Recruitment and Retention Issues in a Technology-Based Intervention Among Korean American Midlife Women With Depressive Symptoms'.

The number of health technology-based intervention studies has grown significantly. However, issues in the recruitment and retention for such studies, especially of Asian Americans, have rarely been discussed. The purpose of this paper was to discuss issues in the recruitment and retention of a specific group of Asian Americans-Korean American midlife women with depressive symptoms-into a technology-based intervention study using computers and mobile devices with a measurement device and to provide directions for future participant recruitment and retention in technology-based intervention studies. The written memos of research team members and the written records of research team meetings were analyzed using a content analysis. The issues in the recruitment and retention process included (1) low recruitment and retention rates; (2) the perceived long intervention period; (3) strict inclusion/exclusion criteria; (4) concerns related to the use of a measurement device; and (5) the perceived adequacy of monetary incentives. Based on the issues identified in the study, several suggestions are made for future recruitment and retention of racial/ethnic minorities in technology-based intervention studies (eg, appropriate intervention period, innovative and creative motivation strategies, acceptable measurement scales and devices, and adequate monetary reimbursement).

Relationships Between Socio-behavioral Factors and the Symptoms Among Asian American Breast Cancer Survivors: A Structural Equation Modeling.

BACKGROUND: Despite increased research on breast cancer survivors, little is known about how socio-behavioral factors influence the symptoms among racial/ethnic minority breast cancer survivors, particularly Asian American breast cancer survivors (AABCS). OBJECTIVE: This study examined the relationship between multiple socio-behavioral factors in AABCS, including attitudes, perceived barriers, and social influences, and their symptom experiences, with an emphasis on the mediating effect of self-efficacy. METHODS: This secondary analysis used data collected from 195 AABCS women recruited through online and offline communities from January 2017 to June 2020. Study variables were measured using validated instruments such as the Questions on Attitudes, Self-Efficacy, Perceived Barriers, and Social Influences; the Cancer Behavior Inventory; and the Memorial Symptom Assessment Scale-Short Form. For structural equation modeling based on Bandura's self-efficacy theory, mediation analysis was performed using SPSS version 26.0 and AMOS 28. RESULTS: The overall fitness of the hypothetical model to the data is acceptable (χ2 = 51.36, P < .001; goodness-of-fit index = 0.95, adjusted goodness-of-fit index = 0.89, comparative fit index = 0.96, Tucker-Lewis index = 0.94, normed fit index = 0.94, and root-mean-square error of approximation index = 0.08). Both attitudes and social influences indirectly influenced symptom distress through self-efficacy (ß = -0.054, P = .019, and ß = -0.053, P = .017, respectively). Perceived barriers had indirect effects through self-efficacy (ß = 0.121, P = .024) and significant direct effects (ß = 0.605, P = .003) on symptom distress. CONCLUSIONS: Our findings supported that the self-efficacy for coping mediated their symptom experience among AABCS. In addition, there were significant relationships among attitudes, perceived barriers, social influences, and symptom experience. IMPLICATIONS FOR PRACTICE: Future theory-driven interventions need to consider self-efficacy and socio-behavioral factors in symptom management among AABCS.

Five Dimensions of Needs for Help: The Efficacy of a Technology-Based Intervention Among Asian American Breast Cancer Survivors.

Cancer survivors including Asian American breast cancer survivors have reported their high needs for help during their survivorship process. With the COVID-19 pandemic, the necessity of technology-based programs to address their needs for help without face-to-face interactions has been highlighted. The purpose of this randomized intervention study was to determine the efficacy of a technology-based program in reducing various types of needs for help among this specific population. This was a randomized clinical trial with repeated measures. A total of 199 participants were included in the data analysis. The recruitment settings included both online and offline communities/groups for Asian Americans. The needs for help were assessed using the Support Care Needs Survey-34 Short Form (SCNS) subscales measuring psychological, information, physical, support, and communication needs. Data analysis was conducted through an intent-to-treat approach. In the mixed effect models, psychological needs, information needs, physical needs, and communication needs decreased over time (P < .001). However, there were no significant group * time effects. Social support significantly mediated the effects of a technology-based intervention on psychological, information, and support needs at the pre-test and the post-1 month. This study supported significant decreases in the needs for help of Asian American breast cancer survivors by a technology-based intervention. Further studies are needed with other racial/ethnic groups of cancer survivors to confirm the efficacy of a technology-based intervention in reducing cancer survivors' needs for help during their survivorship process.

A randomized controlled trial testing a virtual program for Asian American women breast cancer survivors.

A culturally tailored virtual program could meet the survivorship needs of Asian American women breast cancer survivors (AABC). This study aims to determine the efficacy of a culturally tailored virtual information and coaching/support program (TICAA) in improving AABC's survivorship experience. A randomized clinical trial (NCT02803593) was conducted from January 2017 to June 2020 among 199 AABC. The intervention group utilized TICAA and the American Cancer Society [ACS] website while the control group used only ACS website for 12 weeks. The outcomes were measured using the SCNS-34SF (needs; primary), the MSAS-SF (symptoms; secondary), and the FACT-B (quality of life; secondary). The data were analyzed using an intent-to-treat approach. The intervention group showed significant reductions in their needs from the baseline (T0) to post 4 weeks (T1) and to post 12 weeks (T2). Although the changes were not statistically significant, the intervention group had decreased symptoms from T0 to T2 while the control group had an increase in their symptoms. The intervention group had a significant increase in their quality of life from T0 to T2. A culturally tailored virtual program could therefore improve quality of life in AABC patients. Trial Registration: To Enhance Breast Cancer Survivorship of Asian Americans (TICAA), NCT02803593, https://clinicaltrials.gov/ct2/show/NCT02803593?titles=TICAA&draw=2&rank=1.

The combination of osimertinib with Raf inhibitor overcomes osimertinib resistance induced by KRAS amplification in EGFR-mutated lung cancer cells.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR)1 tyrosine kinase inhibitor (TKI) approved for the treatment of EGFR-positive patients exhibiting a T790 M resistance mutation after treatment with an earlier generation of EGFR TKIs. However, resistance to osimertinib inevitably develops despite its efficacy, and the resistance mechanisms are complex and not fully understood. We established cell lines with acquired resistance to osimertinib from gefitinib- or erlotinib-resistant NSCLC cells using a dose-escalation method, and found that they had upregulated levels of phosphorylated ERK1/2. Targeted next-generation sequencing of 143 genes was performed, and interestingly, amplification of KRAS was observed in osimertinib-resistant cells. Transfection of siRNA against the KRAS gene notably reduced the activation of ERK1/2 and AKT and significantly enhanced the induction of apoptosis by osimertinib treatment in osimertinib-resistant cells. LY3009120, a RAF inhibitor, showed a significant synergistic effect with osimertinib on apoptotic cell death in osimertinib-resistant cells. Combined treatment with osimertinib and LY3009120 also demonstrated remarkable synergistic anti-tumor activity in mouse xenografts of these cells. This could be a potential new treatment option for KRAS amplification-induced osimertinib failure.

Practical Issues in a Culturally Tailored Technology-Based Intervention for Asian American Colorectal Cancer Survivors.

BACKGROUND: Despite an increasing number of culturally tailored technology-based interventions for racial/ethnic minorities, little is known about practical issues in conducting a culturally tailored technology-based intervention study among racial/ethnic minority groups, especially among Asian American colorectal cancer survivors. OBJECTIVE: The aim of this study was to describe the practical issues in conducting a study using a culturally tailored technology-based intervention among Asian American colorectal cancer survivors. METHODS: In a technology-based colorectal cancer intervention study, research team members wrote memos on issues in conducting a culturally tailored technology-based intervention study among the specific population and plausible reasons for the issues. Then, a content analysis was used to analyze the research diaries and written records of the research team. RESULTS: The practical issues found in the research process included (a) unauthentic cases, (b) a low response rate, (c) high dropout rates, (d) technological literacy, (e) language issues, (f) cultural tailoring issues, and (g) time and geographical limitations. CONCLUSIONS: These practical issues need to be considered in planning and implementing culturally tailored technology-based interventions among Asian American colorectal cancer survivors. IMPLICATIONS FOR PRACTICE: Multiple implications such as detailed information sheets, flexibility in languages, open attitudes toward cultural differences and variances, and continuous training of interventionists are proposed for culturally tailored technology-based interventions among this specific population.

Knowledge, attitudes, and perceptions associated with HPV vaccination among female Korean and Chinese university students.

BACKGROUND: Human papillomavirus (HPV) vaccination is a form of primary prevention for cervical cancer. The HPV vaccination rate of female university students is not high in Korea and China. Therefore, the purpose of this study was to identify and compare the factors associated with intention to receive HPV vaccination between Korean and Chinese female university students. METHODS: The participants were 273 Korean and 317 Chinese female university students who had not been vaccinated for HPV, and data were collected using a self-reported questionnaire about attitudes toward HPV vaccination, HPV knowledge, perceptions of HPV infection, and intention to receive HPV vaccine. RESULTS: There were no significant differences between the Korean and Chinese female university students in HPV knowledge, attitudes, perceptions, and vaccination intention. The factors influencing the intention of HPV vaccination in Korean students were a positive attitude toward the HPV vaccine and a high HPV knowledge score. For Chinese students, sexual experience, awareness of genital warts, a positive attitude toward the HPV vaccine, a high HPV knowledge scores, a perception of the seriousness of HPV infection, and negative emotions regarding HPV infection were significant factors. CONCLUSIONS: It is important to improve attitudes and knowledge about HPV and the HPV vaccine in order to enhance HPV vaccination both in Korea and China. Perceived seriousness and negative emotions regarding HPV infection should be used as a framework to develop subject-tailored interventions in China.

An access to highly enantioenriched cis-3,5-disubstituted γ-lactones from α-bromoacetate and silyl enol ether.

A novel synthetic strategy for highly enantioenriched cis-3,5-disubstituted γ-lactones has been developed by the AgOTf-promoted nucleophilic substitution of α-bromoacetates with silyl enol ethers and subsequent reductive lactonization. The utility of this synthetic method was further demonstrated through the concise stereodivergent synthesis of cis- and trans-2,4-disubstituted tetrahydrofurans.

The Combination of Trametinib, a MEK Inhibitor, and Temsirolimus, an mTOR Inhibitor, Radiosensitizes Lung Cancer Cells.

BACKGROUND/AIM: We evaluated the radiosensitizing effect of the combination treatment of trametinib, a MEK inhibitor, and temsirolimus, an mTOR inhibitor, on non-small-cell lung carcinoma (NSCLC) cells. MATERIALS AND METHODS: The effects of combining trametinib and temsirolimus with radiation in NSCLC cell lines were evaluated using clonogenic survival and apoptosis assays. DNA double-strand breaks and cell cycle distribution were analyzed using flow cytometry. Tumor volume was measured to determine the radiosensitivity in lung cancer xenograft models. RESULTS: Exposure of lung cancer cells to a combination of trametinib and temsirolimus reduced clonogenic survival and promoted radiation-induced apoptosis. Combined inhibition of MEK and mTOR induced prolonged expression of γH2AX after irradiation and resulted in prolonged G2/M cell cycle arrest after irradiation in A549 cells. In vivo studies revealed that co-administration of the drugs sensitizes lung cancer xenografts to radiotherapy. CONCLUSION: The combination of trametinib and temsirolimus can enhance lung cancer radiosensitivity in vitro and in vivo.

Association of EGFR mutations in second primary lung cancer and HER2 expression in breast cancer survivors.

BACKGROUND: The incidence of second primary lung cancer (SPLC) is increasing with longer survival rates from breast cancer. Despite of studies to suggest the mutual exclusivity of epidermal growth factor receptor (EGFR) and human epidermal growth receptor 2 (HER2) in several cancers, the effect of HER2 expression in breast cancer on EGFR mutations in SPLC is unclear. Therefore, this study aimed to determine the association between HER2 expression and EGFR mutations. METHODS: We conducted a retrospective cohort study of breast cancer survivors diagnosed with SPLC after breast cancer treatment between 1997 and 2018. We investigated the association between HER2 expression in breast cancer and EGFR mutations in SPLC, specifically focusing on negative correlations by using logistic regression analysis. RESULTS: EGFR mutations in SPLC were detected in 19 of 38 patients. Analysis for HER2 revealed a statistically significant difference in the proportion of EGFR mutations between patients with SPLC and previous HER2 positive breast cancer (43.5%) and those with SPLC and previous HER2 negative breast cancer (90.0%; P=0.021). The ratio of EGFR mutations decreased with the degree of HER2 expression in patients with previous breast cancer (90.0%: for no HER2 expression, 62.5% for HER2 1+, 0.0% for HER2 2+, and 41.7% for HER2 3+; P=0.018). Multivariate logistic analyses revealed that EGFR mutations in SPLC were significantly associated with age [odds ratio (OR): 1.11, 95% confidence interval (CI): 1.01-0.23, P=0.039] and HER2 positive status (OR: 0.04, 95% CI: 0.01-0.56, P=0.017). CONCLUSIONS: This study suggests that the frequency of EGFR mutations in SPLC may be associated with low HER2 expression in previous breast cancer.

Radiation Induces Autophagy via Histone H4 Lysine 20 Trimethylation in Non-small Cell Lung Cancer Cells.

BACKGROUND/AIM: Radiotherapy-induced autophagy affects radiation-sensitivity and radiotherapy efficacy. Histone modifications also occur during radiotherapy. This study assessed radiotherapy effects on histone modification and autophagy in non-small cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: NSCLC cells were subjected to γ-irradiation. Autophagy was detected using western blotting and acridine orange staining. Radiation effect on cell growth was evaluated by clonogenic assay. Histone modifications were assessed by western blotting. Next generation sequencings (NGSs) were conducted to identify histone modification target genes. RESULTS: Radio-protective autophagy and histone H4 lysine 20 trimethylation (H4K20me3) were up-regulated after irradiation. By NGSs, genes that are differentially expressed upon irradiation were identified, including the candidate H4K20me3 target gene GABARAPL1. Furthermore, we showed that GABARAPL1 is essential for the radiation-induced autophagy. CONCLUSION: Our findings revealed the regulatory axis of radiation-induced H4K20me3-GABARAPL1 in radio-protective autophagy. Modulation of this axis may be a new strategy to enhance radiotherapy efficacy in NSCLC.

Factors that Predict Clinical Benefit of EGFR TKI Therapy in Patients with EGFR Wild-Type Lung Adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR. METHODS: We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. RESULTS: The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH-positive, and 11 were EGFR SISH-negative, with no significant difference in tumor response and survival between EGFR SISH-positive and -negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were independent predictors of PFS. ECOG PS 0-1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. CONCLUSION: Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells.

BACKGROUND: Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of non-small cell lung cancer (NSCLC). Although the discovery of driver mutations and their targeted drugs has remarkably improved the treatment outcomes for lung adenocarcinoma, currently no such molecular target is clinically available for SqCLC. The CDKN2A locus at 9p21 encodes two alternatively spliced proteins, p16INK4a (p16) and p14ARF (p14), which function as cell cycle inhibitors. The Cancer Genome Atlas (TCGA) project revealed that CDKN2A is inactivated in 72% of SqCLC cases. In addition, it was found that CDKN2A mutations are significantly more common in SqCLC than in adenocarcinoma. Down-regulation of p16 and p14 by CDKN2A gene inactivation leads to activation of cyclin-dependent kinases (CDKs), thereby permitting constitutive phosphorylation of Rb and subsequent cell cycle progression. Here, we hypothesized that CDK inhibition may serve as an attractive strategy for the treatment of CDKN2A-defective SqCLC. METHODS: We investigated whether the CDK inhibitors flavopiridol and dinaciclib may exhibit antitumor activity in CDKN2A-defective SqCLC cells compared to control cells. The cytotoxic effect of the CDK inhibitors was evaluated using cell viability assays, and the induction of apoptosis was assessed using TUNEL assays and Western blot analyses. Finally, anti-tumor effects of the CDK inhibitors on xenografted cells were investigated in vivo. RESULTS: We found that flavopiridol and dinaciclib induced cytotoxicity by enhancing apoptosis in CDKN2A-defective SqCLC cells, and that epithelial to mesenchymal transition (EMT) decreased and autophagy increased during this process. In addition, we found that autophagy had a cytoprotective role. CONCLUSION: Our data suggest a potential role of CDK inhibitors in managing CDKN2A-defective SqCLC.

Molecular basis for unique specificity of human TRAF4 for platelets GPIbß and GPVI.

Tumor necrosis factor (TNF)-receptor associated factor 4 (TRAF4), an adaptor protein with E3-ligase activity, is involved in embryogenesis, cancer initiation and progression, and platelet receptor (GPIb-IX-V complex and GPVI)-mediated signaling for reactive oxygen species (ROS) production that initiates thrombosis at arterial shears. Disruption of platelet receptors and the TRAF4 interaction is a potential target for therapeutic intervention by antithrombotic drugs. Here, we report a crystal structure of TRAF4 (amino acid residues 290∼470) in complex with a peptide from the GPIbß receptor (amino acid residues 177∼181). The GPIbß peptide binds to a unique shallow surface composed of two hydrophobic pockets on TRAF4. Further studies revealed the TRAF4-binding motif Arg-Leu-X-Ala. The TRAF4-binding motif was present not only in platelet receptors but also in the TGF-ß receptor. The current structure will provide a template for furthering our understanding of the receptor-binding specificity of TRAF4, TRAF4-mediated signaling, and related diseases.

Altered expression of cellular proliferation, apoptosis and the cell cycle-related genes in lung cancer cells with acquired resistance to EGFR tyrosine kinase inhibitors.

Non-small cell lung cancers harboring somatic gain-of-function mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain respond well to treatment with EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib. However, all patients who experience a marked improvement with these drugs eventually develop disease progression due to the acquisition of drug resistance. Approximately half of the cases with acquired resistance to EGFR TKIs can be accounted for by a second-site mutation in exon 20 of the EGFR kinase domain (T790M). However, the changes of gene expression involved in EGFR TKI resistance due to the T790M mutation remain poorly defined. The present study established lung cancer cell lines that were resistant to gefitinib or erlotinib, and these cell lines were verified to contain the EGFR T790M mutation. The differential expression of genes associated with acquired resistance was verified in the present study by mRNA microarray analysis. Among the genes whose expression was significantly altered, genes whose expression was altered in gefitinib- and erlotinib-resistant cells were focused on. Notably, a total of 1,617 genes were identified as being differentially expressed in gefitinib- and erlotinib-resistant cells. Indeed, Gene ontology analysis revealed altered expression of genes involved in the regulation of cellular proliferation, apoptosis, and the cell cycle in EGFR TKI-resistant cells. The present results demonstrate distinctive gene expression patterns of EGFR TKI-resistant lung cancer cells with the EGFR T790M mutation. The present study can provide key insights into gene expression profiles involved in conferring resistance to EGFR TKI therapy in lung cancer cells.

Sex-specific incidence of EGFR mutation and its association with age and obesity in lung adenocarcinomas: a retrospective analysis.

PURPOSE: Age and obesity are well-known risk factors for various cancers, but the potential roles of age and obesity in lung cancer, especially in those with activating EGFR mutations, have not been thoroughly evaluated. The aim of this retrospective study is to evaluate the associations between the sex-specific incidence of EGFR mutations and age and obesity. METHODS: We conducted a retrospective study based on the data from 1378 lung adenocarcinoma cases. The degree of obesity was categorized by body mass index (BMI). The associations between EGFR mutational status and clinical factors, including stage, smoking history, age group (≤45 years, 46-55, 56-65 and >65), and BMI group (<18.5 kg/m2, 18.5-22.9, 23.0-24.9 and ≥25.0) were analyzed using logistic regression models for each sex. RESULTS: In men, the incidence of EGFR mutation was inversely associated with age (adjusted odds ratio [OR] for age group = 0.76, p-trend = 0.003) and positively associated with obesity (adjusted OR for BMI group = 1.23, p-trend = 0.04). In contrast, in women, the incidence of EGFR mutation was positively associated with age (adjusted OR for age group = 1.19, p-trend = 0.02). However, the incidence of EGFR mutation was not statistically associated with obesity (adjusted OR for BMI group = 1.03, p-trend = 0.76). CONCLUSIONS: Our data suggests that age and obesity may contribute to the sex-specific incidence of EGFR mutation in lung adenocarcinoma in different manners.

Fhit, a tumor suppressor protein, induces autophagy via 14-3-3τ in non-small cell lung cancer cells.

Inactivation of the fragile histidine triad (Fhit) gene has been reported in the majority of human cancers, particularly in lung cancer. The role of Fhit as a tumor suppressor gene has been well documented, and restoration of Fhit expression suppresses tumorigenicity in tumor cell lines and in mouse models by inducing apoptosis and inhibiting proliferation of tumor cells. Autophagy is a catabolic pathway, whereby cytoplasmic proteins and organelles are sequestered in vacuoles and delivered to lysosomes for degradation and recycling. Although autophagy is necessary for cell survival under stress conditions, recent studies have shown that autophagy can also promote cell death. Due to the fact that both autophagy induction and Fhit expression are commonly associated with nutrient starvation, we hypothesized that Fhit expression may be related to autophagy induction. In the present study, we assessed whether Fhit overexpression by gene transfer induces autophagy in Fhit-deficient non-small cell lung cancer (NSCLC) cells. The results of our study indicate that Fhit protein induces autophagy in NSCLC cells, and that this autophagy prevents apoptotic cell death in vivo and in vitro in a 14-3-3τ protein-dependent manner. To the best of our knowledge, this is the first report to describe Fhit-induced autophagy. Suppressing autophagy might be a promising therapeutic option to enhance the efficacy of Fhit gene therapy in NSCLC.

Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer.

BACKGROUND: The aim of this study was to investigate the association between epidermal growth factor receptor (EGFR) mutation and thyroid cancer in female patients with nonsmall-cell lung cancer (NSCLC). METHODS: In a retrospective study, we examined 835 female patients who were diagnosed with NSCLC and underwent an EGFR mutation test between June 2003 and August 2013. The associations of EGFR mutation with thyroid cancer and a family history of thyroid cancer were evaluated using logistic regression models. RESULTS: EGFR mutation was found in 378 of 835 patients. In addition to adenocarcinoma (P < 0.001), EGFR mutations were positively associated with a personal history of thyroid cancer (5.8% versus 2.6%; P = 0.020), while showing a trend toward inverse association with a personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Likewise, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while showing a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066). Multivariate logistic regression showed that the incidence of EGFR mutations was different in women with thyroid or nonthyroid cancer (P = 0.035) and in women with a family history of thyroid or nonthyroid cancer (P = 0.023). CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change.

Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis.

The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer.

To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed. However, clinical data on their efficacy in treating T790M mutant tumors are lacking. Histone deacetylase (HDAC) inhibitors have been reported to arrest cell growth and to lead to differentiation and apoptosis of various cancer cells, both in vitro and in vivo. In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells. While treatment with BIBW2992 or WZ4002 alone slightly reduced the viability of PC-9G and H1975 cells, which possess T790M mutation, combining them with SAHA resulted in significantly decreased cell viability through the activation of the apoptotic pathway. This combination also enhanced autophagy occurrence and inhibition of autophagy significantly reduced the apoptosis induced by the combination treatment, showing that autophagy is required for the enhanced apoptosis. Caspase-independent autophagic cell death was also induced by the combination treatment with SAHA and either BIBW2992 or WZ4002. Finally, the combined treatment with SAHA and either BIBW2992 or WZ4002 showed an enhanced anti-tumor effect on xenografts of H1975 cells in vivo. In conclusion, the combination of new generation EGFR TKIs and SAHA may be a new strategy to overcome the acquired resistance to EGFR TKIs in T790M mutant lung cancer.