Significance of the photosystem II core phosphatase PBCP for plant viability and protein repair in thylakoid membranes.

PSII undergoes photodamage, which results in photoinhibition-the light-induced loss of photosynthetic activity. The main target of damage in PSII is the reaction center protein D1, which is buried in the massive 1.4 MDa PSII holocomplex. Plants have evolved a PSII repair cycle that degrades the damaged D1 subunit and replaces it with a newly synthesized copy. PSII core proteins, including D1, are phosphorylated in high light. This phosphorylation is important for the mobilization of photoinhibited PSII from stacked grana thylakoids to the repair machinery in distant unstacked stroma lamellae. It has been recognized that the degradation of the damaged D1 is more efficient after its dephosphorylation by a protein phosphatase. Recently a protein phosphatase 2C (PP2C)-type PSII core phosphatase (PBCP) has been discovered, which is involved in the dephosphorylation of PSII core proteins. Its role in PSII repair, however, is unknown. Using a range of spectroscopic and biochemical techniques, we report that the inactivation of the PBCP gene affects the growth characteristic of plants, with a decreased biomass and altered PSII functionality. PBCP mutants show increased phosphorylation of core subunits in dark and photoinhibitory conditions and a diminished degradation of the D1 subunit. Our results on D1 turnover in PBCP mutants suggest that dephosphorylation of PSII subunits is required for efficient D1 degradation.

Intraventricular Pilocytic Astrocytoma in Adults: A 25-year Single-Center Case Series and Systematic Review of the Literature.

BACKGROUND: Pilocytic astrocytomas (PA) are the most common gliomas in children/adolescents but are less common and poorly studied in adults. Here, we describe the clinical presentation, surgical management, and outcomes of surgically treated adult patients with intraventricular (IV) PA and review the literature. METHODS: Consecutive adult patients treated for IV brain tumors at a tertiary academic center over 25 years (1997-2023) were identified. Clinical data were reviewed retrospectively for adult IV PA patients. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: Eight patients with IV PA were included. Median age was 25 years (range, 18-69 years), and 4 (50%) were female. The most common tumor location was the lateral ventricle (5, 63%), followed by the fourth ventricle (3, 37%). Subtotal and near total resection were the most common surgical outcomes (6 patients, 75%), followed by gross total resection in 2 (25%). Progression or recurrence occurred in 3 patients (37%), requiring repeat resection in 2 patients. The 5-year overall survival and progression-free survival were 67% and 40%, respectively. In addition, 42 cases were identified in the literature. CONCLUSIONS: PAs in adults are rare and an IV location is even more uncommon. The findings demonstrate the challenges in caring for these patients, with overall- and progression-free survival outcomes being poorer than the general adult PA population. Findings support the employment of surgical techniques and approaches that favor gross total resection when possible. Further studies are needed to better characterize this unique presentation.

Intrasaccular Flow Disruption: Examining Global Access and Research Trends.

The Woven EndoBridge (WEB) and other intrasaccular flow disruptors show promise in treating intracranial aneurysms. We performed a bibliometric analysis to provide novel insights into the trends and trajectory of these devices. We systematically assessed bibliometric data such as citations, journals, study designs, open access status, and multi-institutional involvement for the top-cited articles on WEB and other disruptors. The top 100 cited studies on the WEB had citations from 7 to 144 (mean±s.d. 35.6 ± 29.5), while only 33 studies were published for other intrasaccular flow disruptors (4.24 ± 8.45). Of the other devices, the Contour has the most publications (n=21). Retrospective reviews were the most common study design for both WEB and other intrasaccular devices. France published the most studies in top 100 WEB papers (n=35), while Germany led for other flow disruptors (n=10). In all studies analyzed, no senior authors from Africa are present. The top 100 WEB publications had a higher mean citation count (35.6 vs. 4.24, p < 0.001), higher mean citations per year (5.24 vs. 1.03, p < 0.01), and a higher proportion of multi-institutional collaborations (44.0% vs. 12.1%, p < 0.01) than other intrasaccular flow disruptors. In conclusion, countries with the most publications on WEB are not necessarily the ones leading the way with newer intrasaccular devices, while study designs remain similar. There is limited contribution to the literature outside of Europe and North America. Our findings identify notable collaborators and trends, providing a snapshot of the field and a roadmap for future research.

The function of histone methylation and acetylation regulators in GBM pathophysiology.

Glioblastoma (GBM) is the most common and lethal primary brain malignancy and is characterized by a high degree of intra and intertumor cellular heterogeneity, a starkly immunosuppressive tumor microenvironment, and nearly universal recurrence. The application of various genomic approaches has allowed us to understand the core molecular signatures, transcriptional states, and DNA methylation patterns that define GBM. Histone posttranslational modifications (PTMs) have been shown to influence oncogenesis in a variety of malignancies, including other forms of glioma, yet comparatively less effort has been placed on understanding the transcriptional impact and regulation of histone PTMs in the context of GBM. In this review we discuss work that investigates the role of histone acetylating and methylating enzymes in GBM pathogenesis, as well as the effects of targeted inhibition of these enzymes. We then synthesize broader genomic and epigenomic approaches to understand the influence of histone PTMs on chromatin architecture and transcription within GBM and finally, explore the limitations of current research in this field before proposing future directions for this area of research.

Endoscopic Reconstruction of the Anterior Skull Base Following Tumor Resection: Application of a Novel Bioabsorbable Plate.

OBJECTIVE: Endoscopic repair of skull base defects is required following resection of intracranial pathology via the endoscopic endonasal approach (EEA). Many closure techniques have been described, but choosing between techniques remains controversial. We report outcomes of 560 EEA procedures of skull base reconstruction performed on 508 patients over a 15-year-period. Halfway through this period, we adopted the use of a rigid, bioabsorbable extrasellar plate for reconstruction, enabling a comparison between this technique and those used previously. METHODS: All patients undergoing EEA from 2005 to 2019 at our institution were retrospectively reviewed. Demographic information, surgical pathology, tumor dimensions and radiographic features, reconstructive technique, and patient-related outcomes were collected and analyzed with univariate and multivariate statistical modeling. RESULTS: Five-hundred sixty procedures were performed on 508 patients. The series complication rate was 8.2%. Overall, cerebrospinal fluid (CSF) leak rate was 5.0% but varied significantly across closure techniques (p < 0.001). Critically, the CSF leak rate in the 272 cases prior to our 2013 adoption of the Resorb-X Plate (RXP) was 8.5%, whereas leak rate in the subsequent 288 cases was 1.7%. RXP was protective against CSF leak (p = 0.001), whereas gross total resection (GTR) correlated with increased leak rate (p = 0.001). Patient BMI was significantly associated with risk of leak (p = 0.047). Other variables did not impact leak risk. CONCLUSION: Reconstructive technique, extent of resection, and patient BMI significantly contributed to CSF leak rate. GTR was associated with increased leak risk while the RXP was protective. The bioabsorbable RXP is an effective option for rigid skull base repair with comparatively few complications. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1092-1098, 2023.

Stochastic growth pattern of untreated human glioblastomas predicts the survival time for patients.

Glioblastomas are highly malignant brain tumors. Knowledge of growth rates and growth patterns is useful for understanding tumor biology and planning treatment logistics. Based on untreated human glioblastoma data collected in Trondheim, Norway, we first fit the average growth to a Gompertz curve, then find a best fitted white noise term for the growth rate variance. Combining these two fits, we obtain a new type of Gompertz diffusion dynamics, which is a stochastic differential equation (SDE). Newly collected untreated human glioblastoma data in Seattle, US, re-verify our model. Instead of growth curves predicted by deterministic models, our SDE model predicts a band with a center curve as the tumor size average and its width as the tumor size variance over time. Given the glioblastoma size in a patient, our model can predict the patient survival time with a prescribed probability. The survival time is approximately a normal random variable with simple formulas for its mean and variance in terms of tumor sizes. Our model can be applied to studies of tumor treatments. As a demonstration, we numerically investigate different protocols of surgical resection using our model and provide possible theoretical strategies.

Anti-PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma.

BACKGROUND: Most glioblastomas recur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an "abscopal effect," whereby unirradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti-programmed cell death ligand 1 (PD-L1) demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remain unknown. METHODS: We modified an immune-competent, genetically driven mouse glioma model (forced platelet derived growth factor [PDGF] expression + phosphatase and tensin homolog loss) where a portion of the tumor burden is irradiated (PDGF) and another unirradiated luciferase-expressing tumor (PDGF + luciferase) is used as a readout of the abscopal effect following systemic anti-PD-L1 immunotherapy. We assessed relevance of tumor neoepitope during the abscopal response by inducing expression of epidermal growth factor receptor variant III (EGFRvIII) (PDGF + EGFRvIII). Statistical tests were two-sided. RESULTS: Following radiation of one lesion, anti-PD-L1 immunotherapy enhanced the abscopal response to the unirradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF + luciferase, n = 8), the abscopal response occurred via anti-PD-L1 driven, extracellular signal-regulated kinase-mediated, bone marrow-derived macrophage phagocytosis of adjacent unirradiated tumor cells, with modest survival implications (median survival 41 days vs radiation alone 37.5 days, P = 0.03). In PDGF-driven gliomas with tumor neoepitope (PDGF + EGFRvIII, n = 8), anti-PD-L1 enhanced abscopal response was associated with macrophage and T-cell infiltration and increased survival benefit (median survival 36 days vs radiation alone 28 days, P = 0.001). CONCLUSION: Our results indicate that anti-PD-L1 immunotherapy enhances a radiation- induced abscopal response via canonical T-cell activation and direct macrophage activation in glioblastoma.

Predicting Chronic Subdural Hematoma Recurrence and Stroke Outcomes While Withholding Antiplatelet and Anticoagulant Agents.

Introduction: The aging of the western population and the increased use of oral anticoagulation (OAC) and antiplatelet drugs (APD) will result in a clinical dilemma on how to balance the recurrence risk of chronic subdural hematoma (cSDH) with the risk of withholding blood thinners. Objective: To identify features that predicts recurrence, thromboembolism (TEE), hospital stay and mortality. To identify the optimal window for resuming APD or OAC. Methods: We performed a retrospective multivariate analysis of a prospectively collected database. We then build machine learning models for outcomes prediction. Results: We identified 596 patients. The rate of recurrence was 22.17%, that of thromboembolism was 0.9% and that of mortality was 14.78%. Smoking, platelet dysfunction, CKD, and alcohol use were independent predictors of higher recurrence, while resolution of the SDH was protective. OAC use had higher odds of developing TEEs. CKD, developing a new neurological deficit or a TEEs were independent predictors of higher mortality. We find the optimal time of resuming OAC to be after 2 days but before 21 days as these patients had the lowest recurrence of bleeding associated with a low risk of stroke. The ML model achieved an accuracy of 93, precision of 0.84 and recall of 0.80 for recurrence prediction. ML models for hospital stay performed poorly (R 2 = 0.33). ML model for stroke was overfitted given the low number of events. Conclusion: ML modeling is feasible. However, large well-designed prospective multicenter studies are needed for accurate ML so that clinicians can balance the risks of recurrence with the risk of TEEs, especially for high-risk anticoagulated patients.