Transcription factor Nrf2 (NF-E2-related factor 2) is essential for oxidative and electrophilic stress responses. While it has been well characterized that Nrf2 activity is tightly regulated at the protein level through proteasomal degradation via Keap1 (Kelch-like ECH-associated protein 1)-mediated ubiquitination, not much attention has been paid to the supply side of Nrf2, especially regulation of Nrf2 gene transcription. Here we report that manipulation of Nrf2 transcription is effective in changing the final Nrf2 protein level and activity of cellular defense against oxidative stress even in the presence of Keap1 and under efficient Nrf2 degradation, determined using genetically engineered mouse models. In excellent agreement with this finding, we found that minor A/A homozygotes of a single nucleotide polymorphism (SNP) in the human NRF2 upstream promoter region (rs6721961) exhibited significantly diminished NRF2 gene expression and, consequently, an increased risk of lung cancer, especially those who had ever smoked. Our results support the notion that in addition to control over proteasomal degradation and derepression from degradation/repression, the transcriptional level of the Nrf2 gene acts as another important regulatory point to define cellular Nrf2 levels. These results thus verify the critical importance of human SNPs that influence the levels of transcription of the NRF2 gene for future personalized medicine.
A case of sustained recovery from a solid type pancreatic ductal carcinoma originating in the pancreas tail is presented. To discover the reasons why the patient has experienced more than five years of sustained recovery, we reviewed the history of this case. The original condition was found incidentally at endoscopic retrograde pancreatography (ERP) under an asymptomatic state originating from pancreatic disorders. As a result, two non-extensive operations were performed. Histologically, the carcinoma was limited to within the pancreas. This case report therefore indicates that even if the lesion is a carcinoma of the body and/or tail of the pancreas, early diagnosis in patients with ductal adenocarcinoma appears to lead to an improvement in the prognosis. Also, this case report suggests that ERP is one of the most effective techniques for the detection of an early carcinoma.
Oesophageal squamous cell carcinoma (OSCC) is considered a difficult cancer to cure. The detection of environmental and genetic factors is important for prevention on an individual basis.
Objective
To identify groups at high risk for OSCC by simultaneously analysing both genetic and environmental risk factors.
Methods
A multistage genome-wide association study of OSCC in Japanese individuals with a total of 1071 cases and 2762 controls was performed.
Results
Two associated single-nucleotide polymorphisms (SNPs), as well as smoking and alcohol consumption, were evaluated as genetic and environmental risk factors, respectively, and their interactions were also evaluated. Risk alleles of rs1229984 (ADH1B) and rs671 (ALDH2) were highly associated with OSCC (odds ratio (OR)=4.08, p=4.4×10−40 and OR=4.13, p=8.4×10−76, respectively). Also, smoking and alcohol consumption were identified as risk factors for OSCC development. By integrating both genetic and environmental risk factors, it was shown that the combination of rs1229984 and rs671 risk alleles with smoking and alcohol consumption was associated with OSCC. Compared with subjects with no more than one environmental or genetic risk factor, the OR reached 146.4 (95% CI 50.5 to 424.5) when both environmental and genetic risk factors were present. Without the genetic risks, alcohol consumption did not correlate with OSCC. In people with one or two genetic risk factors, the combination of alcohol consumption and smoking increased OSCC risk.
Conclusions
Analysis of ADH1B and ALDH2 variants is valuable for secondary prevention of OSCC in high-risk patients who smoke and drink alcohol. In this study, SNP genotyping demonstrated that the ADH1B and/or ALDH2 risk alleles had an interaction with smoking and, especially, alcohol consumption. These findings, if replicated in other groups, could demonstrate new pathophysiological pathways for the development of OSCC.
This study evaluated whether the presence of epidermal growth factor receptor (EGFR) mutations is a predictive marker for survival benefit from gefitinib and/or a prognostic marker in patients with advanced lung adenocarcinoma.Overall survival (OS) was compared between patients with advanced lung adenocarcinoma who began first-line systemic therapy before and after gefitinib approval in Japan (January 1999 to July 2001 and July 2002 to December 2004, respectively). Deletional mutations in exon 19 or the L858R mutation in exon 21 of EGFR were evaluated using high-resolution melting analysis.EGFR mutations were detected in 136 (41%) of the 330 patients included in this study. OS was significantly longer among the EGFR-mutant patients treated after gefitinib approval compared with the OS of patients treated before gefitinib approval (median survival time [MST], 27.2 v 13.6 months, respectively; P < .001), whereas no significant survival improvement was observed in patients without EGFR mutations (MST, 13.2 v 10.4 months, respectively; P = .13). A significant interaction between the presence of EGFR mutations and a survival improvement was seen (P = .045). Among patients treated before gefitinib approval, those with EGFR mutations lived longer than those without EGFR mutations (MST, 13.6 v 10.4 months, respectively; P = .034). The response rates to first-line cytotoxic chemotherapy were not significantly different between patients with and without EGFR mutations (31% v 28%, respectively; P = .50).EGFR mutations significantly predict both a survival benefit from gefitinib and a favorable prognosis in patients with advanced lung adenocarcinoma.
Background. There have been no reports about the incidence and characteristics of carcinoids and endocrine cell micronests (ECM) of the minor and major duodenal papillae. Methods and Results. The minor and major duodenal papillae of 78 consecutive autopsy and 117 surgical specimens were examined histologically using mirror-image paraffin-embedded tissue samples. ECM were found frequently in these areas in hematoxylin and eosin-stained sections, and their aggregation patterns were classified into four types: nodular type (Type 1,2 of 167 in the minor papilla and 1 of 145 in the major papilla), scattered type (Type 2, 39 of 167 and 6 of 145), orifice type (Type 3, 7 of 167 and 0 of 145), and islet-like type (Type 4, 14 of 145 and 0 of 145, respectively). Criteria of neoplastic or nonneoplastic ECM were defined tentatively by histologic and immunohistochemical analyses of the ECM. Type 4 was regarded to be atrophic or regenerating islets of Langerhans. Distinct carcinoids (Type I), neoplastic ECM (39% of all Type 2 and 3), and nonneoplastic ECM (61% of all Type 2 and 3) were found in 1.2%, 9.0%, and 16.20/0 of 167 samples of the minor papilla and 0.7%, 1.470, and 2.8% of 145 specimens of the major papilla, respectively. The endocrine cells composing the carcinoids and the ECM usually were immunoreactive for somatostatin and/or pancreatic polypeptide (PP). They were negative for S-l00β. Conclusion. In duodenal papillae, especially in the minor duodenal papilla, carcinoids and ECM seem to occur more frequently than generally thought, and predominantly consist of somatostatin and/or PP containing cells. Cancer 1992; 70:1825–1833.
Recent advances in biotechnology are making it possible to advance science and improve healthcare with increasing speed and precision. Biobanking, as a foundation of the biotechnology infrastructure, is critical to the assurance of quality for many of the key components for these advancing technologies in both the human and nonhuman domains. Biobanking must advance to support the increased complexity and required precision needs of biological resources. Standards development can provide an important link for the research and development community by providing tools to ensure quality, fitness-for-purpose, and reproducibility in biobanking. ISBER has been developing the ISBER Best Practices revision. At the same time, ISO/TC276/ WG2 has been developing an International Standard (IS) ISO/DIS 20387 General requirements for biobanking standard. It is important that ISBER and ISO/TC276/WG2 harmonize and/or align their products to enable members of the diverse biobanking community to tailor their own suite of tools to support their specific needs. The availability of both standards and best practices that are complementary will maximize available support for all biobanks. The increased availability of complementary standards, tools, and best practices will facilitate the path to new biotechnology advances and a better future.
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