Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

Incidence of Lung Adenocarcinoma by Age, Sex, and Smoking Status in Taiwan.

Importance: Knowing whether the effects of smoking and other risk factors with lung adenocarcinoma (ADC) incidence varies by sex would provide information on lung cancer prevention strategies. Objective: To evaluate whether women in Taiwan have higher age- and tumor stage-specific lung ADC incidence rates than men irrespective of smoking status (ie, ever smoker or never smoker). Design, Setting, and Participants: This population-based cohort study used data sets synthesized from the Taiwan Cancer Registry (TCR) from 1979 to 2019; the TCR Long Form (TCRLF) from 2011 to 2019, which provides individual-level smoking and tumor stage information; the Taiwan Cause of Death Database (TCOD) from 1985 to 2019; the National Health Insurance Research Database (NHIRD) from 2000 to 2020; the Monthly Bulletin of Interior Statistics (MBIS) from 2011 to 2019; the National Health Interview Survey from 2001, 2005, 2009, 2013, and 2017; and Taiwan Biobank data from 2008 to 2021. Included patients were aged 40 to 84 years and had any invasive lung cancer from January 1, 2011, to December 31, 2019. Exposure: Smoking status. Main Outcomes and Measures: The main outcomes were age-specific female-to-male incidence rate ratios (IRRs) of lung ADC by smoking status and tumor stage. Linked data from the TCR, TCOD, NHIRD, Taiwan National Health Interview Survey, and MBIS were used to estimate the age- and sex-specific numbers of cancer-free individuals at midyears from 2011 to 2019 by smoking status. Using the TCR and TCRLF, age-, sex-, tumor stage-, and diagnosis year-specific numbers of patients with lung ADC from 2011 to 2019 by smoking status were estimated. Results: A total of 61 285 patients (32 599 women [53.2%]) aged 40 to 84 years (mean [SD] age, 64.66 [10.79] years) in the Taiwanese population of approximately 23 million were diagnosed with invasive lung ADC as their first lifetime cancer between 2011 and 2019. Among smokers, men had higher tobacco use by almost all examined metrics, including nearly twice the mean (SD) number of pack-years smoked (eg, 7.87 [8.30] for men aged 30-34 years vs 4.38 [5.27] for women aged 30-34 years). For 5-year age bands between 40 and 84 years, incidence of lung ADC was significantly higher among females than males for nearly all age groups irrespective of tumor stage and smoking status (eg, for the age group 70-74 years, the female-to-male IRR for late-stage lung ADC among never smokers was 1.38 [95% CI, 1.30-1.50]). Conclusions and Relevance: In this cohort study, women had higher age- and stage-specific lung ADC incidence rates than men in Taiwan for both never and ever smokers, suggesting the possibility of differential exposures between sexes to risk factors other than smoking and the potential modification of ADC risk factors by sex. Further work is needed to determine whether this pattern replicates in other populations, discover the causes of lung ADC, and put preventive measures in place.

Prevalence of comorbidities and their impact on survival among older adults with the five most common cancers in Taiwan: a population study.

Because of the cancer incidence increase and population aging in Taiwan, we aimed to assess the cancer prevalence, to summarize the comorbidities of older patients with the five most common cancers (i.e., breast, colorectal, liver, lung, and oral), and to develop a Taiwan cancer comorbidity index (TCCI) for studying their actual prognosis. The linkage of the Taiwan Cancer Registry, Cause of Death Database, and National Health Insurance Research Database was used. We followed the standard statistical learning steps to obtain a survival model with good discriminatory accuracy in predicting death due to noncancer causes, from which we obtained the TCCI and defined comorbidity levels. We reported the actual prognosis by age, stage, and comorbidity level. In Taiwan, cancer prevalence nearly doubled in 2004-2014, and comorbidities were common among older patients. Stage was the major predictor of patients' actual prognoses. For localized and regional breast, colorectal, and oral cancers, comorbidities correlated with noncancer-related deaths. Compared with the US, the chances of dying from comorbidities in Taiwan were lower and the chances of dying from cancer were higher for breast, colorectal, and male lung cancers. These actual prognoses could help clinicians and patients in treatment decision-making and help policymakers in resource planning.

Recalibrating Risk Prediction Models by Synthesizing Data Sources: Adapting the Lung Cancer PLCO Model for Taiwan.

BACKGROUND: Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan. METHODS: Using Taiwanese multiple data sources, we formed an age-matched case-control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011-2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem. RESULTS: The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40+ pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%). CONCLUSIONS: The adapted PLCOT models had high predictive performance. IMPACT: The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Comparison of annual percentage change in breast cancer incidence rate between Taiwan and the United States-A smoothed Lexis diagram approach.

Recent studies compared the age effects and birth cohort effects on female invasive breast cancer (FIBC) incidence in Asian populations with those in the US white population. They were based on age-period-cohort model extrapolation and estimated annual percentage change (EAPC) in the age-standardized incidence rates (ASR). It is of interest to examine these results based on cohort-specific annual percentage change in rate (APCR) by age and without age-period-cohort model extrapolation. FIBC data (1991-2010) were obtained from the Taiwan Cancer Registry and the U.S. SEER 9 registries. APCR based on smoothed Lexis diagrams were constructed to study the age, period, and cohort effects on FIBC incidence. The patterns of age-specific rates by birth cohort are similar between Taiwan and the US. Given any age-at-diagnosis group, cohort-specific rates increased overtime in Taiwan but not in the US; cohort-specific APCR by age decreased with birth year in both Taiwan and the US but was always positive and large in Taiwan. Given a diagnosis year, APCR decreased as birth year increased in Taiwan but not in the US. In Taiwan, the proportion of APCR attributable to cohort effect was substantial and that due to case ascertainment was becoming smaller. Although our study shows that incidence rates of FIBC have increased rapidly in Taiwan, thereby confirming previous results, the rate of increase over time is slowing. Continued monitoring of APCR and further investigation of the cause of the APCR decrease in Taiwan are warranted.

Imiquimod activates p53-dependent apoptosis in a human basal cell carcinoma cell line.

BACKGROUND: The tumor suppressor p53 controls DNA repair, cell cycle, apoptosis, autophagy and numerous other cellular processes. Imiquimod (IMQ), a synthetic toll-like receptor (TLR) 7 ligand for the treatment of superficial basal cell carcinoma (BCC), eliminates cancer cells by activating cell-mediated immunity and directly inducing apoptosis and autophagy in cancer cells. OBJECTIVE: To evaluate the role of p53 in IMQ-induced cell death in skin cancer cells. METHODS: The expression, phosphorylation and subcellular localization of p53 were detected by real-time PCR, luciferase reporter assay, cycloheximide chase analysis, immunoblotting and immunocytochemistry. Using BCC/KMC1 cell line as a model, the upstream signaling of p53 activation was dissected by over-expression of TLR7/8, the addition of ROS scavenger, ATM/ATR inhibitors and pan-caspase inhibitor. The role of p53 in IMQ-induced apoptosis and autophagy was assessed by genetically silencing p53 and evaluated by a DNA content assay, immunoblotting, LC3 puncta detection and acridine orange staining. RESULTS: IMQ induced p53 mRNA expression and protein accumulation, increased Ser15 phosphorylation, promoted nuclear translocation and up-regulated its target genes in skin cancer cells in a TLR7/8-independent manner. In BCC/KMC1 cells, the induction of p53 by IMQ was achieved through increased ROS production to stimulate the ATM/ATR-Chk1/Chk2 axis but was not mediated by inducing DNA damage. The pharmacological inhibition of ATM/ATR significantly suppressed IMQ-induced p53 activation and apoptosis. Silencing of p53 significantly decreased the IMQ-induced caspase cascade activation and apoptosis but enhanced autophagy. Mutant p53 skin cancer cell lines were more resistant to IMQ-induced apoptosis than wildtype p53 skin cancer cell lines. CONCLUSION: IMQ induced ROS production to stimulate ATM/ATR pathways and contributed to p53-dependent apoptosis in a skin basal cell carcinoma cell line BCC/KMC1.

Large-area, uniform white light LED source on a flexible substrate.

This study demonstrates the flexible white LED structure with high lumen efficiency and uniform optical performance for neutral white and warm white CCT. Flip-chip LEDs were attached on a polyimide substrate with copper strips as electrical and thermal conduction paths. Yellow phosphors are mixed with polydimenthysiloxane (PDMS) to provide mechanical support and flexibility. The light efficiency of this device can reach 120 lm/W and 85% of light output uniformity of the emission area can be achieved. Moreover, the optical simulation is employed to evaluate various designs of this flexible film in order to obtain uniform output. Both the pitch between the individual devices and the thickness of the phosphor film are calculated for optimization purpose. This flexible white LED with high lumen efficiency and good reliability is suitable for the large area fixture in the general lighting applications.

Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer.

There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-ß-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.

Growth and characterization of Cu(In,Ga)Se2 thin films by nanosecond and femtosecond pulsed laser deposition.

In this work, CuIn1 - x Ga x Se2 (CIGS) thin films were prepared by nanosecond (ns)- and femtosecond (fs)-pulsed laser deposition (PLD) processes. Different film growth mechanisms were discussed in perspective of the laser-produced plasmas and crystal structures. The fs-PLD has successfully improved the inherent flaws, Cu2 - x Se, and air voids ubiquitously observed in ns-PLD-derived CIGS thin films. Moreover, the prominent antireflection and excellent crystalline structures were obtained in the fs-PLD-derived CIGS thin films. The absorption spectra suggest the divergence in energy levels of radiative defects brought by the inhomogeneous distribution of elements in the fs-PLD CIGS, which has also been supported by comparing photoluminescence (PL) spectra of ns- and fs-PLD CIGS thin films at 15 K. Finally, the superior carrier transport properties in fs-PLD CIGS were confirmed by fs pump-probe spectroscopy and four-probe measurements. The present results indicate a promising way for preparing high-quality CIGS thin films via fs-PLD.