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.

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.

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.

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.

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.

Temperature mediated the balance between stochastic and deterministic processes and reoccurrence of microbial community during treating aniline wastewater.

Seasonal temperature changes significantly affect microbial community diversity, composition, and performance in wastewater treatment plants. However, the community assembly mechanisms under seasonal temperature variations remain unclear. Here, we carried out temperature cycling experiments (30 °C, 35 °C, 37 °C, 40 °C, 42 °C, 45 °C, 40 °C, and 30 °C) to investigate how temperature impacts microbial performance and co-occurrence network and how assembly processes determine the structure and function of microbial communities during treating aniline wastewater. During the 195-day operation, the system achieved an efficient and stable aniline removal of 99%. Interestingly, α-diversity and network complexity were negatively correlated with temperature but could be recovered when the temperature was returned to 30 °C. The results showed that functional redundancy was probably responsible for the excellent microbial performance during the whole process. Null model analyses presented that deterministic process dominated the community when the temperature was 30 °C, and stochasticity dominated the assembly process when the temperature was over 30 °C. Overall, the balance between stochastic and deterministic processes in the treatment of aniline wastewater mediated the reoccurrence of microbial community and co-occurrence network at different temperatures. This study provides new insights into microbial community reoccurrence under seasonal temperature changes and a theoretical basis for regulating microbial communities in wastewater treatment plants.

Tet1 Regulates Astrocyte Development and Cognition of Mice Through Modulating GluA1.

Tet (Ten eleven translocation) family proteins-mediated 5-hydroxymethylcytosine (5hmC) is highly enriched in the neuronal system, and is involved in diverse biological processes and diseases. However, the function of 5hmC in astrocyte remains completely unknown. In the present study, we show that Tet1 deficiency alters astrocyte morphology and impairs neuronal function. Specific deletion of Tet1 in astrocyte impairs learning and memory ability of mice. Using 5hmC high-throughput DNA sequencing and RNA sequencing, we present the distribution of 5hmC among genomic features in astrocyte and show that Tet1 deficiency induces differentially hydroxymethylated regions (DhMRs) and alters gene expression. Mechanistically, we found that Tet1 deficiency leads to the abnormal Ca2+ signaling by regulating the expression of GluA1, which can be rescued by ectopic GluA1. Collectively, our findings suggest that Tet1 plays important function in astrocyte physiology by regulating Ca2+ signaling.

Contralateral subdural effusion after decompressive craniectomy: What is the optimal treatment?

OBJECTIVE: Contralateral subdural effusion after decompressive craniectomy (CSEDC) is rare, and the optimal treatment is not determined. We present 11 cases of CSEDC and give an overview of the English literature pertaining to this disease. METHODS: We searched the database at our institution and performed a search of English literature in PubMed and Google Scholar. Keywords used were as follows (single word or combination): "subdural hygroma"; "subdural effusion"; "decompressive craniectomy". Only patients with CSEDC and contained adequate clinical information pertinent to the analysis were included. RESULTS: 11 cases of CSEDC were recorded at our institution. They comprised ten men and one woman with an average age of 41.9 years. All the 8 symptomatic patients underwent surgery and the CSEDC resolved gradually. 68 cases of CSEDC were found in the literature. Including ours, a total of 79 patients were analyzed. Conservative treatment was effective in the asymptomatic patients. 41.7% of the symptomatic CSEDC underwent burr hole drainage and successfully drained the CSEDC. However, 76% of them received subsequent surgery to manage the reaccumulation of CSEDC. 25% of the symptomatic patients underwent cranioplasty, while 13.3% of them received Ommaya drainage later because of CSEDC recurrence. 18.3% of the symptomatic patients underwent cranioplasty plus subduroperitoneal shunting, and all CSEDC resolved completely. CONCLUSIONS: Burr hole drainage appears to be only a temporary measure. Early cranioplasty should be performed for patients with CSEDC. CSF shunting procedures may be required for patients in whom CSEDC have not been solved or hydrocephalus manifest after cranioplasty.

Evolutionary, genomic, and biogeographic characterization of two novel xenobiotics-degrading strains affiliated with Dechloromonas.

Xenobiotics are generally known as man-made refractory organic pollutants widely distributed in various environments. For exploring the bioremediation possibility of xenobiotics, two novel xenobiotics-degrading strains affiliated with Azonexaceae were isolated. We report here the phylogenetics, genome, and geo-distribution of a novel and ubiquitous Azonexaceae species that primarily joins in the cometabolic process of some xenobiotics in natural communities. Strains s22 and t15 could be proposed as a novel species within Dechloromonas based on genomic and multi-phylogenetic analysis. Pan-genome analysis showed that the 63 core genes in Dechloromonas include genes for dozens of metabolisms such as nitrogen fixation protein (nifU), nitrogen regulatory protein (glnK), dCTP deaminase, C4-dicarboxylate transporter, and fructose-bisphosphate aldolase. Strains s22 and t15 have the ability to metabolize nitrogen, including nitrogen fixation, NirS-dependent denitrification, and dissimilatory nitrate reduction. Moreover, the novel species possesses the EnvZ-OmpR two-component system for controlling osmotic stress and QseC-QseB system for quorum sensing to rapidly sense environmental changes. It is intriguing that this new species has a series of genes for the biodegradation of some xenobiotics such as azathioprine, 6-Mercaptopurine, trinitrotoluene, chloroalkane, and chloroalkene. Specifically, glutathione S-transferase (GST) and 4-oxalocrotonate tautomerase (praC) in this novel species play important roles in the detoxification metabolism of some xenobiotics like dioxin, trichloroethene, chloroacetyl chloride, benzo[a]pyrene, and aflatoxin B1. Using data from GenBank, DDBJ and EMBL databases, we also demonstrated that members of this novel species were found globally in plants (e.g. rice), guts (e.g. insect), pristine and contaminated regions. Given these data, Dechloromonas sp. strains s22 and t15 take part in the biodegradation of some xenobiotics through key enzymes.

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.

Immune Checkpoint-Associated Locations of Diffuse Gliomas Comparing Pediatric With Adult Patients Based on Voxel-Wise Analysis.

Objective: Pediatric diffuse gliomas (pDGs) are relatively rare and molecularly distinct from pediatric pilocytic astrocytoma and adult DGs. Immunotherapy is a promising therapeutic strategy, requiring a deep understanding of tumor immune profiles. The spatial locations of brain tumors might be related to the molecular profiles. We aimed to analyze the relationship between the immune checkpoint molecules with the locations of DGs comparing pediatric with adult patients. Method: We studied 20 pDGs patients (age ≤ 21 years old), and 20 paired adult patients according to gender and histological types selected from 641 adult patients with DGs. Immune checkpoint molecules including B7-H3, CD47, and PD-L1, as well as tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs), were manifested by immunohistochemical staining. Expression difference analyses and Spearman's correlation were performed. MRI data were voxel-wise normalized, segmented, and analyzed by Fisher's exact test to construct the tumor frequency and p value heatmaps. Survival analyses were conducted by Log-rank tests. Result: The median age of pediatric patients was 16 years. 55% and 30% of patients were WHO II and III grades, respectively. The left frontal lobe and right cerebellum were the statistically significant locations for pDGs, while the anterior horn of ventricles for adult DGs. A potential association between the expression of PD-L1 and TAMs was found in pDGs (p = 0.002, R = 0.670). The right posterior external capsule and the lateral side of the anterior horn of the left ventricle were predominant locations for the adult patients with high expression of B7-H3 and low expression of PD-L1 compared to pediatric ones, respectively. Pediatric patients showed significantly improved overall survival compared with adults. The prognostic roles of immune checkpoint molecules and TILs/TAMs were not significantly different between the two groups. Conclusion: Immune checkpoint-associated locations of diffuse gliomas comparing pediatric with adult patients could be helpful for the immunotherapy decisions and design of clinical trials.

Mitochondria's Role in the Maintenance of Cancer Stem Cells in Glioblastoma.

Glioblastoma (GBM), one of the deadliest primary brain malignancies, is characterized by a high recurrence rate due to its limited response to existing therapeutic strategies such as chemotherapy, radiation therapy, and surgery. Several mechanisms and pathways have been identified to be responsible for GBM therapeutic resistance. Glioblastoma stem cells (GSCs) are known culprits of GBM resistance to therapy. GSCs are characterized by their unique self-renewal, differentiating capacity, and proliferative potential. They form a heterogeneous population of cancer stem cells within the tumor and are further divided into different subpopulations. Their distinct molecular, genetic, dynamic, and metabolic features distinguish them from neural stem cells (NSCs) and differentiated GBM cells. Novel therapeutic strategies targeting GSCs could effectively reduce the tumor-initiating potential, hence, a thorough understanding of mechanisms involved in maintaining GSCs' stemness cannot be overemphasized. The mitochondrion, a regulator of cellular physiological processes such as autophagy, cellular respiration, reactive oxygen species (ROS) generation, apoptosis, DNA repair, and cell cycle control, has been implicated in various malignancies (for instance, breast, lung, and prostate cancer). Besides, the role of mitochondria in GBM has been extensively studied. For example, when stressors, such as irradiation and hypoxia are present, GSCs utilize specific cytoprotective mechanisms like the activation of mitochondrial stress pathways to survive the harsh environment. Proliferating GBM cells exhibit increased cytoplasmic glycolysis in comparison to terminally differentiated GBM cells and quiescent GSCs that rely more on oxidative phosphorylation (OXPHOS). Furthermore, the Warburg effect, which is characterized by increased tumor cell glycolysis and decreased mitochondrial metabolism in the presence of oxygen, has been observed in GBM. Herein, we highlight the importance of mitochondria in the maintenance of GSCs.

The Infratentorial Localization of Brain Metastases May Correlate with Specific Clinical Characteristics and Portend Worse Outcomes Based on Voxel-Wise Mapping.

The infratentorial regions are vulnerable to develop brain metastases (BMs). However, the associations between the infratentorial localization of BMs and clinical characteristics remained unclear. We retrospectively studied 1102 patients with 4365 BM lesions. Voxel-wise mapping of MRI was applied to construct the tumor frequency heatmaps after normalization and segmentation. The analysis of differential involvement (ADIFFI) was further used to obtain statistically significant clusters. Kaplan-Meier method and Cox regression were used to analyze the prognosis. The parietal, insular and left occipital lobes, and cerebellum were vulnerable to BMs with high relative metastatic risks. Infratentorial areas were site-specifically affected by the lung, breast, and colorectal cancer BMs, but inversely avoided by melanoma BMs. Significant infratentorial clusters were associated with young age, male sex, lung neuroendocrine and squamous cell carcinomas, high expression of Ki-67 of primaries and BMs, and patients with poorer prognosis. Inferior OS was observed in patients with ≥3 BMs and those who received whole-brain radiotherapy alone. Infratentorial involvement of BMs was an independent risk factor of poor prognosis for patients who received surgery (p = 0.023, hazard ratio = 1.473, 95% confidence interval = 1.055-2.058). The current study may add valuable clinical recognition of BMs and provide references for BMs diagnosis, treatment evaluation, and prognostic prediction.

The Preferred Locations of Meningioma According to Different Biological Characteristics Based on Voxel-Wise Analysis.

Objective: Meningiomas presented preferred intracranial distribution, which may reflect potential biological natures. This study aimed to analyze the preferred locations of meningioma according to different biological characteristics. Method: A total of 1,107 patients pathologically diagnosed with meningiomas between January 2012 and December 2016 were retrospectively analyzed. Preoperative MRI were normalized, and lesions were semiautomatically segmented. The stereospecific frequency and p value heatmaps were constructed to compare two biological phenotypes using two-tailed Fisher's exact test. Age, sex, WHO grades, extent of resection (EOR), recurrence, and immunohistochemical markers including p53, Ki67, epithelial membrane antigen (EMA), progesterone receptor (PR), and CD34 were statistically analyzed. Recurrence-free survival (RFS) were analyzed by Kaplan-Meier method. Result: Of 1,107 cases, convexity (20.8%), parasagittal (16.1%), and falx (11.4%) were the most predominant loci of meningiomas. The p-value heatmap suggested lesion predominance in the left frontal and occipital convexity among older patients while in the left sphenoid wing, and right falx, parasellar/cavernous sinus, and middle fossa among younger patients. Lesions located at anterior fossa and frontal structures were more frequently seen in the male while left parietal falx and tentorial regions, and right cerebellopontine angle in the female. Grades II and III lesions presented predominance in the frontal structures compared with grade I ones. Meningiomas at the left parasagittal sinus and falx, tentorium, intraventricular regions, and skull-base structures were significantly to receive subtotal resection. Lesions with p53 positivity were statistically located at the left frontal regions and parasellar/cavernous sinus, higher Ki67 index at the left frontal and bilateral parietal convexity and right parasellar/cavernous sinus, EMA negativity at the right olfactory groove and left middle fossa, and CD34 positivity at the sellar regions and right sphenoid wing. Tumor recurrence rates for grades I, II, and III were 2.8, 7.9, and 53.8%, respectively. Inferior RFS, higher Ki67 index, grades II and III, and a larger preoperative volume were observed in older patients. Recurrent meningiomas were more frequently found at the occipital convexity, tentorium, sellar regions, parasagittal sinus, and left sphenoid wing. Conclusion: The preferred locations of meningioma could be observed according to different biological characteristics, which might be helpful for clinical decisions.

Heme Oxygenase 1 Inhibits Adult Neural Stem Cells Proliferation and Survival via Modulation of Wnt/ß-Catenin Signaling.

BACKGROUND: Adult hippocampal neurogenesis is critical for renewing hippocampal neural circuits and maintaining hippocampal cognitive function and is closely associated with age-related neurodegenerative diseases. Heme oxygenase 1 (HO-1) is a stress protein that catalyzes the degradation of heme into free iron, biliverdin, and carbon monoxide. Elevated HO-1 level constitutes a pathological feature of Alzheimer's disease, Parkinson's disease, and many other age-related neurodegenerative diseases. OBJECTIVE: Here we research the precise role of HO-1 in adult hippocampal neurogenesis. METHODS: To explore the effect of HO-1 overexpression on adult neural stem cells (aNSCs) and elucidate its mechanisms, Tg(HO-1) was constructed. The transgenic mice and aNSCs were subjected to neurosphereing assay, clonal analysis, and BrdU labelling to detect the proliferation and self-renewal ability. LiCl, MG132, CHX, and IGF-1 treatment were used to research the signaling pathways which regulated by HO-1. RESULTS: HO-1 overexpression decreased proliferation ability and induced apoptosis of aNSCs in subgranular zoon (SGZ) in vivo and in vitro. Furthermore, HO-1 overexpression inactivated canonical WNT/ß-catenin pathway. Re-activate canonical WNT/ß-catenin pathway rescued aNSCs proliferation and survival upon HO-1 overexpression. More importantly, phosphorylation of AKTS473 and GSK3ßS9 was found to be significantly decreased in HO-1 overexpressed aNSCs. Re-activation of AKT signaling proved that HO-1 inhibited Wnt/ß-catenin signaling pathway via AKT/GSK3ß signaling pathway. CONCLUSION: These results demonstrated a critical role of HO-1 in regulating aNSCs survival and proliferation by inhibiting Wnt/ß-catenin pathway through repression of AKT/GSK3ß, which provide a novel insight into the role of HO-1 in Alzheimer's disease pathogenesis.

Tumor circulome in the liquid biopsies for cancer diagnosis and prognosis.

Liquid biopsy is a convenient, fast, non-invasive and reproducible sampling method that can dynamically reflect the changes in tumor gene expression profile, and provide a robust basis for individualized therapy and early diagnosis of cancer. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the currently approved diagnostic biomarkers for screening cancer patients. In addition, tumor-derived extracellular vesicles (tdEVs), circulating tumor-derived proteins, circulating tumor RNA (ctRNA) and tumor-bearing platelets (TEPs) are other components of liquid biopsies with diagnostic potential. In this review, we have discussed the clinical applications of these biomarkers, and the factors that limit their implementation in routine clinical practice. In addition, the most recent developments in the isolation and analysis of circulating tumor biomarkers have been summarized, and the potential of non-blood liquid biopsies in tumor diagnostics has also been discussed.

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.

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.