IntroductionThe renin-angiotensin system plays a critical role in blood pressure regulation and fluid hemodynamics. Pharmacologic inhibitors of this system are routinely used to treat hypertension and congestive heart failure. One of the most controversial effects of the reninangiotensin system has been the interplay of this system with erythrocyte production. A variety of clinical reports have noted an association between activation of the renin-angiotensin system and increased erythropoiesis (1-3). These studies have come from analyses of patients with a variety of chronic diseases including chronic obstructive pulmonary disease, heart failure, and renal transplantation. Other investigators have suggested a link between angiotensin-converting enzyme (ACE) inhibitors and worsened anemia, particularly in patients with chronic renal failure (4-6). While research has focused on the interplay of the renin-angiotensin system and erythropoietin, no mechanistic explanation for these observations has been generally accepted.Central to the renin-angiotensin system is ACE, a peptidase that converts angiotensin I to angiotensin II (7). In mammals, most ACE is bound to tissues such as endothelium, but enzymatic cleavage results in a circulating form within plasma. In vitro, ACE is capable of cleaving many small peptides besides angiotensin I. However, in vivo, with the exception of bradykinin, the significance of nonangiotensin peptides as ACE substrates is not well understood. ACE is a protein with two independent catalytic domains. While both catalytic sites hydrolyze angiotensin I with roughly equal efficiency, the amino-and carboxy-terminal catalytic domains differ in their rate constants for other peptides.Using targeted homologous recombination in embryonic stem (ES) cells, our laboratory created two lines of mice with modifications of the ACE gene (8, 9). These animals are termed ACE.1 and ACE.2. Mice homozygous for the ACE.1 allele (ACE.1 knockout mice) are null for all ACE production. They have a marked reduction of blood pressure, and a renal lesion characterized by hypoplasia of the renal medulla and papilla. In contrast to this null phenotype, animals homozygous for the ACE.2 allele (ACE.2 knockout mice) have a partial restoration of ACE activity. These animals express a truncated ACE protein containing only the amino-terminal catalytic domain. Since this shortened ACE protein lacks the carboxy-terminal domain that normally anchors ACE to cell membranes, the ACE.2 protein is exported from cells into blood and other extracellular fluids. Thus, while the plasma of ACE.2 mice converts angiotensin I to angiotensin II with about 34% of the activity of wild-type mouse plasma, tissues such as the lung and kidney completely lack ACE protein or activity. The systolic blood pressure of ACE.2 knockout mice averaged 75 mmHg, as low as that of the ACE.1 knockout animals.Here, we investigate an unexpected finding concerning the phenotypes of both the ACE.1 and ACE.2 mice. These animals are anemic. ACE.2 knockout mice are a p...

Hypoxia can lead to solid tumor aggressiveness by driving multiple signaling pathways. Long non-coding RNAs respond to several extrinsic stimuli, causing changes in cancer cells by participating in multiple steps of gene expression. However, genomic profiling of long non-coding RNAs regulated by oxygen in breast cancer remained unclear. Therefore, the aims of this study were to identify oxygen-responsive long non-coding RNAs in breast cancer cells, and to delineate their regulatory mechanisms. The expression profiling of long non-coding RNAs in breast cancer cells growing under normoxic, hypoxic, and re-oxygenated conditions was examined using next-generation sequencing technology. Four hundred and seventy-two lncRNAs oxygen-responsive lncRNAs were identified. After examining the top three differentially expressed lncRNAs in hypoxia, we selected N-Myc Downstream Regulated Gene 1-Overlapping 1 (NDRG1-OT1) for further study, especially the most responsive isoform, NDRG1-OT1_v4. We overexpressed NDRG1-OT1_v4 under normoxia and performed microarray analysis to identify 108 NDRG1-OT1_v4 regulated genes and their functions. Among these genes, we found that both NDRG1 mRNA expression and NDRG1 protein levels were inhibited by NDRG1-OT1_v4. Finally, we used co-immunoprecipitation to show that NDRG1-OT1_v4 destabilizes NDRG1 by promoting ubiquitin-mediated proteolysis. Our findings reveal a new type of epigenetic regulation of NDRG1 by NDRG1-OT1_v4 in breast cancer cells.

Background: Palliative chemotherapy is the preferred standard of care for patients with metastatic gastric cancer (mGC). It remains uncertain whether older patients with mGC would benefit from palliative chemotherapy. This study aimed to investigate the clinical impact of palliative chemotherapy in older patients with mGC. Methods: This single-institute, retrospective, and real-world study included 428 patients with mGC between January 2009 and December 2019. Among them, 306 who received palliative chemotherapy were further stratified into 2 groups according to age: ≤70 (n = 236) and >70 (n = 70) years. The clinical demographics, outcomes, and hematologic toxicities of chemotherapy were compared between the 2 groups. Prognostic factors were determined using the Cox proportional hazards model. Results: Of the screened 428 patients, older patients had worse overall survival (OS) than younger patients. Among patients who received chemotherapy (n = 306), patients aged >70 and ⩽70 years had comparable progression-free survival (PFS) and OS. The incidence of severe hematologic toxicity was similar between the 2 groups. The Eastern Cooperative Oncology Group performance status of 2 or more metastatic sites, elevated carbohydrate antigen 19-9 level, high neutrophil-to-lymphocyte ratio (NLR), and undergoing palliative gastrectomy were independent prognostic factors for OS. Notably, age >70 years was not a significant factor for poor OS. Conclusions: Older age of >70 years might not be considered an obstacle to administering palliative chemotherapy to patients with mGC.

673 Background: Current clinical guidelines recommended adjuvant chemotherapy for all resectable pancreatic cancer after operation. The treatment choices included Gemcitabine monotherapy, S1 monotherapy, Gemcitabine+Capecitabine or mFOLFIRINOX. However, the role of Gemcitabine+S1 combination as adjuvant chemotherapy was not clear. We aimed to investigate the benefit of adjuvant chemotherapy with Gemcitabine+S1 in resectable pancreatic cancer. Methods: We retrospectively reviewed the medical records of patients with resectable pancreatic cancer who underwent curative surgery and adjuvant treatments at Taichung Veterans General Hospital (Taichung, Taiwan) between January 2014 and July 2021. The clinical characteristics and outcomes were analyzed. Results: A total of 102 patients received operation were analyzed. 73 patients received adjuvant chemotherapy, including 35 patients received Gemcitabine+S1 combination. Median follow-up period was 22.7 months. The disease-free survival (DFS) and overall survival (OS) among patients received Gemcitabine+S1 combination were 15.5 months and 32.8 months, respectively. Compared with Gemcitabine monotherapy, there was a trend of superior DFS (10.5 months in Gemcitabine monotherapy, p = 0.071), but no OS benefits (23.1 months, p = 0.441) with Gemcitabine+S1 combination. When focusing on more advanced disease status (stage II and III), the Gemcitabine+S1 combination had statistically significant longer DFS (14.7 months vs. 8.6 months; p = 0.015) and OS (30.3 months vs. 21.7 months; p = 0.036), compared with Gemcitabine monotherapy. Conclusions: In our retrospective study, Gemcitabine+S1 combination could be another choice for resectable pancreatic cancer, especially in more advanced disease (stage II and III). Further result from prospective study (JSAP-04) is pending.

303 Background: Current clinical guidelines recommended adjuvant chemotherapy for stage II and stage III gastric cancer after operation. The older patients were underrepresented in clinical trials and the role of adjuvant chemotherapy for older patients is unclear. We aimed to investigate the benefit of adjuvant chemotherapy in older patients with stage II and stage III gastric cancer. Methods: We retrospectively reviewed the medical records of patients with stage II-III gastric adenocarcinoma and underwent curative surgery at Taichung Veterans General Hospital (Taichung, Taiwan) between January 2009 and June 2017. The clinical characteristics and outcomes of patients ≥70-year-old were compared between patients received adjuvant chemotherapy or not received adjuvant chemotherapy. Results: A total of 357 patients were analyzed and 164 patients were older or equal to 70 years old. Majority of the young patients received adjuvant chemotherapy but only two-thirds of the old patients received adjuvant chemotherapy (93.8% vs. 61%; P<0.001). Among older patients, receipt of adjuvant chemotherapy was associated with longer disease-free survival (DFS) (10-year DFS, 45.89% vs. 17.55%; P<0.001) and overall survival (OS) (10-year OS, 61.71% vs. 36.27%; P=0.023) compared with patients who did not receive adjuvant chemotherapy. The total gastrectomy (hazard ratio (HR): 2.26; P=0.015), more advanced stage (HR: 2.71; P=0.018), positive surgical margin (HR: 2.56; P=0.02), elevated baseline carcinoembryonic antigen (HR: 2.37; P=0.026) were independent prognostic factors for OS in patients ≥70-year-old. Notably, the benefit adjuvant chemotherapy in older patients was significant in univariate analysis (HR: 0.53; P=0.025) but was not confirmed in multivariate analysis (HR: 0.52; P=0.072). Conclusions: The benefit of adjuvant chemotherapy in older patients with stage II-III gastric cancer was controversial in this retrospective study. Further prospective studies are needed to investigate this issue.