Benign to Malignant, Malignant to Metastatic: Phyllodes Tumor Biology Transformation.

Phyllodes tumors (PTs) of the breast are rare fibroepithelial neoplasms, typically characterized by their benign nature. We present a unique case of a 29-year-old Pakistani female who initially presented with a benign PT in her left breast. Despite undergoing multiple surgical resections over the course of a decade, the tumor exhibited a remarkable transformation in biology, progressing from a benign phenotype to malignancy. Subsequent recurrences manifested with increasing aggressiveness, ultimately culminating in distant metastasis to the bones, axillary nodes, chest wall, and abdominal wall. This case underscores the unpredictable nature of PTs and highlights the challenges in managing recurrent cases with malignant transformation. The clinical course described herein emphasizes the importance of vigilant monitoring and individualized treatment strategies in such cases.

Effect of Solution-to-Binder Ratio and Alkalinity on Setting and Early-Age Properties of Alkali-Activated Slag-Fly Ash Binders.

The growing use of blends of low- and high-calcium solid precursors in combination with different alkaline activators requires simple, efficient, and accurate experimental means to characterize their behavior, particularly during the liquid-to-solid transition (setting) at early material ages. This research investigates slag-fly ash systems mixed at different solution-to-binder (s/b) ratios with sodium silicate/sodium hydroxide-based activator solutions of varying concentrations. Therefore, continuous non-destructive tests-namely ultrasonic pulse velocity (UPV) measurements and isothermal calorimetry tests-are combined with classical slump flow, Vicat, and uniaxial compressive strength tests. The experimental results highlight that high alkali and silica contents and a low s/b ratio benefit the early-age hydration, lead to a faster setting, and improve the early-age strength. The loss of workability, determined from the time when the slump flow becomes negligible, correlates well with ultrasonic P-wave velocity evolutions. This is, however, not the case for Vicat or calorimetry tests.

hSSB2 (NABP1) is required for the recruitment of RPA during the cellular response to DNA UV damage.

Maintenance of genomic stability is critical to prevent diseases such as cancer. As such, eukaryotic cells have multiple pathways to efficiently detect, signal and repair DNA damage. One common form of exogenous DNA damage comes from ultraviolet B (UVB) radiation. UVB generates cyclobutane pyrimidine dimers (CPD) that must be rapidly detected and repaired to maintain the genetic code. The nucleotide excision repair (NER) pathway is the main repair system for this type of DNA damage. Here, we determined the role of the human Single-Stranded DNA Binding protein 2, hSSB2, in the response to UVB exposure. We demonstrate that hSSB2 levels increase in vitro and in vivo after UVB irradiation and that hSSB2 rapidly binds to chromatin. Depletion of hSSB2 results in significantly decreased Replication Protein A (RPA32) phosphorylation and impaired RPA32 localisation to the site of UV-induced DNA damage. Delayed recruitment of NER protein Xeroderma Pigmentosum group C (XPC) was also observed, leading to increased cellular sensitivity to UVB. Finally, hSSB2 was shown to have affinity for single-strand DNA containing a single CPD and for duplex DNA with a two-base mismatch mimicking a CPD moiety. Altogether our data demonstrate that hSSB2 is involved in the cellular response to UV exposure.

COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks.

Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks.

Redox Regulation in the Base Excision Repair Pathway: Old and New Players as Cancer Therapeutic Targets.

BACKGROUND: Reactive Oxygen Species (ROS) are by-products of normal cellular metabolic processes, such as mitochondrial oxidative phosphorylation. While low levels of ROS are important signalling molecules, high levels of ROS can damage proteins, lipids and DNA. Indeed, oxidative DNA damage is the most frequent type of damage in the mammalian genome and is linked to human pathologies such as cancer and neurodegenerative disorders. Although oxidative DNA damage is cleared predominantly through the Base Excision Repair (BER) pathway, recent evidence suggests that additional pathways such as Nucleotide Excision Repair (NER) and Mismatch Repair (MMR) can also participate in clearance of these lesions. One of the most common forms of oxidative DNA damage is the base damage 8-oxoguanine (8-oxoG), which if left unrepaired may result in G:C to A:T transversions during replication, a common mutagenic feature that can lead to cellular transformation. OBJECTIVE: Repair of oxidative DNA damage, including 8-oxoG base damage, involves the functional interplay between a number of proteins in a series of enzymatic reactions. This review describes the role and the redox regulation of key proteins involved in the initial stages of BER of 8-oxoG damage, namely Apurinic/Apyrimidinic Endonuclease 1 (APE1), human 8-oxoguanine DNA glycosylase-1 (hOGG1) and human single-stranded DNA binding protein 1 (hSSB1). Moreover, the therapeutic potential and modalities of targeting these key proteins in cancer are discussed. CONCLUSION: It is becoming increasingly apparent that some DNA repair proteins function in multiple repair pathways. Inhibiting these factors would provide attractive strategies for the development of more effective cancer therapies.

Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage.

The DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor-Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the ageing process are unknown. Here, we report that Banf1 controls the DNA damage response to oxidative stress via regulation of poly [ADP-ribose] polymerase 1 (PARP1). Specifically, oxidative lesions promote direct binding of Banf1 to PARP1, a critical NAD+-dependent DNA repair protein, leading to inhibition of PARP1 auto-ADP-ribosylation and defective repair of oxidative lesions, in cells with increased Banf1. Consistent with this, cells from patients with NGPS have defective PARP1 activity and impaired repair of oxidative lesions. These data support a model whereby Banf1 is crucial to reset oxidative-stress-induced PARP1 activity. Together, these data offer insight into Banf1-regulated, PARP1-directed repair of oxidative lesions.

Prostate cancer is known by the companionship with ATM and miRNA it keeps: craftsmen of translation have dual behaviour with tailors of life thread.

Research on prostate cancer progression has focused extensively on the concept of miRNA, which can operate either as promoters or as suppressors of carcinogenesis. Moreover, recent genetic studies and emerging functional work show that strikingly similar and overlapping pathways are involved in prostate carcinogenesis. Unswervingly, these elements constitute a recently explored 'network of networks' that dynamically reorganizes during DNA damage and is responsible for positively or negatively regulating genome organization and integrity. We consider these facets of convergence and discuss how insights from diametrically opposed interactions of ataxia-telangiectasia mutated and mitrons can inform us about, and possibly help us to get a step closer to personalized medicine.

ATM protein kinase: the linchpin of cellular defenses to stress.

ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration. Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying the complex phenotypes observed in AT patients.