Explore the vast range of titles available.

Despite several decades of intense research focused on understanding function(s) and disease-associated malfunction of p53, there is no sign of any “mid-life crisis” in this rapidly advancing area of biomedicine. Firmly established as the hub of cellular stress responses and tumor suppressor targeted in most malignancies, p53’s many talents continue to surprise us, providing not only fresh insights into cell and organismal biology, but also new avenues to cancer treatment. Among the most fruitful lines of p53 research in recent years have been the discoveries revealing the multifaceted roles of p53-centered pathways in the fundamental processes of DNA replication and ribosome biogenesis (RiBi), along with cellular responses to replication and RiBi stresses, two intertwined areas of cell (patho)physiology that we discuss in this review. Here, we first provide concise introductory notes on the canonical roles of p53, the key interacting proteins, downstream targets and post-translational modifications involved in p53 regulation. We then highlight the emerging involvement of p53 as a key component of the DNA replication Fork Speed Regulatory Network and the mechanistic links of p53 with cellular checkpoint responses to replication stress (RS), the driving force of cancer-associated genomic instability. Next, the tantalizing, yet still rather foggy functional crosstalk between replication and RiBi (nucleolar) stresses is considered, followed by the more defined involvement of p53-mediated monitoring of the multistep process of RiBi, including the latest updates on the RPL5/RPL11/5 S rRNA-MDM2-p53-mediated Impaired Ribosome Biogenesis Checkpoint (IRBC) pathway and its involvement in tumorigenesis. The diverse defects of RiBi and IRBC that predispose and/or contribute to severe human pathologies including developmental syndromes and cancer are then outlined, along with examples of promising small-molecule-based strategies to therapeutically target the RS- and particularly RiBi- stress-tolerance mechanisms to which cancer cells are addicted due to their aberrant DNA replication, repair, and proteo-synthesis demands.

Following the discovery in 1998 of γ-H2AX, the first histone modification induced by DNA damage 1 , interest in the changes to chromatin induced by DNA damage has exploded, and a vast amount of information has been generated. However, there has been a discrepancy between our rapidly advancing knowledge of how chromatin responds to DNA damage and the understanding of why cells mobilize large segments of chromatin to protect the genome against destabilizing effects posed by tiny DNA lesions. Recent research has provided insights into these issues and suggests that chromatin responses induced by DNA damage are not simply the accumulation of 'nuclear foci' but are mechanisms required to guard genome integrity.

Abstract BACKGROUND There are examples of incongruence between the WHO grade and clinical course in meningioma patients. This incongruence between WHO grade and recurrence has led to search for other prognostic histological markers. OBJECTIVE To study the correlation between the Ki-67 proliferative index (PI), risk of recurrence, and recurrence rates in meningioma patients. METHODS We prospectively collected pathological diagnosis of de novo consecutive meningiomas. In total, we followed 159 patients with clinical controls until recurrence, death, or emigration. We estimated the correlation between risk of recurrence and Ki-67 PI when adjusted for age at diagnosis, sex, WHO grade, extent of surgical resection, and tumor location. We estimated the cumulative incidence of recurrence when considering death without recurrence a competing risk. We report recurrence rates per 100 person-years. RESULTS A 1%-point increase of Ki-67 PI yielded a hazard ratio of 1.12 (95% CI: 1.01-1.24) in a multivariate analysis. The cumulative incidence of recurrence was 3% for Ki-67 0% to 4% vs 19% for Ki-67 > 4% meningiomas after 1 yr, but 24% vs 35%, respectively, after 10 yr. There was no significant difference in mean Ki-67 PI between nonrecurrent and recurrent meningioma in a 2-sample t-test (P = .08). The strongest relationship was detected between Ki-67 PI and time to recurrence: Ki-67 < 4% meningiomas recurred after median 4.8 yr, compared to 0.60 to 0.75 yr for patients with higher Ki-67 PI. CONCLUSION Ki-67 PI was a marker for time to recurrence rather than a predictor of recurrence. Ki-67 PI may be utilized for patient tailored follow-up. Graphical Abstract Graphical Abstract

Accurate replication of DNA requires stringent regulation to ensure genome integrity. In human cells, thousands of origins of replication are coordinately activated during S phase, and the velocity of replication forks is adjusted to fully replicate DNA in pace with the cell cycle 1 . Replication stress induces fork stalling and fuels genome instability 2 . The mechanistic basis of replication stress remains poorly understood despite its emerging role in promoting cancer 2 . Here we show that inhibition of poly(ADP-ribose) polymerase (PARP) increases the speed of fork elongation and does not cause fork stalling, which is in contrast to the accepted model in which inhibitors of PARP induce fork stalling and collapse 3 . Aberrant acceleration of fork progression by 40% above the normal velocity leads to DNA damage. Depletion of the treslin or MTBP proteins, which are involved in origin firing, also increases fork speed above the tolerated threshold, and induces the DNA damage response pathway. Mechanistically, we show that poly(ADP-ribosyl)ation (PARylation) and the PCNA interactor p21 Cip1 (p21) are crucial modulators of fork progression. PARylation and p21 act as suppressors of fork speed in a coordinated regulatory network that is orchestrated by the PARP1 and p53 proteins. Moreover, at the fork level, PARylation acts as a sensor of replication stress. During PARP inhibition, DNA lesions that induce fork arrest and are normally resolved or repaired remain unrecognized by the replication machinery. Conceptually, our results show that accelerated replication fork progression represents a general mechanism that triggers replication stress and the DNA damage response. Our findings contribute to a better understanding of the mechanism of fork speed control, with implications for genomic (in)stability and rational cancer treatment. Inhibition of PARP is shown to accelerate the speed of replication fork elongation, which prevents fork stalling and induces DNA damage, with implications for genomic instability and cancer treatment.

Poly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors. Krastev et al. report that trapped PARP1 undergoes SUMOylation, followed by ubiquitylation, resulting in the recruitment of the p97 ATPase to remove trapped PARP1 from chromatin and prevent PARP inhibitor-induced cytotoxicity.

Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is accompanied by serious cytotoxic complications and safety concerns at innate immune levels, which impedes the development of therapeutic polycationic nucleic acid carriers in general and their clinical applications. In recent years, the dilemma between transfection efficacy and adverse PEI activities has been addressed from in-depth investigations of cellular processes during transfection and elucidation of molecular mechanisms of PEI-mediated toxicity and translation of these integrated events to chemical engineering of novel PEI derivatives with an improved benefit-to-risk ratio. This review addresses these perspectives and discusses molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity, including membrane destabilization, mitochondrial dysfunction, and perturbations of glycolytic flux and redox homeostasis as well as chemical strategies for the generation of better tolerated polycations. We further examine the effect of PEI and its derivatives on complement activation and interaction with Toll-like receptors. These perspectives are intended to lay the foundation for an improved understanding of interlinked mechanisms controlling transfection and toxicity and their translation for improved engineering of polycation-based transfectants. [Display omitted] Polycations such as polyethylenimines (PEIs) are widely used as non-viral transfectants, but they often induce cytotoxicity and may trigger immune reactions. Here we examine and discuss molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity and immune system modulation and their translation for improved and safer engineering of polycation-based transfectants.

The nucleolus is the major site for synthesis of ribosomes, complex molecular machines that are responsible for protein synthesis. A wealth of research over the past 20 years has clearly indicated that both quantitative and qualitative alterations in ribosome biogenesis can drive the malignant phenotype via dysregulation of protein synthesis. However, numerous recent proteomic, genomic, and functional studies have implicated the nucleolus in the regulation of processes that are unrelated to ribosome biogenesis, including DNA-damage response, maintenance of genome stability and its spatial organization, epigenetic regulation, cell-cycle control, stress responses, senescence, global gene expression, as well as assembly or maturation of various ribonucleoprotein particles. In this review, the focus will be on features of rDNA genes, which make them highly vulnerable to DNA damage and intra- and interchromosomal recombination as well as built-in mechanisms that prevent and repair rDNA damage, and how dysregulation of this interplay affects genome-wide DNA stability, gene expression and the balance between euchromatin and heterochromatin. We will also present the most recent insights into how malfunction of these cellular processes may be a central driving force of human malignancies, and propose a promising new therapeutic approach for the treatment of cancer.

ObjectivesWith regard to the generally slow growth of meningioma, it is essential to analyse clinical treatment results in a long-term perspective. The purpose of the present analysis is to provide clinical data after Gamma Knife radiosurgery of meningioma in a 10-year perspective together with a review of the current literature.MethodsThe current study is a retrospective analysis of 86 consecutive Swedish patients with meningiomas treated using Gamma Knife radiosurgery at the Karolinska Hospital Stockholm between March 1991 and May 2001. A total of 130 tumours were treated in 115 treatment sessions. The median radiological follow-up was 10 years (1.8–16.5 years), and the median clinical follow-up was 9.4 years (2.1–17.4 years).ResultsAfter a median follow-up period of 10 years, local tumour control was achieved in 87.8% of meningiomas (108/123 tumours). The median latency between initial treatment and local (in-field) recurrence (n = 15) was 5.8 years (1.9–11.5). Recurrences adjacent but outside the initial radiation field occurred in 15.1% of patients (13/86) at a median of 7.5 years (1.3–15.7). New meningiomas were seen in 10.5% after a median of 5.4 years (0.9–10.8). In 72% of patients, no further treatment was required, 17.4% (15/86) underwent a second Gamma Knife treatment, 4.7% (4/86) required later open surgery and 5.8% (5/86) required both secondary treatments. Eighty-six percent of patients were neurologically unchanged or improved. A significantly lower rate of local (in-field) recurrences was seen in meningiomas treated with a prescription dose of > 13.4 Gy (7.1% vs. 24%, p = 0.02).ConclusionsThe current retrospective analysis provides a 10-year follow-up and comprises one of the longest available follow-up studies of radiosurgically treated meningiomas. The current series documents a persistent high local tumour control after Gamma Knife treatment, while providing an estimation of a necessary minimum dose for long-term tumour control in meningiomas. The study confirms the validity of previous short-term data in a long-term perspective.

Objective: The precision of neuronavigation systems relies on the correct registration of the patient’s position in space and aligning it with radiological 3D imaging data. Registration is usually performed by the acquisition of anatomical landmarks or surface matching based on facial features. Another possibility is automatic image registration using intraoperative imaging. This could provide better accuracy, especially in rotated or prone positions where the other methods may be difficult to perform. The aim of this study was to validate automatic image registration (AIR) using intraoperative cone-beam computed tomography (CBCT) for cranial neurosurgical procedures and compare the registration accuracy to the traditional surface matching (SM) registration method based on preoperative MRI. The preservation of navigation accuracy throughout the surgery was also investigated. Methods: Adult patients undergoing intracranial tumor surgery were enrolled after consent. A standard SM registration was performed, and reference points were acquired. An AIR was then performed, and the same reference points were acquired again. Accuracy was calculated based on the referenced and acquired coordinates of the points for each registration method. The reference points were acquired before and after draping and at the end of the procedure to assess the persistency of accuracy. Results: In total, 22 patients were included. The mean accuracy was 6.6 ± 3.1 mm for SM registration and 1.0 ± 0.3 mm for AIR. The AIR was superior to the SM registration (p < 0.0001), with a mean improvement in accuracy of 5.58 mm (3.71–7.44 mm 99% CI). The mean accuracy for the AIR registration pre-drape was 1.0 ± 0.3 mm. The corresponding accuracies post-drape and post-resection were 2.9 ± 4.6 mm and 4.1 ± 4.9 mm, respectively. Although a loss of accuracy was identified between the preoperative and end-of-procedure measurements, there was no statistically significant decline during surgery. Conclusions: AIR for cranial neuronavigation consistently delivered greater accuracy than SM and should be considered the new gold standard for patient registration in cranial neuronavigation. If intraoperative imaging is a limited resource, AIR should be prioritized in rotated or prone position procedures, where the benefits are the greatest.

Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process by interfering with the transcription of ribosomal RNA (rRNA) in the nucleolus through the blockade of RNA polymerase I or by limiting the nucleotide building blocks of RNA, thereby ultimately preventing the synthesis of new ribosomes. Perturbations in RiBi activate nucleolar stress response pathways, including those controlled by p53. While compounds such as actinomycin D and oxaliplatin effectively disrupt RiBi, there is an ongoing effort to improve the specificity further and find new potent RiBi-targeting compounds with improved pharmacological characteristics. A few recently identified inhibitors have also become popular as research tools, facilitating our advances in understanding RiBi. Here we provide a comprehensive overview of the various compounds targeting RiBi, their mechanism of action, and potential use in cancer therapy. We discuss screening strategies, drug repurposing, and common problems with compound specificity and mechanisms of action. Finally, emerging paths to discovery and avenues for the development of potential biomarkers predictive of therapeutic outcomes across cancer subtypes are also presented.