Anticoagulation for splanchnic vein thrombosis in myeloproliferative neoplasms: a systematic review and meta-analysis.

BACKGROUND: Optimal anticoagulation management in patients with myeloproliferative neoplasms (MPN) experiencing splanchnic vein thrombosis (SpVT) requires balancing risks of bleeding and recurrent thrombosis. OBJECTIVES: We conducted a systematic review and meta-analysis to assess the incidence of bleeding and thrombosis recurrence in patients with MPN-SpVT. METHODS: We included retrospective or prospective studies in English with ≥10 adult patients with MPN-SpVT. Outcomes included recurrent venous thrombosis (SpVT and non-SpVT), arterial thrombosis, and major bleeding. Pooled rates per 100 patient years with 95% CIs were calculated by DerSimonian-Laird method using random-effects model. RESULTS: Out of 4624 studies screened, 9 studies with a total of 443 patients were included in the meta-analysis with median follow-up of 3.5 years. In the 364 patients with MPN-SpVT treated with anticoagulation, pooled event rate for major bleeding was 2.8 (95% CI, 1.5-5.1; I2 = 95%), for recurrent venous thrombosis was 1.4 (95% CI, 0.8-2.2; I2 = 72%), and for arterial thrombosis was 1.4 (95% CI, 0.6-3.3; I2 = 92%) per 100 patient years. Among 79 patients (n = 4 studies) who did not receive anticoagulation, pooled event rate for major bleeding was 3.2 (95% CI, 0.7-12.7; I2 = 97%), for recurrent venous thrombosis 3.5 (95% CI, 1.8-6.4; I2 = 88%), and for arterial thrombosis rate 1.6 (95% CI, 0.4-6.6; I2 = 95%) per 100 patient years. CONCLUSION: Patients with MPN-SpVT treated with anticoagulation have significant risks for both major bleeding and thrombosis recurrence. Further studies are necessary to determine the optimal anticoagulation approach in patients with MPN-SpVT.

Prognostic and Predictive Biomarkers in Oligometastatic Disease.

Metastatic lesions are largely responsible for cancer-related deaths and are synonymous with a poor prognosis. However, this is not always true for patients with oligometastases whose disease may be amenable to curative-intent local therapies. It has been proposed that an "intermediate state" (oligometastasis) exists in between locoregional and advanced disease states; however, the clinical definition of oligometastasis varies, and there is limited understanding of how tumor biology differs between oligometastases and polymetastases. There is evidence that local therapies can extend survival in patients with oligometastases, yet patient selection for local intervention and/or systemic therapy remains a challenge. Prognostic and predictive biomarkers of oligometastatic disease are strongly needed to identify patient candidates most likely to gain survival benefit from local therapies and to aid in the incorporation of ablative treatments in the context of existing systemic therapies.

XPG-related nucleases are hierarchically recruited for double-stranded rDNA break resection.

dsDNA breaks (DSBs) are resected in a 5'→3' direction, generating single-stranded DNA (ssDNA). This promotes DNA repair by homologous recombination and also assembly of signaling complexes that activate the DNA damage checkpoint effector kinase Chk1. In fission yeast (Schizosaccharomyces pombe), genetic screens have previously uncovered a family of three xeroderma pigmentosum G (XPG)-related nucleases (XRNs), known as Ast1, Exo1, and Rad2. Collectively, these XRNs are recruited to a euchromatic DSB and are required for ssDNA production and end resection across the genome. Here, we studied why there are three related but distinct XRN enzymes that are all conserved across a range of species, including humans, whereas all other DSB response proteins are present as single species. Using S. pombe as a model, ChIP and DSB resection analysis assays, and highly efficient I-PpoI-induced DSBs in the 28S rDNA gene, we observed a hierarchy of recruitment for each XRN, with a progressive compensatory recruitment of the other XRNs as the responding enzymes are deleted. Importantly, we found that this hierarchy reflects the requirement for different XRNs to effect efficient DSB resection in the rDNA, demonstrating that the presence of three XRN enzymes is not a simple division of labor. Furthermore, we uncovered a specificity of XRN function with regard to the direction of transcription. We conclude that the DSB-resection machinery is complex, is nonuniform across the genome, and has built-in fail-safe mechanisms, features that are in keeping with the highly pathological nature of DSB lesions.

Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe.

Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, and mutants show partial transcriptional overlap with set2 deletions. H3-G34R mutants exhibit genomic instability and increased replication stress, including slowed replication fork restart, although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and have altered HR protein dynamics in both damaged and untreated cells. These data suggest H3-G34R slows resolution of HR-mediated repair and that unresolved replication intermediates impair chromosome segregation. This analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.

Molecular mechanisms involved in initiation of the DNA damage response.

DNA is subject to a wide variety of damage. In order to maintain genomic integrity, cells must respond to this damage by activating repair and cell cycle checkpoint pathways. The initiating events in the DNA damage response entail recognition of the lesion and the assembly of DNA damage response complexes at the DNA. Here, we review what is known about these processes for various DNA damage pathways.

Cell cycle regulation by checkpoints.

Cell cycle checkpoints are surveillance mechanisms that monitor the order, integrity, and fidelity of the major events of the cell cycle. These include growth to the appropriate cell size, the replication and integrity of the chromosomes, and their accurate segregation at mitosis. Many of these mechanisms are ancient in origin and highly conserved, and hence have been heavily informed by studies in simple organisms such as the yeasts. Others have evolved in higher organisms, and control alternative cell fates with significant impact on tumor suppression. Here, we consider these different checkpoint pathways and the consequences of their dysfunction on cell fate.