A machine learning-based integrated clinical model for predicting prognosis in atypical meningioma patients.

PURPOSE: Atypical meningioma (AM) recurs in up to half of patients after surgical resection and may require adjuvant therapy to improve patient prognosis. Various clinicopathological features have been shown to have prognostic implications in AM, but an integrated prediction model is lacking. Thus, in this study, we aimed to develop and validate an integrated prognostic model for AM. METHODS: A retrospective cohort of 528 adult AM patients surgically treated at our institution were randomly assigned to a training or validation group in a 7:3 ratio. Sixteen baseline demographic, clinical, and pathological parameters, progression-free survival (PFS), and overall survival (OS) were analysed. Sixty-five combinations of machine learning (ML) algorithms were used for model training and validation to predict tumour recurrence and patient mortality. RESULTS: The random survival forest (RSF) model was the best model for predicting recurrence and death. Primary or secondary tumour, Ki-67 index, extent of resection, tumour size, brain involvement, tumour necrosis, and age contributed significantly to the model. The C-index value of the RSF recurrence prediction model reached 0.8080. The AUCs for 1-, 3-, and 5-year PFS were 0.83, 0.82, and 0.86, respectively. The C-index value of the RSF death prediction model reached 0.8890. The AUCs for 3-year and 5-year OS were 0.88 and 0.89, respectively. CONCLUSION: A high-performing integrated RSF predictive model for AM recurrence and patient mortality was proposed that may guide therapeutic decision-making and long-term monitoring.

Recurrent CYP2A6 gene mutation in biphasic hyalinizing psammomatous renal cell carcinoma: Additional support of three cases.

Biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC) with NF2 gene mutations is a newly described provisional category of renal cell carcinoma (RCC). Here we described three additional cases of BHP RCC with CYP2A6 gene mutation besides NF2 gene. The carcinomas were predominantly unencapsulated, and two of them had a rounded, nodular interface with the native kidney while one had perirenal adipose tissue invasion. Histopathologically, all neoplasms had a characteristic biphasic appearance of smaller cells clustering around basement membrane material within larger acini, forming pseudorosettes or a glomeruloid pattern. The smaller cells were focally spindle-shaped in two carcinomas. Psammoma bodies were shown in two carcinomas. Cellular necrosis and perineural invasion was identified in one case. Immunohistochemically, Vimentin, EMA, P504s were extensively expressed while RCC and CD10 were only expressed in larger cells. CK7 was positive in one tumor. CYP2A6 gene mutation (CYP2A6 NM_000762.6: exon4:c.A580G:p.K194E) was revealed in three tumors by Whole-genome exome sequencing, which was further confirmed by Sanger sequencing. Only one case harbored a somatic termination mutation in NF2 gene. NF2 promoter methylation was observed in the other two cases. Clinically, one patient died of disease with widespread bone metastases confirmed by biopsy at the ninth month after surgery but the other two patients had no evidence of recurrence or metastases (follow-up period 9-90 months). Our findings validated previously described clinicopathological features and NF2 gene mutation or promoter methylation of BHP RCC. In addition, we reported different IHC pattern of BHP RCC and further revealed the recurrent CYP2A6 genetic alteration.

Discovery and Structural and Functional Characterization of a Novel A-Superfamily Conotoxin Targeting α9α10 Nicotinic Acetylcholine Receptor.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels widely distributed in the central peripheral nervous system and muscles which participate in rapid synaptic transmission. The α9α10 nAChR is an acetylcholine receptor subtype and is involved in chronic pain. In the present study, a new A-superfamily conotoxin Bt14.12 cloned from Conus betulinus was found to selectively inhibit α9α10 nAChRs with an IC50 of 62.3 nM. Unlike α-conotoxins and other A-superfamily conotoxins, Bt14.12 contains a four Cys (C-C-C-C) framework with a unique disulfide bond connection "C1-C4, C2-C3". The structure-activity studies of Bt14.12 demonstrate that all amino acid residues contribute to its potency. Interestingly, mutation experiments show that the deletion of Asp2 or the addition of three Arg residues at the N-terminus of Bt14.12 significantly enhances its inhibitory activity (IC50 is 21.9 nM or 12.7 nM, respectively) by 2- or 4-fold compared to the wild-type Bt14.12. The NMR structure of Bt14.12 shows that it contains α-helix- and ß-turn-like elements, and further computational modelings of the interaction between Bt14.12 and the α9α10 nAChR demonstrate that Bt14.12 possesses a distinctive mode of action and displays a different structure-activity relationship from known α9α10 nAChR targeting α-conotoxins. Our findings provide a novel conotoxin that potently targets α9α10 nAChRs and a new motif for designing potent inhibitors against α9α10 nAChRs.

Integrative analyses identify HIF-1α as a potential protective role with immune cell infiltration in adamantinomatous craniopharyngioma.

Craniopharyngiomas (CPs) are histologically benign tumors located in the sellar-suprasellar region. Although the transcriptome development in recent years have deepened our knowledge to the tumorigenesis process of adamantinomatous craniopharyngioma (ACP), the peritumoral immune infiltration of tumor is still not well understood. In this study, weighted gene coexpression network analysis (WGCNA) was applied to identify different gene modules based on clinical characteristics and gene expression, and then, the protein-protein interaction (PPI) network with the Cytohubba plug-in were performed to screen pivotal genes. In addition, immune cell infiltration (ICI) analysis was used to evaluate the immune microenvironment of ACP patients. In total, 8,568 differential expression genes were identified based on our datasets and two microarray profiles from the public database. The functional enrichment analysis revealed that upregulated genes were mainly enriched in immune-related pathways while downregulated genes were shown in the hormone and transduction of signaling pathways. The WGCNA investigated the most relevant modules, and 1,858 hub genes was detected, from which the PPI network identified 14 pivotal genes, and the Hypoxia-inducible factor 1-alpha (HIF-1α) pathway including four critical genes may be involved in the development of ACP. Moreover, naïve CD4+ and CD8+ T cells were decreased while specific subtypes of T cells were significantly increased in ACP patients according to ICI analysis. Validation by immunofluorescence staining revealed a higher expression of HIF-1α in ACP (ACP vs. control) and adult-subtype (adult vs. children), suggesting a possible state of immune system activation. Notably, children with low HIF-1α scores were related to the hypothalamus involvement and hydrocephalus symptoms. In this study, we successfully identified HIF-1α as a key role in the tumorigenesis and development of ACP through comprehensive integrated analyses and systematically investigated the potential relationship with immune cells in ACP. The results may provide valuable resources for understanding the underlying mechanisms of ACP and strengthen HIF-1α as a potential immunotherapeutic target in clinical application.

Papillary renal neoplasm with reverse polarity may be a novel renal cell tumor entity with low malignant potential.

AIMS: This study retrospectively investigated the morphological, immunohistochemical and molecular genetic features of papillary renal neoplasm with reverse polarity (PRNRP), a recently described renal tumor. METHODS AND RESULTS: Eleven cases of PRNRP were collected, and 16 cases of type I and 9 cases of type II papillary renal cell carcinoma were included as a control series. Pathological features were evaluated based on HE staining and immunohistochemistry. KRAS exon 2 and BRAF V600E mutations were detected by Real-time PCR and Sanger sequencing. Fluorescence in situ hybridization was conducted for identification of chromosomal abnormalities. Hemosiderin deposition was found in a small amount of tumor cells in 6 cases. Multifocal or patchy necrosis (5/11), small focal invasion of the pseudocapsules or renal parenchyma (6/11), and breakthrough of renal capsule with nerve invasion (1/11) were revealed, inconsistent with the previous view that the tumor lacks necrosis and intercellular hemosiderin. Immunohistochemical staining (diffusely positive for CK7 and GATA3, negative for CD117 and vimentin, and negative to weakly positive for P504S) and high frequency of KRAS mutations in exon 2 (9/10) supported the identification and inclusion of our cases. Chromosome 7 trisomy (1/7), chromosome 17 trisomy (0/7) and chromosome Y deletion (0/5 male patients) were seldom detected in this tumor. All patients were alive without metastasis or recurrence at the end of the follow-up. CONCLUSION: Our findings may highlight the possibility of a low malignant potential of this emerging entity. We suggest that the tumor be classified as a novel renal cell tumor subtype independent of papillary renal cell carcinoma.

Bronchiolar adenoma-like tumour with monolayered component: Represent malignant transformation of bronchiolar adenoma? A series of five cases.

Pulmonary bronchiolar adenoma (BA) is a rare lung tumour, it is unclear whether BA can develop into a malignancy. We presented five cases of BA-like tumour with monolayered components. This type of tumour may represent the malignant transformation of BA. Histologically, these tumours showed acinar and lepidic growth patterns. The acinar components were well-differentiated. The glandular tumour cells in these tumours contained cuboidal to columnar cells resembling type II pneumocytes or club (Clara) cells. A small number of mucinous cells were found in two cases. A few scattered ciliated cells were detected in three cases. The ciliated cells only existed in the bilayered components. The basal cells were highlighted by CK5/6 and p40 in a partial region of the tumour rather than in the entire tumour. The glandular tumour cells, including those in the bilayered component, were diffusely positive for TTF-1 and napsin-A. EGFR Exon19 deletions were found in four cases, and BRAF V600E mutation was found in one case. These BA-like tumours have biphasic morphological and molecular characteristics of BA and lung adenocarcinoma, suggesting distal-type BA may develop into a malignancy. More cases should be studied and especially cases with metastasis should be searched to further prove the malignant transformation.

Exploring the prognostic differences in patients of Chiari malformation type I with syringomyelia undergoing different surgical methods.

Background: The best surgical treatment of Chiari malformation patients with syringomyelia remains controversial, and whether cerebellar tonsillectomy should be performed has not been decided. Objective: To evaluate the efficacy of posterior fossa decompression with duraplasty (PFDD) and Posterior fossa decompression with resection of tonsils (PFDRT) in patients of Chiari malformation type I (CM-I) with syringomyelia and explore relevant factors affecting prognosis. Patients and methods: We retrospectively analyzed 182 adult patients of CM-I with syringomyelia who underwent PFDD or PFDRT over a 6-year period, and analyzed their clinical manifestations, imaging features, and follow-up data. Clinical outcomes were assessed using the Chicago Chiari Outcome Scale (CCOS), and imaging outcomes were assessed using the syrinx remission rate. Difference comparisons were performed to compare the differences between different surgical groups. Influencing factors associated with outcome were investigated using bivariate analysis and multiple linear regression analysis. Results: There were statistically significant differences in CCOS score (p = 0.034) and syrinx remission rates (p = 0.046) between the PFDRT group and the PFDD group after surgery. Regression analysis showed that preoperative motor dysfunction, cerebellar-related symptoms and different surgical methods may have influenced the CCOS score and that brainstem-related symptoms and age may have influenced the syrinx remission rates in the total patient group (p < 0.05). Regression analysis showed that the duration of symptoms, cerebellar-related symptoms and preoperative syrinx diameter may have influenced the CCOS score and that the preoperative cerebellar tonsillar hernia distance may have influenced the postoperative syrinx remission rate in the PFDRT group (p < 0.05). Age and length of hospital stay may have influenced the CCOS score, and brainstem-related symptoms and age may have influenced the syrinx remission rates in the PFDD group (p < 0.05). Conclusion: This study showed that the CCOS score in the PFDRT group was better than that in the PFDD group. Preoperative motor dysfunction, cerebellar-related symptoms, and different surgical methods in patients of CM-I with syringomyelia affected postoperative CCOS score. Both the duration of symptoms and the age of the patients should be actively considered as factors influencing prognosis. Symptomatic CM-I patients with syringomyelia should undergo surgical treatment as early as possible.

Gastrointestinal Goblet Cell Adenocarcinomas Harbor Distinctive Clinicopathological, Immune, and Genomic Landscape.

Goblet cell adenocarcinoma (GCA) is a rare amphicrine tumor and difficult to diagnose. GCA is traditionally found in the appendix, but extra-appendiceal GCA may be underestimated. Intestinal adenocarcinoma with signet ring cell component is also very rare, and some signet ring cell carcinomas are well cohesive, having some similar morphological features to GCAs. It is necessary to differentiate GCA from intestinal adenocarcinomas with cohesive signet ring cell component (IACSRCC). The goal of this study is to find occurrence of extra-appendiceal GCA and characterize the histological, immunohistochemical, transcriptional, and immune landscape of GCA. We collected 12 cases of GCAs and 10 IACSRCCs and reviewed the clinicopathologic characters of these cases. Immunohistochemical stains were performed with synaptophysin, chromogranin A, CD56, somatostatin receptor (SSTR) 2, and Ki-67. Whole transcriptome RNA-sequencing was performed, and data were used to analyze differential gene expression and predict immune cell infiltration levels in GCA and IACSRCC. RNA-sequencing data for colorectal adenocarcinoma were gathered from TCGA data portal. Of the 12 patients with GCA, there were 4 women and 8 men. There were three appendiceal cases and nine extra-appendiceal cases. GCAs were immunohistochemically different from IACSRCC. GCA also had different levels of B-cell and CD8+ T-cell infiltration compared to both colorectal adenocarcinoma and cohesive IACSRCCs. Differential gene expression analysis showed distinct gene expression patterns in GCA compared to colorectal adenocarcinoma, with a number of cancer-related differentially expressed genes, including upregulation of TMEM14A, GOLT1A, DSCC1, and HSD17B8, and downregulation of KCNQ1OT1 and MXRA5. GCA also had several differentially expressed genes compared to IACSRCCs, including upregulation of PRSS21, EPPIN, RPRM, TNFRSF12A, and BZRAP1, and downregulation of HIST1H2BE, TCN1, AC069363.1, RP11-538I12.2, and REG4. In summary, the number of extra-appendiceal GCA was underestimated in Chinese patients. GCA can be seen as a distinct morphological, immunohistochemical, transcriptomic, and immunological entity. The classic low-grade component of GCA and the immunoreactivity for neuroendocrine markers are the key points to diagnosing GCA.

MED12 exon 2 and TERT promoter mutations in primary and recurrent breast fibroepithelial lesions.

The genetic alterations in the recurrent breast fibroepithelial tumors are poorly understood. In the present study, we aimed to investigate mediator protein complex subunit 12 (MED12) exon 2 and telomerase reverse transcriptase (TERT) promoter mutations in a series of primary and recurrent fibroepithelial tumors. Sanger sequencing for MED12 exon 2 and TERT promoter was performed in 26 pairs of primary and recurrent fibroepithelial tumors (19 pairs of phyllodes tumors and seven pairs of fibroadenomas). The relationship between the genotypes and clinicopathological variables was also analyzed. MED12 mutation was identified in 19 primary tumors (12 phyllodes tumors and 7 fibroadenomas) and 17 recurrences (14 phyllodes tumors and three fibroadenomas). Most recurrent phyllodes tumors retained the original MED12 variants (17/19). Six recurrent fibroadenomas showed different MED12 variants from their paired primary tumors (6/7). TERT promoter mutation was identified in 13 primary phyllodes tumors (13/19) and 15 recurrent phyllodes tumors (15/19). However, it was only identified in one primary fibroadenoma (1/7). Recurrent phyllodes tumors often retained the original MED12 and TERT promoter mutations, while recurrent fibroadenomas often acquired new MED12 mutations. Our findings suggest that recurrent phyllodes tumors may be "true recurrence," and TERT mutant "benign fibroepithelial tumors" should be treated as phyllodes tumors.

Development and Validation of Predicting Nomograms for Craniopharyngioma: A Retrospective, Multiple-Center, Cohort Study.

Craniopharyngiomas (CPs) are benign tumors arising from the sellar region. However, little is known about their clinical features and long-term recurrence due to low morbidity and the lack of large cohort studies. Thus, we aimed to develop nomograms to accurately predict the extent of resection and tumor recurrence using clinical parameters. A total of 545 patients diagnosed with CP between 2009 and 2019 were examined: 381 in the development cohort and 164 in the validation cohort. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were performed to establish two nomograms. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA) and Kaplan-Meier (KM) curves were used to evaluate their predictive performance and discriminative power, respectively, in the two cohorts. In addition, the EORTC QLQ-BN20 questionnaire was used to assess neuropsychological status in the follow-up. In the development cohort, the area under the curve (AUC) and C-index were 0.760 and 0.758, respectively, for predicting the extent of resection and 0.78 and 0.75, respectively, for predicting 3-year progression-free survival (PFS) and 5-year PFS. Additionally, the model had a predictive accuracy of 0.785. Both nomograms showed acceptable discrimination in the two cohorts. Moreover, DCA demonstrated excellent clinical benefits from the two nomograms. Finally, participants were classified into two distinct risk groups according to the risk score, and an online calculator was created for convenient clinical use. During long term follow-up, hypothyroidism (77.61%) and hypocortisolism (76.70%) were the most common endocrine dysfunction after surgery and significant deficits were observed concerning visual disorder, motor dysfunction and seizures in the recurrent groups. In particular, better quality of life was associated with gross total resection (GTR), postoperative radiation, anterior interhemispheric (AI) approach and transsphenoidal approach. To our knowledge, these are the first nomograms based on a very large cohort of patients with CP that show potential benefits for guiding treatment decisions and long-term surveillance. The current study demonstrated the online calculator serve as the practical tool for individual strategies based on the patient's baseline characteristics to achieve a better prognosis.

α-Conotoxin Bt1.8 from Conus betulinus selectively inhibits α6/α3ß2ß3 and α3ß2 nicotinic acetylcholine receptor subtypes.

α-Conotoxins are small disulfide-rich peptides found in the venom of marine cone snails and are potent antagonists of nicotinic acetylcholine receptors (nAChRs). They are valuable pharmacological tools and have potential therapeutic applications for the treatment of chronic pain or neurological diseases and disorders. In the present study, we synthesized and functionally characterized a novel α-conotoxin Bt1.8, which was cloned from Conus betulinus. Bt1.8 selectively inhibited ACh-evoked currents in Xenopus oocytes expressing rat(r) α6/α3ß2ß3 and rα3ß2 nAChRs with an IC50 of 2.1 nM and 9.4 nM, respectively, and similar potency for human (h) α6/α3ß2ß3 and hα3ß2 nAChRs. Additionally, Bt1.8 had higher binding affinity with a slower dissociation rate for the rα6/α3ß2ß3 subtype compared to rα3ß2. The amino acid sequence of Bt1.8 is significantly different from other reported α-conotoxins targeting the two nAChR subtypes. Further Alanine scanning analyses demonstrated that residues Ile9, Leu10, Asn11, Asn12 and Asn14 are critical for its inhibitory activity at the α6/α3ß2ß3 and α3ß2 subtypes. Moreover, the NMR structure of Bt1.8 indicated the presence of a relatively larger hydrophobic zone than other α4/7-conotoxins which may explain its potent inhibition at α6/α3ß2ß3 nAChRs.

Sphingosine-1-phosphate receptor 3 is implicated in BBB injury via the CCL2-CCR2 axis following acute intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a catastrophic cerebrovascular disease with high morbidity and mortality. Evidence demonstrated that sphingosine-1-phosphate receptor (S1PR) plays a vital role in inflammatory damage via the upregulation of CCL2 expression. However, whether S1PR3 is involved in blood-brain barrier (BBB) breakdown via CCL2 activation after ICH has not been described. METHODS: We investigated the expression profiles of all S1PRs using high-throughput RNA-seq analysis and RT-PCR. The potential role of S1PR3 and interaction between S1PR3 and CCL2 were evaluated via Western blotting, immunofluorescence, and flow cytometry. BBB disruption was examined via magnetic resonance imaging, transmission electron microscopy, and Evans blue extravasation. Microglial activation, proliferation, and polarization were assessed via histopathological analysis. The expression levels of CCL2, p-p38 MAPK, ICAM-1, and ZO-1 were examined in vitro and in vivo. RESULTS: The present results showed that the levels of S1PR3 and its ligand, sphingosine 1-phosphate (S1P), were dramatically increased following ICH, which regulated the expression of CCL2 and p38MAPK. Moreover, reductions in brain edema volume, amelioration of BBB integrity, and improvements in behavioral deficits were achieved after the administration of CAY10444, an S1PR3 antagonist, to rats. Remarkably increased CCL2, p-p38MAPK, and ICAM-1 expression and decreased ZO-1 expression were observed in cocultured human astrocytes (HAs) and hCMEC/D3 cells after S1P stimulation. However, the expression levels of CCL2, p-p38 MAPK, and ICAM-1 were decreased and ZO-1 expression was increased after S1PR3 inhibition. In addition, microglial proliferation and M1 polarization were attenuated after CAY10444 administration. CONCLUSION: To the best of our knowledge, this is the first demonstration of the neuroprotective role of S1PR3 modulation in maintaining BBB integrity by inhibiting the S1PR3-CCL2 axis after ICH, providing a novel treatment for ICH by targeting S1PR3.

Identification and Characterization of TF-lncRNA Regulatory Networks Involved in the Tumorigenesis and Development of Adamantinomatous Craniopharyngioma.

Craniopharyngiomas (CPs) are rare tumors arising from the sellar region. Although the best outcome for patients with one subtype, adamantinomatous craniopharyngioma (ACP), is obtained by gross total resection, little is known about the roles of long noncoding RNAs (lncRNAs) and transcription factors (TFs) in ACP tumorigenesis. In total, 12 human ACP and 5 control samples were subjected to transcriptome-level sequencing. We built an integrated algorithm for identifying lncRNAs and TFs regulating the CP-related pathway. Furthermore, ChIP-Seq datasets with binding domain information were used to further verify and identify TF-lncRNA correlations. RT-PCR and immunohistochemistry staining were performed to validate the potential targets. Five pathways associated with ACP were identified and defined by an extensive literature search. Based on the specific pathways and the whole gene expression profile, 266 ACP-related lncRNAs and 39 TFs were identified by our integrating algorithm. Comprehensive analysis of the ChIP-Seq datasets revealed that 29 TFs were targeted by 12000 lncRNAs in a wide range of tissues, including 161 ACP-related lncRNAs that were identified by the computational method. These 29 TFs and 161 lncRNAs, constituting 1004 TF-lncRNA pairs, were shown to potentially regulate different ACP-related pathways. A total of 232 TF-lncRNA networks were consequently established based on differential gene expression. Validation by RT-PCR and immunohistochemistry staining revealed positive expression of the ACP-related TFs E2F2 and KLF5 in ACP. Moreover, the expression of the lncRNA RP11-360P21.2 was shown to be upregulated in ACP tissues. In this study, we introduced an integrated algorithm for identifying lncRNAs and TFs regulating the ACP-related pathway. This is the first comprehensive study to systematically investigate the potential TF and lncRNA regulatory network in ACP. The resulting data serve as a valuable resource for understanding the mechanisms underlying ACP-related lncRNAs and TFs.

PKM2 Promotes Breast Cancer Progression by Regulating Epithelial Mesenchymal Transition.

Breast cancer is the leading cause of females characterized by high invasive potential. It is necessary to explore the underlying mechanism of breast cancer metastases and to find specific therapeutic targets. PKM2 is considered a new biomarker of cancer with upregulated expression in tumor tissue. PKM2 participates in the cancer-specific Warburg effect to regulate fast glucose intake consumption. Besides, PKM2 also contributes to cancer progression, especially tumor metastasis. In this study, we showed that PKM2 is upregulated in breast cancer tissues and the upregulating of PKM2 in breast cancer correlates with poor prognosis. PKM2 can regulate tumor progression by promoting tumor cell viability and mobility. Furthermore, overexpression of PKM2 can promote EMT to encourage tumor metastasis. These findings indicate PKM2 is a potentially useful diagnostic biomarker and therapeutic target in breast cancer.

Primary mucinous cystadenocarcinoma of the breast: a clinicopathologic analysis of one case and review of the literature.

OBJECTIVE: To explore the clinicopathologic features and differential diagnosis of breast primary mucinous cystadenocarcinoma (MCA). METHODS: Pathological characteristics and immunophenotype of one case of MCA were analyzed. Literature was reviewed. RESULTS: Grossly, the area of the tumor cut surface was gelationous. Microscopcally, the tumor was composed of variably sized cystic spaces lined by mucus-rich tumor cells with single columnar, stratified appearance and papillary formation. The degree of cytologic atypia varied from region to region. The tumor cells were positive for CK7, GATA3, negative for CK20, ER, PR and HER2. Most peripheral myoepithelial cells were negative for P63 and SMMHC. CONCLUSIONS: MCA is a rare primary breast cancer and strikingly similar to ovarian, pancreatic and gastrointestinal counterparts. The diagnosis cannot be made until the metastatic lesion is ruled out. On the other hand, the biologic behavior of MCA is reportedly favorable despite a high proliferation index and triple negative biomarker status. Therefore, the role of adjuvant chemotherapy or radiation is questionable.

Fetal Dermal Mesenchymal Stem Cell-Derived Exosomes Accelerate Cutaneous Wound Healing by Activating Notch Signaling.

Fetal dermal mesenchymal stem cells (FDMSCs), isolated from fetal skin, are serving as a novel MSC candidate with great potential in regenerative medicine. More recently, the paracrine actions, especially MSC-derived exosomes, are being focused on the vital role in MSC-based cellular therapy. This study was to evaluate the therapeutic potential of exosomes secreted by FDMSCs in normal wound healing. First, the in vivo study indicated that FDMSC exosomes could accelerate wound closure in a mouse full-thickness skin wound model. Then, we investigated the role of FDMSC-derived exosomes on adult dermal fibroblast (ADFs). The results demonstrated that FDMSC exosomes could induce the proliferation, migration, and secretion of ADFs. We discovered that after treatment of exosomes, the Notch signaling pathway was activated. Then, we found that in FDMSC exosomes, the ligands of the Notch pathway were undetectable expect for Jagged 1, and the results of Jagged 1 mimic by peptide and knockdown by siRNA suggested that Jagged 1 may lead the activation of the Notch signal in ADFs. Collectively, our findings indicated that the FDMSC exosomes may promote wound healing by activating the ADF cell motility and secretion ability via the Notch signaling pathway, providing new aspects for the therapeutic strategy of FDMSC-derived exosomes for the treatment of skin wounds.

Heat treatment to improve the wear resistance of PTFE/PMMA composites.

Polytetrafluoroethylene/poly(methyl methacrylate) (PTFE/PMMA) composites were prepared by a self-curing method. The influence of heat treatment processes on the friction and wear behaviors of PTFE/PMMA composites against bearing steel balls were studied by a ball-on-disk tribometer. The thermal performance of PTFE/PMMA composites with heat treatment was analyzed by Thermogravimetric Analysis (TGA). The surface morphologies and element distribution of PTFE/PMMA composites in a PMMA matrix were detected by Field Emission Scanning Electron Microscopy (FE-SEM) and Energy Dispersive Spectroscopy (EDS). The results indicated that the wear rates of PTFE/PMMA composites with different heat treatments significantly declined compared with the unheated treatment composite. The wear rate of the PTFE/PMMA composite decreased firstly and then increased with molding temperature and time increasing, and reduced with the molding pressure increasing. The main wear mechanisms of PTFE/PMMA composites with different heat treatments were fatigue wear and abrasive wear.

Interleukin 17 (IL-17)-Induced Mesenchymal Stem Cells Prolong the Survival of Allogeneic Skin Grafts.

BACKGROUND Mesenchymal stem cells (MSCs) have the potential of self-renewal and multi-differentiation and have a wide application prospect in organ transplantation for the effect of inducing immune tolerance. It has found that interleukin 17 (IL-17) could enhance the inhibition effect of MSCs on T cell proliferation and increase the immunosuppressive effect of MSCs. In this study, we aimed to investigate the effect of IL-17-induced MSCs on allograft survival time after transplantation. MATERIAL AND METHODS BMSCs were characterized by differential staining. The allogenic skin transplantations were performed and the BMSCs pre-treated by IL-17 were injected. To assess the immunosuppressive function of IL-17-induced BMSCs, the morphology of the grafts, the homing ability of the BMSCs, and the survival time of the grafts were analyzed. RESULTS BMSCs from BALB/c have multidirectional differentiation potential to differentiate into osteogenic, chondrogenic, and adipogenic lineage cells. IL-17-induced BMSCs prolonged the survival time of allogeneic skin grafts dramatically. We found that there were more labeled MSCs in the skin grafts, and the Treg subpopulations percentage, IL-10, and TGF-ß were significantly increased, while the IFN-γ level was decreased compared to the control group and MSCs group. In conclusion, IL-17 can enhance the homing ability of MSCs and regulate the immunosuppressive function of MSC. CONCLUSIONS Our data demonstrate that IL-17 plays the crucial role in MSC homing behaviors and promotes immunosuppression of MSCs during transplantation procedures, suggesting that IL-17-pre-treated MSCs have potential to prolong graft survival and reduce transplant rejection.

Cloning, Synthesis and Functional Characterization of a Novel α-Conotoxin Lt1.3.

α-Conotoxins (α-CTxs) are small peptides composed of 11 to 20 amino acid residues with two disulfide bridges. Most of them potently and selectively target nicotinic acetylcholine receptor (nAChR) subtypes, and a few were found to inhibit the GABAB receptor (GABABR)-coupled N-type calcium channels (Cav2.2). However, in all of α-CTxs targeting both receptors, the disulfide connectivity arrangement "C¹-C³, C²-C4" is present. In this work, a novel α4/7-CTx named Lt1.3 (GCCSHPACSGNNPYFC-NH2) was cloned from the venom ducts of Conus litteratus (C. litteratus) in the South China Sea. Lt1.3 was then chemically synthesized and two isomers with disulfide bridges "C¹-C³, C²-C4" and "C¹-C4, C²-C³" were found and functionally characterized. Electrophysiological experiments showed that Lt1.3 containing the common disulfide bridges "C¹-C³, C²-C4" potently and selectively inhibited α3ß2 nAChRs and not GABABR-coupled Cav2.2. Surprisingly, but the isomer with the disulfide bridges "C¹-C4, C²-C³" showed exactly the opposite inhibitory activity, inhibiting only GABABR-coupled Cav2.2 and not α3ß2 nAChRs. These findings expand the knowledge of the targets and selectivity of α-CTxs and provide a new structural motif to inhibit the GABABR-coupled Cav2.2.

Significant Reduction of the Friction and Wear of PMMA Based Composite by Filling with PTFE.

Polytetrafluoroethylene/Poly(methyl methacrylate) (PTFE/PMMA) composite was prepared by mixing PTFE into PMMA matrix which synthesized by the PMMA powder mixture and methyl methacrylate (MMA) liquid mixture. The effects of the filling mass ratio of PTFE and powder/liquid (P/L) ratio on the friction and wear properties of PTFE/PMMA composites against bearing steel were studied by a ball-on-disk tribometer. Fourier transform infrared (FTIR), field emission scanning electron microscopy (FESEM), and energy dispersive X-ray spectroscopy (EDS) were used to characterize the synthesis of PTFE/PMMA composite. The shore hardness and glass transition temperature (Tg) were obtained respectively by shore hardness tester and differential scanning calorimetry (DSC). The results show that the friction coefficient and wear rate of PMMA based composite, comparing with the unfilled PMMA, can be significantly reduced by filling with PTFE. With the increasing of PTFE filling mass ratio, the wear rate of PTFE/PMMA composite increases. The friction coefficient and wear rate of the unfilled PMMA and PTFE/PMMA composite generally decrease with the P/L ratio increasing. The main wear mechanism of the unfilled PMMA is adhesive wear. While the main wear mechanisms of PTFE/PMMA composites are fatigue wear and abrasive wear.