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Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; p(combined) = 3.9 x 10(-20) and 1.6 x 10(-19), respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; p(combined) = 8.97 x 10(-17)) and HLA-F (rs3129055 and rs9258122; p(combined) = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p < 5 x 10(-4)) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA(B) receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.

Taken together, our data suggest that pathological margins and pathological tumor depth are major independent prognosticators not only for local tumor control, but also for DSS and OS.

Inflammasomes sense infection and cellular damage and are critical for triggering inflammation through IL-1β production. In carcinogenesis, inflammasomes may have contradictory roles through facilitating antitumour immunity and inducing oncogenic factors. Their function in cancer remains poorly characterized. Here we show that the NLRP3, AIM2 and RIG-I inflammasomes are overexpressed in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), and expression levels correlate with patient survival. In tumour cells, AIM2 and RIG-I are required for IL-1β induction by EBV genomic DNA and EBV-encoded small RNAs, respectively, while NLRP3 responds to extracellular ATP and reactive oxygen species. Irradiation and chemotherapy can further activate AIM2 and NLRP3, respectively. In mice, tumour-derived IL-1β inhibits tumour growth and enhances survival through host responses. Mechanistically, IL-1β-mediated anti-tumour effects depend on infiltrated immunostimulatory neutrophils. We show further that presence of tumour-associated neutrophils is significantly associated with better survival in NPC patients. Thus, tumour inflammasomes play a key role in tumour control by recruiting neutrophils, and their expression levels are favourable prognostic markers and promising therapeutic targets in patients.

The most recently discovered enterovirus, enterovirus 71 (EV71), is neurotropic and may cause severe disease and sudden death in children. In 1998, a large outbreak of enterovirus infection occurred in Taiwan that resulted in 405 severe cases in children and 78 deaths. Of the 78 children who died, 71 (91%) were <5 years old. EV71 was the primary agent in fatal cases of infection. Most of these patients died within 1-2 days of admission to the hospital. We hypothesize that EV71 directly attacks the central nervous system and causes neurogenic pulmonary edema and cardiac decompensation through the mechanism of sympathetic hyperactivity and inflammatory responses. Early recognition of risk factors and intensive care are crucial to successful treatment of this fulminant infection. After poliovirus is eradicated, EV71 will become the most important enterovirus that affects children, and development of a vaccine may be the only effective measure against it.

Background-Fabry disease is a treatable lysosomal storage disorder, which is often misdiagnosed or belatedly diagnosed. Methods and Results-To determine the disease incidence in the Taiwan Chinese population, a Fabry disease newborn screening study was initiated. A total of 110 027 newborns were screened by assaying the ␣-galactosidase A (␣-Gal A) activity using dry blood spots. Low plasma ␣-Gal A activity and presence of a Fabry mutation was demonstrated in 45 neonates (3 females). Eight different mutations were identified, including 3 known missense mutations (R112H, A143T, and R356W), 4 novel missense mutations (G104V, M296L, G360C, and K391T), and one known intronic mutation (IVS4ϩ919G3 A). The IVS4ϩ919G3 A mutation was most common (82% of patients). A total of 20 maternal grandparents of infants harboring this intronic mutation were evaluated by echocardiography, mutation analysis and ␣-Gal A activity assay. The intronic mutation was found in 9 grandfathers and 11 grandmothers. Of these grandparents, 3 grandfathers (33%) but none of the grandmothers had hypertrophic cardiomyopathy. Additionally, 16 males who had been diagnosed with idiopathic hypertrophic cardiomyopathy were screened by mutation analysis and ␣-Gal A activity; 4 (25%) showed deficient plasma ␣-Gal A activity in combination with the intronic mutation. Conclusion-We found an unexpected high prevalence of the cardiac variant Fabry mutation IVS4ϩ919G3 A among both newborns (Ϸ1 in 1600 males) and patients with idiopathic hypertrophic cardiomyopathy in the Taiwan

Thyroid nodule is common disorder in endocrine clinics. In Taiwan, thyroid ultrasonography with fine-needle aspiration cytology (FNAC) is the first-line examination procedure. Data in large series on the incidence of thyroid malignancy presenting with thyroid nodules are lacking in this area. To determine the incidence of malignancy in thyroid nodules and compare the results with other populations, this investigation retrospectively reviewed 21,748 subjects who were examined in one medical center from January 1986 to December 1999. All patients underwent thyroid ultrasonography studies using a real-time ultrasonographic machine and a 10-MHz transducer. Fine-needle aspirations were made in the suspected thyroid nodule and stained using the Romanowsky- based method developed by Liu. By the end of 2002, some 3629 patients (16.7%) had thyroid nodules after surgical treatment. This group comprised 3011 women with a mean age of 41.5 +/- 13.9 years, and 618 men with a mean age of 45.7 +/- 14.9 years. Of patients undergoing surgical treatment, 2761 (76.1%) patients were diagnosed with benign nodules, 858 (23.6%) with malignant nodules, and 10 (0.3%) with atypical adenoma (7 follicular and 3 Hürthle cells). The percentages of thyroid malignancy in each age group revealed two peaks in both genders, namely in patients aged 20 to 29 years and in elderly patients (aged over 65 years). The peak age for thyroid malignancy in both genders was 41 to 60 years (male) and 21 to 40 years (female). The highest ratio of malignancy occurred in the elderly group (37.2%) receiving surgical treatment. In young patients (below 19 years) the percentage of malignancy was no greater than for the whole age group (20.2% versus 25.6%). Anaplastic and metastatic cancers affecting the thyroid were the main subjects in the age group. The present results demonstrated a younger distribution for well-differentiated thyroid cancer, particularly papillary thyroid carcinoma, compared to previous studies. This outcome may have resulted from the routine application of ultrasonography with FNAC in assessing the thyroid nodules, possibly helping to achieve more timely detection. The incidence of thyroid malignancy in young patients was no higher than in adults. Early detection of thyroid malignancy may be the main reason for this phenomenon. Male subjects with thyroid nodules displayed a higher incidence of this malignancy than females. Aging subjects with thyroid nodules suffered a higher rate of malignancy and were poorly differentiated. In conclusion, this retrospective large-series study demonstrated that 3.9% (858/21,748 cases) of patients with thyroid nodules showed histopathologically proven malignancy. Thyroid cancer detected by ultrasonography with FNAC occurred an average of 10 years younger than in prior studies.

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