The role of mitochondrial DNA (mtDNA) mutations in cancer remains controversial. Ulcerative colitis is an inflammatory bowel disease that increases the risk of colorectal cancer and involves mitochondrial dysfunction, making it an ideal model to study the role of mtDNA in tumorigenesis. Our goal was to comprehensively characterize mtDNA mutations in ulcerative colitis tumorigenesis using Duplex Sequencing, an ultra-accurate next-generation sequencing method. We analyzed 46 colon biopsies from non-ulcerative colitis control patients and ulcerative colitis patients with and without cancer, including biopsies at all stages of dysplastic progression. mtDNA was sequenced at a median depth of 1,364x. Mutations were classified by mutant allele frequency: clonal > 0.95, subclonal 0.01-0.95, and very low frequency (VLF) < 0.01. We identified 208 clonal and subclonal mutations and 56,764 VLF mutations. Mutations were randomly distributed across the mitochondrial genome. Clonal and subclonal mutations increased in number and pathogenicity in early dysplasia, but decreased in number and pathogenicity in cancer. Most clonal, subclonal, and VLF mutations were C>T transitions in the heavy strand of mtDNA, which likely arise from DNA replication errors. A subset of VLF mutations were C>A transversions, which are probably due to oxidative damage. VLF transitions and indels were less abundant in the non-D-loop region and decreased with progression. Our results indicate that mtDNA mutations are frequent in ulcerative colitis preneoplasia but negatively selected in cancers.Implications: While mtDNA mutations might contribute to early ulcerative colitis tumorigenesis, they appear to be selected against in cancer, suggesting that functional mitochondria might be required for malignant transformation in ulcerative colitis.

CHA2DS2-VASc and HAS-BLED clinical risk score. Results: Totally, 10,099 patients fulfilled our study criterions. The total annualized direct cost of NVAF patient was 1,627.9 euro ±1,076.6. The main cost component was the hospitalization (68.0%), followed by drug use (24.6%) and outpatient services (7.4%). The predictors of the total cost were male (

to TMA, the effect sizes were significantly larger in NMA. ConClusions: Network meta-analysis of multiple sclerosis trials shows fingolimod as the best treatment. Compared to traditional meta-analysis, network meta-analysis enables more robust estimation of effect sizes.

Our study showed that CT genotype for C1772T polymorphism of HIF-1α predisposes to aggressive tumor phenotype in patients with OSCC. Moreover, patients with CT genotype had poor survival rate as compared to CC genotype. A cut-off value of 460 pg/mL of HIF-1α can help to segregate patients with OSCC from healthy controls.

were 74.0% and 47.7%(p ¼ 0.0199); the 5-year disease-specific survival rates,83.4% and 61.7% (p ¼ 0.1158); and the 5-year local control rates, 70.7% and 57.4% (p ¼ 0.1170) for the surgery and RT groups, respectively. Of the 81 cases, 43 (53.1%) were multiple primary cancers, of which 22 (27.2%) were in the head and neck region and all were metachronous. Conclusions: Initial surgery for stage I/II OPC is a useful therapeutic strategy considering the high incidence of multiple primary cancers.