Citations

DNA double-strand breaks (DSBs) that occur during mitosis are primarily repaired by Polθ-mediated microhomology-mediated end joining (MMEJ). The CIP2A–TOPBP1 complex has been shown to tether broken chromatin at mitotic DSBs, but whether it coordinates with or functions independently of Polθ remains unknown. Here, we show that the CIP2A–TOPBP1 complex is recruited to mitotic DSB sites, where it directly interacts with Polθ and corecruits Polθ to chromatin. CIP2A sustains Polθ phosphorylation by inhibiting PP2A, thereby prolonging Polθ chromatin retention and enabling efficient repair. Upon repair completion, the CIP2A–TOPBP1 complex dissociates, PP2A dephosphorylates Polθ, and Polθ is released from chromatin. Loss of CIP2A impairs tumor growth, while disruption of CIP2A–Polθ binding leads to persistent DNA damage, micronucleus formation, and synthetic lethality in BRCA1/2-deficient cells. These findings uncover a cooperative mechanism by which CIP2A–TOPBP1 dynamically regulates Polθ in mitotic DSB repair and provide insights into the synthetic lethal interaction of CIP2A with BRCA1/2 under radiotherapy.

Background Sex affects the prevalence of atherosclerotic cardiovascular disease (ASCVD) risk factors but whether sex differences exist in the associations between ASCVD risk burden and cognitive function is unclear. Methods This cross‐sectional study included participants from a population‐based cohort study in China that recruited community‐dwelling adults aged 50 to 75 years without baseline cardiovascular disease and stroke. The 10‐year ASCVD risk burden was quantified with 3 multivariate risk prediction equations. Cognitive domains of memory, attention, visuospatial function, executive function, and processing speed were assessed. Multivariable linear regression models were used to examine the interaction terms between sex and ASCVD risk scores on cognition. Results The final analytical sample included 2180 participants. Mean±SD age was 60.14 (6.38) and 52.1% were women. Men showed significantly higher ASCVD risk burden than women at baseline but the effect of ASCVD risk on 2‐year cognition were amplified in women compared with men, for the domains of memory (eg, β=−0.20 [95% CI, –0.26 to −0.13] versus β=−0.11 [95% CI, –0.16 to −0.07]), executive function (eg, β=−0.23 [95% CI, –0.31 to −0.16] versus β=−0.16 [95% CI, –0.21 to −0.10]), and processing speed (eg, β=−0.33 [95% CI, –0.39 to −0.27] versus β=−0.17 [95% CI, –0.21 to −0.13]). Sex‐stratified analyses showed different neuropsychological profiles at moderate ASCVD risk burden levels, suggesting sex‐specific ASCVD‐risk related cognitive phenotypes. Conclusions Sex differences in cognitive health affected by ASCVD risk underscore the importance of sex‐specific cognitive monitoring during ASCVD risk management and better vascular risk control in women to prevent cognitive decline.

Introduction: In recent years, multiple myeloma (MM) research has increasingly focused on unraveling the complex interactions between malignant plasma cells and their surrounding bone marrow microenvironment (BMME). To further elucidate these interactions, we developed a comprehensive single-cell atlas of the MM BMME, integrating both coding and noncoding (ncRNA) transcriptional profiles. By correlating these profiles with specific cytogenetic abnormalities in myeloma cells, we aim to uncover how ncRNAs regulate the phenotypic and functional states of myeloma cells and, consequently, shape the cellular landscape of the BMME. A detailed understanding of how the noncoding transcriptome affects the cellular components and immune landscape of the BMME is essential for advancing our knowledge of MM pathogenesis and identifying novel biomarkers and therapeutic targets. Methods: Our atlas was constructed using single-cell RNA sequencing data from 481 samples of CD138neg cells sorted from bone marrow aspirates of MM patients enrolled in the MMRF CoMMpass study. This dataset includes accompanying whole-genome sequencing and survival data, enabling correlative analysis between transcriptional profiles, cytogenetic abnormalities, and patient outcomes. To generate a combined coding and non-coding transcriptome, we developed an expanded human reference genome by systematically merging mRNA and ncRNA transcripts from the LncBook2.0 and GENECODEv42 reference genomes. The sequencing data was aligned to this expanded genome, followed by quality control processing, batch correction, clustering, and supervised analysis. Results: The resulting coding and non-coding atlas comprises over 1.9 million cells, spanning immune, plasma, and stromal compartments. Remarkably, ncRNAs constituted 46% of the associated genes, including 22,102 long ncRNAs (lncRNAs) and 3,112 small ncRNAs. Subclustering analysis of the major immune compartments (B lymphoid, myeloid, and NK and T lymphoid) yielded 70 subclusters, with ncRNAs representing 24-38% of the top 100 differentially expressed genes within each compartment. This underscores the significant role of ncRNAs in distinguishing immune subpopulations. Moreover, examining the association between specific cytogenetic abnormalities and the immune composition of the BMME, 30 subclusters were found to be differentially abundant (P < 0.05) between cytogenetic abnormalities, supporting our hypothesis that myeloma cell genotypes significantly shape the immune microenvironment. For instance, patients with CCND1 amplification displayed an increase CD4+ central memory T cells with a decrease in CD8+ cytotoxic T cells. Similarly, patients with 1q21 gain exhibited an increase in TGFβ-stimulated monocytes, while a decrease in cytotoxic CD8+ T and CD56dim NK cells was observed in patients with 17p13 deletion. Next, examining which ncRNAs are associated with specific cytogenetic abnormalities, we identified 14 ncRNAs significantly differentially expressed across cytogenetic abnormalities. Increased expression of six of these ncRNAs were associated with poor overall survival both independently and in combination (P < 0.05, HR = 3.7). Notably, three of these ncRNAs have documented roles in cancer progression but have not been previously studied in the context of MM. Subsequently stratifying patients based on their enrichment of these outcome-associated ncRNAs revealed even stronger associations with immune composition, including an increase in CD4+ regulatory T cells (P < 0.05). This further supports our hypothesis that myeloma cell genotypes shape the BMME. Lastly, by constructing a gene regulatory network to predict the interactions between coding and noncoding RNAs, we illustrate the regulatory networks of ncRNAs modulating the phenotypes of myeloma and immune cell subpopulations. Conclusion: In summary, we present the first high-resolution transcriptomic atlas of the MM BMME, integrating both coding and noncoding RNAs. This study reveals distinct immune subpopulations associated with specific myeloma cell genotypes and highlights the central role of ncRNAs in modulating the phenotypic and functional states of both malignant and non-malignant cells in the MM BMME. Our findings emphasize the potential of ncRNAs as therapeutic targets and prognostic markers for MM, offering new avenues for research and clinical intervention.

Abstract Background There are limited data on the use of stereotactic radiosurgery (SRS) for pediatric patients. The aim of this systematic review was to summarize indications and outcomes specific to pediatric cranial SRS to inform consensus guidelines on behalf of the International Stereotactic Radiosurgery Society. Methods A systematic review, using the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses, analyzed English-language articles on SRS, published between 1989 and 2021, that included outcomes for at least 5 pediatric patients. MEDLINE database terms included tumor types and locations, and radiosurgical and age-specific terms. We excluded nonclinical reports, expert opinions, commentaries, and review articles. Meta-regressions for associations with local control were performed for medulloblastoma, craniopharyngioma, ependymoma, glioma, and arteriovenous malformation (AVM). Results Of the 113 articles identified for review, 68 met the inclusion criteria. These articles described approximately 400 pediatric patients with benign and malignant brain tumors and 5119 with AVMs who underwent cranial SRS. The rates of local control for benign tumors, malignant tumors, and AVMs were 89% (95% CI, 82%–95%), 71% (95% CI, 59%–82%), and 65% (95% CI, 60%–69%), respectively. No significant associations were identified for local control with the patient-, tumor-, or treatment-related variables. Conclusions This review is the first to summarize outcomes specific to SRS for pediatric brain tumors and AVMs. Although data reporting is limited for pediatric patients, SRS appears to provide acceptable rates of local control. We present ISRS consensus guidelines to inform the judicious use of cranial SRS for pediatric patients.

BACKGROUND AND OBJECTIVES: Consensus guidelines do not exist to guide the role of stereotactic radiosurgery (SRS) in the management of patients with Spetzler-Martin Grade III-V arteriovenous malformations (AVMs). We sought to establish SRS practice guidelines for Grade III-V AVMs based on a critical systematic review of the published literature. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant search of Medline, Embase, and Scopus, 1986 to 2023, for publications reporting post-SRS outcomes in ≥10 Grade III-V AVMs with the median follow-up ≥24 months was performed. Primary end points were AVM obliteration and post-SRS hemorrhage. Secondary end points included dosimetric variables, Spetzler-Martin parameters, and neurological outcome. RESULTS : In total, 2463 abstracts were screened, 196 manuscripts were reviewed, and 9 met the strict inclusion criteria. The overall sample of 1634 AVMs consisted of 1431 Grade III (88%), 186 Grade IV (11%), and 11 Grade V lesions (1%). Total median post-SRS follow-up was 53 months for Grade III and 43 months for Grade IV-V AVMs (ranges, 2-290; 12-262). For Grade III AVMs, the crude obliteration rate was 72%, and among Grade IV-V lesions, the crude obliteration rate was 46%. Post-SRS hemorrhage was observed in 7% of Grade III compared with 17% of Grade IV-V lesions. Major permanent deficits or death from hemorrhage or radiation-induced complications occurred in 86 Grade III (6%) and 22 Grade IV-V AVMs (12%). CONCLUSION: Most patients with Spetzler-Martin Grade III AVMs have favorable SRS treatment outcomes; however, the obliteration rate for Grade IV-V AVMs is less than 50%. The available studies are heterogenous and lack nuanced, long-term, grade-specific outcomes.

BACKGROUND AND OBJECTIVES: Repeat stereotactic radiosurgery (SRS) for residual arteriovenous malformations (AVMs) can be considered as a salvage approach after failure of initial SRS. There are no published guidelines regarding patient selection, timing, or SRS parameters to guide clinical practice. This systematic review aimed to review outcomes and complications from the published literature to inform practice recommendations provided on behalf of the International Stereotactic Radiosurgery Society. METHODS: We performed a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of MEDLINE, Scopus, Web of Science, and Embase was conducted. Fourteen studies with 925 patients met the inclusion criteria. Patients were treated between 1985 and 2022. All studies were retrospective, except for one prospective cohort. RESULTS: The median patient age at repeat SRS ranged from 32 to 60 years. Four studies (630 patients) reported detailed information on Spetzler–Martin grade at the time of repeat SRS; 12.54% of patients had Spetzler–Martin grade I AVMs (79/630 patients), 46.51% had grade II (293/630), 34.92% had grade III (220/630), 5.08% had grade IV (32/630), and 0.95% had grade V (6/630). The median prescription doses varied between 15 and 25 Gy (mean, 13.06-22.8 Gy). The pooled overall obliteration rate at the last follow-up after repeat SRS was 59% (95% CI 51%-67%) with a median follow-up between 21 and 50 months. The pooled hemorrhage incidence at the last follow-up was 5% (95% CI 4%-7%), and the pooled overall radiation-induced change incidence was 12% (95% CI 7%-20%). CONCLUSION: For an incompletely obliterated AVM, repeat radiosurgery after 3 to 5 years of follow-up from the first SRS provides a reasonable benefit to the risk profile. After repeat SRS, obliteration is achieved in the majority of patients. The risk of hemorrhage or radiation-induced change appears low, and International Stereotactic Radiosurgery Society recommendations are presented.

Acute pancreatitis (AP) is among the most common hospital gastrointestinal diagnoses; understanding the mechanisms underlying the severity of AP is critical for development of new treatment options for this disease. Here, we evaluate the biological function of phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in AP pathogenesis in 2 independent genetically engineered mouse models of AP. PFKFB3 was elevated in AP and severe AP (SAP), and KO of Pfkfb3 abrogated the severity of alcoholic SAP (FAEE-SAP). Using a combination of genetic, pharmacological, and molecular studies, we defined the interaction of PFKFB3 with inositol 1,4,5-trisphosphate receptor (IP3R) as a key event mediating this phenomenon. Further analysis demonstrated that the interaction between PFKFB3 and IP3R promotes FAEE-SAP severity by altering intracellular calcium homeostasis in acinar cells. Together, our results support a PFKFB3-driven mechanism controlling AP pathobiology and define this enzyme as a therapeutic target to ameliorate the severity of this condition.

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Abstract Background The choice of an appropriate strategy for intracanalicular vestibular schwannoma (ICVS) is still debated. We conducted a systematic review and meta-analysis with the aim to compare treatment outcomes amongst management strategies (conservative surveillance (CS), microsurgical resection (MR), or stereotactic radiosurgery (SRS)) aiming to inform guideline recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). Methods Using PRISMA guidelines, we reviewed manuscripts published between January 1990 and October 2021 referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical studies or case series reporting a cohort of ICVS managed with CS, MR, or SRS. Primary outcome measures included tumor control, the need for additional treatment, hearing outcomes, and posttreatment neurological deficits. These were pooled using meta-analytical techniques and compared using meta-regression with random effect. Results Forty studies were included (2371 patients). The weighted pooled estimates for tumor control were 96% and 65% in SRS and CS series, respectively (P < .001). Need for further treatment was reported in 1%, 2%, and 25% for SRS, MR, and CS, respectively (P = .001). Hearing preservation was reported in 67%, 68%, and 55% for SRS, MR, and CS, respectively (P = .21). Persistent facial nerve deficit was reported in 0.1% and 10% for SRS and MR series, respectively (P = .01). Conclusions SRS is a noninvasive treatment with at least equivalent rates of tumor control and hearing preservation as compared to MR, with the caveat of better facial nerve preservation. As compared to CS, upfront SRS is an effective treatment in achieving tumor control with similar rates of hearing preservation.

Introduction Newly-diagnosed multiple myeloma (MM) patients often share tumor genetic abnormalities associated with a high risk of progression and poor survival. We hypothesized that single-cell transcriptomic characterization of the tumor immune microenvironment (TIME) may be combined with tumor-based risk stratification to uncover novel disease biology mechanisms associated with clinical outcomes and improve risk stratification. Methods We performed single-cell RNA sequencing of 361 CD138 negative sorted bone marrow mononuclear cells (BMMCs) samples from 263 MM patients enrolled at time of diagnosis in the Multiple Myeloma Research Foundation CoMMpass study (NCT01454297). Specimens were analyzed at baseline (n=263) across a network of five collaborating academic research centers following assay harmonization. Genetic factors that determine risk were defined as one or more of the following gain- or loss-of-function events derived from baseline genomic sequencing data: del17p14, translocations of the Ig locus with the MAF/A/B or WHSC1/MMSET/NSD2 loci, and gain of chromosome 1q21. Statistical modeling strategies were used to assess single-cell populations or RNA signatures associations with known risk factors or disease progression (FDR<0.05). Results The study generated high-quality single-cell profiles of 731,643 cells from 123 high-risk and 107 standard-risk MM patients based on genetics. Based on distinct transcriptome profiles, BMMCs formed 106 clusters corresponding to 5 major compartments: NK and T cells, B cells, erythrocytes, myeloid cells, and plasma cells. Our preliminary differential abundance analysis comparing high- vs standard-risk patients at baseline uncovered significant differences in the TIME associated with genetic risk. The high-risk group was identified as enriched in effector CD8+, and CD4+ T cells. In contrast, the high-risk group exhibited depletion of naive CD8+ and interferon-associated CD4+ and CD8+ T as compared to the standard-risk group. Within subclusters in the T and NK cells compartment, a higher cytotoxicity signature was observed in high-risk patients, characterized by the expression of granzymes and perforin. Finally, our preliminary survival and progression analysis associated a higher frequency of IDO1-expressing macrophages in worst progression patients, while better outcomes were associated with CD8+ T and B cells expressing androgen response and IL6/STAT3/EMT programs, respectively. Conclusions Current approaches for risk stratification are based on bulk measurements of tumor's genetic or epigenetics features, which do not capture the diversity and dynamics of the TIME. Through single-cell transcriptomics, we were able to capture, in high granularity, the TIME and correlate specific immune cell populations and phenotypes with relapse risk and poor prognostic outcomes. These results suggest that immune subpopulations may be an essential novel aspect for improving current risk stratification models.