DNA repair and anti-cancer mechanisms in the long-lived bowhead whale.

At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto's Paradox.

The KU70-SAP domain has an overlapping function with DNA-PKcs in limiting the lateral movement of KU along DNA.

Unlabelled: The non-homologous end-joining (NHEJ) pathway is critical for DNA double-strand break repair and is essential for lymphocyte development and maturation. The Ku70/Ku80 heterodimer (KU) binds to DNA ends, initiating NHEJ and recruiting additional factors, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs) that caps the ends and pushes KU inward. The C-terminus of Ku70 in higher eukaryotes includes a flexible linker and a SAP domain, whose physiological role remains poorly understood.

Accidental Encounter of Repair Intermediates in Alkylated DNA May Lead to Double-Strand Breaks in Resting Cells.

In clinics, chemotherapy is often combined with surgery and radiation to increase the chances of curing cancers. In the case of glioblastoma (GBM), patients are treated with a combination of radiotherapy and TMZ over several weeks. Despite its common use, the mechanism of action of the alkylating agent TMZ has not been well understood when it comes to its cytotoxic effects in tumor cells that are mostly non-dividing.

Anatomical location of the surgically identifiable bladder branch of the inferior hypogastric plexus for nerve-sparing radical hysterectomy.

Objective: We aimed to demonstrate the entire structure of the inferior hypogastric plexus in the female pelvis focusing on surgically identifiable nerve bundles to the urinary bladder.

Methods: Surgical videos of transabdominal nerve-sparing radical hysterectomy for 10 patients with cervical cancer at International Federation of Gynecology and Obstetrics (FIGO 2009) stage IB1-IIB were retrospectively analyzed. The paracervical tissue dorsal to the ureter was separated into the lateral component (dorsal layer of the vesicouterine ligament) and medial component (paracolpium) using Okabayashi's technique.

Avascular spaces in radical hysterectomy.

The most common cancer in women worldwide is cervical cancer. For early-stage disease the standard treatment is radical hysterectomy. One of the main issues faced by surgeons performing a radical hysterectomy is the wide variation in the terminology used to define the procedure and the nomenclature used to describe the anatomical spaces critical to the success of the surgery.

Double-strand breaks: When DNA repair events accidentally meet.

The cellular response to alkylation damage is complex, involving multiple DNA repair pathways and checkpoint proteins, depending on the DNA lesion, the cell type, and the cellular proliferation state. The repair of and response to O-alkylation damage, primarily O-methylguaine DNA adducts (O-mG), is the purview of O-methylguanine-DNA methyltransferase (MGMT). Alternatively, this lesion, if left un-repaired, induces replication-dependent formation of the O-mG:T mis-pair and recognition of this mis-pair by the post-replication mismatch DNA repair pathway (MMR).

Crosstalk between repair pathways elicits double-strand breaks in alkylated DNA and implications for the action of temozolomide.

Temozolomide (TMZ), a DNA methylating agent, is the primary chemotherapeutic drug used in glioblastoma treatment. TMZ induces mostly N-alkylation adducts (N7-methylguanine and N3-methyladenine) and some O-methylguanine (OmG) adducts. Current models propose that during DNA replication, thymine is incorporated across from OmG, promoting a futile cycle of mismatch repair (MMR) that leads to DNA double-strand breaks (DSBs).

Enrichment of plasmid pool from for mass sequencing to detect untargeted mutagenic events.

Translesion synthesis (TLS) is an event to cope with DNA damages. During TLS, the responsible TLS polymerase frequently elicits untargeted mutagenesis as potentially a source of genetic diversity. Identifying such untargeted mutations is challenging due to the bulk of DNA that does not undergo TLS.

Targeting Dormant Ovarian Cancer Cells and in an Mouse Model of Platinum Resistance.

Spheroids exhibit drug resistance and slow proliferation, suggesting involvement in cancer recurrence. The protein kinase C inhibitor UCN-01 (7-hydroxystaurosporine) has shown higher efficacy against slow proliferating and/or quiescent ovarian cancer cells. In this study, tumorigenic potential was assessed using anchorage-independent growth assays and spheroid-forming capacity, which was determined with ovarian cancer cell lines as well as primary ovarian cancers.

A Comprehensive View of Translesion Synthesis in Escherichia coli.

The lesion bypass pathway, translesion synthesis (TLS), exists in essentially all organisms and is considered a pathway for postreplicative gap repair and, at the same time, for lesion tolerance. As with the saying "a trip is not over until you get back home," studying TLS only at the site of the lesion is not enough to understand the whole process of TLS. Recently, a genetic study uncovered that polymerase V (Pol V), a poorly expressed TLS polymerase, is not only involved in the TLS step but also participates in the gap-filling reaction over several hundred nucleotides.

Chromatin Pull-Down Methodology Based on DNA Triple Helix Formation.

Identification of the protein complexes associated with defined DNA sequence elements is essential to understand the numerous transactions in which DNA is involved, such as replication, repair, transcription, and chromatin dynamics. Here we describe two protocols, IDAP (Isolation of DNA Associated Proteins) and CoIFI (Chromatin-of-Interest Fragment Isolation), that allow for isolating DNA/protein complexes (i.e.

Nerve-sparing radical hysterectomy: steps to standardize surgical technique.

Aim: The primary objective of this review was to study and analyze techniques of nerve-sparing radical hysterectomy so as to be able to characterize and elucidate intricate steps for the dissection of each component of the pelvic autonomic nerve plexuses during nerve-sparing radical hysterectomy.

Methods: This review was based on a five-step study design that included searching for relevant publications, selecting publications by applying inclusion and exclusion criteria, quality assessment of the identified studies, data extraction, and data synthesis.

Results: There are numerous differences in the published literature concerning nerve-sparing radical hysterectomy including variations in techniques and surgical approaches.

Chronological Switch from Translesion Synthesis to Homology-Dependent Gap Repair .

Cells are constantly exposed to endogenous and exogenous chemical and physical agents that damage their genome by forming DNA lesions. These lesions interfere with the normal functions of DNA such as transcription and replication, and need to be either repaired or tolerated. DNA lesions are accurately removed via various repair pathways.

Pol V-Mediated Translesion Synthesis Elicits Localized Untargeted Mutagenesis during Post-replicative Gap Repair.

In vivo, replication forks proceed beyond replication-blocking lesions by way of downstream repriming, generating daughter strand gaps that are subsequently processed by post-replicative repair pathways such as homologous recombination and translesion synthesis (TLS). The way these gaps are filled during TLS is presently unknown. The structure of gap repair synthesis was assessed by sequencing large collections of single DNA molecules that underwent specific TLS events in vivo.

Versatile and efficient chromatin pull-down methodology based on DNA triple helix formation.

The goal of present paper is to develop a reliable DNA-based method for isolation of protein complexes bound to DNA (Isolation of DNA Associated Proteins: IDAP). We describe a robust and versatile procedure to pull-down chromatinized DNA sequences-of-interest by formation of a triple helix between a sequence tag present in the DNA and a complementary triple helix forming oligonucleotide (TFO) coupled to a desthiobiotin residue. Following optimization to insure efficient recovery of native plasmids via TFO probe in vitro, the procedure is shown to work under various experimental situations.

Processing closely spaced lesions during Nucleotide Excision Repair triggers mutagenesis in E. coli.

It is generally assumed that most point mutations are fixed when damage containing template DNA undergoes replication, either right at the fork or behind the fork during gap filling. Here we provide genetic evidence for a pathway, dependent on Nucleotide Excision Repair, that induces mutations when processing closely spaced lesions. This pathway, referred to as Nucleotide Excision Repair-induced Mutagenesis (NERiM), exhibits several characteristics distinct from mutations that occur within the course of replication: i) following UV irradiation, NER-induced mutations are fixed much more rapidly (t ½ ≈ 30 min) than replication dependent mutations (t ½ ≈ 80-100 min) ii) NERiM specifically requires DNA Pol IV in addition to Pol V iii) NERiM exhibits a two-hit dose-response curve that suggests processing of closely spaced lesions.

Identification and prevalence of adverse drug events caused by potentially inappropriate medication in homebound elderly patients: a retrospective study using a nationwide survey in Japan.

Objectives: A nationwide large-scale survey was conducted to identify the prevalence and causal medications of adverse drug events (ADEs) that are caused by potentially inappropriate medications (PIMs) given to homebound elderly patients, factors associated with ADEs, and measures taken by pharmacists to manage ADEs and their effects on ADEs.

Settings: A questionnaire was mailed to 3321 pharmacies nationwide. It asked about the details of PIMs and ADEs of up to 5 patients for whom home visits were provided by a pharmacist.

[Nationwide study on relations between workload and outcomes of home visiting service by community pharmacists].

A nationwide survey was conducted to verify relations between the workload of home-visiting service by community pharmacists and outcomes. Data were collected on 5447 patients from 1890 pharmacies. Most (61.

Surgical and systemic management of endometrial cancer: an international survey.

Purpose: To ascertain the spectrum of clinical management of endometrial carcinoma (EC) the largest international survey was conducted to evaluate and identify differences worldwide.

Methods: After validation of a 15-item questionnaire regarding surgical and adjuvant treatment of EC in Germany, an English-adapted questionnaire was put online and posted to all the major gynecological cancer Societies worldwide for further distribution commencing in 2010 and continued for 26 months.

Results: A total of 618 Institutions around the world participated: Central Europe (CE), Southern Europe (SE), Northern Europe (NE), Asia and USA/Canada/UK.

Translesion DNA synthesis and mutagenesis in prokaryotes.

The presence of unrepaired lesions in DNA represents a challenge for replication. Most, but not all, DNA lesions block the replicative DNA polymerases. The conceptually simplest procedure to bypass lesions during DNA replication is translesion synthesis (TLS), whereby the replicative polymerase is transiently replaced by a specialized DNA polymerase that synthesizes a short patch of DNA across the site of damage.

Expression of p53 and p21(WAF-1), apoptosis, and proliferation of smooth muscle cells in normal myometrium during the menstrual cycle: implication of DNA damage and repair for leiomyoma development.

Uterine leiomyoma is the most common tumor in the female genital tract, although its pathogenesis remains unclear. Molecular analyses have demonstrated that each leiomyoma nodule is monoclonal and harbors various DNA abnormalities, suggesting that DNA damage in normal smooth muscle cells plays an important role in the pathogenesis of leiomyoma. The aim of this study is to evaluate precisely when and where DNA damage occurs in the myometrium.

Escherichia coli DNA polymerase III is responsible for the high level of spontaneous mutations in mutT strains.

Reactive oxygen species induce oxidative damage in DNA precursors, i.e. dNTPs, leading to point mutations upon incorporation.

Clinical value of FDG-PET for preoperative evaluation of endometrial cancer.

Objective: Whole body positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) has been widely used in various malignancies, but the clinical value of FDG-PET for endometrial cancer has not been fully investigated. The purpose of this study was to evaluate the usefulness of FDG-PET for preoperative evaluation of endometrial cancer.

Methods: Forty female patients suspected of having endometrial cancer were included in this study.

Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer.

Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis.