Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis.

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

Multi-regional sequencing reveals the genetic and immune heterogeneity of non-cancerous tissues in gastric cancer.

Gastric cancer (GC) is one of the most heterogeneous tumors. However, research on normal tissue adjacent to the tumor (NAT) is very limited. We performed multi-regional omics sequencing on 150 samples to assess the genetic basis and immune microenvironment in NAT and matched primary tumor or lymph node metastases. NATs demonstrated different mutated genes compared with GC, and NAT genomes underwent independent evolution with low variant allele frequency. Mutation profiles were predominated by aging and smoking-associated signatures in NAT instead of signatures associated with genetic instability. Although the immune microenvironment within NATs shows substantial intra-patient heterogeneity, the proportion of shared TCR clones among NATs is five times higher than that of tumor regions. These findings support the notion that subclonal expansion is not pronounced in NATs. We also demonstrated remarkable intra-patient heterogeneity of GCs and revealed heterogeneity of focal amplification of CD274 (encoding PD-L1) that leads to differential expression. Finally, we identified that monoclonal seeding is predominant in GC, which is followed by metastasis-to-metastasis dissemination in individual lymph nodes. These results provide novel insights into GC carcinogenesis. © 2024 The Pathological Society of Great Britain and Ireland.

Construction and validation of an immune infiltration-related risk model for predicting prognosis and immunotherapy response in low grade glioma.

BACKGROUND: Low grade glioma (LGG) is considered a heterogeneous tumor with highly variable survival and limited efficacy of immunotherapy. To identify high-risk subsets and apply immunotherapy effectively in LGG, the status and function of immune infiltration in the glioma microenvironment must be explored. METHODS: Four independent glioma cohorts comprising 1,853 patients were enrolled for bioinformatics analysis. We used ConsensusClusterPlus to cluster patients into four different immune subtypes based on immune infiltration. The immune-infiltration signature (IIS) was constructed by LASSO regression analysis. Somatic mutation and copy number variation (CNV) analyses were performed to explore genomic and transcriptomic traits in the high- and low- risk groups. The correlation between response to programmed cell death 1 (PD-1) blockade and the IIS risk score was confirmed in an in vivo glioma model. RESULTS: Patients were clustered into four different immune subtypes based on immune infiltration, and the high immune infiltration subtype was associated with worse survival in LGG. The high immune infiltration subtype had stronger inflammatory response, immune response and immune cell chemotaxis. The IIS, consisting of EMP3, IQGAP2, METTL7B, SLC1A6 and TNFRSF11B, could predict LGG malignant progression, which was validated with internal clinical samples. M2 macrophage infiltration positively correlated with the IIS risk score. The high-risk group had significantly more somatic mutations and CNVs. The IIS risk score was related to immunomodulatory molecules and could predict immunotherapy clinical benefit. In vivo, immunotherapy-sensitive glioma model exhibited higher IIS risk score and more infiltration of immune cells, especially M2 macrophages. The IIS risk score was decreased in an immunotherapy-sensitive glioma model after anti-PD1 immunotherapy. CONCLUSION: Different immune subtypes of LGG had unique immune cell infiltration characteristics, and the high immune infiltration subtype was associated with immunosuppressive signaling pathways. A novel IIS prognostic model based on immune infiltration status was constructed for immunophenotypic classification, risk stratification, prognostication and immunotherapy response prediction in LGG.

Bacterial communities associated with mushrooms in the Qinghai-Tibet Plateau are shaped by soil parameters.

Fungi capable of producing fruit bodies are essential food and medicine resources. Despite recent advances in the study of microbial communities in mycorrhizospheres, little is known about the bacterial communities contained in fruit bodies. Using high-throughput sequencing, we investigated the bacterial communities in four species of mushrooms located on the alpine meadow and saline-alkali soil of the Qinghai-Tibet Plateau (QTP). Proteobacteria (51.7% on average) and Actinobacteria (28.2% on average) were the dominant phyla in all of the sampled fairy ring fruit bodies, and Acidobacteria (27.5% on average) and Proteobacteria (25.7% on average) dominated their adjacent soils. For the Agria. Bitorquis, Actinobacteria was the dominant phylum in its fruit body (67.5% on average) and adjacent soils (65.9% on average). The alpha diversity (i.e., Chao1, Shannon, Richness, and Simpson indexes) of the bacterial communities in the fruit bodies were significantly lower than those in the soil samples. All of the fungi shared more than half of their bacterial phyla and 16.2% of their total operational taxonomic units (OTUs) with their adjacent soil. Moreover, NH4+ and pH were the key factors associated with bacterial communities in the fruit bodies and soils, respectively. These results indicate that the fungi tend to create a unique niche that selects for specific members of the bacterial community. Using culture-dependent methods, we also isolated 27 bacterial species belonging to three phyla and five classes from fruit bodies and soils. The strains isolated will be useful for future research on interactions between mushroom-forming fungi and their bacterial endosymbionts.

Spontaneous intramuscular hemorrhage in cancer-associated dermatomyositis: a case and literature review.

BACKGROUND: Spontaneous intramuscular hemorrhage (SIH) is a rare but life-threatening complication of dermatomyositis (DM). The pathogenetic mechanism and management of intramuscular hematoma in these patients remains unclear. Here we discuss a case of recurrent hemorrhage in a patient with cancer-associated DM, and review the relevant literature for timely diagnosis and treatment. CASE PRESENTATION: A 53-year-old male patient presented with rashes, muscle weakness, and dysphagia and was diagnosed with DM. During treatment, he developed SIH of the arm and right psoas major muscle successively. MRI showed extensive edema of the right shoulder girdle muscle and muscle groups of the upper arm. During the second SIH, a CT scan showed new-onset hematoma formation in the right psoas major muscle. The detection of D-dimer, thrombin-antithrombin III complex (TAT), plasmin-α2-plasmininhibitor complex (PIC) and tissue plasminogen activator-inhibitor complex (t-PAIC) indicated predominant hyperfibrinolysis over thrombosis. Blood transfusion and supportive treatment were immediately performed, and the hematoma did not expand. However, his abdominal distension was not relieved after active treatment. Further electronic gastroscopy discovered gastric sinus ulcers, and histopathology of the biopsy confirmed signet-ring cell carcinoma. CONCLUSIONS: Although patients with cancer-associated DM have an increased risk of thrombosis, prophylactic anticoagulation therapy needs deliberate consideration. It is important to monitor the coagulation parameters dynamically during anticoagulation therapy. Especially when the level of D-dimer is high, and it is uncertain whether the patient is in a state of thrombosis or hyperfibrinolysis, the detection of TAT, PIC, t-PAIC can help to determine whether to initiate anticoagulation therapy.

[Screening and expression analysis of transcription factors involved in genuineness of Codonopsis pilosula in Shanxi].

This study aims to mine the transcription factors that affect the genuineness of Codonopsis pilosula in Shanxi based on the transcriptome data of C. pilosula samples collected from Shanxi and Gansu, and then analyze the gene expression patterns, which will provide a theoretical basis for the molecular assisted breeding of C. pilosula. Gene ontology(GO) functional annotation, conserved motif prediction, and gene expression pattern analysis were performed for the differential transcription factors predicted based on the transcriptome data of C. pilosula from different habitats. A total of 61 differentially expressed genes(DEGs) were screened out from the transcriptome data. Most of the DEGs belonged to AP2/ERF-ERF family, with the conserved motif of [2X]-[LG]-[3X]-T-[3X]-[AARAYDRAA]-[3X]-[RG]-[2X]-A-[2X]-[NFP]. Forty-three of the DEGs showed significantly higher gene expression in C. pilosula samples from Shanxi than in the samples from Gansu, including 11 genes in the AP2/ERF-ERF family, 5 genes in the NAC fa-mily, 1 gene in the bHLH family, and 2 genes in the RWP-RK family, while 18 transcription factors showed higher expression levels in the samples from Gansu. GO annotation predicted that most of the DEGs were enriched in GO terms related to transcriptional binding activity(103), metabolic process(26), and stress response(23). The expression of transcription factor genes, CpNAC92, CpNAC100, CpbHLH128, and CpRAP2-7 was higher in the samples from Shanxi and in the roots of C. pilosula. CpNAC92, CpbHLH128, and CpRAP2-7 responded to the low temperature, temperature difference, and iron stresses, while CpNAC100 only responded to low temperature and iron stresses. The screening and expression analysis of the specific transcription factors CpNAC92, CpNAC100, CpbHLH128, and CpRAP2-7 in C. pilosula in Shanxi laid a theoretical foundation for further research on the mechanism of genuineness formation of C. pilosula.

DHHC5 facilitates oligodendrocyte development by palmitoylating and activating STAT3.

Myelin sheath is an important structure to maintain functions of the nerves in central nervous system. Protein palmitoylation has been established as a sorting determinant for the transport of myelin-forming proteins to the myelin membrane, however, its function in the regulation of oligodendrocyte development remains unknown. Here, we show that an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC5, is involved in the control of oligodendrocyte development. Loss of Zdhhc5 in oligodendrocytes inhibits myelination and remyelination by reducing total myelinating oligodendrocyte population. STAT3 is the primary substrate for DHHC5 palmitoylation in oligodendrocytes. Zdhhc5 ablation reduces STAT3 palmitoylation and suppresses STAT3 phosphorylation and activation. As a result, the transcription of the myelin-related and anti-apoptosis genes is inhibited, leading to suppressed oligodendrocyte development and myelination. Our findings demonstrate a key role DHHC5 in controlling myelinogenesis.

Plastome structure, phylogenomics and evolution of plastid genes in Swertia (Gentianaceae) in the Qing-Tibetan Plateau.

BACKGROUND: The genus Swertia is of great medicinal importance and one of the most taxonomically challenging taxa within Gentianaceae, largely due to the morphological similarities of species within this genus and with its closely related genera. Previous molecular studies confirmed its polyphyly but suffered from low phylogenetic resolutions because only limited sequence loci were used. Thus, we conducted the structural, gene evolutionary, and phylogenetic analyses of 11 newly obtained plastomes of Swertia. Our result greatly improved the phylogenetic resolutions in Swertia, shed new light on the plastome evolution and phylogenetic relationships of this genus. RESULTS: The 11 Swertia plastomes together with the published seven species proved highly similar in overall size, structure, gene order, and content, but revealed some structural variations caused by the expansion and contraction of the IRb region into the LSC region, due to the heterogeneous length of the ψycf1. The gene rps16 was found to be in a state flux with pseudogenes or completely lost. Similar situation was also documented in other genera of Gentianaceae. This might imply loss of the gene in the common ancestor of Gentianaceae. The distribution plot of ENC vs. GC3 showed all these plastomes arranging very close in the Wright line with an expected ENC value (49-52%), suggesting the codon usage of Swertia was mainly constrained by a GC mutation bias. Most of the genes remained under the purifying selection, however, the cemA was identified under positive selection, possibly reflecting an adaptive response to low CO2 atmospheric conditions during the Late Miocene. Our phylogenomic analyses, based on 74 protein-coding genes (CDS), supported the polyphyly of Swertia with its close allies in the subtribe Swertiinae, presumably due to recent rapid radiation. The topology inferred from our phylogenetic analyses partly supported the current taxonomic treatment. Finally, several highly variable loci were identified, which can be used in future phylogenetic studies and accurate identification of medicinal genuineness of Swertia. CONCLUSIONS: Our study confirmed the polyphyly of Swertia and demonstrated the power of plastome phylogenomics in improvement of phylogenetic resolution, thus contributing to a better understanding of the evolutionary history of Swertia.

Toxicity in Takifugu rubripes exposed to acute ammonia: Effects on immune responses, brain neurotransmitter levels, and thyroid endocrine hormones.

Exposure to ammonia can cause convulsions, coma, and death. In this study, we investigate the effects of ammonia exposure on immunoregulatory and neuroendocrine changes in Takifugu rubripes. Fish were sampled at 0, 12, 24, 48, and 96 h following exposure to different ammonia concentrations (0, 5, 50, 100, and 150 mg/L). Our results showed that exposure to ammonia significantly reduced the concentrations of C3, C4, IgM, and LZM whereas the heat shock protein 70 and 90 levels significantly increased. In addition, the transcription levels of Mn-SOD, CAT, GRx, and GR in the liver were significantly upregulated following exposure to low ammonia concertation, however, downregulated with increased exposure time. These findings suggest that ammonia poisoning causes oxidative damage and suppresses plasma immunity. Ammonia exposure also resulted in the elevation and depletion of the T3 and T4 levels, respectively. Furthermore, ammonia stress induced an increase in the corticotrophin-releasing hormone, adrenocorticotropic hormone, and cortisol levels, and a decrease in dopamine, noradrenaline, and 5-hydroxytryptamine levels in the brain, illustrating that ammonia poisoning can disrupt the endocrine and neurotransmitter systems. Our results provide insights into the mechanisms underlying the neurotoxic effects of ammonia exposure, which helps to assess the ecological and environmental health risks of this contaminant in marine fish.

A Nanoantidote Alleviates Glioblastoma Chemotoxicity without Efficacy Compromise.

Cancer patients suffer from the toxicity of chemotherapy. Antidote, given as a remedy limiting poison, is an effective way to counteract toxicity. However, few antidotes abrogate chemotoxicity without compromising the therapeutic efficacy. Herein, a rationally designed nanoantidote can neutralize chemo-agents in normal cells but not enter tumors and thus would not interfere with the efficacy of tumor treatment. The nanoantidote, consisting of a dendrimer core wrapped by reductive cysteine, captures Temozolomide (TMZ, the glioblastoma standard chemotherapy). Meanwhile, thanks to the blood-brain barrier (BBB) and the size of the nanoantidote, the nanoantidote cannot enter glioblastoma. In murine models, the nanoantidote distributes in normal tissues without crossing the BBB, so it markedly reduces the chemotoxicity of TMZ and retains the original TMZ therapeutic efficacy. With most nanotechnologies focusing on antitumor treatment, this detoxicating strategy demonstrates a nanoplatform to reduce chemotoxicity using physiology barriers and introduces a new approach to nanomedicine for cancer chemotherapy.

Effect of winter feeding frequency on growth performance, biochemical blood parameters, oxidative stress, and appetite-related genes in Takifugu rubripes.

Tiger pufferfish (Takifugu rubripes) is one of Asia's most economically valuable aquaculture species. However, winter production of this species in North China is limited by low water temperature and unavailability of high-quality feed, resulting in high mortality and low profitability. Therefore, the aim of this study was to evaluate the effect of feeding frequency (F1: one daily meal; F2: two daily meals; F3: four daily meals; F4: continuous diurnal feeding using a belt feeder) on the growth performance, plasma biochemistry, digestive and antioxidant enzyme activities, and expression of appetite-related genes in T. rubripes (initial weight: 266.80 ± 12.32 g) cultured during winter (18.0 ± 1.0 °C) for 60 days. The results showed that fish in the F3 group had the highest final weight, weight gain rate, specific growth rate, survival rate, and best feed conversion ratio. Additionally, daily feed intake increased significantly with increasing feeding frequency. The protein efficiency and lipid efficiency ratios of fish in the F3 group were significantly higher than those of fish in the other groups. Furthermore, total cholesterol, triglycerides, and glucose levels increased with increasing feeding frequency, peaking in the F2 group and decreasing under higher feeding frequencies. The antioxidant (superoxide dismutase, catalase, glutathione, and glutathione peroxidase) and digestive (trypsin, amylase, and lipase) enzyme activities of fish in the F1 group were significantly higher than those of fish in the F3 and F4 groups. Additionally, there was a decrease in orexin expression with increasing feeding frequency. In contrast, the expression levels of tachykinin, cholecystokinin, and leptin increased with increasing feeding frequency, peaking in the F4 group. Overall, the findings of this study indicated that a feeding frequency of four meals per day was optimal for improved growth performance of pufferfish juveniles cultured during winter.

The effect of ventilator-associated pneumonia on the prognosis of intensive care unit patients within 90 days and 180 days.

BACKGROUND: Mechanical ventilation (MV) is often applied in critically ill patients in intensive care unit (ICU) to protect the airway from aspiration, and supplement more oxygen. MV may result in ventilator-associated pneumonia (VAP) in ICU patients. This study was to estimate the 90-day and 180-day mortalities of ICU patients with VAP, and to explore the influence of VAP on the outcomes of ICU patients. METHODS: Totally, 8182 patients who aged ≥18 years and received mechanical ventilation (MV) in ICU from Medical Information Mart for Intensive Care III (MIMIC III) database were involved in this study. All subjects were divided into the VAP group (n = 537) and the non-VAP group (n = 7626) based on the occurrence of VAP. Clinical data of all participants were collected. The effect of VAP on the prognosis of ICU patients was explored by binary logistic regression analysis. RESULTS: The results delineated that the 90-day mortality of VAP patients in ICU was 33.33% and 180-day mortality was 37.62%. The 90-day and 180-day mortality rates were higher in the VAP group than in the non-VAP group. After adjusting the confounders including age, ethnicity, heart failure, septicemia, simplified acute physiology score II (SAPSII) score, sequential organ failure assessment (SOFA) score, serum lactate, white blood cell (WBC), length of ICU stay, length of hospital stay, length of ventilation, antibiotic treatment, Pseudomonas aeruginosa (P.aeruginosa), methicillin-resistant Staphylococcus aureus (MRSA), other pathogens, the risk of 90-day and 180-day mortalities in VAP patients were 1.465 times (OR = 1.465, 95%CI: 1.188-1.807, P < 0.001) and 1.635 times (OR = 1.635, 95%CI: 1.333-2.005, P < 0.001) higher than those in non-VAP patients, respectively. CONCLUSIONS: Our study revealed that ICU patients with VAP had poorer prognosis than those without VAP. The results of this study might offer a deeper insight into preventing the occurrence of VAP.

A multicenter, prospective study to observe the initial management of patients with differentiated thyroid cancer in China (DTCC study).

BACKGROUND: To assess the gaps between the initial management of patients with differentiated thyroid cancer (DTC) in real clinical practice and the recommendations of the 2012 Chinese DTC guidelines. METHODS: This multicenter, prospective study was conducted at nine tertiary hospitals across China. Eligible patients were those having intermediate or high-risk DTC after first-time thyroidectomy. During 1 year of follow-up, comprehensive medical records were collected and summarized using descriptive statistics. RESULTS: Of 2013 patients, 1874 (93.1%) underwent standard surgery according to the guidelines (including total lobectomy plus isthmusectomy and total/near total thyroidectomy), and 1993 (99.0%) underwent lymph node dissection; only 56 (2.8%) had postoperative complications. Overall, 982/2013 patients (48.8%) received radioactive iodine (RAI) therapy after thyroidectomy. Of all enrolled patients, 61.4% achieved the target serum thyroid-stimulating hormone level, with a median time to target of 234.0 days (95% CI: 222.0-252.0). At 1 year of follow-up, proportions of patients with excellent response, incomplete structural response, biochemical incomplete response, and indeterminate response were 34.6, 11.2, 6.6, and 47.5%, respectively; recurrence or metastasis occurred in 27 patients (1.3%). During the overall study period, 209 patients (10.4%) had at least one adverse event: 65.1% of cases were mild, 24.9% moderate, and 10.1% severe. CONCLUSIONS: This was the first large-scale prospective study of how patients with DTC in China are treated in actual practice. Initial DTC management is generally safe and adheres to the 2012 Chinese guidelines but could be improved, and the level of guideline adherence did not produce the anticipated treatment response at 1 year of follow-up.

BioRel: towards large-scale biomedical relation extraction.

BACKGROUND: Although biomedical publications and literature are growing rapidly, there still lacks structured knowledge that can be easily processed by computer programs. In order to extract such knowledge from plain text and transform them into structural form, the relation extraction problem becomes an important issue. Datasets play a critical role in the development of relation extraction methods. However, existing relation extraction datasets in biomedical domain are mainly human-annotated, whose scales are usually limited due to their labor-intensive and time-consuming nature. RESULTS: We construct BioRel, a large-scale dataset for biomedical relation extraction problem, by using Unified Medical Language System as knowledge base and Medline as corpus. We first identify mentions of entities in sentences of Medline and link them to Unified Medical Language System with Metamap. Then, we assign each sentence a relation label by using distant supervision. Finally, we adapt the state-of-the-art deep learning and statistical machine learning methods as baseline models and conduct comprehensive experiments on the BioRel dataset. CONCLUSIONS: Based on the extensive experimental results, we have shown that BioRel is a suitable large-scale datasets for biomedical relation extraction, which provides both reasonable baseline performance and many remaining challenges for both deep learning and statistical methods.

Lymph Node Metastasis Prediction from Primary Breast Cancer US Images Using Deep Learning.

Background Deep learning (DL) algorithms are gaining extensive attention for their excellent performance in image recognition tasks. DL models can automatically make a quantitative assessment of complex medical image characteristics and achieve increased accuracy in diagnosis with higher efficiency. Purpose To determine the feasibility of using a DL approach to predict clinically negative axillary lymph node metastasis from US images in patients with primary breast cancer. Materials and Methods A data set of US images in patients with primary breast cancer with clinically negative axillary lymph nodes from Tongji Hospital (974 imaging studies from 2016 to 2018, 756 patients) and an independent test set from Hubei Cancer Hospital (81 imaging studies from 2018 to 2019, 78 patients) were collected. Axillary lymph node status was confirmed with pathologic examination. Three different convolutional neural networks (CNNs) of Inception V3, Inception-ResNet V2, and ResNet-101 architectures were trained on 90% of the Tongji Hospital data set and tested on the remaining 10%, as well as on the independent test set. The performance of the models was compared with that of five radiologists. The models' performance was analyzed in terms of accuracy, sensitivity, specificity, receiver operating characteristic curves, areas under the receiver operating characteristic curve (AUCs), and heat maps. Results The best-performing CNN model, Inception V3, achieved an AUC of 0.89 (95% confidence interval [CI]: 0.83, 0.95) in the prediction of the final clinical diagnosis of axillary lymph node metastasis in the independent test set. The model achieved 85% sensitivity (35 of 41 images; 95% CI: 70%, 94%) and 73% specificity (29 of 40 images; 95% CI: 56%, 85%), and the radiologists achieved 73% sensitivity (30 of 41 images; 95% CI: 57%, 85%; P = .17) and 63% specificity (25 of 40 images; 95% CI: 46%, 77%; P = .34). Conclusion Using US images from patients with primary breast cancer, deep learning models can effectively predict clinically negative axillary lymph node metastasis. Artificial intelligence may provide an early diagnostic strategy for lymph node metastasis in patients with breast cancer with clinically negative lymph nodes. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Bae in this issue.

Deltex-1 is indispensible for the IL-6 and TGF-ß treatment-triggered differentiation of Th17 cells.

CSL(CBF1, Su(H) and LAG-1)-dependent Hes-1 signaling plays an important part in regulating Th17 cell differentiation. However, little is known about influence of CSL-independent Deltex-1 signaling on this subset. The current focus is on roles of the Deltex-1 signaling in the Th17 cell differentiation. IL-17-producing CD4+ T cell subpopulation could be induced in vitro by treatment of both IL-6 and TGF-ß. This could be reversed by knockdown of the deltex-1 gene, following the attenuation of retinoic acid-related orphan receptor γt (RORγt) and its DNA-binding activity in nuclei. Subsequently, Th17-associated cytokines generated by the treated cells were also diminished by the inhibition of Deltex-1 signaling, but the production of IL-10 was enhanced. Contrary to the alteration of RORγt, both zinc-finger transcription factor-3 (GATA3) and transcription factor Forkhead box P3 (Foxp3) were augmented at their mRNA and protein levels as well as DNA-binding activities with the emerging phenotypes of the corresponding cellular subpopulation and T-bet (encoded by TBX21) was not changed. These results reveal for the first time that Deltex-1 is indispensible for the IL-6 and TGF-ß treatment-triggered differentiation of Th17 cells, indicating that CSL-independent Deltex-1 signaling favors naïve CD4+ T cells to deviate into Th17 cells via the enhancement of RORγt/IL-17A.

Androgen receptor variant 12 promotes migration and invasion by regulating MYLK in gastric cancer.

Androgen receptor (AR) and its variants (AR-Vs) promote tumorigenesis and metastasis in many hormone-related cancers, such as breast, prostate and hepatocellular cancers. However, the expression patterns and underlying molecular mechanisms of AR in gastric cancer (GC) are not fully understood. This study aimed to detect the expression of AR-Vs in GC and explored their role in metastasis of GC. Here, the AR expression form was identified in GC cell lines and tissues by RT-PCR and qPCR. Transwell assays and experimental lung metastasis animal models were used to assess the function of AR in cell migration and invasion. Downstream targets of AR were screened by bioinformatics, and identified by luciferase reporter assays and electrophoretic mobility shift assays. AR-v12 was identified as the main expression form in GC cell lines and tissues. Different from full length of AR, AR-v12 was localized to the nucleus independent of androgen. Upregulation of AR-v12 in primary GC tissues was significantly associated with metastasis. Overexpression of AR-v12 promoted migration and invasion independent of androgen. Knockdown of AR-v12 inhibited migration and invasion in vitro, as well as metastasis in vivo. Furthermore, AR-v12, serving as a transcription factor, promoted metastasis through regulating the promoter activity of MYLK. In AR-v12 overexpressing cells, knockdown of MYLK inhibited cell migration and invasion, while in AR-v12 knocked-down cells, overexpression of MYLK promoted cell migration and invasion. Collectively, our study demonstrates that AR-v12 is highly expressed in GC tissues and promotes migration and invasion through directly regulating MYLK. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Grading of Glioma: combined diagnostic value of amide proton transfer weighted, arterial spin labeling and diffusion weighted magnetic resonance imaging.

BACKGROUND: To investigate the ability of amide proton transfer (APT) weighted magnetic resonance imaging (MRI), arterial spin labeling (ASL), diffusion weighted imaging (DWI) and the combination for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). METHODS: Twenty-seven patients including nine LGGs and eighteen HGGs underwent conventional, APT, ASL and DWI MRI with a 3.0-T MR scanner. Histogram analyses was performed and quantitative parameters including mean apparent diffusion coefficient (ADC mean), 20th-percentile ADC (ADC 20th), mean APT (APT mean), 90th-percentile APT (APT 90th), relative mean cerebral blood flow (rCBF mean) and relative 90th-percentile CBF (rCBF 90th) were compared between HGGs and LGGs. The diagnostic performance was evaluated with receiver operating characteristic (ROC) analysis of each parameter and their combination. Correlations were analyzed among the MRI parameters and Ki-67. RESULTS: The APT values were significantly higher in the HGGs compared to the LGGs (p <  0.005), whereas ADC values were significantly lower in HGGs than LGGs (P <  0.0001). The ADC 20th and APT mean had higher discrimination abilities compared with other single parameters, with the area under the ROC curve (AUC) of 0.877 and 0.840. Adding ADC parameter, the discrimination ability of APT and rCBF significantly improved. The ADC was negatively correlated with the APT and rCBF value, respectively, while APT value was positively correlated with rCBF value. Significant correlations between ADC values and Ki-67 were also observed. CONCLUSIONS: APT and DWI are valuable in differentiating HGGs from LGGs. The combination of APT, DWI and ASL imaging could improve the ability for discriminating HGGs from LGGs.

The potential diagnostic power of CD138+ microparticles from the plasma analysis for multiple myeloma clinical monitoring.

Multiple myeloma (MM) is malignant tumor with abnormal proliferation of bone marrow plasma cells. The existing clinical tools used to determine treatment response and tumor relapse are limited in sensitivity. We investigated the CD138+ microparticles (MPs) of MM patients to find out whether MPs could provide a novel means to monitor the malignant cells in MM patients. Our study showed that the levels of MPs were significantly elevated in MM patients. The MP counts in peripheral blood from new diagnosed MM patients were significantly higher than patients in CR and HD. Consist with the total MPs, the number of the PC-derived MPs (CD138+) increased in BM from MM patients compared with CR and HD. The ratio of the PC-derived MPs (CD138+) in BM increased in MM patients compared with CR and HD. The correlation test revealed that the CD138+ MPs in BM and PB were all positively correlated with the plasmacyte ratio in bone marrow (BMPC) and the ß2 -MG. New diagnosed MM patients and controls were compared, and ROC curves were used to identify cutoff points with optimal sensitivity and specificity concerning the ratios and counts of CD138+ MPs in BM and PB. The AUC of the CD138+ MP counts in BM was 0.767, and in PB was 0.680. The AUC of the CD138+ MP ratios in BM was 0.714, and in PB was 0.666. According to this, the counts of CD138+ MPs in BM showed to be a powerful marker of diagnosis. We demonstrated that CD138+ MPs from the plasma provide support for a potential monitoring biomarker of MM.