Effects of Low- Versus High-Velocity-Loss Thresholds With Similar Training Volume on Maximal Strength and Hypertrophy in Highly Trained Individuals.

Aims: In the present intervention study, low-velocity-loss (LVL) versus high-velocity-loss (HVL) thresholds in the squat and bench press were compared for changes in muscle strength, power, and hypertrophy.

Methods: Strength-trained volunteers (7♀ and 9♂; age: 27.2 [3.

H2G-Net: A multi-resolution refinement approach for segmentation of breast cancer region in gigapixel histopathological images.

Over the past decades, histopathological cancer diagnostics has become more complex, and the increasing number of biopsies is a challenge for most pathology laboratories. Thus, development of automatic methods for evaluation of histopathological cancer sections would be of value. In this study, we used 624 whole slide images (WSIs) of breast cancer from a Norwegian cohort.

Visual and digital assessment of Ki-67 in breast cancer tissue - a comparison of methods.

Background: In breast cancer (BC) Ki-67 cut-off levels, counting methods and inter- and intraobserver variation are still unresolved. To reduce inter-laboratory differences, it has been proposed that cut-off levels for Ki-67 should be determined based on the in-house median of 500 counted tumour cell nuclei. Digital image analysis (DIA) has been proposed as a means to standardize assessment of Ki-67 staining in tumour tissue.

Code-Free Development and Deployment of Deep Segmentation Models for Digital Pathology.

Application of deep learning on histopathological whole slide images (WSIs) holds promise of improving diagnostic efficiency and reproducibility but is largely dependent on the ability to write computer code or purchase commercial solutions. We present a code-free pipeline utilizing free-to-use, open-source software (QuPath, DeepMIB, and FastPathology) for creating and deploying deep learning-based segmentation models for computational pathology. We demonstrate the pipeline on a use case of separating epithelium from stroma in colonic mucosa.

AID expression in B-cell lymphomas causes accumulation of genomic uracil and a distinct AID mutational signature.

The most common mutations in cancer are C to T transitions, but their origin has remained elusive. Recently, mutational signatures of APOBEC-family cytosine deaminases were identified in many common cancers, suggesting off-target deamination of cytosine to uracil as a common mutagenic mechanism. Here we present evidence from mass spectrometric quantitation of deoxyuridine in DNA that shows significantly higher genomic uracil content in B-cell lymphoma cell lines compared to non-lymphoma cancer cell lines and normal circulating lymphocytes.

Error-free versus mutagenic processing of genomic uracil--relevance to cancer.

Genomic uracil is normally processed essentially error-free by base excision repair (BER), with mismatch repair (MMR) as an apparent backup for U:G mismatches. Nuclear uracil-DNA glycosylase UNG2 is the major enzyme initiating BER of uracil of U:A pairs as well as U:G mismatches. Deficiency in UNG2 results in several-fold increases in genomic uracil in mammalian cells.

Multiple microRNAs may regulate the DNA repair enzyme uracil-DNA glycosylase.

Human nuclear uracil-DNA glycosylase UNG2 is essential for post-replicative repair of uracil in DNA, and UNG2 protein and mRNA levels rapidly decline in G2/M phase. Previous work has demonstrated regulation of UNG2 at the transcriptional level, as well as by protein phosphorylation and ubiquitylation. UNG2 mRNA, encoded by the UNG gene, contains a long 3'untranslated region (3'UTR) of previously unknown function.

UNG-initiated base excision repair is the major repair route for 5-fluorouracil in DNA, but 5-fluorouracil cytotoxicity depends mainly on RNA incorporation.

Cytotoxicity of 5-fluorouracil (FU) and 5-fluoro-2'-deoxyuridine (FdUrd) due to DNA fragmentation during DNA repair has been proposed as an alternative to effects from thymidylate synthase (TS) inhibition or RNA incorporation. The goal of the present study was to investigate the relative contribution of the proposed mechanisms for cytotoxicity of 5-fluoropyrimidines. We demonstrate that in human cancer cells, base excision repair (BER) initiated by the uracil-DNA glycosylase UNG is the major route for FU-DNA repair in vitro and in vivo.

Uracil-DNA glycosylase in base excision repair and adaptive immunity: species differences between man and mouse.

Genomic uracil is a DNA lesion but also an essential key intermediate in adaptive immunity. In B cells, activation-induced cytidine deaminase deaminates cytosine to uracil (U:G mispairs) in Ig genes to initiate antibody maturation. Uracil-DNA glycosylases (UDGs) such as uracil N-glycosylase (UNG), single strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), and thymine-DNA glycosylase remove uracil from DNA.

Direct interaction between XRCC1 and UNG2 facilitates rapid repair of uracil in DNA by XRCC1 complexes.

Uracil-DNA glycosylase, UNG2, interacts with PCNA and initiates post-replicative base excision repair (BER) of uracil in DNA. The DNA repair protein XRCC1 also co-localizes and physically interacts with PCNA. However, little is known about whether UNG2 and XRCC1 directly interact and participate in a same complex for repair of uracil in replication foci.

Uracil in DNA and its processing by different DNA glycosylases.

Uracil in DNA may result from incorporation of dUMP during replication and from spontaneous or enzymatic deamination of cytosine, resulting in U:A pairs or U:G mismatches, respectively. Uracil generated by activation-induced cytosine deaminase (AID) in B cells is a normal intermediate in adaptive immunity. Five mammalian uracil-DNA glycosylases have been identified; these are mitochondrial UNG1 and nuclear UNG2, both encoded by the UNG gene, and the nuclear proteins SMUG1, TDG and MBD4.

Uracil-DNA glycosylases SMUG1 and UNG2 coordinate the initial steps of base excision repair by distinct mechanisms.

DNA glycosylases UNG and SMUG1 excise uracil from DNA and belong to the same protein superfamily. Vertebrates contain both SMUG1 and UNG, but their distinct roles in base excision repair (BER) of deaminated cytosine (U:G) are still not fully defined. Here we have examined the ability of human SMUG1 and UNG2 (nuclear UNG) to initiate and coordinate repair of U:G mismatches.