Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.
Population activity in the cortex is poorly understood. In this report we use voltage-sensitive dye imaging to examine the spatiotemporal patterns of a 7-10 Hz oscillation in neocortical slices from rat somatosensory areas. This oscillation appeared as a component of spontaneous epochs when the preparation was bathed in low [Mg] artificial CSF (ACSF) (Silva et al., 1991). Each epoch started with a synchronized spike, and 3-200 cycles of oscillation emerged afterward. Voltage-sensitive dye imaging revealed that the oscillations in the local field potential recordings were actually caused by a propagating population activation. This activation propagated in a relatively uniform size (not expanding). We call this confined, propagating activation a "dynamic ensemble." During each oscillation cycle, one (occasionally two) dynamic ensemble(s) appeared in the slice and was sustained for 60-200 msec. Dynamic ensembles propagated at approximately 30 mm/sec; the activity could propagate in both directions in cortical slices. The propagation consisted in part of "jumps," the locations of which were not fixed. Dynamic ensembles were distinguishable from the epileptiform spikes that occurred in low [Mg] ACSF. Population events similar to dynamic ensembles were also evoked under conditions of unaltered excitability (slice in normal ACSF) by electrical stimulation that activated a low density of neurons in a large area. Our data suggest that self-sustained, spatially confined, and propagating dynamic ensembles might be related to the epoch oscillations in somatosensory cortex seen in vivo (Nicolelis et al., 1995) and thus resemble one form of population activation in the neocortex.
To understand the role of environmental and genetic influences on nasopharyngeal carcinoma (NPC) in populations at high risk of NPC, we have performed a case-control study in Guangxi Province of Southern China in 2004-2005. NPC cases (n=1049) were compared to 785 NPC-free matched controls who were seropositive for IgA antibodies (IgA) to Epstein-Barr virus (EBV) capsid antigen (VCA)—a predictive marker for NPC in Chinese populations. A questionnaire was used to capture exposure and NPC family history data. Risk factors associated with NPC in a multivariant analysis model were the following: 1) a first, second or third degree relative with NPC [Attributable risk (AR)= 6%, Odds ratio (OR) = 3.1, 95%CI = 2.0-4.9, p < 0.001]; 2) consumption of salted fish 3 or more than 3 times per month (AR=3%, OR = 1.9, 95%CI = 1.1-3.5, p = 0.035); 3) exposure to domestic wood cooking fires for more than 10 years (AR=69%, OR = 5.8, 95%CI = 2.5-13.6, p < 0.001); and 4) exposure to occupational solvents for 10 or less years (AR=4%, OR = 2.6, 95%CI = 1.4-4.8, p = 0.002). Consumption of preserved meats or a history of tobacco smoking were not associated with NPC (P>0.05). We also assessed the contribution of EBV/IgA/VCA antibody serostatus to NPC risk—32.2% of NPC can be explained by IgA+ status. However, family history and environmental risk factors cumulatively explained only 2.7% of NPC development in NPC high risk population. These findings should have important public health implications for NPC risk reduction in endemic regions.
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide due to its high difficulty in early diagnosis, high mortality rate and short life span. Recent publications have demonstrated the involvement of the commensal gut microbiota in the initiation, progression and chemoresistance of CRC. However, this microbial community has not been explored within CRC patients after anti-cancer treatments. To this end, we performed next generation sequencing-based metagenomic analysis to determine the composition of the microbiota in CRC patients after anti-cancer treatments. The microbial 16S rRNA genes were analyzed from a total of 69 fecal samples from four clinical groups, including healthy individuals, CRC patients, and CRC patients treated with surgery or chemotherapy. The findings suggested that surgery greatly reduced the bacterial diversity of the microbiota in CRC patients. Moreover, Fusobacterium nucleatum were shown to confer chemoresistance during CRC therapy, and certain bacterial strains or genera, such as the genus Sutterella and species Veillonella dispar, were specifically associated with CRC patients who were treated with chemotherapeutic cocktails, suggesting their potential relationships with chemoresistance. These candidate bacterial genera or strains may have the ability to enhance the dosage response to conventional chemotherapeutic cocktails or reduce the side effects of these cocktails. A combination of common CRC risk factors, such as age, gender and BMI, identified in this study improved our understanding of the microbial community and its compositional variation during anti-cancer treatments. However, the underlying mechanisms of these microbial candidates remain to be investigated in animal models. Taken together, the findings of this study indicate that fecal microbiome-based approaches may provide additional methods for monitoring and optimizing anti-cancer treatments.
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