Lung cancer cells detection by a photoelectrochemical MoS2 biosensing chip.

This research aims to explore the potential application of this approach in the production of biosensor chips. The biosensor chip is utilized for the identification and examination of early-stage lung cancer cells. The findings of the optical microscope were corroborated by the field emission scanning electron microscopy, which provided further evidence that the growth of MoS2 is uniform and that there is minimal disruption in the electrode, hence minimizing the likelihood of an open circuit creation. Furthermore, the bilayer structure of the produced MoS2 has been validated through the utilization of Raman spectroscopy. A research investigation was undertaken to measure the photoelectric current generated by three various types of clinical samples containing lung cancer cells, specifically the CL1, NCI-H460, and NCI-H520 cell lines. The findings from the empirical analysis indicate that the coefficient of determination (R-Square) for the linear regression model was approximately 98%. Furthermore, the integration of a double-layer MoS2 film resulted in a significant improvement of 38% in the photocurrent, as observed in the device's performance.

Synchronous pulmonary adenocarcinoma and primary leptomeningeal large B-cell lymphoma-Diagnostic challenge in cerebrospinal fluid: A brief report.

Lung cancer is one of the most common causes of cancer-related deaths worldwide. During or after the treatment of lung cancer, patients might develop another malignant neoplasm. To our knowledge, synchronous pulmonary adenocarcinoma and leptomeningeal large B-cell lymphoma have not been reported in the literature. Herein, we report the first case of synchronous pulmonary adenocarcinoma and primary leptomeningeal lymphoma, which is challenging in cytological diagnosis using cerebrospinal fluid (CSF). Knowledge of this rare situation by cytopathologists might avoid misdiagnosis or erroneous tumor classification during the cytological diagnosis of CSF in the future.

The relative importance of predictive factors for single first-generation EGFR-TKI use for more than 5 years in patients with advanced non-small cell lung cancer: Taiwan multicenter TIPS-5 study.

BACKGROUND: The relative importance of predictive factors for advanced non-small cell lung cancer (NSCLC) patients on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment remains unclear. MATERIALS AND METHODS: We retrospectively enrolled advanced NSCLC patients with single first-generation EGFR-TKI treatment for ⩾5 years (Y) in Taiwan. Clinical data was collected and compared with those of another cohort with single first-line EGFR-TKI treatment for <5 Y. Plasma cell-free DNA (cfDNA) samples were collected from patient subsets, pre- and post-TKI, in the >5 Y group. RESULTS: Overall, 128 and 278 patients were enrolled in the ⩾5 Y and <5 Y groups, respectively. Significant factors in the multivariate analysis of patients' characteristics including Eastern Cooperative Oncology Group performance status 0-1, postoperative recurrence, without brain metastasis, oligometastasis (each score of 2), female sex, erlotinib use, and without bone metastasis (each score of 1), were incorporated into a risk scoring system. The area under the receiver operating characteristic curve was 0.82 [95% confidence interval (CI): 0.78-0.86]. Of the plasma cfDNA samples from 33 patients in the ⩾5 Y group, only 1 had a T790M in 25 patients without progressive disease. In 27 patients with single agent use for ⩾96 months, 22 (81.5%) received local treatment (surgery or radiotherapy) for the primary lung tumor before and during TKI treatment. CONCLUSION: For NSCLC patients with single first-generation EGFR-TKI use for ⩾5 Y, factors with different relative importance exist and the risk-scoring model is feasible with modest accuracy. The role of local treatment for primary tumors in patients with long-term TKI use requires further investigation.

Impact of 23-valent pneumococcal polysaccharide vaccination on the frequency of pneumonia-related hospitalization and survival in elderly patients with prostate cancer: A seven-year nationwide matched cohort study.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is indicated for adults who have a high risk of pneumonia; however, its effectiveness in patients with prostate cancer who are at a risk of pneumonia because of age and cancer treatments, including androgen-deprivation therapy, is unknown. METHODS: Between 2000 and 2010, 38,735 patients with prostate cancer were diagnosed in Taiwan. After exclusions and exact matching for age, previous pneumonia, and influenza vaccination, 2188 vaccinated patients and 2188 unvaccinated patients were recruited. The incidence density of all-cause bacterial pneumonia hospitalizations was analyzed. RESULTS: Over 7 years of follow-up, patients who received the PPSV23 had a significantly lower incidence density, with 142.8 per 1000 person-years versus 162.0 per 1000 person-years for unvaccinated patients. More patients in the vaccinated cohort were never hospitalized for pneumonia compared with those in the unvaccinated cohort (64.2% vs 62.2%, respectively). After adjusting for the Charlson comorbidity index, cancer treatment modalities, and socioeconomic levels, the risk of pneumonia-related hospitalization in the PPSV23 vaccination cohort was 0.48 times lower than that in the unvaccinated cohort (adjusted incidence rate ratio, 0.48; P = .046). For patients who received the influenza vaccination, subgroup analysis demonstrated that PPSV23 vaccination significantly decreased the risk (adjusted incidence rate ratio, 0.45; P < .001). Compared with unvaccinated controls, PPSV23-vaccinated patients had a lower cumulative incidence for the first occurrence of pneumonia-related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% and 42.3%, respectively; P < .001). CONCLUSIONS: Vaccination of elderly patients who have prostate cancer with the relatively common and inexpensive PPSV23 can decrease the risk of pneumonia and prolong survival.

Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy.

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.

S-1 plus cisplatin as first-line treatment of patients with advanced non-small cell lung cancer in Taiwan.

AIM: S-1 combined with cisplatin is known to be noninferior to taxanes plus platinum as the first-line treatment for patients with advanced nonsmall cell lung cancer (NSCLC) in the Japanese population. This study aimed to evaluate the efficacy and safety profiles of oral S-1 plus cisplatin (SP) in Taiwanese patients. METHODS: Patients with previously untreated stage IIIB or IV NSCLC were prospectively recruited to receive 40-60 mg of S-1 twice daily on days 1-21 plus 60 mg/m2 of cisplatin on day 8 in a 5-week cycle for up to six cycles. RESULTS: A total of 55 patients from five cancer centers in Taiwan were enrolled. Among the 46 evaluable patients, those administered with SP achieved disease control rate of 69.6% (partial response, 19.6%; stable disease, 50.0%), with median overall survival and progression-free survival (PFS) of 15.1 and 5.7 months, respectively. Moreover, a better survival trend was observed in epidermal growth factor receptor mutation-positive patients versus mutation-negative patients treated with SP (PFS, 8.6 vs 5.6 months). The most commonly observed treatment-related adverse events (AEs) were nausea (41.8%), followed by decreased appetite, anemia, and diarrhea. Grade of ≥3 AEs related to the study treatment occurred in 11 patients (20.0%). No febrile neutropenia or treatment-related death was found in this study. CONCLUSIONS: This study demonstrated that SP is an effective and safe first-line regimen for Taiwanese patients with advanced NSCLC.

Irradiation enhanced risks of hospitalised pneumonopathy in lung cancer patients: a population-based surgical cohort study.

OBJECTIVE: Pulmonary radiotherapy has been reported to increase a risk of pneumonopathy, including pneumonitis and secondary pneumonia, however evidence from population-based studies is lacking. The present study intended to explore whether postoperative irradiation increases occurrence of severe pneumonopathy in lung cancer patients. DESIGN, SETTING AND PARTICIPANTS: The nationwide population-based study analysed the Taiwan National Health Insurance Research Database (covered >99% of Taiwanese) in a real-world setting. From 2000 to 2010, 4335 newly diagnosed lung cancer patients were allocated into two groups: surgery-RT (n=867) and surgery-alone (n=3468). With a ratio of 1:4, propensity score was used to match 11 baseline factors to balance groups. INTERVENTIONS/EXPOSURES: Irradiation was delivered to bronchial stump and mediastinum according to peer-audited guidelines. OUTCOMES/MEASURES: Hospitalised pneumonia/pneumonitis-free survival was the primary end point. Risk factors and hazard effects were secondary measures. RESULTS: Multivariable analysis identified five independent risk factors for hospitalised pneumonopathy: elderly (>65 years), male, irradiation, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Compared with surgery-alone, a higher risk of hospitalised pneumonopathy was found in surgery-RT patients (HR, 2.20; 95% CI, 1.93-2.51; 2-year hospitalised pneumonia/pneumonitis-free survival, 85.2% vs 69.0%; both p<0.0001), especially in elderly males with COPD and CKD (HR, 13.74; 95% CI, 6.61-28.53; p<0.0001). Unexpectedly, we observed a higher risk of hospitalised pneumonopathy in younger irradiated-CKD patients (HR, 13.07; 95% CI, 5.71-29.94; p<0.0001) than that of elderly irradiated-CKD patients (HR, 4.82; 95% CI, 2.88-8.08; p<0.0001). CONCLUSIONS: A high risk of hospitalised pneumonopathy is observed in irradiated patients, especially in elderly males with COPD and CKD. For these patients, close clinical surveillance and aggressive pneumonia/pneumonitis prevention should be considered. Further investigations are required to define underlying biological mechanisms, especially for younger CKD patients.

Enhancing clinical effectiveness of pre-radiotherapy workflow by using multidisciplinary-cooperating e-control and e-alerts: A SQUIRE-compliant quality-improving study.

Radiotherapy (RT) is useful in managing cancer diseases. In clinical practice, early initiation of RT is crucial for enhancing tumor control. But, delivering precise RT requires a series of pre-RT working processes in a tight staff-cooperation manner. In this regard, using information system to conduct e-control and e-alerts has been suggested to improve practice effectiveness; however, this effect is not well defined in a real-world RT setting.We designed an information system to perform e-control and e-alerts for the whole process of pre-RT workflow to shorten processing time, to improve overall staff satisfaction, and to enhance working confidence.A quality-improving study conducted in a large RT center.Externally validated data were retrospectively analyzed for comparison before (from Sep. 2012 to Dec. 2012, n = 223) and after (from Sep. 2013 to Dec. 2013, n = 240) implementation of pre-RT e-control and e-alerts.Applying the e-control with delay-working e-alerts in pre-RT workflow was the main intervention.Nine workstations were identified in pre-RT workflow. The primary outcome measure was the processing time in each pre-RT workstations before and after implementing the e-control and e-alerts. Secondary measures were staff-working confidence and near-missing cases during the process of pre-RT workflow.After implementing e-control, overall processing time of pre-RT workflow was shortened from 12.2 days to 8.9 days (P < .001). Follow-up data (till Jul. 2016) showed a durable effect of 9.2 days, being still below the predefined threshold of <10 days.Using a multidisciplinary-cooperating information system is useful to conduct e-control and e-alerts in the whole process of pre-RT workflow. Clinical effectiveness, staff satisfaction, and working confidence are able to be enhanced obviously.

Implementing web-based ping-pong-type e-communication to enhance staff satisfaction, multidisciplinary cooperation, and clinical effectiveness: A SQUIRE-compliant quality-improving study.

BACKGROUND: Frequent multidisciplinary communication is essential in conducting daily radiotherapy (RT) practice. However, traditional oral or paper-based communication has limitations. E-communication has been suggested, but its effects are still not well demarcated in the field of radiation oncology. OBJECTS: In our web-based integrated information platform, we constructed a ping-pong-type e-communication function to transfer specific notations among multidisciplinary RT staffs. The purpose was to test whether applying this e-communication can increase effectiveness of multidisciplinary cooperation when compared with oral or paper-based practice. Staff satisfaction and clinical benefits were also demonstrated. DESIGN AND SETTING: A real-world quality-improving study was conducted in a large center of radiation oncology. PARTICIPANTS AND DATASET USED: Before and after applying multidisciplinary e-communication (from 2014 to 2015), clinical RT staffs were surveyed for their user experience and satisfaction (n = 23). For measuring clinical effectiveness, a secondary database of irradiated head and neck cancer patients was re-analyzed for comparing RT toxicities (n = 402). INTERVENTIONS: Applying ping-pong-type multidisciplinary reflective e-communication was the main intervention. OUTCOME MEASURES: For measuring staff satisfaction, eight domains were surveyed, such as timeliness, convenience, and completeness. For measuring clinical effectiveness of multidisciplinary cooperation, event rates of severe (i.e., grade 3-4) RT mucositis and dermatitis were recorded. RESULTS: Overall, when compared with oral communication only, e-communication demonstrated multiple benefits, particularly on notation-review convenience (2.00 ±â€Š1.76 vs 9.19 ±â€Š0.81; P < 0.0001).When compared with paper-based practice, e-communication showed statistically significant benefits on all eight domains, especially on notation-review convenience (5.05 ±â€Š2.11 vs 9.19 ±â€Š0.81; P < 0.0001) and convenience of feedback notation (4.81 ±â€Š1.72 vs 8.76 ±â€Š1.09; P < 0.0001).Moreover, staff satisfaction was gradually increased from oral (3.57 ±â€Š1.94), paper-based (5.57 ±â€Š2.06), to e-communication (8.76 ±â€Š0.70; P < 0.0001). Secondary measurement confirmed these observations.Before and after facilitating multidisciplinary cooperation by using e-communication, severe (i.e., grade 3-4) mucositis and dermatitis were decreased from 21.7% to 10% then to 5.1%. CONCLUSIONS: Replacing oral or paper-based practice with e-communication is useful in facilitating RT multidisciplinary teamwork. Staff satisfaction and clinical effectiveness can be increased.

Cigarette smoking and health-promoting behaviours among tuberculosis patients in rural areas.

AIMS AND OBJECTIVES: To explore cigarette smoking and health-promoting behaviours among disadvantaged adults before their tuberculosis diagnosis and after their tuberculosis treatment. BACKGROUND: Although tuberculosis infection is associated with impaired immune function, healthy lifestyle habits can play a role in improving the immune system. However, limited research has explored the health-promoting behaviours and cigarette smoking habits among tuberculosis patients in Taiwan. DESIGN: A cross-sectional retrospective study with a convenience sample. METHODS: This study was conducted between May 2013-June 2014 with 123 patients at a rural district hospital in Chiayi County, Taiwan. Statistical analyses included descriptive statistics, univariate analysis and stepwise regression analysis. RESULTS: Tuberculosis tended to be associated with less education, male sex, malnutrition, cigarette smoking and unhealthy lifestyle habits before the tuberculosis diagnosis. The percentage of smoking decreased from 46·9% before to 30·2% after the tuberculosis diagnosis. Body mass index and health-promoting behaviours also significantly improved after tuberculosis treatment. After controlling for potential confounding factors, multivariate analysis identified chronic disease and completed treatment as significant factors that were associated with current health-promoting behaviours. CONCLUSIONS: A high prevalence of cigarette smoking and low levels of health-promoting behaviours were observed before the diagnosis and during or after completing tuberculosis treatment. RELEVANCE TO CLINICAL PRACTICE: This study's findings indicate the importance of promoting healthy lifestyle changes among tuberculosis patients; aggressive measures should be implemented immediately after the first diagnosis of tuberculosis. Furthermore, health promotion and smoking cessation programmes should be initiated in the general population to prevent activation of latent tuberculosis infection, and these programmes should specifically target men and rural residents.

Human herpesvirus type 8 in tuberculosis patients with effusion.

BACKGROUND: Many patients with tuberculosis (TB) are seropositive for human herpesvirus type 8 (HHV-8), and many patients with primary effusion lymphoma have high levels of HHV-8 DNA in their effusions. However, the status of HHV-8 in the effusions of patients with TB remains unclear. METHODS: Blood samples were collected from 129 patients with pulmonary TB and 129 age- and sex-matched healthy controls. Forty of the TB patients had pleural or peritoneal effusions, and 38 of these effusions were available. Both blood and effusion samples were analyzed for lymphocyte and monocyte counts and/or HHV-8 antibodies and DNA. RESULTS: TB patients with or without effusions had significantly greater HHV-8 seropositivity (p = 0.009) and titers of HHV-8 antibodies (p = 0.005) than healthy controls. The seropositivity and blood titers of HHV-8 antibodies were similar in TB patients with and without effusions. Among TB patients with effusions, similar percentages had seropositive plasma and seropositive effusions. Plasma samples of 6 TB patients, but none of the healthy controls, were positive for HHV-8 DNA (p = 0.03). TB patients with or without effusions had lower blood lymphocyte counts and higher blood monocyte counts than healthy controls (p < 0.0001 for both). TB patients with effusions had significantly lower blood lymphocyte counts than those without effusions (p = 0.035). CONCLUSIONS: HHV-8 had similar seroprevalence in TB patients with and without effusions. However, TB patients with effusions had lower blood lymphocyte counts than those without effusions.

Effect of 23-Valent Pneumococcal Polysaccharide Vaccine Inoculated During Anti-Cancer Treatment Period in Elderly Lung Cancer Patients on Community-Acquired Pneumonia Hospitalization: A Nationwide Population-Based Cohort Study.

To evaluate effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPSV23) inoculated during defined "vaccination period," first 6 months post cancer diagnosis (ie, an anti-cancer treatment period), in elderly lung cancer patients on community-acquired pneumonia (CAP) hospitalization incidence.This was a nationwide population-based cohort study of 157 newly diagnosed elderly lung cancer patients receiving PPSV23 during "vaccination period", and 628 age and sex one-to-one matched controls enrolled in the National Health Insurance Research Database (NHIRD) of Taiwan between 2007 and 2010. All patients were ≥75 years old and still survival post "vaccination period." Incidence density (ID) of all-cause inpatient CAP and cumulative survival risk were analyzed by multivariate Poisson regression and Kaplan-Meier method, respectively.After a 4-year follow-up, IDs of all-cause inpatient CAP for vaccination and control cohorts were 297 and 444 per 1000 PYs, respectively. Less vaccinated patients had CAP incidence density >1 time per PY (12.7% vs 21.2%) than non-vaccinated patients. After adjusting for potential confounding variables, like influenza vaccination, comorbidities, cancer treatment modalities, and socioeconomic status, adjusted inpatient CAP incidence rate in PPSV23 vaccination cohort was 0.74 times lower than control cohort (incidence rate ratio [IRR] = 0.740, P = 0.0339). Two-year cumulative CAP hospitalization rates and overall survival rates were 37.1% vs. 55.4%, and 46.6% vs. 26.2%, respectively, for lung cancer patients with and without PPSV23 (both P < 0.001). Subgroup analysis showed that for elderly lung cancer patients not ever receiving influenza vaccine, PPSV23 still had trend to reduce all-cause inpatient CAP.For elderly lung cancer patients aged ≥75 years, PPSV23 inoculated during anti-cancer treatment period could reduce CAP hospitalizations and improve survival.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear. METHODS: A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations. RESULTS: One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p < 0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p < 0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005). CONCLUSION: Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.

High seroprevalence of human herpesvirus type 8 infection in males with advanced lung carcinoma.

Human herpesvirus type 8 (HHV-8) DNA is consistently found in all types of Kaposi's sarcoma, which is prevalent in immunocompromised patients. Patients with advanced lung carcinoma often showed immunologic abnormalities, and prevalence of HHV-8 infection is unclear. In this study, blood samples from 109 lung carcinoma patients and 109 age- and sex-matched healthy controls were analyzed for lymphocyte and monocyte counts, and for antibody, DNA, and genotype of HHV-8. Lung carcinoma patients had significantly lower lymphocyte and higher monocyte counts than healthy controls (p < 0.0001, both). HHV-8 seropositivity was more prevalent in lung carcinoma patients (41.3%), particularly in male patients (50.8%), than in controls (24.8%) (p = 0.01 and 0.002, respectively). The seropositivity was also significantly higher in male (50.8%) than female patients (27.3%, p = 0.01). Titers of HHV-8 antibody in patients also significantly exceeded those in controls (p = 0.004). Under a higher threshold (antibody titer ≥1:160) which is equivalent to that of enzyme-linked immunosorbent assay, lung carcinoma patients still had higher HHV-8 seropositivity than controls (p = 0.006). Three patients with stage IV lung carcinoma were positive for HHV-8 DNA with K1 gene subtype C3, D1, and E, respectively; they had much lower lymphocyte counts (658 ± 132 µL) than patients positive for HHV-8 antibodies only (1,449 ± 873 µL). The study indicates that lung carcinoma patients, particularly males, have a high seroprevalence of HHV-8. HHV-8 DNA detected in the patients with advanced lung carcinoma may be a result of virus reactivation in the immunocompromised status.

Discovery of 4-aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 inhibitors. Part I: optimization of in vitro potencies and pharmacokinetic properties.

A series of 4-aryl-N-arylcarbonyl-2-aminothiazoles of scaffold 4 was designed and synthesized as Hec1/Nek2 inhibitors. Structural optimization of 4 led to compound 32 bearing C-4' 4-methoxyphenoxy and 4-(o-fluoropyridyl)carbonyl groups that showed low nanomolar in vitro antiproliferative activity (IC50: 16.3-42.7 nM), high intravenous AUC (64.9 µM·h, 2.0 mg/kg) in SD rats, and significant in vivo antitumor activity (T/C = 32%, 20 mg/kg, IV) in mice bearing human MDA-MB-231 xenografts. Cell responses resulting from Hec1/Nek2 inhibition were observed in cells treated with 32, including a reduced level of Hec1 coimmunoprecipitated with Nek2, degradation of Nek2, mitotic abnormalities, and apoptosis. Compound 32 showed selectivity toward cancer cells over normal phenotype cells and was inactive in a [(3)H]astemizole competitive binding assay for hERG liability screening. Therefore, 32 is as a good lead toward the discovery of a preclinical candidate targeting Hec1/Nek2 interaction.

High incidence of ischemic stroke occurrence in irradiated lung cancer patients: a population-based surgical cohort study.

BACKGROUND AND PURPOSE: A high risk of stroke occurrence has been reported in several types of irradiated cancer patients. However, clinical data are lacking in irradiated lung cancer patients. The present study intended to explore a risk level of ischemic stroke occurrence in irradiated lung cancer patients. METHODS: A nationwide population-based database obtained from the Taiwan National Health Insurance was analyzed. Between 2003 and 2006, we recruited 560 resected lung cancer patients into two study groups: surgery-plus-irradiation (n = 112) and surgery-alone (n = 448). Patients treated with chemotherapy were excluded. Propensity score match was used for pairing cases with a ratio of 1∶4. Two-year ischemic-stroke-free survival was defined as the primary endpoint. RESULTS: Three observations supported a high risk of ischemic stroke occurrence in patients with postoperative irradiation when compared with those patients with surgery alone: first, a high incidence per 1,000 person-year (22.3 versus 11.2, 1.99 folds); second, a low two-year ischemic-stroke-free survival rate (92.2% versus 98.1%, P = 0.019); and third, a high adjusted hazard ratio (HR, 4.19; 95% CI, 1.44-12.22; P = 0.009). More notably, the highest risk of ischemic stroke occurrence was found in irradiated patients who had diabetes mellitus (HR, 34.74; 95% CI, 6.35->100; P<0.0001). CONCLUSIONS: A high incidence of ischemic stroke was observed in irradiated lung cancer patients, especially in those with diabetes mellitus. For these patients, close clinical surveillance and strict diabetes control should be considered. Further studies to define detail biological mechanisms are encouraged.

Combined epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and chemotherapy in non-small-cell lung cancer: chemo-refractoriness of cells harboring sensitizing-EGFR mutations in the presence of gefitinib.

BACKGROUND: Combined epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with chemotherapy is believed to be more effective in treating non-small-cell lung cancer (NSCLC) with sensitizing-EGFR mutation (SEM). This hypothesis failed to be realized clinically and needs to be examined in vitro. MATERIALS AND METHODS: Using the tetrazolium colorimetric assay and classical isobole method, we investigated the combination effects of 6 gefitinib-chemotherapeutic doublets (gefitinib/cisplatin, gemcitabine, pemetrexed, paclitaxel, docetaxel, or vinorelbine) in a panel of 15 NSCLC cell lines. RESULTS: Upon treatment with the 6 gefitinib-chemotherapeutic doublets, the 12 cell lines that did not harbor SEM displayed a broad spectrum of group results, from obvious synergism to robust antagonism. The values of group mean combination index (mCIs) ranged from 0.769 to 1.201. In contrast, the 3 cell lines with SEM showed a tendency toward consistent antagonism to the tested doublets, impressively, with a narrow range of higher group mCIs (0.993-1.141). In the presence of gefitinib, the SEM or gefitinib-sensitive group was more chemo-refractory than the non-SEM (index of chemo-refractoriness (RI): 69.33 versus 42.67; P = 0.036) or gefitinib-resistant group (68.25 versus 40.64, P = 0.0108), respectively. The results of using the gefitinib/drug combinations with the gefitinib-sensitive non-SEM cell line H322 and the gefitinib-resistant EGFR mutant H820 shared patterns similar to those with the SEM and non-SEM cell lines, respectively. CONCLUSION: Gefitinib-treated EGFR-TKI-sensitive NSCLC cells showed a wide spectrum of chemo-refractoriness, suggesting that concomitantly combined EGFR-TKI-chemotherapy might not be a good treatment strategy for NSCLC harboring SEM.

Molecular mechanism of membrane binding of the GRP1 PH domain.

The pleckstrin homology (PH) domain of the general receptor of phosphoinositides 1 (GRP1) protein selectively binds to a rare signaling phospholipid, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), in the membrane. The specific PIP3 lipid docking of GRP1 PH domain is essential to protein cellular function and is believed to occur in a stepwise process, electrostatic-driven membrane association followed by the specific PIP3 binding. By a combination of all-atom molecular dynamics (MD) simulations, coarse-grained analysis, electron paramagnetic resonance (EPR) membrane docking geometry, and fluorescence resonance energy transfer (FRET) kinetic studies, we have investigated the search and bind process in the GRP1 PH domain at the molecular scale. We simulated the two membrane binding states of the GRP1 PH domain in the PIP3 search process, before and after the GRP1 PH domain docks with the PIP3 lipid. Our results suggest that the background anionic phosphatidylserine lipids, which constitute around one-fifth of the membrane by composition, play a critical role in the initial stages of recruiting protein to the membrane surface through non-specific electrostatic interactions. Our data also reveal a previously unseen transient membrane association mechanism that is proposed to enable a two-dimensional "hopping" search of the membrane surface for the rare PIP3 target lipid. We further modeled the PIP3-bound membrane-protein system using the EPR membrane docking structure for the MD simulations, quantitatively validating the EPR membrane docking structure and augmenting our understanding of the binding interface with atomic-level detail. Several observations and hypotheses reached from our MD simulations are also supported by experimental kinetic studies.

Diagnostic value of tumor markers in lung adenocarcinoma-associated cytologically negative pleural effusions.

BACKGROUND: Cytology fails to detect neoplastic cells in approximately 40% to 50% of malignant pleural effusions (PEs), which commonly accompany lung adenocarcinomas. The diagnostic accuracy of various tumor markers in lung adenocarcinoma-associated cytologically negative pleural effusions (LAC-CNPEs) has been poor. The current study attempted to maximize diagnostic efforts in distinguishing LAC-CNPEs from benign PEs. METHODS: PE samples were collected from 74 patients with lung adenocarcinoma with associated cytologically positive (41 patients) and negative (33 patients) PEs, and from 99 patients with benign conditions including tuberculosis (26 patients), pneumonia (28 patients), congestive heart failure (25 patients), and cirrhosis (20 patients). The authors evaluated the diagnostic sensitivity and optimal cutoff points for the tumor markers HER2/neu, CYFRA 21-1, and carcinoembryonic antigen (CEA) to distinguish LAC-CNPEs from benign PEs. RESULTS: Mean levels of HER2/neu, CYRFA 21-1, and CEA were found to be significantly higher in LAC-CNPEs compared with benign PEs (P = .0050, P = .0039, and P < .0001, respectively). The cutoff points for HER2/neu, CYFRA 21-1, and CEA were optimally set at 3.6 ng/mL, 60 ng/mL, and 6.0 ng/mL, respectively. Their sensitivities ranged from 12.1%, to 30.3%, to 63.6%, respectively. CEA combined with CYFRA 21-1 increased diagnostic sensitivity to 66.7%. The false-positive rates of these markers in benign PEs were 6.1%, 2.0%, and 0%, respectively. CONCLUSIONS: The combination of CEA with CYFRA 21-1 appears to provide the best differentiation between LAC-CNPEs and benign PEs to date using 2 tumor markers, and allows for the early diagnosis and early treatment of approximately two-thirds of affected patients.