FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis.

Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria.

Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.

Meta-analysis of HNF1A-MODY3 variants among human population.

Background: Previously, numerous case-control studies have highlighted variants responsible for Maturity onset diabetes of young (MODY). However, these studies have been conducted among diverse populations and hence yielded contradictory results. We, therefore, performed a meta-analysis to precisely find the association of SNPs with the disease for the HNF1A gene. Objective: Meta-analysis of clinically defined studies deciphering mutations in the HNF1A gene responsible for the development of MODY3 was conducted among various populations to determine associations using statistical approaches. Methods: The curation of 505 research articles published between the years 2000-2021 was carried out. Visualization of data-related protocols and statistical-analysis were conducted, which led to the identification of highly prevalent mutations among different populations (majorly Europe). Further comparison between the frequencies of the control (healthy population) and test (diseased population) dataset generated through curation was performed. Results: We identified nine MODY3 mutations (rs587776825, rs1169288, rs1800574, rs2464196, rs137853244, rs137853238, rs587780357, rs137853240 and rs137853243) at the genome-wide significance level ( p < 5.0 × 10-8). The present study confirmed that the data does not follow a normal distribution. Further, the data was confirmed to be a more homogenous type with frequencies having a significant association with the disease. Conclusion: This meta-analysis found significant associations of mutations in HNF1A with MODY3, consistent with previous studies. Our findings should help elucidate the mutations in a compiled form responsible for causing MODY3. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-00975-8.

A three-dimensional matrix system containing melatonin and neural stem cells repairs damage from traumatic brain injury in rats.

Brain lesions can cause neural stem cells to activate, proliferate, differentiate, and migrate to the injured area. However, after traumatic brain injury, brain tissue defects and microenvironment changes greatly affect the survival and growth of neural stem cells; the resulting reduction in the number of neural stem cells impedes effective repair of the injured area. Melatonin can promote the survival, proliferation, and differentiation of neural stem cells under adverse conditions such as oxidative stress or hypoxia that can occur after traumatic brain injury. Therefore, we investigated the therapeutic effects of melatonin combined with neural stem cells on traumatic brain injury in rats. First, in vitro studies confirmed that melatonin promoted the survival of neural stem cells deprived of oxygen and glucose. Then, we established a three-dimensional Matrigel-based transplantation system containing melatonin and neural stem cells and then used it to treat traumatic brain injury in rats. We found that treatment with the Matrigel system containing melatonin and neural stem cells decreased brain lesion volume, increased the number of surviving neurons, and improved recovery of neurological function compared with treatment with Matrigel alone, neural stem cells alone, Matrigel and neural stem cells combined, and Matrigel and melatonin combined. Our findings suggest that the three-dimensional Matrigel-based transplantation system containing melatonin and neural stem cells is a potential treatment for traumatic brain injury.

Long-term Outcomes and Risk Factors Related to Hydrocephalus After Intracerebral Hemorrhage.

Hydrocephalus after intracerebral hemorrhage (ICH) is a common and treatable complication. However, the long-term outcomes and factors for predicting hydrocephalus have seldom been studied. The goal of this study was to determine the long-term outcomes and analyze the risk factors of hydrocephalus after ICH. A consecutive series of 1342 patients with ICH were reviewed from 2010 to 2016 to identify significant risk factors for hydrocephalus. Patients with a first-ever ICH without any prior diagnosis of hydrocephalus after ICH were followed up for survival status and cause of death. Risk factors for hydrocephalus were evaluated by using logistic regression analysis. Out of a total of 1342 ICH patients, 120 patients (8.9%) had hydrocephalus. The risk factors for hydrocephalus (≤ 3 days) were infratentorial hemorrhage (p = 0.000), extension to ventricles (p = 0.000), greater ICH volume (p = 0.09), and hematoma expansion (p = 0.01). Extension to ventricles (p = 0.022) was the only independent risk factor for hydrocephalus (4-13 days), while extension to ventricles (p = 0.028), decompressive craniotomy (p = 0.032), and intracranial infection (p = 0.001) were independent predictors of hydrocephalus (≥ 14 days). Patients were followed up for a median of 5.2 years (IQR 3.3-7.3 years). Estimated all-cause mortality was significantly higher in the ICH patients with hydrocephalus than that without hydrocephalus (HR 3.22, 95% CI 2.42-4.28; p = 0.000). Fifty-nine (49.2%) died and 40 (33.3%) had a favorable outcome in patients with hydrocephalus. Of all deaths, 30.5% were from ICH and 64.4% from infection. Hydrocephalus is a frequent complication of ICH and most commonly occurs at the onset of ICH. Patients with hydrocephalus show relatively higher mortality. ClinicalTrials.gov Identifier: NCT02135783 (May 7, 2014).

Corrigendum to "Ambroxol Improves Neuronal Survival and Reduces White Matter Damage through Suppressing Endoplasmic Reticulum Stress in Microglia after Intracerebral Hemorrhage".

[This corrects the article DOI: 10.1155/2020/8131286.].

Development and validation of a nomogram for predicting hematoma expansion in intracerebral hemorrhage.

BACKGROUND AND OBJECTIVE: To develop and validate a clinical nomogram for individualized predicting hematoma expansion (HE) in patients with Intracerebral Hemorrhage (ICH). METHODS: A total of 1025 patients with ICH were retrospectively enrolled in the development cohort between 2010 and 2016. We identified and integrated significant factors for HE to build a nomogram. The model was subjected to validation with a separate cohort of 397 patients from the 2017-2019. The predictive accuracy and discriminative ability were measured by concordance index (C-index). The primary outcome was HE, defined as hematoma growth more than 6 mL or 33% increase in the volume. RESULTS: A total of 1025 patients were included for univariable analysis. HE occurred in 180 patients (17.6%). The time to initial CT (≤6h vs. >6 h; p = 0.001), NIHSS score (0-4 vs. 5-14 vs. ≥15; p = 0.031), CTA spot sign (yes vs. no vs. absent; p = 0.018), hypodensities (p = 0.000), blend sign (p = 0.005), and INR (<1.2 vs. ≥1.2; p = 0.009) were identified and entered into the nomogram. The calibration curves for probability of HE showed optimal agreement between nomogram prediction and actual observation. The C-index was 0.751. The validation cohort consisted of 397 patients and HE occurred in 78 patients (19.6%). The C-index was 0.743. CONCLUSIONS: We developed and validated a nomogram that can individually predict HE for ICH in Chinese populations. This practical prognostic nomogram may help clinicians make decision of clinical practice and design of clinical studies.

Corrigendum to "Actin Alpha 2 (ACTA2) Downregulation Inhibits Neural Stem Cell Migration through Rho GTPase Activation".

[This corrects the article DOI: 10.1155/2020/4764012.].

Actin Alpha 2 (ACTA2) Downregulation Inhibits Neural Stem Cell Migration through Rho GTPase Activation.

Although neural stem cells (NSCs) could migrate towards lesions after central nervous system (CNS) injury, the migration ability always is restricted due to the disturbed composition and density of the adhesion ligands and extracellular matrix (ECM) gradient after CNS injury. To date, various methods have been developed to enhance NSC migration and a number of factors, which are affecting NSC migration potential, have been identified. Here, primary NSCs were cultured and the expression of actin alpha 2 (ACTA2) in NSCs was determined using reverse transcription polymerase chain reaction (RT-PCR) and immunostaining. Next, the role of ACTA2 in regulating NSC migration and the potential mechanism was explored. Our results demonstrated that ACTA2 expressed in NSCs. Meanwhile, downregulated ACTA2 using siRNA inhibited NSC migration through hindering actin filament polymerization via increasing RhoA expression and decreasing Rac1 expression. The present study might enrich the basic knowledge of ACTA2 in NSC migration and open an avenue for enhancing NSC migration potential, subsequently providing an intervention target for functional recovery after CNS injury.

Ambroxol Improves Neuronal Survival and Reduces White Matter Damage through Suppressing Endoplasmic Reticulum Stress in Microglia after Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) has been becoming a serious public health problem. Pneumonia, occurring in 43% of all ICH patients, is a common complication heavily influencing outcome and accounting for more than 1/3 of the overall mortality in patients with ICH. Ambroxol may be an effective additional treatment for ICH patients with pneumonia. But its effect and potential mechanism on functional recovery post-ICH still remain elusive. In the present study, the results indicated that 35 mg/kg and 70 mg/kg ambroxol facilitated neuronal survival and reduced white matter fiber bundle damage due to mitigating microglial activation and reducing proinflammatory cytokine accumulation in mice with ICH. The possible mechanism might be due to suppressing endoplasmic reticulum stress involving the IRE1α/TRAF2 signaling pathway, which paves a new path for the treatment of ICH and opens a new window for the use of ambroxol in clinical practice.

Comparison of epidemiological and clinical features between two chronological cohorts of patients with intracerebral hemorrhage.

To investigate the differences in the epidemiological and clinical characteristics of patients with intracerebral hemorrhage (ICH) treated at our institution over the last few decades. Two chronological cohorts with ten-year-interval were established and epidemiological and clinical data were retrospectively collected from patients with ICH, and data were analyzed using SPSS 13.0. The time windows for the two cohorts were from January 1, 2010 to December 31, 2014 (2010-2014 cohort) and January 1, 2000 to December 31, 2004 (2000-2004 cohort). 1598 patients with ICH were enrolled: 360 patients in the 2000-2004 cohort and 1238 patients in the 2010-2014 cohort. ICH often occurred in patients aged from 45 to 75 years, without a sex bias, accounting for 69.6% of patients. Hypertension (60.7%) was still the main risk factors. Meanwhile, the risk factors of smoking (28.9%) and drinking (23.3%) were often present in male patients but not female patients (p ≤ 0.001). The incidence of pulmonary infection, the main complication during hospitalization, was 40.8% in the 2000-2004 cohort and 61.8% in the 2010-2014 cohort (p ≤ 0.001). Moreover, the incidence of gastrointestinal hemorrhage was 12.5% in the 2000-2004 cohort and 6.0% in the 2010-2014 cohort (p ≤ 0.001). The epidemiological and clinical features have changed over the past 10 years. The mortality was reduced but still high, as evidenced by the increased hospitalization rate of patients with ICH. Current preventions and therapeutic strategies for ICH are effective, but more strategies must be developed to improve the outcome of ICH and decrease the incidence of pulmonary infection.

Ambroxol Upregulates Glucocerebrosidase Expression to Promote Neural Stem Cells Differentiation Into Neurons Through Wnt/ß-Catenin Pathway After Ischemic Stroke.

Ischemic stroke has been becoming one of the leading causes resulting in mortality and adult long-term disability worldwide. Post-stroke pneumonia is a common complication in patients with ischemic stroke and always associated with 1-year mortality. Though ambroxol therapy often serves as a supplementary treatment for post-stroke pneumonia in ischemic stroke patients, its effect on functional recovery and potential mechanism after ischemic stroke remain elusive. In the present study, the results indicated that administration of 70 mg/kg and 100 mg/kg enhanced functional recovery by virtue of decreasing infarct volume. The potential mechanism, to some extent, was due to promoting NSCs differentiation into neurons and interfering NSCs differentiation into astrocytes through increasing GCase expression to activate Wnt/ß-catenin signaling pathway in penumbra after ischemic stroke, which advanced basic knowledge of ambroxol in regulating NSCs differentiation and provided a feasible therapy for ischemic stroke treatment, even in other brain disorders in clinic.

G protein-coupled estrogen receptor 1 negatively regulates the proliferation of mouse-derived neural stem/progenitor cells via extracellular signal-regulated kinase pathway.

G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) has been reported to play a wide range of function in the central nervous system (CNS). However, whether GPER1 is expressed by neural stem/progenitor cells (NSPCs) and its role has not been established. Here, we found the expression of GPER1 in mouse-derived NSPCs via western blot and immunofluorescent staining. Moreover, we revealed that specific activation of GPER1 by the agonist G1 decreased the proliferation of NSPCs in a dose-dependent manner. The neurosphere formation assay and Ki67 staining further demonstrated that activation of GPER1 inhibited the proliferation of NSPCs. Additionally, the inhibitory effect of G1 on the proliferation of NSPCs could be blocked by the specific GPER1 antagonist G15. Intriguingly, ERK pathway was involved in the negative effect of GPER1 on the proliferation of NSPCs, because the phosphorylation level of ERK in NSPCs was remarkably decreased during G1 treatment. However, the antagonist G15 reversed the down-regulated level of p-ERK. Knock-down GPER1 also reversed the inhibitory effect of G1 on NSPCs proliferation. Together, our results provide the first evidence that GPER1 is expressed by NSPCs and its activation negatively modulates the proliferation of NSPCs, highlighting the importance of GPER1 in regulating NSPC behaviors.

Chondroitin sulfate proteoglycan represses neural stem/progenitor cells migration via PTPσ/α-actinin4 signaling pathway.

Neural stem/progenitor cells (NSPCs) are a promising candidate for the cell-replacement therapy after central nervous system (CNS) injury. However, the short of sufficient NSPCs migration and integration into the lesions is an essential challenge for cell-based therapy after CNS injury due to the disturbance of local environmental homeostasis. Chondroitin sulfate proteoglycan (CSPG) is obviously accumulated at the lesions and destroyed local homeostasis after CNS injury. The previous study has demonstrated that the CSPG is a dominating ingredient inhibiting axonal regrowth of newly born neurons after CNS injury. NSPCs, a strain of special neural subtypes, hold the capacity of leading processes formation to regulate NSPCs migration, which has the same mechanism as axonal regrowth. Hence, it is worth investigating the effect of CSPG on NSPCs migration and its underlying mechanism. Here, different concentration of CSPG was used to evaluate its effect on NSPCs migration. The results showed that the CSPG suppressed NSPCs migration in a dose-dependent manner from 10 to 80 µg/mL with phase-contrast microscopy after 24 hours. Meanwhile, transwell assays were performed to certify the above results. Our data indicated that the 40 µg/mL CSPG obviously suppressed NSPCs migration via decreasing filopodia formation using immunofluorescence staining. Furthermore, data indicated that the 40 µg/mL CSPG upregulated protein tyrosine phosphatase receptor σ (PTPσ) expression and decreased α-actinin4 (ACTN4) expression through immunofluorescence, reverse transcription polymerase chain reaction, and Western blot assays. While the inhibitory effect was attenuated using PTPσ-specific small interfering RNA. In addition, data demonstrated that the 40 µg/mL CSPG facilitated NSPCs differentiation into glial fibrillary acidic protein-positive cells and inhibited NSPCs directing into MAP2- and MBP-positive cells. Collectively, these data demonstrated that the CSPG suppressed NSPCs migration through PTPσ/ACTN4 signaling pathway. Meanwhile, CSPG facilitated NSPCs differentiation into astrocytes and inhibited NSPCs directing into neurons and oligodendrocytes.

Biomaterial suture Vicryl Plus reduces wound-related complications.

OBJECTIVE: To compare the wound-related complications following craniotomy in patients with brain gliomas undergoing wound closure using either absorbable antibacterial Vicryl Plus suture or traditional braided silk suture. MATERIALS AND METHODS: Two hundred and forty-five patients undergoing craniotomy for supratentorial gliomas from January 1, 2011 to December 31, 2013 were retrospectively analyzed. We divided the patients into two groups: the Vicryl Plus group (using absorbable antibacterial Vicryl Plus suture) and the control group (using traditional braided silk suture). The clinical data and wound-related complications after surgery between two groups have been summarized. RESULTS: Patients in the Vicryl Plus suture group had lower incidence of wound-related complications compared with traditional braided silk suture group (P<0.05). No statistically significant difference was found between the two groups in terms of total medical expense. CONCLUSION: Incision closure using absorbable antibacterial Vicryl Plus suture had less wound-related complications than using traditional braided silk suture, without increasing medical expense. Vicryl Plus suture could be a better choice for scalp closure in patients undergoing craniotomy surgery.