SOX1 acts as a tumor hypnotist rendering nasopharyngeal carcinoma cells refractory to chemotherapy.

SOX1, a well-known tumor suppressor, delays malignant progression in most cancer types. However, high expression of SOX1 in late-stage head and neck squamous cell carcinoma leads to poor prognosis. In this study, we show that SOX1 induces nasopharyngeal carcinoma (NPC) cells to enter a quiescent state. Using a model that mimics therapeutic resistance and tumor recurrence, a subpopulation of SOX1-induced NPC cells is refractory to paclitaxel, a cell cycle-specific chemotherapy drug. These cells maintain a quiescent state with decreased translational activity and down-regulated cell growth potential. However, once SOX1 expression is decreased, the NPC cells recover and enter a proliferative state. The chemotherapy resistance induced by SOX1 can not pass to next generation, as the cells that undergo re-proliferation become sensitive to paclitaxel again. Moreover, SOX1 directly binds to the promoter region of the MYC gene, leading to transcriptional suppression. When switching to a paclitaxel-free culture environment, the cells with decreased levels of SOX1 re-express MYC, resulting in increased abundance of proliferative cancer cells. Our study presents an evolutionary trade-off between tumor growth and chemoresistance orchestrated by SOX1-MYC in NPC. Basing on the dynamic role of SOX1 in different stages of cancer development, SOX1 would be regarded as a "tumor hypnotist".

Relationship of ERCC5 genetic polymorphisms with metastasis and recurrence of gastric cancer.

OBJECTIVE: This study aims to explore the role of ERCC5 genetic polymorphisms in gastric cancer and their relationship with metastasis and recurrence of gastric cancer. METHODS: A total of 200 patients with gastric cancer and 133 healthy subjects were enrolled. MassARRAY iPLEX® technology was used to genotype ERCC5 rs2016073, rs751402, rs2094258, rs2296147, and rs2296148 between the control group and the gastric cancer group. The relationship of ERCC5 genetic polymorphisms with metastasis and recurrence of gastric cancer was explored. The differences in sociodemographic characteristics between patients with gastric cancer and control subjects were compared using the chi-square test. The genetic loci between the control group and the gastric cancer group were analyzed by the chi-square test. RESULTS: There was no significant difference in the metastasis of gastric cancer between males and females (p=0.628), but there was a significant difference in the metastasis of gastric cancer (p=0.005). Patients aged ≤60 years and >60 years showed no significant difference in the metastasis of gastric cancer (p=0.420), but there was a significant difference in the recurrence of gastric cancer (p<0.001). The loci rs2016073, rs751402, and rs2094258 in the gastric cancer group showed no significant differences compared with the control group (p=0.194), and the loci rs2296147 and rs2296148 showed significant differences. CONCLUSIONS: The results suggested that ERCC5 polymorphisms (e.g., rs201607, rs751402, rs2094258, rs2296147, and rs2296148) may be associated with metastasis and recurrence of gastric cancer.

Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition.

Uncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.

[Research progress of heparinase in the field of medicine].

Heparinases can produce biologically active oligosaccharides by specifically cleaving the α-(1,4) glycosidic linkages of heparin and heparan sulphate. Heparinases are divided into heparinase and heparanase. Because heparinase is an effective biocatalyst, more and more researchers pay attention to the application of heparinase in medical field in the recent years. Combined with the related research work in our group, the application value of heparinase in the medical field was summarized, such as the determination of the structure of heparin, the preparation of low-molecular-weight heparin and ultra-low-molecular-weight heparin, tumor therapy and as a heparin antagonist. In addition, we summarized the definition, source of heparinase and its application in the medicine field. Heparinases have a great application prospect in the field of medicine.

Spatio-temporal variations of black carbon concentrations in the Megacity Beijing.

The spatial and temporal distribution and the flux of black carbon (BC) concentration in Beijing were continuously investigated over a two-year period at five sites to highlight the relative influence of contributing sources. The results demonstrate firstly that there is significant spatio-temporal variability of BC in Beijing. Highest concentrations occurred during winter primarily due to stagnant meteorological conditions, and seasonal BC sources, such as coal combustion for heating purposes. Biomass burning was identified as a minor seasonal source during the summer months. BC also varied spatially with higher concentrations in the SE of Beijing and lower concentrations in the NW, due to the differing emission intensity of various local BC sources such as traffic and industry. Frequently, overnight BC concentrations were higher due to specific meteorological conditions, such as the lower urban mixing layer height and various anthropogenic activities, such as exclusive night-time heavy duty vehicle traffic in the inner-city.

Determination of EGFR mutations in single cells microdissected from enriched lung tumor cells in peripheral blood.

A minimally invasive and repeatable approach for real-time epidermal growth factor receptor (EGFR) mutation surveillance would be highly beneficial for individualized therapy of late stage lung cancer patients whose surgical specimens are often not available. We aim to develop a viable method to detect EGFR mutations in single circulating tumor cells (CTCs). Using a model CTC system of spiked tumor cells in whole blood, we evaluated EGFR mutation determination in single tumor cells enriched from blood. We used magnetic beads labeled with antibody against leukocyte surface antigens to deplete leukocytes and enrich native CTCs independent of epithelial marker expression level. We then used laser cell microdissection (LCM) to isolate individual CTCs, followed by whole-genome amplification of the DNA for exon 19 microdeletion, L858R and T790M mutation detection by PCR sequencing. EGFR mutations were successfully measured in individual spiked tumor cells enriched from 7.5 ml whole blood. Whole-genome amplification provided sufficient DNA for mutation determination at multiple sites. Ninety-five percent of the single CTCs microdissected by LCM (19/20) yielded PCR amplicons for at least one of the three mutation sites. The amplification success rates were 55 % (11/20) for exon 19 deletion, 45 % (9/20) for T790M, and 85 % (17/20) for L858R. Sequencing of the amplicons showed allele dropout in the amplification reactions, but mutations were correctly identified in 80 % of the amplicons. EGFR mutation determination from single captured tumor cells from blood is feasible with the approach described here. However, to overcome allele dropout and to obtain reliable information about the tumor's EGFR status, multiple individual tumor cells should be assayed.

[Evaluation of efficacy and safety of ZD1839 as monotherapy in Chinese patients with advanced non-small cell lung cancer].

OBJECTIVE: To report the outcome of gefitinib for Chinese patients with advanced nonsmall cell lung cancer(NSCLC) at Peking Union Medical College Hospital. METHODS: From Oct. 2002 to Apr. 2006, 204 patients with advanced NSCLC received oral ZD1839 (250 mg/d) treatment. The were 110 (59.9%) men and 94 (40.1%) women aged between 25 and 85 years. Thirty-two patients had squamous cell carcinoma, 125 adenocarcinoma, 30 bronchoalveolar carcinoma or adenocarcinoma with partial bronchoalveolar carcinoma, 6 adenosquamous carcinoma, and 11 unspecified. Twenty-six patients had no history of chemotherapy, 62 had no disease progression after chemotherapy, and 111 failed to prior one or more regimens. Median survival was calculated using the Kaplan-Meier method and a Cox regression analysis was used to detect differences in median survival between strata. RESULTS: The median survival of all patients and of patients failed to prior chemotherapy were 16.3 months (95% confidential interval CI, 14.5 - 18.2) and 12.5 months (95% CI 9.3 - 15.7). The rate of 1-year survival was 57%. The objective tumor response rate and stable disease rate were 31.4% and 41.7% respectively. The median survival were significantly related with ECOG scores, pathology types, disease progression after chemotherapy, objective efficacy of gefitinib and changes of short-breathing. Among 26 patients with no prior chemotherapy, the median survival was not statistically significant compared with that of other patients. Among the enrolled patients, 111 had disease progression and 62 had stable disease after prior chemotherapy, and their median survivals was statistically different. At the time of this analysis, 142 patients had disease progression, 58 of whom withdrew from taking gefitinib, and 84 continued gefitinib therapy until death. The median survivals for these subgroups were not significantly different. Among 142 patients with disease progression, 40 received other systemic treatment, the median survival was statistically significant compared with that of other patients. Objective response was significantly related with age, smoking status, pathological type, change of short-breathing and rashes induced by gefitinib. Adverse events were generally mild (grade 1 and 2) and reversible. The most frequent adverse events were rash 72.6% (138/190) and diarrhea 33.7% (64/190). CONCLUSION: Our study suggests that treatment with gefitinib maybe well tolerate and beneficial for some Chinese patients after failure of prior chemotherapy.

[Efficacy and safety of gefitinib in maintenance therapy for patients with advanced non-small cell lung cancer].

OBJECTIVE: To evaluate the efficacy and safety of gefitinib as maintenance therapy for patient with advanced non-small lung cancer (NSCLC). METHODS: From Oct. 2002 to Apr. 2006, 173 patients with advanced NSCLC received oral gefitinib 250 mg per day after completion of induction chemotherapy (62 patients, maintenance therapy group) or recurrence after one or more regimens of chemotherapy (111 patients, recurrent group). Median survival (MS) and progress free survival (PFS) were calculated using the Kaplan-Meier method, and Cox regression analysis was used to analyze the difference between the sub-groups stratified by smoking, pathological type, liver metastasis and gefitinib treatment result. RESULTS: MS of maintenance therapy group and recurrent group were 25.0 months (95% CI: 19.3-30.7) and 12.5 months (95% CI: 9.3-15.7), respectively. There was a statistically significant difference between the above two groups (P = 0.0004). PFS of maintenance therapy group and recurrent group was 16.5 months (95% CI: 8.7-24.3) and 9.2 months (95% CI: 7.5-10.9), respectively. There was also a statistically significant difference between these two groups (P = 0. 0000). It was found that median MS in maintenance therapy group was significantly correlated with smoking status, pathology type, liver metastasis and objective response of gefitinib. CONCLUSION: Maintenance therapy with gefitinib after induction chemotherapy may improve overall survival in patient with non-small cell lung cancer.

[Efficacy and safety of gefitinib monotherapy for Chinese elderly patients with advanced non-small cell lung cancer].

OBJECTIVE: To report the outcome of Chinese elderly patients with advanced non-small cell lung cancer (NSCLC) of treated with gefitinib at Peking Union Medical College Hospital. METHODS: From Oct. 2002 to Apr. 2006, 63 patients with advanced NSCLC received oral treatment with gefitinib (ZD1839) 250 mg/day. Median survival was calculated using the Kaplan-Meier method and a COX regression analysis was used to detect differences in median survival between strata. RESULTS: Adverse events (AEs) were generally mild (grade 1 and 2) and reversible. The most frequent AEs were rash 76.8% (43/56) and diarrhea 35.7% (20/56). The objective tumor response rate and stable disease rate were 25.4% and 55.6% respectively, and the median survival of all patients was 15.3 months (11.8 - 18.8 months). The rate of 1-year survival was 53%. The median survival was significantly related with ECOG scores, metastasis of liver, pleural effusion, disease progression after chemotherapy, and objective efficacy of gefitinib. Among 16 patients with no prior chemotherapy, the median survival was not significantly different as compared with that of other patients. Among the enrolled patients, 24 had disease progression and 23 had stable disease after prior chemotherapy, and their median survivals were statistically different. At the time of this analysis, 38 patients had disease progression, 15 of whom withdrew from taking gefitinib, and 23 continued gefitinib therapy until death. The median survivals for these subgroups were not significantly different. Objective responses were significantly related with rashes induced by gefitinib. CONCLUSION: Our study suggests that treatment with gefitinib may be well tolerated and beneficial for Chinese elderly patients after failure of prior chemotherapy. Gefitinib could be administered as maintain therapy in patients after chemotherapy. Patients with disease progression should withdraw from taking gefitinib, and receive other systemic treatments.

[Gefitinib in the treatment of advanced non-small cell lung cancer with brain metastasis].

OBJECTIVE: Brain metastasis is frequently found in patient with advanced non-small cell lung cancer. Gefitinib is a inhibitor of epidermal growth factor receptor and can be used for the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the antitumor efficacy of Gefitinib in advanced NSCLC patients with brain metastasis. METHODS: Forty-four consecutive NSCLC patients with brain metastases were treated with gefitinib, which was administered orally at daily dose of 250 mg. Of these patients, 30 had been treated with WBRT and 42 received chemotherapy one month before enrolled into the study. RESULTS: Partial response (PR) was observed in 14 patients (31.8%), stable disease (SD) in 21 (47.7%) with an overall disease control rate of 79.5%. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 13.0 months. The difference in disease control rate between the patients who had previous WBRT and those without was not significant (P = 0.566). The toxicity is mild and tolerable. CONCLUSION: Our data shows that Gefitinib is safe and may be effective on brain metastasis, which may become an alternative treatment option for the patient with advanced NSCLC.

[Treatment of non-small cell lung cancer with gefitinib].

OBJECTIVE: To investigate the antitumor effects and toxicity of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor gefitinib (Iressa) in advanced non-small cell lung cancer (NSCLC). METHODS: The clinical data and quality of life of 66 patients with NSCLC treated with Iressa orally at the dose of 250 mg/d were reviewed, and the data were analyzed by using logistic analysis, chi(2) test and t test. The impact of treatment on disease-related symptoms and quality of life was evaluated with Chinese version of European Organization for Research and Treatment of Cancer-Quality of Life Core Questionnaire-30 (EORTC QLQ-C30) and QLQ-LC13. RESULTS: Tumor response rate was 33%. Disease control rate, which included both tumor responses and stable disease, was 70%. The mean scores of each functioning scales and global quality of life in QLQ-C30 increased significantly. Response rates were 91% - 100%. Mean scores of disease-related symptoms decreased significantly. Response rates were 73% - 100%. Quality of life and symptom response were correlated with objective tumour response. The 250 mg/day dose of Iressa was well tolerated by patients. The majority of adverse events were grade I or grade II skin rash and diarrhea, which were manageable and reversible. CONCLUSION: Iressa offers a new treatment option providing meaningful tumor control and symptom relief for many patients with advanced NSCLC.

[The role of epidermal growth factor receptor inhibitor, gefitinib, in improvement of quality of life of patients with non-small cell lung cancer].

BACKGROUND: Improvement of quality of life (QoL) is an important endpoint for assessment of treatment of non-small cell lung cancer (NSCLC). This study is to report the changes of QoL before and during the treatment with epidermal growth factor receptor inhibitor, gefitinib, for patients with advanced NSCLC. METHODS: Thirty-one eligible patients with NSCLC, who participated in gefitinib compassionate-use program, were enrolled in the study. One oral gefitinib tablet (250mg) was administered every day without interruption unless disease progression or unacceptable toxicity occurred. The impact of treatment on disease-related symptoms and QoL was evaluated with the Chinese versions of European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and QLQ-LC13). RESULTS: After eight weeks of treatment, the mean scores of four functioning scales (physical, role, emotional and social) and global QoL increased significantly. Mean scores of main general symptoms (fatigue and appetite loss) and disease-related symptoms (dyspnoea, coughing, pain in chest, pain in arm and shoulder and pain in other parts) decreased significantly. Response rate of five functioning and global QoL were all more than 50% after gefitinib treatment. Response rate of main general symptoms and disease-related symptoms varied from 44%-84%. QoL and symptom response correlated with objective tumor response. CONCLUSIONS: Gefitinib treatment can improve the QoL and symptoms of advanced NSCLC patients who failed to conventional treatments.

Evaluation of safety and efficacy of gefitinib ('iressa', zd1839) as monotherapy in a series of Chinese patients with advanced non-small-cell lung cancer: experience from a compassionate-use programme.

BACKGROUND: The gefitinib compassionate-use programme has enabled >39,000 patients worldwide to receive gefitinib ('Iressa', ZD1839) treatment. This paper reports the outcome of gefitinib treatment in Chinese patients who enrolled into the 'Iressa' Expanded Access Programme (EAP) at the Peking Union Medical College Hospital. METHODS: Thirty-one patients with advanced or metastatic non-small-cell lung cancer (NSCLC) that had progressed after prior systemic chemotherapy were eligible to receive oral gefitinib 250 mg/day as part of the EAP. Treatment was continued until disease progression or unacceptable toxicity occurred. The impact of treatment on disease-related symptoms and quality of life (QoL) was evaluated with the Chinese versions of European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and QLQ-LC13). RESULTS: Gefitinib was well tolerated. Adverse events (AEs) were generally mild (grade 1 and 2) and reversible. The most frequent AEs were acneform rash and diarrhoea. Only one patient withdrew from the study due to a drug-related AE. The objective tumour response rate was 35.5% (95% confidence interval [CI]: 18.6-52.3); median progression-free survival was 5.5 months (95% CI, 1.6 to 9.4); median overall survival was 11.5 months (95% CI, 5.6 to 17.3). The QoL response rates for five functioning scales and global QoL varied from 56-88%. The main symptom response rates varied from 44-84%. QoL and symptom response were correlated with objective tumour response. CONCLUSION: Gefitinib demonstrated safety and efficacy as monotherapy in this series of Chinese patients with advanced NSCLC and was also associated with remarkable symptom relief and improvement in QoL. Although clinical trials are needed to confirm these positive findings, the data suggest that treatment with gefitinib may be beneficial for some Chinese patients who do not respond to chemotherapy and have poor prognosis.

[Gefitinib for advanced bronchioloalveolar carcinoma].

We described 3 cases of advanced bronchioloalveolar carcinoma (BAC), in whom once-daily treatment with 250 mg Gefitinib (Iressa) demonstrated remarkable antitumor effects. Gefitinib may produce dramatic clinical responses when administered to patients with poor performance status who had received heavy platinum/docetaxel-based prior chemotherapy.

[ZD1839 (Iressa) in the treatment of non-small cell lung cancer patients].

BACKGROUND: To investigate the antitumor effects and toxicity of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor ZD1839 (Iressa) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: From December 2002 to August 2003, 39 patients with unresectable NSCLC were enrolled for 250 mg once-daily oral treatment with ZD1839. Clinical data was analysed using chi-square test, t test and Kaplan-Meier survival analysis. Quality of Life (QoL) was analyzed using Chinese Version of European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 and lung cancer related questionnaire QLQ-LC13. RESULTS: Tumor response rate (complete response and partial response) was 28.2% . Disease control rate, which included both tumor responses and stable disease, was 59.0%. Objective tumor response was correlated with gender and pathological type. Time to progress was (6.6±1.6) months (95% CI, 3.4-9.7), and 1 year survival rate was 54.3%. Response rate of global, functional and lung cancer-related symptom scales were 34.8%, 65.2% and 73.9% respectively. The ZD1839 of 250 mg/d was well tolerated by patients. The majority of adverse events were grade I or grade II skin rash and diarrhea, which were manageable and reversible. CONCLUSIONS: ZD1839 offers a new treatment option providing meaningful tumor control and symptom relief for many patients with advanced NSCLC.