Effects of home-based computerized cognitive training and tai chi exercise on cognitive functions in older adults with mild cognitive impairment.

BACKGROUND: A randomized trial was conducted to investigate the effects of computerized cognitive training (CCT) and tai chi exercise (TCE) vs. health education (HE) on cognitive functions in 189 older adults with mild cognitive impairment (MCI). METHODS: Cognitive functions were assessed by the five-domain Mattis Dementia Rating Scale (MDRS) (attention, initiation/perseveration, construction, conceptualization, and memory) and the modified Telephone Interview of Cognitive Status (TICS-M), while the timed up and go (TUG), Tinetti's balance, activities of daily living (ADLs), and Activities-specific Balance Confidence (ABC) were also evaluated. Each intervention was delivered once a week for 6 months. All outcomes were followed up at 6 and 12 months of the study. RESULTS: Compared to HE, CCT increased scores on the MDRS's total, initiation/perseveration, construction, and conceptualization domains and on the TICS-M at 6 months and those on the MDRS's total, attention, construction, conceptualization, and memory domains and on the TICS-M at 12 months; TCE increased scores on the MDRS's total and construction domains and on the TICS-M at 6 months and those on the MDRS's total, attention, initiation/perseveration, and conceptualization domains and on the TICS-M at 12 months. Moreover, CCT improved the TUG at 6 and 12 months and Tinetti's balance at 12 months, and TCE improved the TUG at 6 and 12 months, Tinetti's balance, and ABC at 6 and 12 months, and ADLs at 12 months. CONCLUSIONS: The effects of CCT and TCE on improving global cognition and certain cognitive domains for older MCI adults may have been small but they lasted for at least 12 months.

Resveratrol Analog 4-Bromo-Resveratrol Inhibits Gastric Cancer Stemness through the SIRT3-c-Jun N-Terminal Kinase Signaling Pathway.

Chemotherapy is the treatment of choice for gastric cancer, but the currently available therapeutic drugs have limited efficacy. Studies have suggested that gastric cancer stem cells may play a key role in drug resistance in chemotherapy. Therefore, new agents that selectively target gastric cancer stem cells in gastric tumors are urgently required. Sirtuin-3 (SIRT3) is a deacetylase that regulates mitochondrial metabolic homeostasis to maintain stemness in glioma stem cells. Targeting the mitochondrial protein SIRT3 may provide a novel therapeutic option for gastric cancer treatment. However, the mechanism by which stemness is regulated through SIRT3 inhibition in gastric cancer remains unknown. We evaluated the stemness inhibition ability of the SIRT3 inhibitor 4'-bromo-resveratrol (4-BR), an analog of resveratrol in human gastric cancer cells. Our results suggested that 4-BR inhibited gastric cancer cell stemness through the SIRT3-c-Jun N-terminal kinase pathway and may aid in gastric cancer stem-cell-targeted therapy.

Chemotherapy alone versus definitive concurrent chemoradiotherapy for cT4b esophageal squamous cell carcinoma: a population-based study.

BACKGROUND: The role of radiotherapy for cT4bNanyM0 esophageal squamous cell carcinoma (ESqCC) is relatively unclear, with both chemotherapy (C/T) alone and definitive concurrent chemoradiotherapy (dCCRT) being treatment options in the current guidelines. We aimed to compare the survival of dCCRT versus C/T for these patients via a population-based approach. METHODS: Eligible cT4b ESqCC patients diagnosed between 2011 and 2017 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance the observable potential confounders between groups. The hazard ratio (HR) of death and incidence of esophageal cancer mortality (IECM) were compared between dCCRT and C/T. We also evaluated OS in subgroups of either low or standard radiotherapy doses. RESULTS: Our primary analysis consisted of 247 patients in whom covariates were well balanced after PS weighing. The HR for death when dCCRT was compared with C/T was 0.36 (95% confidence interval 0.24-0.53, P < 0.001). Similar results were found for IECM. Statistical significance was only observed in the standard RT dose but not in the low dose in subgroup analyses. CONCLUSIONS: In this population-based nonrandomized study of cT4bNanyM0 ESqCC patients from Asia (Taiwan), we found that the use of radiotherapy with chemotherapy was associated with better overall survival than chemotherapy alone. Further studies (especially RCTs) are needed to confirm our findings.

Long-term in vitro degradation and in vivo evaluation of resorbable bioceramics.

An essential criterion for the selection of resorbable bioceramics is their ability to degrade inside human body within a reasonable time frame. Furthermore, if the bioceramic can release beneficial ions, such as strontium, as it degrades, recovery time might be shortened. The present study demonstrates that strontium-containing calcium sulfate (Sr,Ca)SO4 can fulfill these criteria. A long-term in vitro degradation analysis for 12 weeks using sintered (Sr,Ca)SO4 discs in phosphate buffered solution (PBS) was conducted. The sintered (Sr,Ca)SO4 disc was then implanted into defects in the distal femur of rats. The degradation rate of (Sr,Ca)SO4 discs showed a strong dependence on the Sr content. Similar results were observed between the long-term in vitro degradation analysis and the in vivo evaluation. The sintered (3.8%Sr,Ca)SO4 disc lost more than 80% of its initial weight after soaking in PBS with shaking at 37 °C for 12 weeks. After 12 weeks in vivo, the remaining volume of the (3.8%Sr,Ca)SO4 disc within the bone defect was ~25%. Over the same time period, new bone was formed at a relative volume of 40%. This study demonstrates the potential of (Sr,Ca)SO4 bioceramic, and the benefits of using a long-term degradation test during the evaluation of resorbable bioceramics.

Predictors of nasal bacterial culture rates in patients with chronic rhinosinusitis.

All nontechnical factors were analyzed to predict nasal bacterial culture results in patients with chronic rhinosinusitis (CRS). Four hundred and ninety-six CRS patients, who underwent functional endoscopic sinus surgery (FESS), were enrolled. Prior to FESS, the severity of each patient's CRS was evaluated using a questionnaire, endoscopic examination, acoustic rhinometry, smell test, saccharine transit test, and CT scan. Nasal bacterial cultures were collected from both middle meati using a cotton-tipped stick. Our results showed that the symptom severity complained of by patients and their loss of smell function did not influence the bacterial culture rate. We discovered that the bacterial culture rate was significantly higher in nostrils with nasal polyps than those without polyps, along with nostrils experiencing thick, purulent discharge as opposed to those without discharge. Additionally, this result also occurred in nostrils with a saccharin transit time of more than 30 min than it did in those with a saccharin transit time of less than or equal to 30 min. Both the total endoscopic score and anterior group CT score were significantly higher in nostrils with positive culture than those with negative culture, while the second minimal cross-sectional area (MCA2) of the nasal cavity was significantly lower in nostrils with positive culture than those with negative culture. Multiple logistic regression analysis showed that both nasal polyps and MCA2 were the predictors for positive nasal bacterial culture results. It was concluded that nasal polyps and MCA2 were the predictors for positive nasal bacterial culture results in CRS patients.

Effects of Computerized Cognitive Training and Tai Chi on Cognitive Performance in Older Adults With Traumatic Brain Injury.

OBJECTIVE: To compare the effects of computerized cognitive training (CCT) and tai chi (TC) with usual care (UC) on cognitive functions and secondary outcomes in older adults with traumatic brain injury. PARTICIPANTS AND SETTINGS: Ninety-six patients aged 55 years and older who had a diagnosis of traumatic brain injury requiring hospital admission. DESIGN: Randomized controlled trial. MAIN MEASURES: The Mattis Dementia Rating Scale (MDRS), Mini-Mental State Examination, modified Telephone Interview of Cognitive Status, and Trail Making Tests A and B. RESULTS: Compared with UC, CCT increased scores on the MDRS's total, attention, and memory and those on the Mini-Mental State Examination and Telephone Interview of Cognitive Status over the 6-month intervention; TC increased scores on the MDRS's total and conceptualization and those on the Mini-Mental State Examination over the 6-month intervention, while it also increased scores on the MDRS's total and initiation/preservation and those on the Telephone Interview of Cognitive Status and reduced the time to complete the Trail Making Test B over the 12-month study. Furthermore, compared with UC, CCT increased handgrip strength and TC reduced the time to complete 5 sit-to-stands over the 6-month intervention. CONCLUSION: Both CCT and TC may improve global cognition and different specific cognitive domains in older traumatic brain injury patients; the TC's effect may last for at least an additional 6 months.

Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors.

RATIONALE: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patients with advanced NSCLC who have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS. OBJECTIVES: The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs. METHODS: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). MEASUREMENTS AND MAIN RESULTS: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P < 10-8) and with an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression of EGFR, which encodes the TKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene. CONCLUSIONS: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.

Neoadjuvant vs definitive concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma patients.

BACKGROUND: The optimal treatment for locally advanced esophageal squamous cell carcinoma remains unclear. We compared the clinical outcomes of neoadjuvant concurrent chemoradiotherapy (CCRT) followed by esophagectomy [the surgery group] and CCRT without surgery [the CCRT group] in patients with squamous cell carcinoma from an Asian population. METHODS: Eligible patients diagnosed from 2008 to 2015 were identified through the Taiwan Cancer Registry. To balance observable potential confounders, we constructed a 1:1 propensity score-matched cohort [surgery vs CCRT]. We compared the hazard ratios between the surgery and CCRT groups for death using a robust variance estimator. We also evaluated the outcomes of patients for freedom from local regional recurrence (FFLRR) and esophageal cancer-specific survival (ECSS). Extensive supplementary analyses were performed to examine the robustness of our findings. RESULTS: Our study population included 298 patients balanced with respect to the observed covariables. The hazard ratio of death was 0.56 [95% confidence interval 0.42~0.75] when surgery was compared to CCRT. The results remained significant in the FFLRR and ECSS outcomes. In the supplementary analyses, our results also remained significant when additional covariables were taken into consideration or when the definition of the index date was changed. CONCLUSIONS: When compared to definitive CCRT, neoadjuvant CCRT followed by esophagectomy was associated with improved overall survival for locally advanced esophageal squamous cell carcinoma. However, given the nonrandomized nature of the study and the sensitivity to potentially unmeasured confounders, our results should be interpreted cautiously.

Targeting insulin-like growth factor-binding protein-3 by microRNA-125b promotes tumor invasion and poor outcomes in non-small-cell lung cancer.

Insulin-like growth factor-binding protein-3 acts as a tumor suppressor that inhibits the PI3K/AKT signaling pathway due to blocking insulin growth factor-1 binding to its receptor. We hypothesized that insulin-like growth factor-binding protein-3 might be targeted by microRNA-125b and promote tumor invasion and poor outcome in non-small-cell lung cancer via activation of the PI3K/AKT signaling pathway. Real-time polymerase chain reaction and immunohistochemistry were performed to determine the level of microRNA-125b, insulin-like growth factor-binding protein-3 messenger RNA, and phosphorylated-AKT expression in 105 tumors from non-small-cell lung cancer patients. Low insulin-like growth factor-binding protein-3 messenger RNA levels and positive phosphorylated-AKT expression were more commonly found in patients with high microRNA-125b tumors than low microRNA-125b tumors. A poorer overall survival and relapse-free survival were observed in patients with high microRNA-125b tumors than low-microRNA-125b tumors in p53-mutated patients, but not in p53-wild-type patients. Mechanistically, microRNA-125b promotes invasion ability in p53-mutated cells via the PI3K/AKT activation by targeting of insulin-like growth factor-binding protein-3, but this effect was not observed in p53-wild-type cells. An increase in phosphorylated-AKT expression due to targeting of insulin-like growth factor-binding protein-3 by microRNA-125b was responsible for cell invasion in p53-mutated cells. In conclusion, the microRNA-125b level promotes invasive ability in p53-mutated cells via PI3K/AKT activation by targeting of insulin-like growth factor-binding protein-3, thereby resulting in p53-mutated non-small-cell lung cancer patients with poor outcomes.

Patient-Proxy Agreement on the Health-Related Quality of Life One Year After Traumatic Brain Injury.

OBJECTIVE: To examine the level of agreement between patients and their proxies on a measure of health-related quality of life (HRQL) 1 year after traumatic brain injury (TBI). DESIGN: A cross-sectional study. SETTING: Four hospitals in Taipei. PARTICIPANTS: Participants (N=176) were patients with TBI (n=88) identified from discharge records of 4 hospitals in Taiwan and family members or friends (n=88) who could answer questions regarding the patient's health and HRQL 1 year after the injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A health profile of the brief Taiwanese version of the World Health Organization Quality of Life (WHOQOL-BREF) and 2 health utility measures of the time tradeoff (TTO) and standard gamble (SG). RESULTS: Compared with proxy responses, patients provided higher ratings on the domains of the WHOQOL-BREF and lower ratings on the TTO and SG. Intraclass correlation coefficients between patient and proxy ratings varied among the 4 domains of the WHOQOL-BREF, in which levels of agreement were moderate or good for physical capacity (.69) and low for psychological well-being (.45), social relationships (.24), and the environment (.32). Levels of agreement were extremely low for the TTO (0.0) and SG (.10). A profile analysis showed that patients' ratings on the WHOQOL-BREF, on average, were significantly greater than those of their proxies (mean difference, 3.07), with a similar distribution of scatter responses (mean difference, .002) and shape agreement (mean difference, .57). Greater variations in the patient-proxy level of agreement appeared in patients who were younger and had more severe injuries, and also with parent and child proxies. CONCLUSIONS: To assess the HRQL of patients with a TBI, the level of patient-proxy agreement was adequate for the physical domain but was lower for the social and environmental domains, and the agreement was very low for the TTO and SG. Furthermore, a patient's age and injury severity, and the patient-proxy' relationship may affect the agreement.

Validating the Quality of Life After Brain Injury Through Rasch Analysis.

OBJECTIVE: The Quality of Life after Brain Injury (QOLIBRI), a cross-cultural instrument, has been validated in several languages; however, traditional psychometric approaches have critical limitations. Therefore, we applied the Rasch model for validating the 37-item QOLIBRI scale among a Chinese population with traumatic brain injury. PARTICIPANTS AND SETTING: In total, 587 participants (mean age: 44.2 ± 15.4 years; women, 46.3%) were surveyed in neurosurgery departments at 6 hospitals in Taipei, Taiwan. MAIN OUTCOME MEASURE: The QOLIBRI. RESULTS: Of the 6 subscales of the QOLIBRI, 4 (cognition, self, daily life and autonomy, and social relationships) were unidimensional, valid, and reliable, whereas the remaining 2 (emotions and physical problems) exhibited poor unidimensionality, item and person reliability, and person-item targeting. Five items (energy, concentrating, getting out and about, sex life, and achievements) showed considerable differential item functioning among age groups, disability levels, and time since traumatic brain injury. CONCLUSION: According to item response theory, we identified psychometric issues in the emotions and physical problems subscales of the QOLIBRI as well as several differential item functioning items. Future research is required to determine whether similar results are observed in other language versions of the QOLIBRI or in other countries.

Association of cytoplasmic p27 expression with an unfavorable response to cisplatin-based chemotherapy and poor outcomes in non-small cell lung cancer.

Reduced nuclear p27 expression is associated with a poor outcome in various cancers, including non-small cell lung cancer (NSCLC). Cytoplasmic p27 expression was shown to be associated with an unfavorable response to chemotherapy and poor outcomes in some carcinomas, but it has not been well studied in NSCLC. Herein, p27 expression in 219 tumors surgically resected from NSCLC patients was evaluated by immunohistochemistry (IHC). The most common of p27 immunostaining in lung tumors was observed in the cytoplasm (N-/C+, 32 %), followed by negative (N-/C-, 29 %), nucleus (N+/C-, 24 %), and nucleus plus cytoplasm (N+/C+, 15 %). Kaplan-Meier and Cox regression models showed that p27 N-/C+ tumors exhibited the worst overall survival (OS) and relapse-free survival (RFS) among the four categories of tumors. Among 135 of 219 patients who received cisplatin-based chemotherapy, p27 N-/C+ tumors most commonly showed an unfavorable response to cisplatin-based chemotherapy, followed by p27 N-/C- tumors when p27 N+/C- tumors were used as a reference. IHC analysis for phosphorylated extracellular signal-regulated kinase (p-ERK) and Bcl-2 expression in the lung tumors was performed to test whether ERK activation could enhance p27 nuclear export and the expression of Bcl-2 to test whether ERK activation could enhance p27 nuclear export and Bcl-2 expression. The data showed that p-ERK expression was positively correlated with cytoplasmic p27 (N-/C+) and Bcl-2 expression in the lung tumors. Patients with high Bcl-2-expressing tumors treated with cisplatin-based chemotherapy showed unfavorable predictive values in a subset of this study population. Therefore, we suggest that cytoplasmic p27 (N-/C+) via ERK-activated Bcl-2 expression may predict an unfavorable response to cisplatin-based chemotherapy and poor outcomes in NSCLC.

MicroRNA signature predicts survival and relapse in lung cancer.

We investigated whether microRNA expression profiles can predict clinical outcome of NSCLC patients. Using real-time RT-PCR, we obtained microRNA expressions in 112 NSCLC patients, which were divided into the training and testing sets. Using Cox regression and risk-score analysis, we identified a five-microRNA signature for the prediction of treatment outcome of NSCLC in the training set. This microRNA signature was validated by the testing set and an independent cohort. Patients with high-risk scores in their microRNA signatures had poor overall and disease-free survivals compared to the low-risk-score patients. This microRNA signature is an independent predictor of the cancer relapse and survival of NSCLC patients.

Lung cancer screening with low-dose computed tomography: Experiences from a tertiary hospital in Taiwan.

BACKGROUND/PURPOSE: Lung cancer screening using low-dose computed tomography (CT) has been reported to reduce lung cancer-specific mortality for smokers at high risk. However, despite different characteristics of lung cancer in Asia, there are few data concerning this specific population for screening. We aim to analyze the performance of lung cancer screening with low-dose CT concurrent with chest radiography in Taiwan, with reference to international experience. METHODS: During the 1-year period from January 2012 to December 2012, we conducted a retrospective, single-center population-based screening program for lung cancer in the setting of annual medical examinations. Participants were asymptomatic adults without prior history of any cancer. Low-dose CT and chest radiography were offered to all individuals. Baseline CT evaluations were defined as positive if any noncalcified nodule≥4 mm in diameter, which were then classified as solid, pure ground-glass or partial ground-glass opacity. RESULTS: Of 3339 individuals, we detected 34 cancers, yielding an overall cancer detection rate of 1.02%. There was a particularly high cancer detection rate of 6.2% (8/129) in the high-risk group aged younger than 50 years with a positive family history of all types of cancers in first-degree relatives. Adenocarcinomas accounted for 88% (30/34) of cancers and 99% of them were early-stage (including carcinoma in situ and Stage I). The probability of cancers was significant higher in nodules with interval growth (odds ratio 257.89, p = 0.0002). There was no significant difference in the probability of cancers between ground glass opacity nodules and solid nodules (odds ratio 1.16, p=0.72). Of all screen-detected cancers, 61.76% (21/34) were chest radiographically occult. CONCLUSION: Low-dose CT is effective to detect early lung cancers. Further establishment of selection criteria for lung cancer screening, specifically for Asian individuals, is definitely warranted.

Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA).

We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30% increased risk of lung cancer (OR 1.3, 95% CI 1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.

MicroRNA-184 Deregulated by the MicroRNA-21 Promotes Tumor Malignancy and Poor Outcomes in Non-small Cell Lung Cancer via Targeting CDC25A and c-Myc.

BACKGROUND: MicroRNA (miR)-184 has been reported to have a dual role in human cancers. However, the role of miR-184 in non-small cell lung cancer (NSCLC) remains unclear. METHODS: Wild-type or mutant CDC25A promoters were constructed by PCR and site-directed mutagenesis to verify whether miR-184 could inhibit CDC25A expression at post-transcription level. Boyden chamber assay was used to assess whether miR-184 could modulate cell invasiveness via targeting CDC25A and c-Myc. We utilized 124 tumors from NSCLC patients to determine miR-184, miR-21, PDCD4 mRNA, c-Myc mRNA, and CDC25A mRNA expression levels by means of real-time PCR analysis. The prognostic value of CDC25A, c-Myc, and miR-184 on overall survival (OS) and relapse-free survival (RFS) was evaluated by Kaplan-Meier and Cox regression analysis. RESULTS: MiR-184 suppressed CDC25A expression by enhancing the instability of its mRNA as a result of miR-184 binding to its coding region. An increase in CDC25A expression by means of a reduction in miR-184 promotes cell invasiveness. Moreover, a concomitant increase in CDC25A and c-Myc expression as a result of decreased miR-184 via the miR-21-mediated PDCD4 reduction is responsible for cell invasiveness. Among patients, miR-184 expression in lung tumors was found to correlate negatively with CDC25A mRNA, c-Myc mRNA, and miR-21 expression, but was positively related to PDCD4 mRNA expression. High-miR-184, High-CDC25A, or high-c-Myc mRNA tumors exhibited shorter OS and RFS periods than their counterparts. The worst OS and RFS were observed in low-miR-184/high-CDC25A/high-c-Myc tumors, followed by low-miR-184 /high-CDC25A, low-miR-184/high-c-Myc, high-c-Myc, and high-CDC25A tumors. CONCLUSIONS: MiR-184 as a tumor suppressor miR inhibits cell proliferation and invasion capability via targeting CDC25A and c-Myc. Low miR-184 level may predict worse prognosis in NSCLC patients.

Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma.

SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells.

Hospice shared-care saved medical expenditure and reduced the likelihood of intensive medical utilization among advanced cancer patients in Taiwan--a nationwide survey.

PURPOSE: Hospice shared care (HSC) is a new care model that has been adopted to treat inpatient advanced cancer patients in Taiwan since 2005. Our aim was to assess the effect of HSC on medical expenditure and the likelihood of intensive medical utilization by advanced cancer patients. METHODS: This is a nationwide retrospective study. HSC was defined as using "Hospice palliative care (HPC) teams to provide consultation and service to advanced cancer patients admitted in the nonhospice care ward." There were 120,481 deaths due to cancer between 2006 and 2008 in Taiwan. Patients receiving HSC were matched by propensity score to patients receiving usual care. Of the 120,481 cancer deaths, 12,137 paired subjects were matched. Medical expenditures for 1 year before death were assessed between groups using a database from the Bureau of National Health Insurance. Paired t and McNemar's tests were applied for comparing the medical expenditure and intensive medical utilization before death between paired groups. RESULTS: Compared to the non-HSC group, subjects receiving HSC had a lower average medical expenditure per person (US$3,939 vs. US$4,664; p<0.001). The HSC group had an adjusted net savings of US$557 (13.3%; p<0.001) in inpatient medical expenditure per person compared with the non-HSC group. Subjects that received different types of HPC had 15.4-44.9% less average medical expenditure per person and significantly lower likelihood of intensive medical utilization than those that did not receive HPC. CONCLUSIONS: HSC is associated with significant medical expenditure savings and reduced likelihood of intensive medical utilization. All types of HPC are associated with medical expenditure savings.

Inhibitory effect of dihydroaustrasulfone alcohol on the migration of human non-small cell lung carcinoma A549 cells and the antitumor effect on a Lewis lung carcinoma-bearing tumor model in C57BL/6J mice.

There are many major causes of cancer death, including metastasis of cancer. Dihydroaustrasulfone alcohol, which is isolated from marine coral, has shown antioxidant activity, but has not been reported to have an anti-cancer effect. We first discovered that dihydroaustrasulfone alcohol provided a concentration-dependent inhibitory effect on the migration and motility of human non-small cell lung carcinoma (NSCLC) A549 cells by trans-well and wound healing assays. The results of a zymography assay and Western blot showed that dihydroaustrasulfone alcohol suppressed the activities and protein expression of matrix metalloproteinase (MMP)-2 and MMP-9. Further investigation revealed that dihydroaustrasulfone alcohol suppressed the phosphorylation of ERK1/2, p38, and JNK1/2. Dihydroaustrasulfone alcohol also suppressed the expression of PI3K and the phosphorylation of Akt. Furthermore, dihydroaustrasulfone alcohol markedly inhibited tumor growth in Lewis lung cancer (LLC)-bearing mice. We concluded that dihydroaustrasulfone alcohol is a new pure compound with anti-migration and anti-tumor growth activity in lung cancer and might be applied to clinical treatment in the future.

Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.

BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.