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DNA double-strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to the expression of HR proteins, including BRCA1, BRCA2, PALB2, and RAD51, and promotes DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection in LIN37-deficient G0 cells depends on BRCA1 and leads to RAD51 filament formation and HR. LIN37 is not required to protect DNA ends in cycling cells at G1-phase. Thus, LIN37 regulates a novel 53BP1-independent cell phase-specific DNA end protection pathway that functions uniquely in quiescent cells.

SUMMARY The immunoglobulin heavy chain (Igh) locus features a dynamic chromatin landscape to promote class switch recombination (CSR), yet the mechanisms that regulate this landscape remain poorly understood. CHD4, a component of the chromatin remodeling NuRD complex, directly binds H3K9me3, an epigenetic mark present at the Igh locus during CSR. We find that CHD4 is essential for early B cell development but is dispensable for the homeostatic maintenance of mature, naive B cells. However, loss of CHD4 in mature B cells impairs CSR because of suboptimal targeting of AID to the Igh locus. Additionally, we find that CHD4 represses p53 expression to promote B cell proliferation. This work reveals distinct roles for CHD4 in B cell development and CSR and links the H3K9me3 epigenetic mark with AID recruitment to the Igh locus., Graphical Abstract, In Brief Yen et al. demonstrate that CHD4, a component of the NuRD remodeling complex, is essential for early B cell development, represses p53 expression in mature B cells, and influences the recruitment of AID to DNA during class switch recombination.

DNA double strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to expression of HR proteins, including BRCA1, BRCA2, PALB2 and RAD51, and DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection in LIN37-deficient G0 cells depends on BRCA1 and leads to RAD51 filament formation and HR. LIN37 is not required to protect DNA ends in cycling cells at G1-phase. Thus, LIN37 regulates a novel 53BP1-independent cell phase-specific DNA end protection pathway that functions uniquely in quiescent cells.

Since the National Health Insurance system was implemented in Taiwan in 1995, fierce competition in the health care market has led to a shortage of front-line nurses. Such nurses are frequently tasked with an overwhelming amount of complex work, which causes them to experience constant mental stress that elicits anxiety, depression, and negative emotions. Art therapy and horticultural therapy are common stress alleviation methods. Therefore, this study explored the effectiveness of floricultural therapy on relieving the mental stress of nurses. The evaluation grid method of Miryoku engineering was employed in combination with in-depth interviews to compile the attractive factors of floricultural courses. Accordingly, this study examined the experiential cognition and preferences regarding floricultural courses and the perceived therapeutic effect of such courses in highly stressed nurses. The results can be a reference for designing future floricultural therapy courses and promotion.

BRCA1 is essential for homology-directed repair (HDR) of DNA double-strand breaks in part through antagonism of the nonhomologous end-joining factor 53BP1. The ATM kinase is involved in various aspects of DNA damage signaling and repair, but how ATM participates in HDR and genetically interacts with BRCA1 in this process is unclear. To investigate this question, we used the Brca1S1598F mouse model carrying a mutation in the BRCA1 C-terminal domain of BRCA1. Whereas ATM loss leads to a mild HDR defect in adult somatic cells, we find that ATM inhibition leads to severely reduced HDR in Brca1S1598F cells. Consistent with a critical role for ATM in HDR in this background, loss of ATM leads to synthetic lethality of Brca1S1598F mice. Whereas both ATM and BRCA1 promote end resection, which can be regulated by 53BP1, 53bp1 deletion does not rescue the HDR defects of Atm mutant cells, in contrast to Brca1 mutant cells. These results demonstrate that ATM has a role in HDR independent of the BRCA1-53BP1 antagonism and that its HDR function can become critical in certain contexts.

Carcinoid tumors are a group of heterogeneous tumors with neuroendocrine differentiation and are mainly located in the gastrointestinal tract. A high frequency of cytoplasmic accumulation and/or nuclear translocation of beta-catenin with frequent mutations of exon 3 of beta-catenin gene in gastrointestinal carcinoid tumor has been previously described, but the role of Wnt/beta-catenin/APC pathway in the genesis of carcinoid tumor remains largely unknown.To further characterize the role of Wnt/beta-catenin/APC pathway, we investigated 91 gastrointestinal carcinoid tumors and, for comparison, 26 extragastrointestinal carcinoid tumors by immunohistochemical detection of beta-catenin protein and direct sequencing of exon 3 of the beta-catenin gene and exon 15 of the APC gene.Cytoplasmic accumulation and/or nuclear translocation of beta-catenin were found in 27 gastrointestinal carcinoid tumors (29.7%) but not in any extragastrointestinal carcinoid tumors. Interestingly, neither beta-catenin nor APC gene mutation was detected in all of the cases with nuclear expression of beta-catenin.Our results indicate that the role beta-catenin plays in the genesis of gastrointestinal and extragastrointestinal carcinoid tumors is different. Nuclear expression of beta-catenin does not occur in extragastrointestinal carcinoid tumors, and mutation of exon 3 of beta-catenin gene and exon 15 of APC gene does not contribute to the activation of Wnt/beta-catenin/APC pathway in gastrointestinal carcinoid tumors.

Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-catenin into nucleus, leading to downregulation of c-myc and cyclin D1 via the phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in patients with breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and show that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes. Cancer Res; 72(18); 4652–61. ©2012 AACR.

Microenvironment plays an important role in cancer development. We have reported that the cancer-associated stromal cells exhibit phenotypic and functional changes compared to stromal cells neighboring to normal tissues. However, the molecular mechanisms as well as the maintenance of these changes remain elusive. Here we showed that through co-culture with breast cancer cells for at least three to four passages, breast normal tissue-associated fibroblasts (NAFs) gained persistent activity for promoting cancer cell invasion, partly via up-regulating ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1). Furthermore, we demonstrated that the DNA methylation pattern in the ADAMTS1 promoter has no alteration. Instead, the loss of EZH2 binding to the ADAMTS1 promoter and the resulting decrease of promoter-associated histone H3K27 methylation may account for the up-regulation of ADAMTS1. Importantly, the lack of EZH2 binding and the H3K27 methylation on the ADAMTS1 promoter were sustained in cancer cell-precocultured NAFs after removal of cancer cells. These results suggest that cancer cells are capable of inducing stromal fibroblasts to secrete ADAMTS1 persistently for their invasion and the effect is epigenetically inheritable.

Large gastric bezoars are difficult to remove endoscopically. A 78-year-old man presenting with abdominal pain and loss of appetite for 4 months was admitted and evaluated. Gastroscopy disclosed two large phytobezoars within the stomach. Laparoscopic removal was undertaken. The bezoars were removed via a gastrotomy using the three-trocar technique. They were successfully retrieved from the abdominal cavity using an improvised "endobag" made from a simple surgical glove. Such an endobag presents several advantages; they are easy to make, sterile, economical, readily available, disposable, there is ample space to manipulate the specimen within, and there is minimal risk of contamination throughout the procedure. The authors recommend this approach for the treatment of patients with large gastric bezoars in whom laparotomy is indicated.

AIM: To investigate the effect of lipopolysaccharide (LPS) on the diarrheogenic activity, gastrointestinal transit (GIT), and intestinal fluid content and the possible role of nitric oxide (NO) and prostaglandin E2 (PGE2) in gastrointestinal functions of endotoxin-treated mice. METHODS: Diarrheogic activity, GIT, and intestinal fluid content as well as nitric oxide and PGE2 products were measured after intraperitoneal administration of LPS in mice. RESULTS: LPS dose-dependently accumulated abundant fluid into the small intestine, induced diarrhea, but decreased the GIT. Both nitric oxide and PGE2 were found to increase in LPS-treated mice. Western blot analysis indicated that LPS significantly induced the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 in mice intestines. Pretreatment with NG-nitro-L-arginine-methyl ester (L-NAME, a non-selective NOS inhibitor) or indomethacin (an inhibitor of prostaglandin synthesis) significantly attenuated the effects of LPS on the diarrheogenic activity and intestine content, but reversed the GIT. CONCLUSION: The present study suggests that the pathogenesis of LPS treatment may mediate the stimulatory effect of LPS on nitric oxide and PGE2 production and NO/prostaglandin pathway may play an important role on gastrointestinal function.