Lifestyle and behavioral modifications made by patients with interstitial cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) negatively affects the quality of life. In this study, we investigated the lifestyle behavioral changes patients with IC/BPS make to cope with their symptoms. This prospective study was conducted between August 2018 and June 2019. All patients had a primary symptom of suprapubic pain with a full bladder and other lower urinary tract symptoms for more than 6 weeks as well as cystoscopic findings. All participants completed our self-developed questionnaire, which included informations about their living and work environment, occupational garments, dietary habits, and personal habits. Continuous variables were compared using an independent sample t test, and categorical variables were compared using a chi-square test. We recruited 86 patients with IC/BPS and age-matched 86 controls without IC/BPS. In our study, patients with IC/BPS had more cranberry intake (45.34% vs. 5.81%, P < 0.05) than non-IC/BPS controls; the IC/BPS group had decreased consumption of coffee and spicy food; and wore less makeup or special work garments. In conclusion, patients with IC/BPS tend to make several lifestyle behavioral changes to cope with their symptoms.

Surgical and Oncological Outcome of Total Laparoscopic Radical Hysterectomy versus Radical Abdominal Hysterectomy in Early Cervical Cancer in Singapore.

INTRODUCTION: The Wertheim's radical abdominal hysterectomy (RAH) has been the traditional surgical approach for operable Stage IB cervical cancer in Singapore whereas total laparoscopic radical hysterectomy (TLRH) was introduced only in 2009. In this study, we aimed to compare the long-term surgical outcome between the two routes of surgery in our center. METHODS: This is a prospective study performed in a single large tertiary institution in Singapore. Inclusion criteria included surgically fit patients with early cervical cancer and no radiological evidence of regional or distant metastases. RESULTS: From November 2009 to December 2014, 51 TLRHs and 85 RAHs were performed. Median blood loss in the TLRH group was significantly lower than in the RAH group (300 vs. 500 mL; P = 0.002) as was median hospital stay (5 vs. 6 days; P = 0.001). Operative time was significantly higher in the TLRH group (262 vs. 228 min; P < 0.001). There was no significant difference in bladder recovery. Intraoperative complications were encountered in 2 (3.9%) TLRH patients and 1 (1.2%) RAH patient. Postoperative complications occurred in 3 (5.9%) TLRH patients and 8 (9.4%) RAH patients. With a median follow-up of 117 (range 1.6-314.6) weeks in the TLRH group and 143.3 (range 0.4-304.7) weeks in the RAH group, 9 (17.6%) TLRH patients and 7 (8.2%) RAH patients had recurrence. There was no significant difference in the overall 3-year survival between the TLRH group and the RAH group for tumor size ≤2 cm (100.0% vs. 97.0%; P = 0.37). However, there was a trend toward lower survival for the TLRH group for tumor size >2 cm (61.9% vs. 85.4%; P = 0.06). CONCLUSION: The results of our study suggest that with appropriate patient selection, TLRH can be a safe and effective procedure for the management of early cervical cancer in Singapore, especially in women with small tumors ≤2 cm but should be used with caution in women with larger tumors.

Crystal Structure of Human DNA Methyltransferase 1.

DNMT1 (DNA methyltransferase 1) is responsible for propagating the DNA methylation patterns during DNA replication. DNMT1 contains, in addition to a C-terminal methyltransferase domain, a large N-terminal regulatory region that is composed of an RFTS (replication foci targeting sequence) domain, a CXXC zinc finger domain and a pair of BAH (bromo adjacent homology) domains. The regulatory domains of DNMT1 mediate a network of protein-protein and protein-DNA interactions to control the recruitment and enzymatic activity of DNMT1. Here we report the crystal structure of human DNMT1 with all the structural domains (hDNMT1, residues 351-1600) in complex with S-adenosyl-l-homocysteine at 2.62Å resolution. The RFTS domain directly associates with the methyltransferase domain, thereby inhibiting the substrate binding of hDNMT1. Through structural analysis, mutational, biochemical and enzymatic studies, we further identify that a linker sequence between the CXXC and BAH1 domains, aside from its role in the CXXC domain-mediated DNMT1 autoinhibition, serves as an important regulatory element in the RFTS domain-mediated autoinhibition. In comparison with the previously determined structure of mouse DNMT1, this study also reveals a number of distinct structural features that may underlie subtle functional diversity observed for the two orthologues. In addition, this structure provides a framework for understanding the functional consequence of disease-related hDNMT1 mutations.

Arsenite binds to the RING finger domains of RNF20-RNF40 histone E3 ubiquitin ligase and inhibits DNA double-strand break repair.

Arsenic is a widespread environmental contaminant. However, the exact molecular mechanisms underlying the carcinogenic effects of arsenic remain incompletely understood. Core histones can be ubiquitinated by RING finger E3 ubiquitin ligases, among which the RNF20-RNF40 heterodimer catalyzes the ubiquitination of histone H2B at lysine 120. This ubiquitination event is important for the formation of open and biochemically accessible chromatin fiber that is conducive for DNA repair. Herein, we found that arsenite could bind directly to the RING finger domains of RNF20 and RNF40 in vitro and in cells, and treatment with arsenite resulted in substantially impaired H2B ubiquitination in multiple cell lines. Exposure to arsenite also diminished the recruitment of BRCA1 and RAD51 to laser-induced DNA double-strand break (DSB) sites, compromised DNA DSB repair in human cells, and rendered cells sensitive toward a radiomimetic agent, neocarzinostatin. Together, the results from the present study revealed, for the first time, that arsenite may exert its carcinogenic effect by targeting cysteine residues in the RING finger domains of histone E3 ubiquitin ligase, thereby altering histone epigenetic mark and compromising DNA DSB repair. Our results also suggest arsenite as a general inhibitor for RING finger E3 ubiquitin ligases.

Effects of Tet-induced oxidation products of 5-methylcytosine on Dnmt1- and DNMT3a-mediated cytosine methylation.

We investigated systematically the effects of Tet-induced oxidation products of 5-methylcytosine on Dnmt1- and DNMT3a-mediated cytosine methylation in synthetic duplex DNA. We found that the replacement of 5-methylcytosine at a CpG site with a 5-hydroxymethylcytosine, 5-formylcytosine, 5-carboxylcytosine or 5-hydroxymethyluracil resulted in altered methylation of cytosine at both the opposite and the neighboring CpG sites. Our results provided important new knowledge about the implications of the 5-methylcytosine oxidation products in maintenance cytosine methylation.