective cognitive decline (SCD) has been considered a high-risk group preceding mild cognitive impairment (MCI). However, methods to quantify and track the complaints have not been well-established. The present study aimed to develop a questionnaire tailored for Mandarin-speaking individuals with SCD. A total of 175 adults aged above 55 years completed a comprehensive set of items evaluating cognitive problems and neuropsychological examinations. After item reduction, internal consistency, construct, and concurrent validity were examined. The 14-item Subjective Cognitive Decline Scale (SCDS) has acceptable internal consistency (Cronbach's α = .93) and construct validity with a three-factor structure. Individuals with SCD and MCI scored higher than the control group. The SCDS demonstrated significant but small correlations with multiple cognitive tests and emotional variables. The SCDS provides an alternative approach to measure cognitive complaints, while an influence of emotional status shall be taken into consideration when interpreting the results.

Metabolic protein phosphoglycerate kinase 1 confers lung cancer migration by directly binding HIV Tat specific factor 1.

Phosphoglycerate kinase (PGK) is involved in glycolytic and various metabolic events. Dysfunction of PGK may induce metabolic reprogramming and the Warburg effect. In this study, we demonstrated that PGK1, but not PGK2, may play a key role in tumorigenesis and is associated with metastasis. We observed an inverse correlation between PGK1 and the survival rate in several clinical cohorts through bioinformatics statistical and immunohistochemical staining analyses. Surprisingly, we found that PGK1 was significantly increased in adenocarcinoma compared with other subtypes. Thus, we established a PGK1-based proteomics dataset by a pull-down assay. We further investigated HIV-1 Tat Specific Factor 1 (HTATSF1), a potential binding partner, through protein-protein interactions. Then, we confirmed that PGK1 indeed bound to HTATSF1 by two-way immunoprecipitation experiments. In addition, we generated several mutant clones of PGK1 through site-directed mutagenesis, including mutagenesis of the N-terminal region, the enzyme catalytic domain, and the C-terminal region. We observed that even though the phosphoglycerate kinase activity had been inhibited, the migration ability induced by PGK1 was maintained. Moreover, our immunofluorescence staining also indicated the translocation of PGK1 from the cytoplasm to the nucleus and its colocalization with HTATSF1. From the results presented in this study, we propose a novel model in which the PGK1 binds to HTATSF1 and exerts functional control of cancer metastasis. In addition, we also showed a nonenzymatic function of PGK1.

Type V collagen alpha 1 chain promotes the malignancy of glioblastoma through PPRC1-ESM1 axis activation and extracellular matrix remodeling.

Glioblastoma (GBM) is a fatal cancer. Existing therapies do not have significant efficacy for GBM patients. Previous studies have shown that the collagen family is involved in the regulation of the extracellular environment of cancer cells, and these conditions could become an important factor for effective treatment. Therefore, we screened various collagen types and observed that the type V collagen α1 chain (COL5A1) gene plays a pivotal role in GBM. We further examined whether the overexpression of COL5A1 is common in mesenchymal subtypes and is related to the survival rate of GBM patients through several in silico cohorts. In addition, our cohort also showed a consistent trend in COL5A1 protein levels. Most importantly, we validated the cell mobility, metastatic ability and actin polymerization status caused by COL5A1 with two-way models. Based on these results, we established a transcriptomics dataset based on COL5A1. Moreover, PPRC1, GK and ESM1 were predicted by ingenuity pathway analysis (IPA) to be transcription factors or to participate downstream. We investigated the involvement of COL5A1 in extracellular remodeling and the regulation of actin filaments in the metastasis of GBM. Our results indicate that the COL5A1-PPRC1-ESM1 axis may represent a novel therapeutic target in GBM.

Frontal Beta Activity in the Meta-Intention of Children With Attention Deficit Hyperactivity Disorder.

Children with attention deficit hyperactivity disorder (ADHD) have high theta and low beta activity in the frontal lobe. The higher the theta/beta ratio, the lower the level of central nervous system (CNS) cortical arousal. However, there is seldom evidence between electroencephalograms (EEGs) and the patient's intentionality to regulate the cortical activity of executive attention tasks. We investigated whether children with ADHD intended to improve their performance in executive attention tasks and whether that increased their brain activity. Fifty-one children with ADHD (ADHD) and 51 typical developing (TD) children were investigated using focused attention (FA) and search attention (SA) tasks and a simultaneous EEG. The children were then regrouped as faster (ADHD-F, TD-F) and slower (ADHD-S, TD-S) depending on reaction time (RT). Quantitative EEGs of frontal lobe theta and beta activity at frontal F3, F4, and Fz were used. Twenty-eight (54.9%) ADHD children were regrouped as ADHD-S and 14 (27.5%) as TD-S. The ADHD-S group, however, had poorer FA and SA performance than the other 3 groups did: fewer correct answers, more frequent impulsive and missing errors, and higher RT variations. There were no significant differences in theta activity, but the TD-S group had higher beta activity than the ADHD-S group did. We conclude that the ADHD-F and ADHD-S groups had different attention processes. beta activity did not increase in the ADHD-S group, and their executive attention performance in the FA and SA tests was poor. It seems ADHD-S had poor meta-intention function. The frontal beta activity might be a feasible training target of neurofeedback in ADHD-S patients.

Nonenzymatic function of Aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness.

Drug resistance remains a serious issue of clinical importance and is a consequence of cancer stemness. In this study, we showed that the level of Aldolase A (ALDOA) expression is significantly associated with the IC50 value of chemotherapy drugs in lung cancer. Our data revealed that ALDOA overexpression resulted in a significant increase of lung tumor spheres. The use of ingenuity pathway analysis (IPA) resulted in the identification of POU5F1 (Oct4) as the leading transcription factor of ALDOA. We observed high expression of ALDOA, Oct4 and stemness markers in collected spheroid cells. DUSP4 and TRAF4 were confirmed as major downstream targets of the ALDOA-Oct4 axis. Knockdown of these molecules significantly decreased the stemness ability of cells. In addition, we investigated whether miR-145 targets the 3'-UTR of Oct4 and is regulated by ALDOA due to the involvement of ALDOA in glycolysis and metabolic reprogramming. Furthermore, we constructed several mutant forms of ALDOA that disrupted its enzymatic activity and showed that they still induced significant in vitro sphere formation and in vivo tumorigenicity. These results demonstrated that ALDOA-mediated spheroid formation is independent of its enzymatic activity. In the clinical component, we also showed that the combination of ALDOA and TRAF4 or DUSP4 is positively correlated with poor overall survival in a xenograft model and cancer patients through immunohistochemical analyses. The results of our study revealed novel functional roles of ALDOA in inducing cancer stemness via the inhibition of miR-145 expression and the activation of Oct4 transcription. These findings offer new therapeutic strategies for modulation of lung cancer stemness to enhance chemotherapeutic responses in lung cancer patients.

The risk factors of Internet addiction--a survey of university freshmen.

This study was designed to explore the risk factors of Internet addiction in 1360 freshmen of the National Cheng Kung University in Taiwan in 2003. The test battery included a self-administrated structured questionnaire, the Chinese Internet Addiction Scale-Revision (CIAS-R), the 12-item Chinese Health Questionnaire (CHQ-12), the Measurement of Support Functions (MSF), and the neuroticism subscale of the Maudsley Personality Inventory (MPI). Of the total study population, there were 680 college freshmen (17.9%) in the Internet addiction group, as defined by high CIAS-R scores. Using logistic regression analyses, we found positive relationships between Internet addiction and male gender, neuroticism scores and the CHQ score. In addition, the freshmen who skipped breakfast and those who had poorer social support also had a higher probability of Internet addiction. Internet addiction is prevalent among university freshmen in Taiwan. Risk factors included male gender, habit of skipping breakfast, mental health morbidity, deficient social support; and neurotic personality characteristics.

Follistatin-like Protein 1 Inhibits Lung Cancer Metastasis by Preventing Proteolytic Activation of Osteopontin.

Follistatin-like protein 1 (FSTL1) plays a critical role in lung organogenesis, but is downregulated during lung cancer development and progression. The prognostic significance and functional consequences of FSTL1 downregulation in lung cancer are unclear. Here, reduced levels of FSTL1 were detected in various tumors compared with normal tissues and were associated with poor clinical outcome in patients with non-small cell lung cancer, particularly those with lung adenocarcinoma. FSTL1 expression negatively correlated with the metastatic potential of lung cancer cells. Antibody-based neutralization of extracellular FSTL1 increased cellular migration/invasion while addition of recombinant FSTL1 protein diminished the metastatic capacity of lung cancer cells in vitro and in vivo. Notably, treatment with FSTL1 effectively prevented the metastatic progression of lung cancer cells in an orthotopic animal model. Mechanistically, FSTL1 directly bound to the proform of secreted phosphoprotein 1 (SPP1)/osteopontin, restraining proteolytic activation of SPP1, which led to inactivation of integrin/CD44-associated signaling and rearrangement of the actin cytoskeleton. Combined low expression of FSTL1 and high expression of SPP1 predicted a poorer prognosis for patients with lung cancer. This study highlights the novel interaction between FSTL1 and SPP1 and new opportunities to effectively target SPP1-driven metastatic cancers characterized by FSTL1 downregulation. SIGNIFICANCE: These findings describe the novel interaction between FSTL1 and SPP1 and its role in the metastatic progression of lung adenocarcinoma.

Enrichment of Aldolase C Correlates with Low Non-Mutated IDH1 Expression and Predicts a Favorable Prognosis in Glioblastomas.

The aldolases family is one of the main enzymes involved in the process of glycolysis. Aldolase C (ALDOC), which belongs to the aldolase family, is found in normal brain tissue and is responsible for the repair of injured tissue. However, the role of ALDOC in glioblastoma remains unclear. In this study, we data-mined in silico databases to evaluate aldolase family members' mRNA expression in glioblastoma patient cohorts for determining its prognostic values. After that, we also performed immunohistochemical stain (IHC) analysis to evaluate protein expression levels of ALDOC in glioblastoma tissues. From The Cancer Genome Atlas (TCGA) database analyses, higher mRNA expression levels in normal brain tissue compared to glioblastoma was observed. In addition, compared to low-grade glioma, ALDOC expression was significantly downregulated in high-grade glioblastoma. Besides, the expression level of ALDOC was associated with molecular subtypes of glioblastomas and recurrent status in several data sets. In contrast, aldolase A (ALDOA) and aldolase B (ALDOB) revealed no significant prognostic impacts in the glioblastoma cohorts. Furthermore, we also proved that ALDOC mRNA and protein expression inversely correlated with non-mutated IDH1 expressions in glioblastoma patient cohorts. Additionally, the concordance of low ALDOC and high non-mutated IDH1 expressions predicted a stronger poor prognosis in glioblastoma patients compared to each of above tests presented alone. The plausible ALDOC and IDH1 regulatory mechanism was further elucidated. Our results support high ALDOC expression in glioblastomas that might imply the mutated status of IDH1, less possibility of mesenchymal subtype, and predict a favorable prognosis.

ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients.

Metastasis remains the major cause of death from colon cancer. We intend to identify differentially expressed genes that are associated with the metastatic process and prognosis in colon cancer. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial F0F1 ATP synthase subunit epsilon that was overexpressed in tumor cells compared to their normal counterparts, while other genes encoding the ATP synthase subunit were repressed in public microarray datasets. CRC cells in which ATP5E was silenced showed markedly reduced invasive and migratory abilities. ATP5E inhibition significantly reduced the incidence of distant metastasis in a mouse xenograft model. Mechanistically, increased ATP5E expression resulted in a prominent reduction in E-cadherin and an increase in Snail expression. Our data also showed that an elevated ATP5E level in metastatic colon cancer samples was significantly associated with the AMPK-AKT-hypoxia-inducible factor-1α (HIF1α) signaling axis; silencing ATP5E led to the degradation of HIF1α under hypoxia through AMPK-AKT signaling. Our findings suggest that elevated ATP5E expression could serve as a marker of distant metastasis and a poor prognosis in colon cancer, and ATP5E functions via modulating AMPK-AKT-HIF1α signaling.

Overexpression of BZW1 is an independent poor prognosis marker and its down-regulation suppresses lung adenocarcinoma metastasis.

The basic leucine zipper and the W2 domain-containing protein 1 (BZW1) plays a key role in the cell cycle and transcriptionally control the histone H4 gene during G1/S phase. Since cellular proliferation rates are frequently dysregulated in human cancers, we identified the characteristics of BZW1 in cancer cells and analyzed its prognostic value in lung cancer patients. By searching public databases, we found that high BZW1 expression was significantly correlated with poor survival rate in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. Similar trends were also shown in an array comprising NSCLC patient tissue. Knockdown of BZW1 inhibited cell metastatic ability, but did not affect the cell proliferation rate of NSCLC cells. From transcriptomics data mining, we found that coordination between BZW1 and EGFR overexpression was correlated with a worse outcome for lung cancer patients. In summary, BZW1 expression serves as an independent prognostic factor of NSCLC, especially in lung adenocarcinoma. Overexpression of BZW1 in lung cancer cells revealed a novel pathway underlying the induction of lung cancer metastasis.

The Significance of Impulsive Error in Children With ADHD.

A deficit of inhibition ability is a neuropsychological problem in children with attention deficit hyperactivity disorder (ADHD). We investigated whether in children who made impulsive error (IE), less error-related negativity (ERN) would correlate with poorer executive attention functions (EAFs). Ninety children (49 with ADHD and 41 without ADHD) were investigated by a 4-minute simple reaction time task and simultaneous electroencephalogram. When they made IE, the ERN in response-locked event-related potential (ERP) was defined as error awareness. The average area under curve of ERN in the control group with IEs was used as the proper criterion for regrouping the children with ADHD into 2 groups: ADHD children with enough ERN (ADHD-enough ERN) and those with less ERN (ADHD-less ERN). EAFs from Comprehensive Nonverbal Attention Test were used as objective indices, and behavioral questionnaires were used as subjective indices and statistically analyzed within ADHD groups. Forty-eight percent of the children made IEs. ADHD(n = 31, 63%) was significantly more than in the control group (n = 12, 29%; P < .001). The ADHD group had significantly less ERN than did the control group while making IE, especially at frontal and central electrodes ( P < .01). Both ADHD-less ERN and ADHD-enough ERN groups had poorer subjective EAFs on questionnaires. Only the ADHD-less ERN group had significant poorer objective EAFs on the Comprehensive Nonverbal Attention Test than did the ADHD without IE. We conclude that investigating the IE and ERN of IE in children with ADHD might help to differentiate subtypes of ADHD with different neuropsychological abilities, and the possibility that ADHD-less ERN children might be confirmed a meaningful subgroup that needs close follow-up, treatments different from standard, or both.

Anti-NMDA receptor encephalitis with the initial presentation of psychotic mania.

We report a 16-year-old girl with suspected psychotic mania, who subsequently developed amnesia, catatonia, oro-lingual dyskinesia, consciousness disturbance, seizure and respiratory failure. Repeated studies of the cerebrospinal fluid (CSF), viral culture and serology, brain MRI, single photon emission CT scan, and autoimmune profiles were all normal. She was finally diagnosed with anti-N-methyl D-aspartate receptor (NMDAR) encephalitis based on the positive finding of NMDAR antibodies in CSF. Her abdominal CT scan showed no detectable malignancy and pulse steroid therapy failed to have any effect. After administration of intravenous immunoglobulin her consciousness improved gradually. Anti-NMDAR encephalitis, with a characteristic neuropsychiatric syndrome, predominantly affects females with an ovarian tumor and is frequently misdiagnosed as a psychiatric disorder. Immunotherapy and eradication of associated malignancy are the main treatment strategies. Early recognition and early intervention of the disease should improve the outcome.