Toward Lung Ventilation Imaging Using Hyperpolarized Diethyl Ether Gas Contrast Agent.

Hyperpolarized 129Xe gas was FDA-approved as an inhalable contrast agent for magnetic resonance imaging of a wide range of pulmonary diseases in December 2022. Despite the remarkable success in clinical research settings, the widespread clinical translation of HP 129Xe gas faces two critical challenges: the high cost of the relatively low-throughput hyperpolarization equipment and the lack of 129Xe imaging capability on clinical MRI scanners, which have narrow-bandwidth electronics designed only for proton (1H) imaging. To solve this translational grand challenge of gaseous hyperpolarized MRI contrast agents, here we demonstrate the utility of batch-mode production of proton-hyperpolarized diethyl ether gas via heterogeneous pairwise addition of parahydrogen to ethyl vinyl ether. An approximately 0.1-liter bolus of hyperpolarized diethyl ether gas was produced in 1 second and injected in excised rabbit lungs. Lung ventilation imaging was performed using sub-second 2D MRI with up to 2×2 mm2 in-plane resolution using a clinical 0.35 T MRI scanner without any modifications. This feasibility demonstration paves the way for the use of inhalable diethyl ether as a gaseous contrast agent for pulmonary MRI applications using any clinical MRI scanner.

The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor with a poor median survival of less than 15 months. However, clinical strategies and effective therapies are limited. Here, we found that the second-generation small molecule multi-CDK inhibitor AT7519 is a potential drug for GBM treatment according to high-throughput screening via the Approved Drug Library and Clinical Compound Library (2718 compounds). We found that AT7519 significantly inhibited the cell viability and proliferation of U87MG, U251, and patient-derived primary GBM cells in a dose-dependent manner. Furthermore, AT7519 also inhibited the phosphorylation of CDK1/2 and arrested the cell cycle at the G1-S and G2-M phases. More importantly, AT7519 induced intrinsic apoptosis and pyroptosis via caspase-3-mediated cleavage of gasdermin E (GSDME). In the glioblastoma intracranial and subcutaneous xenograft assays, tumor volume was significantly reduced after treatment with AT7519. In summary, AT7519 induces cell death through multiple pathways and inhibits glioblastoma growth, indicating that AT7519 is a potential chemical available for GBM treatment.

Comparison of dural puncture and dural incision in deep brain stimulation surgery: A simple but worthwhile technique modification.

Background: The accuracy of the deep brain stimulation (DBS) electrode placement is influenced by a myriad of factors, among which pneumocephalus and loss of cerebrospinal fluid that occurs with dural opening during the surgery are considered most important. This study aimed to describe an effective method for decreasing pneumocephalus by comparing its clinical efficacy between the two different methods of opening the dura. Materials and methods: We retrospectively compared two different methods of opening the dura in 108 patients who underwent bilateral DBS surgery in our center. The dural incision group comprised 125 hemispheres (58 bilateral and 9 unilateral) and the dural puncture group comprised 91 (41 bilateral and 9 unilateral). The volume of intracranial air, dural opening time, intraoperative microelectrode recordings (MERs), postoperative electrode displacement, clinical efficacy, and complications were examined. Spearman correlation analysis was employed to identify factors associated with the volume of intracranial air and postoperative electrode displacement. Results: The volume of intracranial air was significantly lower (0.35 cm3 vs. 5.90 cm3) and dural opening time was significantly shorter (11s vs. 35s) in the dural puncture group. The volume of intracranial air positively correlated with dural opening time. During surgery, the sensorimotor area was longer (2.47 ± 1.36 mm vs. 1.92 ± 1.42 mm) and MERs were more stable (81.82% vs. 47.73%) in the dural puncture group. Length of the sensorimotor area correlated negatively with the volume of intracranial air. As intracranial air was absorbed after surgery, significant anterior, lateral, and ventral electrode displacement occurred; the differences between the two groups were significant (total electrode displacement, 1.0mm vs. 1.4mm). Electrode displacement correlated positively with the volume of intracranial air. Clinical efficacy was better in the dural puncture group than the dural incision group (52.37% ± 16.18% vs. 43.93% ± 24.50%), although the difference was not significant. Conclusion: Our data support the hypothesis that opening the dura via puncture rather than incision when performing DBS surgery reduces pneumocephalus, shortens dural opening time, enables longer sensorimotor area and more stable MERs, minimizes postoperative electrode displacement, and may permit a better clinical efficacy.

A systematic review of noninflammatory cerebrospinal fluid biomarkers for clinical outcome in neonates with perinatal hypoxic brain injury that could be biologically significant.

Neonatal encephalopathy (NE) that purportedly arises from hypoxia-ischemia is labeled hypoxic-ischemic encephalopathy (HIE). Perinatal asphyxia is a clinical syndrome involving acidosis, a low Apgar score and the need for resuscitation in the delivery room; asphyxia alerts one to the possibility of NE. In the present systematic review, we focused on the noninflammatory biomarkers in cerebrospinal fluid (CSF) that are involved in the development of possible brain injury in asphyxia or HIE. A literature search in PubMed and EMBASE for case-control studies was conducted and 17 studies were found suitable by a priori criteria. Statistical analysis used the Mantel-Haenszel model for dichotomous data. The pooled mean difference and 95% confidence intervals (CIs) were determined. We identified the best biomarkers, based on the estimation approach in evaluating the biological significance, out of hundreds in three categories: cell adhesion and proliferation, oxidants and antioxidants, and cell damage. The following subtotal-population comparisons were made: perinatal asphyxia versus no asphyxia, asphyxia with HIE versus asphyxia without HIE, asphyxia with HIE versus no asphyxia, and term versus preterm HIE newborn with asphyxia. Biological significance of the biomarkers was determined by using a modification of the estimation approach, by ranking the biomarkers according to the difference in the bounds of the CIs. The most promising CSF biomarkers for prognostication especially for the severest HIE include creatine kinase, xanthine oxidase, vascular endothelial growth factor, neuron-specific enolase, superoxide dismutase, and malondialdehyde. Future studies are recommended using such a combined test to prognosticate the most severely affected patients.

Tetrahydrobiopterin in Cell Function and Death Mechanisms.

Significance: Tetrahydrobiopterin (BH4) is most well known as a required cofactor for enzymes regulating cellular redox homeostasis, aromatic amino acid metabolism, and neurotransmitter synthesis. Less well known are the effects dependent on the cofactor's availability, factors governing its synthesis and recycling, redox implications of the cofactor itself, and protein-protein interactions that underlie cell death. This review provides an understanding of the recent advances implicating BH4 in the mechanisms of cell death and suggestions of possible therapeutic interventions. Recent Advances: The levels of BH4 often reflect the sum of synthetic and recycling enzyme activities. Enhanced expression of GTP cyclohydrolase, the rate-limiting enzyme in biosynthesis, increases BH4, leading to improved cell function and survival. Pharmacologically increasing BH4 levels has similar beneficial effects, leading to enhanced production of neurotransmitters and nitric oxide or reducing oxidant levels. The GTP cyclohydrolase-BH4 pairing has been implicated in a type of cell death, ferroptosis. At the cellular level, BH4 counteracts anticancer therapies directed to enhance ferroptosis via glutathione peroxidase 4 (GPX4) activity inhibition. Critical Issues: Because of the multitude of intertwined mechanisms, a clear relationship between BH4 and cell death is not well understood yet. The possibility that the cofactor directly influences cell viability has not been excluded in previous studies when modulating BH4-producing enzymes. Future Directions: The importance of cellular BH4 variations and BH4 biosynthetic enzymes to cell function and viability makes it essential to better characterize temporal changes, cofactor activity, and the influence on redox status, which in turn would help develop novel therapies. Antioxid. Redox Signal. 37, 171-183.

New Autophagy-Ferroptosis Gene Signature Predicts Survival in Glioma.

Background: Ferroptosis plays an important role in glioma and significantly affects the prognosis, but the specific mechanism has not yet been elucidated. Recent studies suggest that autophagy regulates the process of ferroptosis. This study aimed to find potential autophagy-ferroptosis genes and explore the prognostic significance in glioma. Methods: Ferroptosis and autophagy genes were obtained from two online databases (zhounan.org/ferrdb and autophagy.lu/). The RNAseq data and clinical information were obtained from the Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn/). Univariate, multivariate, lasso and Cox regression analysis screened out prognosis-related genes, and a risk model was constructed. Receiver operating characteristic (ROC) curve analysis evaluated the predictive efficiency of the model. Finally, a nomogram was constructed to more accurately predict the prognosis of glioma. Results: We developed a Venn diagram showing 23 autophagy-ferroptosis genes. A total of 660 cases (including RNA sequences and complete clinical information) from two different cohorts (training group n = 413, verification group n = 247) of the CGGA database was acquired. Cohorts were screened to include five prognosis-related genes (MTOR, BID, HSPA5, CDKN2A, GABARAPLA2). Kaplan-Meier curves showed that the risk model was a good prognostic indicator (p < 0.001). ROC analysis showed good efficacy of the risk model. Multivariate Cox analysis also revealed that the risk model was suitable for clinical factors related to prognosis, including type of disease (primary, recurrence), grade (III-IV), age, temozolomide treatment, and 1p19q state. Using the five prognosis-related genes and the risk score, we constructed a nomogram assessed by C-index (0.7205) and a calibration plot that could more accurately predict glioma prognosis. Conclusion: Using a current database of autophagy and ferroptosis genes, we confirmed the prognostic significance of autophagy-ferroptosis genes in glioma, and we constructed a prognostic model to help guide treatment for high grade glioma in the future.

Human Umbilical Cord Blood Cells Ameliorate Motor Deficits in Rabbits in a Cerebral Palsy Model.

Cerebral palsy (CP) has a significant impact on both patients and society, but therapy is limited. Human umbilical cord blood cells (HUCBC), containing various stem and progenitor cells, have been used to treat various brain genetic conditions. In small animal experiments, HUCBC have improved outcomes after hypoxic-ischemic (HI) injury. Clinical trials using HUCBC are underway, testing feasibility, safety and efficacy for neonatal injury as well as CP. We tested HUCBC therapy in a validated rabbit model of CP after acute changes secondary to HI injury had subsided. Following uterine ischemia at 70% gestation, we infused HUCBC into newborn rabbit kits with either mild or severe neurobehavioral changes. Infusion of high-dose HUCBC (5 × 10(6) cells) dramatically altered the natural history of the injury, alleviating the abnormal phenotype including posture, righting reflex, locomotion, tone, and dystonia. Half the high dose showed lesser but still significant improvement. The swimming test, however, showed that joint function did not restore to naïve control function in either group. Tracing HUCBC with either MRI biomarkers or PCR for human DNA found little penetration of HUCBC in the newborn brain in the immediate newborn period, suggesting that the beneficial effects were not due to cellular integration or direct proliferative effects but rather to paracrine signaling. This is the first study to show that HUCBC improve motor performance in a dose-dependent manner, perhaps by improving compensatory repair processes.

Immunopathogenesis of chronic hepatitis B.

Chronic hepatitis B (CHB) is a widespread infectious disease with unfavorable outcomes and life-threatening consequences for patients, in spite of modern vaccination and antiviral treatment modalities. Cutting-edge experimental approaches have demonstrated key pathways that involve cross-talk between viral particles and host immune cells. All events, including penetration of hepatitis B virus (HBV) particles into host cells, establishing persistence, and chronization of CHB infection, and possibility of complete elimination of HBV particles are controlled by the immune system. Researchers have paid special attention to the replication capacity of HBV in host cells, which is associated with cellular changes that reflect presentation of viral antigens and variability of HBV antigen features. In addition, specific HBV proteins have an immune-modulating ability to initiate molecular mechanisms that "avoid" control by the immune system. The relationship between immunological shifts and chronic infection stages has been intensively studied since it was recognized that the immune system is a direct participant in the recurrent (cyclic) nature of CHB. Understanding the wide diversity of molecular pathways and the crosstalk between innate and adaptive immune system components will provide fresh insight into CHB immune pathogenesis and the possibilities of developing new treatment strategies for this disease.

Mother-to-child transmission of HBV: review of current clinical management and prevention strategies.

Mother-to-child transmission (MTCT) of HBV is responsible for approximately half of the HBV transmission routes and continues to be a challenging problem worldwide. Even after the development of effective vaccines and clear World Health Organization guidelines toward HBV several decades ago, 1-9% newborns of HBV-carrying mothers still acquire HBV in early life as a result of in utero infection. The prevention of MTCT is of high importance, because chronically infected individuals function as a reserve for sustained HBV transmission, and 25% of them can develop asymptomatic liver cirrhosis and hepatocellular carcinoma. In this article, we review the canonical and novel HBV infection routes/mechanisms, influencing factors, diagnostic criteria, and interruption strategies for HBV MTCT. The preventative strategy of HBV MTCT has evolved from routine postpartum HB immune globulin (HBIG) plus HB vaccine schedules to administration of HBIG or nucleoside analogs during pregnancy and minimizing the exposure of maternal body fluids to the newborn during delivery.