Discrepant assembly processes of prokaryotic communities between the abyssal and hadal sediments in Yap Trench.

Abyssal and hadal sediments represent two of the most type ecosystems on Earth and have the potential interactions with geochemistry. However, little is known about the prokaryotic community assembly and the response of prokaryotic communities to metal(loid)s in trench sediments due to the lack of adequate and appropriate samples. In this study, a systematic investigation combined the assembly mechanisms and co-occurrence patterns of prokaryotic communities between the hadal and abyssal sediments across the Yap Trench. The results revealed that the hadal prokaryotes had less species diversity, but more abundant function than the abyssal prokaryotes. The prokaryotic communities in the abyssal sediments had more core taxa than the hadal sediments. Twenty-one biomarkers mostly affiliated with Nitrosopumilaceae were detected using Random-Forests machine learning algorithm. Furthermore, stochasticity was dominant in the prokaryotic community assembly processes of the Yap Trench sediments. Meanwhile, homogeneous selection (32.6%-52.9%) belonging to deterministic processes governed the prokaryotic community assembly in hadal sediments with increasing of sediment depth. In addition to total nitrogen and total organic carbon, more metal(loid)s were significantly correlated with the prokaryotic community in the hadal sediments than that in the abyssal sediments. The hadal prokaryotic communities was most positively related to bismuth (r = 0.31, p < 0.01), followed by calcium, chromium, cerium, potassium, plumbum, scandium, titanium, and vanadium. Finally, co-occurrence networks revealed two potential dominant prokaryotic modules in Yap Trench sediments covaried across oceanographic zonation. By contrast, the hadal network had relatively more complexity, more bacterial taxa, and more associations among prokaryotic taxa, relative to the abyssal network. This study reveals potentially metal variables and community assembly mechanisms of the prokaryotic community in abyssal and hadal sediments and provides a better understanding on the prokaryotic diversity and ecology in trench sediment ecosystems.

Epitranscriptomic editing of the RNA N6-methyladenosine modification by dCasRx conjugated methyltransferase and demethylase.

N6-methyladenosine (m6A) is a common modification on endogenous RNA transcripts in mammalian cells. Technologies to precisely modify the RNA m6A levels at specific transcriptomic loci empower interrogation of biological functions of epitranscriptomic modifications. Here, we developed a bidirectional dCasRx epitranscriptome editing platform composed of a nuclear-localized dCasRx conjugated with either a methyltransferase, METTL3, or a demethylase, ALKBH5, to manipulate methylation events at targeted m6A sites. Leveraging this platform, we specifically and efficiently edited m6A modifications at targeted sites, reflected in gene expression and cell proliferation. We employed the dCasRx epitranscriptomic editor system to elucidate the molecular function of m6A-binding proteins YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3), revealing that YTHDFs promote m6A-mediated mRNA degradation. Collectively, our dCasRx epitranscriptome perturbation platform permits site-specific m6A editing for delineating of functional roles of individual m6A modifications in the mammalian epitranscriptome.

Whether surgical resection or biopsy makes difference in single lesion primary central nervous system lymphoma: a single center retrospective cohort study.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease. The role of surgical resection in PCNSL has always been the center of debate. Here we investigated the clinical and follow-up data of single lesion PCNSL operated in our center, focusing on the comparison between surgical resection and biopsy. METHODS: All consecutive cases of single lesion PCNSL between October 2004 and December 2019 were retrospectively collected from the database of the Second Affiliated Hospital of Zhejiang University, School of Medicine. Patients were divided into resection group and biopsy group. Clinical information including age, gender, Karnofsky performance status, imaging features and postoperative treatment was collected from the medical records. All the patients were followed for survival analysis. RESULTS: A total of 105 patients with PCNSL were finally involved in our analysis. Neither PFS nor OS were significantly different between the resection group and biopsy group. The univariate analysis revealed that age < 60 and therapeutic treatment were significant predictors of longer PFS and OS. In the multivariate analysis, age (HR = 3.09, 95% CI 1.31-7.28, p = 0.01) and therapeutic treatment (HR = 0.25, 95% CI 0.07- 0.83, p = 0.02) were independent prognostic markers with OS. Multivariable Cox regression analyses also revealed that only age (HR = 2.29 (95% CI, 1.11-4.71, p = 0.03) was independent prognostic marker for PFS. CONCLUSIONS: In single lesion PCNSL, there was no significant difference between the resection group and biopsy group for both PFS and OS. Younger age and postoperative treatment have been proved to be indicators of better prognosis.

Primary central nervous system lymphoma in China: a single-center retrospective analysis of 167 cases.

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin's lymphoma and a limited number of cases have been reported from China. This study aimed to investigate the clinicopathological features of newly diagnosed PCNSLs from a single center in eastern China and to identify the potential prognostic factors for overall survival (OS) and progression-free survival (PFS). All consecutive patients with histopathologically diagnosed PCNSLs at our center between January 2003 and October 2017 were recruited. Demographic and clinicopathological data were collected and reviewed retrospectively. The potential risk factors for OS and PFS were identified using the log-rank test and Cox regression analysis. A total of 167 immunocompetent cases were enrolled. The median age was 58 years (range 17-96 years), and the male:female ratio was 3:2. Headache (n = 65; 39%) and cerebral hemisphere (n = 96; 57%) were the most common presenting complaint and location, respectively. Out of 167 cases, 150 cases were diffuse large B cell lymphomas. With a median follow-up of 25 months (range 1-152 ), the median OS and PFS were 37 months (95% CI, 25-49) and 17 months (95% CI, 13-20), respectively. Residual tumor after operation, chemotherapy without HD-MTX and palliative treatment was revealed as independent prognostic markers. Moreover, ECOG > 3, multifocal lesions, and palliative treatment were revealed as unfavorable independent prognostic markers for PFS. In conclusion, Chinese patients with PCNSL have distinct characteristics. Further studies are warranted to confirm the prognostic value of these factors and to optimize treatments for these patients.

Aequorivita lutea sp. nov., a novel bacterium isolated from the estuarine sediment of the Pearl River in China, and transfer of Vitellibacter todarodis and Vitellibacter aquimaris to the genus Aequorivita as Aequorivita todarodis comb. nov. and Aequorivita aquimaris comb. nov.

A Gram-negative, aerobic, rod-shaped, non-motile by gliding bacterium was isolated from the estuarine sediment of the Pearl River in PR China and designated as strain q18T. Colonies were circular, smooth and yellow on marine agar after 48 h cultivation. Salinity, temperature and pH for optimal growth were 5 % (NaCl), 30 °C and 7, respectively. The 16S rRNA gene sequence of the strain q18T showed the highest similarity of 97.3 % to the type strain of Aequorivita echinoideorum CC-CZW007T. 16S rRNA gene-based phylogenetic analysis indicated that strain q18T grouped into the genus Aequorivita in the family Flavobacteriaceae of the phylum Bacteroidetes, and was distinct from all known species in the genus. Menaquinone (MK-6) was the main respiratory quinone detected in strain q18T. The major fatty acids were iso-C15 : 0 and iso-C17 : 0 3-OH. The polar lipids of strain q18T mainly comprised phosphatidylethanolamine, two unidentified aminolipids, two unidentified phospholipids and one unidentified polar lipid. The G+C content of the genome was ~42.8 mol%. The draft genome size of strain q18T was 3.3 Mbp. The average nucleotide identity values were around 79.0 % between strain q18T and reference Aequorivita strains. Based on the polyphasic analysis, strain q18T was confirmed to represent a novel species of the genus Aequorivita, for which the name Aequorivita lutea sp. nov., is proposed. The type strain is q18T (=CICC 24821T=KCTC 72764 T). Further, based on the results of phylogenetic, chemotaxonomic and phenotypic analyses, two species previously classified into the genus Vitellibacter, Vitellibacter todarodis Kim et al. 2018 and Vitellibacter aquimaris Thevarajoo et al. 2016, are transferred to the genus Aequorivita as Aequorivita todarodis comb. nov. and Aequorivita aquimaris comb. nov. respectively.

The prognostic value of maximal surgical resection is attenuated in oligodendroglioma subgroups of adult diffuse glioma: a multicenter retrospective study.

PURPOSE: Maximal surgical resection is associated with survival benefit in the majority of studies in adult diffuse glioma. This study aims to characterize the prognostic value of surgical resection in molecular subgroups of diffuse glioma. METHODS: 1178 patients with diffuse glioma from our centers and 422 from TCGA dataset were collected. The Kaplan-Meier analysis and multivariable Cox regression models were conducted to identify the prognostic value of surgical resection through different histological and molecular stratifications. RESULTS: Firstly, we confirmed progression-free survival (PFS) benefit associated with gross total resection (GTR) over sub-total resection (STR) in lower-grade glioma (HR 1.49; 95% CI 1.17-1.90; P = 0.001). Intriguingly however, we were unable to detect a significant PFS or overall survival (OS) benefit in oligodendroglioma (N = 397; HR 1.36; 95% CI 0.86-2.14; P = 0.19 and HR 1.05; 95% CI 0.55-1.99; P = 0.89, respectively). Secondly, when analyzed in molecular subgroups, we were similarly unable to detect a significant PFS or OS benefit in IDH MT/codel subgroup (N = 269; HR 1.47; 95% CI 0.92-2.34; P = 0.11 and HR 1.54; 95% CI 0.78-3.05; P = 0.21, respectively), oligodendroglioma with IDH MT/codel subgroup (N = 233; HR 1.33; 95% CI 0.79-2.21; P = 0.28 and HR 1.16; 95% CI 0.53-2.54; P = 0.70, respectively) or other relevant subgroups. TCGA validation also showed a significant survival benefit in astrocytoma rather than oligodendroglioma. Exploratory RNAseq analysis displayed that fewer cell proliferation-related gene expression features were specific to oligodendroglioma. CONCLUSION: These results suggest that the benefit of maximal surgery may be attenuated in patients within oligodendroglioma relevant subgroups because of the chemosensitive and indolent nature. The aggressive surgery accompanying with risk of neurologic morbidity may be unnecessary for these patients given the lack of survival benefit with gross total resection.

Defluviimonas pyrenivorans sp. nov., a novel bacterium capable of degrading polycyclic aromatic hydrocarbons.

An aerobic, Gram-stain-negative, rod-shaped, non-motile bacterium capable of degrading the polycyclic aromatic hydrocarbon pyrene was isolated from sediment of Pearl River and designated PrR001. 16S rRNA gene sequence analysis revealed that this strain was affiliated within the genus Defluviimonas in the family Rhodobacteraceae of the class Alphaproteobacteria and showed great similarity with the type strain Defluviimonas indica 20V17T (96.3 % similarity). The DNA G+C content of strain PrR001T was 68.3 mol%. The major cellular fatty acids comprised summed feature 8 (C18 : 1ω7c/C18 : 1ω6c), C19 : 0 cyclo ω8c, C18 : 0 3OH, and C18 : 0. The sole respiratory lipoquinone was ubiquinone-10. The main polar lipids were diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, an unidentified aminolipid, an unidentified aminophospholipid and three unidentified phospholipids. Based on physiological, chemotaxonomic and phylogenetic analysis, strain PrR001T is suggested as a novel species in the genus Defluviimonas, for which the name Defluviimonas pyrenivorans sp. nov. is proposed. The type strain of Defluviimonas pyrenivorans is PrR001T (=CICC 24263T=KCTC 62192T).

The Draft Genome Sequence of a Novel High-Efficient Butanol-Producing Bacterium Clostridium Diolis Strain WST.

A wild-type solventogenic strain Clostridium diolis WST, isolated from mangrove sediments, was characterized to produce high amount of butanol and acetone with negligible level of ethanol and acids from glucose via a unique acetone-butanol (AB) fermentation pathway. Through the genomic sequencing, the assembled draft genome of strain WST is calculated to be 5.85 Mb with a GC content of 29.69% and contains 5263 genes that contribute to the annotation of 5049 protein-coding sequences. Within these annotated genes, the butanol dehydrogenase gene (bdh) was determined to be in a higher amount from strain WST compared to other Clostridial strains, which is positively related to its high-efficient production of butanol. Therefore, we present a draft genome sequence analysis of strain WST in this article that should facilitate to further understand the solventogenic mechanism of this special microorganism.

Netrin-1 overexpression improves neurobehavioral outcomes and reduces infarct size via inhibition of the notch1 pathway following experimental stroke.

Stroke is a leading cause of morbidity and mortality worldwide. Administration of Netrin-1 during the peri-infarct period has been shown to decrease infarct size in rats; however, the underlying mechanism is unclear. We addressed this question in the present study by inducing stroke in rats via middle cerebral artery occlusion (MCAO), and evaluating the effects of Netrin-1 treatment by neurobehavioral testing, immunocytochemistry, and western blotting. Netrin-1 overexpression increased neurobehavioral test scores and reduced cerebral infarct volume following MCAO via inhibition of the Notch1 signaling pathway. These results demonstrate that early administration of Netrin-1 can is an effective therapeutic approach for improving outcome after stroke. © 2017 Wiley Periodicals, Inc.

Frozen tissue preparation for high-resolution multiplex histological analyses of human brain specimens.

The availability of a comprehensive tissue library is essential for elucidating the function and pathology of human brains. Considering the irreplaceable status of the formalin-fixation-paraffin-embedding (FFPE) preparation in routine pathology and the advantage of ultra-low temperature to preserve nucleic acids and proteins for multi-omics studies, these methods have become major modalities for the construction of brain tissue libraries. Nevertheless, the use of FFPE and snap-frozen samples is limited in high-resolution histological analyses because the preparation destroys tissue integrity and/or many important cellular markers. To overcome these limitations, we detailed a protocol to prepare and analyze frozen human brain samples that is particularly suitable for high-resolution multiplex immunohistological studies. As an alternative, we offered an optimized procedure to rescue snap-frozen tissues for the same purpose. Importantly, we provided a guideline to construct libraries of frozen tissue with minimal effort, cost and space. Taking advantage of this new tissue preparation modality to nicely preserve the cellular information that was otherwise damaged using conventional methods and to effectively remove tissue autofluorescence, we described the high-resolution landscape of the cellular composition in both lower-grade gliomas and glioblastoma multiforme samples. Our work showcases the great value of fixed frozen tissue in understanding the cellular mechanisms of CNS functions and abnormalities.

Notch1 Signaling Activation Contributes to Adult Hippocampal Neurogenesis Following Traumatic Brain Injury.

BACKGROUND Neural stem cells are reported to exist in the hippocampus of adult mammals and are important sources of neurons for repair. The Notch1 signaling pathway is considered as one of the important regulators of neural stem cells, but its role in adult brains is unclear. We aimed to describe the role of Notch1 signaling in the adult rat hippocampus after traumatic brain injury. MATERIAL AND METHODS The model rats were randomly divided into 4 groups as follows: sham, sham-TBI, sham-Ad-TBI, and NICD-Ad-TBI. We used adenovirus-mediated gene transfection to upregulate endogenous NICD in vivo. Firstly, a TBI rat model was constructed with lateral fluid percussion. Then, the hippocampus was collected to detect the expression of Notch1 markers and stem cell markers (DCX) by Western blot analysis, immunohistochemistry, and immunofluorescence. The prognosis after TBI treatment was evaluated by the Morris Water Maze test. RESULTS First, we found the expression of NICD in vivo was significantly increased by adenovirus-mediated gene transfection as assessed by Notch1 immunofluorescence and Western blot analysis. Second, enhancing NICD stimulated the regeneration of neural stem cells in the DG of the adult rat brain following traumatic brain injury, as evaluated by DCX and NeuN double-staining. Furthermore, Notch1 signaling activation can promote behavioral improvement after traumatic brain injury, including spatial learning and memory capacity. CONCLUSIONS Our findings suggest that targeted regulation of Notch1 signaling may have a useful effect on stem cell transformation. Notch1 signaling may have a potential brain-protection effect, which may result from neurogenesis.

3D bone subtraction CT angiography for the evaluation of intracranial aneurysms: a comparison study with 2D bone subtraction CT angiography and conventional non-subtracted CT angiography.

BACKGROUND: Bone subtraction computed tomography angiography (BSCTA) is better able to facilitate the detection of intracranial aneurysms adjacent to bone structures compared to conventional non-subtracted CTA (CNSCTA). However, the comparison of the diagnostic accuracy of three-dimensional (3D) and two-dimensional (2D) BSCTA and conventional CTA in evaluating intracranial aneurysms remains unclear. PURPOSE: To evaluate whether 3D BSCTA has a superior diagnostic accuracy to those of 2D BSCTA and CNSCTA in a single center with the same instrument. MATERIAL AND METHODS: Sixty-three patients received 3D BSCTA, 2D BSCTA, and NSCTA for the detection and treatment planning of suspected intracranial aneurysms. The angiography readouts were reviewed by two independent radiologists. The sensitivity of CTA in detecting aneurysm was analyzed on a per-aneurysm and per-patient basis, using 3D digital subtraction angiography (DSA) and surgical findings as the gold standard. The potential of endovascular treatment or surgical clipping was also assessed based on information provided by the CTA. RESULTS: A total of 66 aneurysms were detected in 54 patients. The overall sensitivity, specificity, positive, and negative predictive values of 3D BSCTA were all 100%, and these values for 2D BSCTA were 98.1%, 100%, 100%, and 90%, respectively. The total sensitivity, specificity, positive, and negative predictive values of CNSCTA were 94.4%, 100%, 100%, and 75%, respectively. Finally, 100%, 98.1%, and 85.2% patients received appropriate treatment decisions after 3D BSCTA, 2D BSCTA, and CNSCTA imaging, respectively. CONCLUSION: 3D BSCTA has a higher sensitivity for the detection of small aneurysms and aneurysms adjacent to bone compared to 2D BSCTA or CNSCTA, which were still able to obtain sufficient information for the detection of intracranial aneurysms and therapeutic decision-making.

Conditional ablation of neuroprogenitor cells in adult mice impedes recovery of poststroke cognitive function and reduces synaptic connectivity in the perforant pathway.

The causal relationship between neurogenesis and the recovery of poststroke cognitive function has not been properly explored. The current study aimed to determine whether depleting neuroprogenitor cells (NPCs) affects poststroke functional outcome in nestin-δ-HSV-TK-EGFP transgenic mice, in which the expression of a truncated viral thymidine kinase gene and EGFP was restricted to nestin-expressing NPCs. Ganciclovir (GCV; 200 mg/kg/d) or saline was continuously administered via osmotic pumps in mice for 4 weeks before the induction of experimental stroke. Both baseline and stroke-induced type 1 and type 2 NPCs were conditionally ablated. GCV eliminated NPCs in a duration-dependent fashion, but it did not attenuate the genesis of astroglia or oligodendrocytes in the peri-infarct cortex, nor did it affect infarct size or cerebral blood reperfusion after stroke. Transgenic stroke mice given GCV displayed impaired spatial learning and memory in the Barnes maze test compared with saline control or wild-type stroke mice given GCV, suggesting a contributing role of stroke-induced neurogenesis in the recovery of cognitive function. However, there was no significant difference in poststroke motor function between transgenic mice treated with GCV and those treated with vehicle, despite a significant ablation of NPCs in the subventricular zone of the former. Furthermore, nestin-δ-HSV-TK-EGFP mice treated with GCV had fewer retrogradely labeled neurons in the entorhinal cortex (EC) when injected with the polysynaptic viral marker PRV614 in the dentate gyrus (DG), suggesting that there might be reduced synaptic connectivity between the DG and EC following ablation of NPCs, which may contribute to impaired poststroke memory function.

Single-Cell Transcriptomics Reveals the Heterogeneity of the Immune Landscape of IDH-Wild-Type High-Grade Gliomas.

Isocitrate dehydrogenase (IDH)-wild-type (WT) high-grade gliomas, especially glioblastomas, are highly aggressive and have an immunosuppressive tumor microenvironment. Although tumor-infiltrating immune cells are known to play a critical role in glioma genesis, their heterogeneity and intercellular interactions remain poorly understood. In this study, we constructed a single-cell transcriptome landscape of immune cells from tumor tissue and matching peripheral blood mononuclear cells (PBMC) from IDH-WT high-grade glioma patients. Our analysis identified two subsets of tumor-associated macrophages (TAM) in tumors with the highest protumorigenesis signatures, highlighting their potential role in glioma progression. We also investigated the T-cell trajectory and identified the aryl hydrocarbon receptor (AHR) as a regulator of T-cell dysfunction, providing a potential target for glioma immunotherapy. We further demonstrated that knockout of AHR decreased chimeric antigen receptor (CAR) T-cell exhaustion and improved CAR T-cell antitumor efficacy both in vitro and in vivo. Finally, we explored intercellular communication mediated by ligand-receptor interactions within the tumor microenvironment and PBMCs and revealed the unique cellular interactions present in the tumor microenvironment. Taken together, our study provides a comprehensive immune landscape of IDH-WT high-grade gliomas and offers potential drug targets for glioma immunotherapy.

Comparison between routine and improved decompressive craniectomy on patients with malignant cerebral artery infarction without traumatic brain injury.

BACKGROUND: Malignant cerebral artery infarction is one kind of ischemic stroke with high mortality. The aim of this study was to analyze comparatively the preoperative and postoperative clinical data as well as the prognostic factors in these patients who underwent improved decompressive craniectomy or routine decompressive craniectomy. METHODS: A total of 131 patients with malignant cerebral artery infarction were included during the period from January 2000 to December 2012. The patients were divided into 2 groups: the improved decompressive craniectomy group (n = 85) and the routine decompressive craniectomy group (control group) (n = 46). We reviewed the detailed information of the patients; moreover, a comparative analysis of the 2 groups based on age (≤ 60 or >60 y) was performed. RESULTS: The improved decompressive craniectomy group had a significant decrease (P < 0.05) in mortality without clinical functional improvement. The patients who were treated through routine decompressive craniectomy had a higher incidence of hydrocephalus and pulmonary infection (P = 0.011 and 0.003). Moreover, younger patients usually took less resident time in the hospital than did the patients in the elderly group (P = 0.047 vs P < 0.05). Statistical results indicated that the younger patients took a better recovery than did the elderly patients. There was a significant difference between the groups A and B both in the Barthel index and the modified Rankine scale for 3 or 6 months after discharge (P < 0.05). CONCLUSIONS: In comparison with the routine decompressive craniectomy, the improved decompressive craniectomy can reduce the mortality rate and improve the neurologic outcome. However, it increases the incidence of encephalocele and pulmonary infection, which may cause secondary vital injury to patients after surgery. In addition, younger patients can gain a better further functional recovery by undergoing improved decompressive craniectomy.

Enriching the endophytic bacterial microbiota of Ginkgo roots.

Bacterial endophytes of Ginkgo roots take part in the secondary metabolic processes of the fossil tree and contribute to plant growth, nutrient uptake, and systemic resistance. However, the diversity of bacterial endophytes in Ginkgo roots is highly underestimated due to the lack of successful isolates and enrichment collections. The resulting culture collection contains 455 unique bacterial isolates representing 8 classes, 20 orders, 42 families, and 67 genera from five phyla: Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Deinococcus-Thermus, using simply modified media (a mixed medium without any additional carbon sources [MM)] and two other mixed media with separately added starch [GM] and supplemented glucose [MSM]). A series of plant growth-promoting endophytes had multiple representatives within the culture collection. Moreover, we investigated the impact of refilling carbon sources on enrichment outcomes. Approximately 77% of the natural community of root-associated endophytes were predicted to have successfully cultivated the possibility based on a comparison of the 16S rRNA gene sequences between the enrichment collections and the Ginkgo root endophyte community. The rare or recalcitrant taxa in the root endosphere were mainly associated with Actinobacteria, Alphaproteobacteria, Blastocatellia, and Ktedonobacteria. By contrast, more operational taxonomic units (OTUs) (0.6% in the root endosphere) became significantly enriched in MM than in GM and MSM. We further found that the bacterial taxa of the root endosphere had strong metabolisms with the representative of aerobic chemoheterotrophy, while the functions of the enrichment collections were represented by the sulfur metabolism. In addition, the co-occurrence network analysis suggested that the substrate supplement could significantly impact bacterial interactions within the enrichment collections. Our results support the fact that it is better to use the enrichment to assess the cultivable potential and the interspecies interaction as well as to increase the detection/isolation of certain bacterial taxa. Taken together, this study will deepen our knowledge of the indoor endophytic culture and provide important insights into the substrate-driven enrichment.

Skull defect increases the tumor treating fields strength without detrimental thermogenic effect: A computational simulating research.

BACKGROUND: Tumor treating fields (TTFields) is an FDA-approved adjuvant therapy for glioblastoma. The distribution of an applied electric field has been shown to be governed by distinct tissue structures and electrical conductivity. Of all the tissues the skull plays a significant role in modifying the distribution of the electric field due to its large impedance. In this study, we studied how remodeling of the skull would affect the therapeutic outcome of TTFields, using a computational approach. METHODS: Head models were created from the head template ICBM152 and five realistic head models. The electric field distribution was simulated using the default TTFields array layout. To study the impact of the skull on the electric field, we compared three cases, namely, intact skull, defective skull, and insulating process, wherein a thin electrical insulating layer was added between the transducer and the hydrogel. The electric field strength and heating power were calculated using the FEM (finite element method). RESULTS: Removing the skull flap increased the average field strength at the tumor site, without increasing the field strength of "brain". The ATVs of the supratentorial tumors were enhanced significantly. Meanwhile, the heating power of the gels increased, especially those overlapping the skull defect site. Insulation lightly decreased the electric field strength and significantly decreased the heating power in deep tumor models. CONCLUSION: Our simulation results showed that a skull defect was beneficial for superficial tumors but had an adverse effect on deep tumors. Skull removal should be considered as an optional approach in future TTFields therapy to enhance its efficacy. An insulation process could be used as a joint option to reduce the thermogenic effect of skull defect. If excessive increase in heating power is observed in certain patients, insulating material could be used to mitigate overheating without sacrificing the therapeutic effect of TTFields.

Synthetic Biology Technologies And Genetically Engineering Strategies For Enhanced Cell Therapeutics.

Stem cell therapy mainly uses natural stem cells for transplantation, and the use of genetic engineering to optimize stem cell products is a very important process. This article reviews successful gene modification methods in the field of immune cell therapy and summarizes some attempts at stem cell gene editing in current research. Cell bridging is an innovative cutting-edge strategy that includes the specific recognition and signal transduction of artificial receptors. The "off-the-shelf" cell strategies mainly introduce the advantages of allogeneic cell therapy and how to overcome issues such as immunogenicity. Gene regulatory systems allow us to manipulate cells with small molecules to control cellular phenotypes. In addition, we also summarize some important genes that can provide a reference for cell genetic engineering. In conclusion, we summarize a variety of technical strategies for gene editing cells to provide useful ideas and experiences for future stem cell therapy research.

Beneficial effect of hydrogen-rich saline on cerebral vasospasm after experimental subarachnoid hemorrhage in rats.

Cerebral vasospasm (CV) remains a common and devastating complication in patients with subarachnoid hemorrhage (SAH). Despite its clinical significance and extensive research, the underlying pathogenesis and therapeutic perspectives of CV remain incompletely understood. Recently, it has been suggested that molecular hydrogen (H(2)) can selectively reduce levels of hydroxyl radicals (·OH) and ameliorate oxidative and inflammatory injuries to organs in many models. However, whether H(2) can ameliorate CV after SAH is still unknown. This study was designed to evaluate the efficacy of H(2) in preventing SAH-induced CV. Experimental SAH was induced in Sprague-Dawley rats using cisterna magna blood injection. Hydrogen-rich saline (HS) was injected intraperitoneally (5 ml/kg) immediately and at 24 hr after injury. All rats were sacrificed 48 hr after the neurological examination scores had been recorded following SAH. Levels of oxidative stress and inflammation were evaluated. Basilar artery vasospasm was assessed by histological examination using light and transmission electron microscopy. HS treatment significantly improved neurological outcomes and attenuated morphological vasospasm of the basilar artery after SAH. In addition, we found that the beneficial effects of HS treatment on SAH-induced CV were associated with decreased levels of lipid peroxidation, increased activity of antioxidant enzymes, and reduced levels of proinflammatory cytokines in the basilar artery. These results indicate that H(2) has the potential to be a novel therapeutic strategy for the treatment of CV after SAH, and its neuroprotective effect might be partially mediated via limitation of vascular inflammation and oxidative stress.

The dual role of the CD95 and CD95L signaling pathway in glioblastoma.

Binding of CD95, a cell surface death receptor, to its homologous ligand CD95L, transduces a cascade of downstream signals leading to apoptosis crucial for immune homeostasis and immune surveillance. Although CD95 and CD95L binding classically induces programmed cell death, most tumor cells show resistance to CD95L-induced apoptosis. In some cancers, such as glioblastoma, CD95-CD95L binding can exhibit paradoxical functions that promote tumor growth by inducing inflammation, regulating immune cell homeostasis, and/or promoting cell survival, proliferation, migration, and maintenance of the stemness of cancer cells. In this review, potential mechanisms such as the expression of apoptotic inhibitor proteins, decreased activity of downstream elements, production of nonapoptotic soluble CD95L, and non-apoptotic signals that replace apoptotic signals in cancer cells are summarized. CD95L is also expressed by other types of cells, such as endothelial cells, polymorphonuclear myeloid-derived suppressor cells, cancer-associated fibroblasts, and tumor-associated microglia, and macrophages, which are educated by the tumor microenvironment and can induce apoptosis of tumor-infiltrating lymphocytes, which recognize and kill cancer cells. The dual role of the CD95-CD95L system makes targeted therapy strategies against CD95 or CD95L in glioblastoma difficult and controversial. In this review, we also discuss the current status and perspective of clinical trials on glioblastoma based on the CD95-CD95L signaling pathway.