Junhua Zhang

LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling

LKB1 loss-of-function mutations, observed in ∼30% of human lung adenocarcinomas, contribute significantly to lung cancer malignancy progression. We show that lysyl oxidase (LOX), negatively regulated by LKB1 through mTOR-HIF-1α signaling axis, mediates lung cancer progression. Inhibition of LOX activity dramatically alleviates lung cancer malignancy progression. Up-regulated LOX expression triggers excess collagen deposition in Lkb1-deficient lung tumors, and thereafter results in enhanced cancer cell proliferation and invasiveness through activation of β1 integrin signaling. High LOX level and activity correlate with poor prognosis and metastasis. Our findings provide evidence of how LKB1 loss of function promotes lung cancer malignancy through remodeling of extracellular matrix microenvironment, and identify LOX as a potential target for disease treatment in lung cancer patients.

Spectrum of LKB1, EGFR, and KRAS Mutations in Chinese Lung Adenocarcinomas

Introduction: Somatic LKB1 mutations are found in lung adenocarcinomas at different frequencies in Caucasian and East Asian (Japanese and Korean) populations. This study was designed to characterize the frequency of LKB1 mutations, their relationship to EGFR and KRAS mutations, and their associated clinicopathologic characteristics in Chinese patients. Methods: Two hundred thirty-nine lung adenocarcinomas consecutively collected from October 2007 to July 2009 were dissected into 3 to 4 small (3 mm) pieces for histopathological analyses of tumor content. Genomic DNA and/or cDNA from 86 samples with more than 70% tumor content were used for sequencing of LKB1 (exons 1–9), EGFR (exons 18–21), and KRAS (exon 2). LKB1 germline mutation status was determined by sequencing of genomic DNA from matched histologically distant lung tissues that are histologically normal. Results: 6.9% of lung adenocarcinomas harbored LKB1 somatic mutations. A total of 10.5% of patients had an LKB1 germline polymorphism, F354L. Interestingly, in two of these patients, tumors displayed loss of heterozygosity at this allele. EGFR kinase domain and KRAS mutations were found in 66.3% and 2.3% of Chinese lung adenocarcinomas, respectively. Concurrent LKB1 and EGFR somatic mutations were observed in one patient. Both KRAS-mutant tumors harbored LKB1 mutations. Conclusions: These data provide important clinical and molecular characteristics of lung adenocarcinomas from Chinese patients.

Adjuvant Chemotherapy in Oesophageal Cancer: a Meta-analysis and Experience from the Shanghai Cancer Hospital

Whether adjuvant chemotherapy increases survival of oesophageal cancer patients has been widely debated. The present study used meta-analysis software to combine data from six studies up to July 2007 that were found and selected as suitable, comprising a total of 1001 oesophageal cancer patients. The results indicated that adjuvant chemotherapy did not significantly improve outcome in oesophageal cancer patients. A trend towards improved outcome from adjuvant chemotherapy was found in lymph node-positive patients, but did not reach significance. In our own study including 270 oesophageal cancer patients, adjuvant chemotherapy did not improve overall patient survival, but did improve survival for patients with metastases in cervical and/or celiac lymph nodes (stage IVa). Although our study had the largest patient sample, more prospective clinical trials with large numbers of patients are necessary to confirm the value of adjuvant chemotherapy in stage IVa patients.

Plasma Cathepsin L and Its Related Pro/Antiangiogenic Factors Play Useful Roles in Predicting Rich Coronary Collaterals in Patients with Coronary Heart Disease

Cathepsin L enhances angiogenesis by increasing extracellular matrix degradation and remodelling. This study investigated whether plasma cathepsin L could be used as a biomarker to predict collateral formation in patients with coronary heart disease (CHD). Patients with CHD (n = 218; aged 67 ± 11 years) underwent coronary angiography and were categorized as having either ‘poor’ or ‘rich’ collaterals. Plasma cathepsin L, the proangiogenic placenta growth factor (PLGF) and the antiangiogenic factors, cystatin C and endostatin, were measured. Elevated cathepsin L and PLGF levels were independently and significantly associated with enhanced collateral formation in patients with CHD; subgroup analyses also showed a significant correlation in patients with diabetes and acute coronary syndrome. Plasma endostatin and cystatin C levels were not significantly correlated with coronary collateral formation. Plasma cathepsin L and PLGF, acting as important modulators of angiogenesis, could be used as biomarkers to predict coronary collateral formation in patients with CHD.

Prevalence of the Metabolic Syndrome in the Yan-an Region of Northwest China

OBJECTIVES: To evaluate the prevalence of the metabolic syndrome in a sample population from northwest China, and to determine the optimal cut-off point for waist circumference for diagnosing the metabolic syndrome in this population. METHODS: A total of 1290 residents of the Yan-an region of China completed a cross-sectional survey, physical examination and laboratory tests. The International Diabetes Federation (IDF), Chinese Diabetes Society (CDS), and the National Cholesterol Education Program Adults Treatment Panel-III (NCEP—ATPIII) criteria were used to assess the prevalence of the metabolic syndrome and its relationship with age and gender. RESULTS: According to the NCEP—ATPIII, CDS and IDF diagnostic criteria, the prevalence of the metabolic syndrome was 15.8%, 20.4% and 26.4%, respectively. The optimal cut-off point for waist circumference was ≥ 86.5 cm for men and ≥ 80.5 cm for women. CONCLUSIONS: The prevalence of the metabolic syndrome in the Yan-an region was significantly higher than that in other regions of China, and participants with the metabolic syndrome were much younger than those in other Chinese regions.

Secretory expression of heterologous protein in Kluyveromyces cicerisporus.

To explore the potential of heterologous protein expression in Kluyveromyces cicerisporus, three expression plasmids, pUK1-PIT, pUKD-PIT and pUKD-S-PIT, based on the vector pUK1 or pUKD were constructed and transformed, respectively, into yeast strain K. cicerisporus Y179U. Human interferon α-2a, used as an example protein, was successfully expressed and secreted by transformant Y179U/pUKD-PIT and Y179U/pUKD-S-PIT. In the flask culture, strain Y179U/pUKD-S-PIT could express interferon at 60 mg/l. The stability of plasmid pUKD-S-PIT in the host was higher than that of pUKD-PIT. This was consistent with their expression levels of interferon. There were two interferon-related bands found by Western blotting analysis. The possible reason for this is discussed.

Methylation and expression of PTPN22 in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a fatal disease contributed by both genetic and epigenetic factors. The epigenetic alteration of protein tyrosine phosphatase non-receptor type 22 (PTPN22) and its clinical significance in ESCC were still not yet clarified. A quantitative methylation study of PTPN22 and its expression were conducted in 121 and 31 paired tumor and adjacent normal tissue (ANT), respectively. Moreover, the association between PTPN22 methylation and clinicopathological parameters was evaluated. We found that the methylation level of PTPN22 was significantly elevated in tumor tissues (66.3%) relative to ANT (62.1%) (p=0.005). The methylation level of non-smoking ANT (59.1%) was significant lower than smoking ESCC tissue (65.8%) (p=0.03); similarly, the methylation levels in ANT with no lymph node invasion (57.6%) were significant lower than tumor tissues with lymph node invasion (67.5%) (p=0.001). PTPN22 expression in ESCC was lower than normal tissues, however the difference was not statistically significant (p=0.55). Lower expression was more frequently occurred in N1-3 and III stage patients, while higher expression was more likely to occur in N0 and I-II stage patients. Lower expression of PTPN22 was associated with poor overall survival (p=0.04). Taken together, PTPN22 was hypermethylationed in ESCC. Hypermethylation was associated with lymph node invasion. The PTPN22 expression may act as a prognostic biomarker to identify patients at risk of high grade.

HLA-B*1502 Allele is Associated with a Cross-Reactivity Pattern of Cutaneous Adverse Reactions to Antiepileptic Drugs

The US Food and Drug Administration has recommended genetic screening for the human leucocyte antigen-B (HLA-B)* 1502 allele in patients of Asian ethnicity before starting carbamazepine therapy, to avoid the fatal adverse treatment-related events associated with this drug. The association between cross-reactivity to antiepileptic drugs (AEDs) and the HLA-B*1502 allele has been only rarely reported. Here, two cases of cross-reactivity to AEDs, where cutaneous adverse drug reactions (cADRs) developed in female Han Chinese patients with epilepsy who tested positive for the HLA-B*1502 allele, are described. If the genetic association could be confirmed in larger studies, the HLA-B*1502 allele should be tested for in any patient experiencing cADRs, to avoid cross-reactivity to AEDs.

A phase II study of concurrent chemoradiotherapy combined with a weekly paclitaxel and 5-fluorouracil regimen to treat patients with advanced oesophageal carcinoma

BackgroundA phase II study was performed to investigate the safety and efficacy of weekly doses of combined paclitaxel and 5-fluorouracil (5-FU) with concurrent radiation therapy, followed by 2 cycles of consolidation chemotherapy to treat patients with advanced oesophageal carcinoma.MethodsThe eligibility criteria included local, advanced, newly diagnosed and postoperative local regional lymph node metastasis; an Eastern Cooperative Oncology Group (ECOG) score ofu2009≤u20092; and adequate organ function. Patients received chemoradiotherapy consisting of radiotherapy (50.4 Gy/28 Fx or 61.2 Gy/34 Fx) and concurrent paclitaxel (50 mg/m2) and 5-FU (300 mg/m2) for 96 h on days 1, 8, 15, 22, and 29. The two-cycle consolidation chemotherapy protocol included paclitaxel (175 mg/m2) plus continuously infused 5-FU (1800 mg/m2) for 72 h administered on days 57 and 85, after concurrent chemoradiotherapy.ResultsBetween February 2012 and August 2013, 53 patients with oesophageal carcinoma were enrolled in the study. Among these patients, 33 (62.2%) were newly diagnosed and 20 (37.7%) had postoperative local regional lymph node metastasis. The median overall survival (OS) time was 17.9 months (95% CIsu2009=u200911.9-23.9), and the median progression-free survival (PFS) time was 12.4 months (95% CIsu2009=u20098.6-16.1). Approximately 84.9% (45/53) and 50.9% (27/53) of the patients completedu2009≥u20095 cycles and all 7 cycles of chemotherapy, respectively. Approximately 86.7% (46/53) of patients completed radiation therapy. The 1-, 2-, and 3-year OS rates were 66.0%, 37.7%, and 35.8%, respectively. The 1-, 2-, andxa03-year local control rates were 76.9%, 66.4%, and 66.4%, respectively. Seventeen patients (32%) experienced grade 3 or higher toxicity. Grade 3 to 5 toxicity during chemoradiotherapy included neutropaenia (7.5%), thrombocytopaenia (1.8%), fatigue (7.5%), anaemia (1.8%), dermatitis radiation (1.8%), pneumonitis (5.6%), oesophagitis (9.4%) and vomiting (3.7%).ConclusionsThe combination of weekly doses of paclitaxel and 5-FU was well tolerated and produced comparable results among patients with locally advanced oesophageal cancer. A randomised phase III trial (NCT01591135) comparing paclitaxel plus 5-FU with cisplatin plus 5-FU is on-going at our hospital.

Comparative genomic analysis of esophageal squamous cell carcinoma between Asian and Caucasian patient populations

Esophageal squamous cell carcinoma is a major histological type of esophageal cancer, with distinct incidence and survival patterns among races. Although previous studies have characterized somatic mutations in this disease, a rigorous comparison between different patient populations has not been conducted. Here we sequence the samples of 316 Chinese patients, combine them with those from The Cancer Genome Atlas, and perform a comparative analysis between Asian and Caucasian patients. We find that mutated CSMD3 is associated with better prognosis in Asian patients. Applying a robust computational strategy that adjusts for both technical and biological confounding factors, we find that TP53, EP300, and NFE2L2 show higher mutational frequencies in Asian patients. Moreover, NFE2L2 mutations correlate with the allele status of a nearby high-Fst SNP, suggesting their potential interaction. Our study provides insights into the molecular basis underlying the striking racial disparities of this disease, and represents a general computational framework for such a cross-population comparison.Esophageal squamous cell carcinoma (ESCC) exhibits differences in incidence and survival patterns among races. Here, analysis of Chinese and TCGA ESCC patients reveals that Asian patients exhibit higher TP53, EP300 and NFE2L2 mutational frequencies, and mutated CSMD3 associates with better prognosis.