Comprehensive mutation profiling of mucinous gastric carcinoma.

Mucinous gastric carcinoma (MGC) is a unique subtype of gastric cancer with a poor survival outcome. Comprehensive molecular profiles and putative therapeutic targets of MGC remain undetermined. We subjected 16 tumour-normal tissue pairs to whole-exome sequencing (WES) and an expanded set of 52 tumour-normal tissue pairs to subsequent targeted sequencing. The latter focused on 114 genes identified by WES. Twenty-two histologically differentiated MGCs (D-MGCs) and 46 undifferentiated MGCs (U-MGCs) were analysed. Chromatin modifier genes, including ARID1A (21%), MLL2 (19%), MLL3 (15%), and KDM6A (7%), were frequently mutated (47%) in MGC. We also identified mutations in potential therapeutic target genes, including MTOR (9%), BRCA2 (9%), BRCA1 (7%), and ERBB3 (6%). RHOA mutation was detected only in 4% of U-MGCs and in no D-MGCs. MYH9 was recurrently (13%) mutated in MGC, with all these being of the U-MGC subtype (p = 0.023). Three U-MGCs harboured MYH9 nonsense mutations. MYH9 knockdown enhanced cell migration and induced intracytoplasmic mucin and cellular elongation. BCOR mutation was associated with improved survival. In U-MGCs, the MLH1 expression status and combined mutation status (TP53/BCL11B or TP53/MLL2) were prognostic factors. A comparative analysis of driver genes revealed that the mutation profile of D-MGC was similar to that of intestinal-type gastric cancer, whereas U-MGC was a distinct entity, harbouring a different mutational profile to intestinal- and diffuse-type gastric cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Survey of spike-specific immunoglobulin G antibodies at approximately 3 months and 9 months after vaccination against coronavirus disease 2019 (severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]) in health care workers].

OBJECTIVE: We investigated the antibody titer of spike-specific immunoglobulin G (IgG) antibodies after receiving coronavirus repair uridine ribonucleic acid (RNA) vaccine (BNT162b2, Pfizer) in health care workers. METHODS: At one hospital, health care workers received the vaccination between February and May 2021. A survey using questionnaires and spike-specific IgG antibody tests (Abbott) was conducted in 293 participants who had been vaccinated at least once and consented to this study at the time of medical checkups between April and May 2021. We calculated the antibody titer in each age group and days post-vaccination. We examined whether antibody titers of 4,000 AU/mL or higher (probability of high titer: approximately 95%, Abbott) were associated with adverse reactions after vaccination. In addition (1), the antibody titers at approximately 100 days after the second vaccination in 11 participants were remeasured. Furthermore (2), the antibody titers at approximately 260 days after the second vaccination in 13 participants were remeasured and compared with the initial measurements. RESULTS: Of the participants, 276 were post-2 doses (A), 14 were post-1 dose (B), and 3 discontinued the second vaccination (C) at the time of health checkup. The median antibody titer was 11,045.8 AU/mL (50.7-40,000) in group A, 122.7 AU/mL (2.6-1,127.0) in group B, 27,099.3 AU/mL in one of group C who had recovered from coronavirus disease 2019 (COVID-19), and 574.2 AU/mL (283.3 and 865.1) in the other two of group C. The median antibody titer was the highest in those in their 20s, and there was a significant difference between those under and above 40 years of age. The median titer was the highest in 2 weeks to 1 month after the second vaccination. After the second dose, fatigue (≥ moderate) was associated with antibody titers of 4,000 AU/mL or higher. The antibody titers of 11 and 13 participants at approximately 100 and 260 days after the second vaccination were significantly lower than those at the first measurement, with median values of 2,838.0 AU/mL (832.9-5,698.6) and 512.0 AU/mL (154.0-1,220.0), respectively. CONCLUSIONS: Antibody titers were higher in participants under 40 years of age than those 40 years or older. In addition, the percentage of high antibody titer (≧ 4,000 AU/mL) was higher in those who had severe fatigue after the second vaccination. The peak of antibody titer after the second dose was approximately 1 month, and the titer may decline gradually.

NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth.

Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating antioxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2, cancer chemoprevention and cancer cell growth enhancement, can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice, which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd-derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis. Cancer Res; 76(10); 3088-96. ©2016 AACR.