Combined therapy of dabrafenib and an anti-HER2 antibody-drug conjugate for advanced BRAF-mutant melanoma.

BACKGROUND: Melanoma is the most lethal skin cancer characterized by its high metastatic potential. In the past decade, targeted and immunotherapy have brought revolutionary survival benefits to patients with advanced and metastatic melanoma, but these treatment responses are also heterogeneous and/or do not achieve durable responses. Therefore, novel therapeutic strategies for improving outcomes remain an unmet clinical need. The aim of this study was to evaluate the therapeutic potential and underlying molecular mechanisms of RC48, a novel HER2-target antibody drug conjugate, either alone or in combination with dabrafenib, a V600-mutant BRAF inhibitor, for the treatment of advanced BRAF-mutant cutaneous melanoma. METHODS: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy. RESULTS: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway. CONCLUSION: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.

PIVKA-II combined with alpha-fetoprotein for the diagnostic value of hepatic tumors in children: a multicenter, prospective observational study.

BACKGROUND: To investigate whether protein induced by vitamin K antagonist-II (PIVKA-II) combined with alpha-fetoprotein (AFP) can improve the diagnostic and differential diagnostic accuracy of childhood hepatic tumors. METHODS: A multi-center prospective observational study was performed at nine regional institutions around China. Children with hepatic mass (Group T) were divided into hepatoblastoma group (Group THB) and hemangioendothelioma group (Group THE), children with extrahepatic abdominal mass (Group C). Peripheral blood was collected from each patient prior to surgery or chemotherapy. The area under the curve (AUROC) was used to evaluate the diagnostic efficiency of PIVKA-II and the combined tumor markers with AFP. RESULTS: The mean levels of PIVKA-II and AFP were both significantly higher in Group T than Group C (p = 0.001, p < 0.001), in Group THB than Group THE (p = 0.018, p = 0.013) and in advanced HB than non-advanced HB (p = 0.001, p = 0.021). For the diagnosis of childhood hepatic tumors, AUROC of PIVKA-II (cut-off value 32.6 mAU/mL) and AFP (cut-off value 120 ng/mL) was 0.867 and 0.857. The differential diagnostic value of PIVKA-II and AFP in hepatoblastoma from hemangioendothelioma was further assessed, AUROC of PIVKA-II (cut-off value 47.1mAU/mL) and AFP (cut-off value 560 ng/mL) was 0.876 and 0.743. The combined markers showed higher AUROC (0.891, 0.895 respectively) than PIVKA-II or AFP alone. CONCLUSIONS: The serum level of PIVKA-II was significantly higher in children with hepatic tumors, especially those with malignant tumors. The combination of PIVKA-II with AFP further increased the diagnostic performance. TRIAL REGISTRATION: Clinical Trials, NCT03645655. Registered 20 August 2018, https://www. CLINICALTRIALS: gov/ct2/show/NCT03645655 .

Combined inhibition of HER2 and VEGFR synergistically improves therapeutic efficacy via PI3K-AKT pathway in advanced ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is a prevalent malignancy in the female reproductive system, and developing effective targeted therapies for this disease remains challenging. The aim of this study was to use clinically-relevant OC models to evaluate the therapeutic effectiveness of RC48, an antibody-drug conjugate (ADC) targeting HER2, either alone or in combination with the VEGFR inhibitor Cediranib Maleate (CM), for the treatment of advanced OC. METHODS: OC tumor specimens and cell lines were analyzed to determine HER2 and VEGFR expression by Western blot, immunocytochemistry and immunofluorescence. Moreover, the OC cell lines, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were treated with RC48 and/or CM and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for OC both in vitro and in vivo. Additionally, RNA-Seq was performed to investigate the critical mechanism underlying the combination therapy of RC48 and CM. RESULTS: Our results demonstrated that RC48 alone effectively targeted and inhibited the growth of HER2-positive OC tumors in both cell lines and PDX models. Furthermore, the combination of RC48 and CM synergistically induced tumor regression in human OC cell lines, as well as CDX and PDX models. Mechanistically, we observed that the combination treatment inhibited the growth of OC cells involved inducing apoptosis and suppressing cell motility. RNA-seq analysis provided further mechanistic insights and revealed that co-administration of RC48 and CM downregulated multiple cancer-related pathways, including the AKT/mTOR pathway, cell cycle, and cell proliferation. Notably, our data further confirmed that the PI3K-AKT pathway played a key role in the inhibition of proliferation triggered by combinational treatment of RC48 and CM in OC cells. CONCLUSIONS: These findings provide a preclinical framework supporting the potential of dual targeting HER2 and VEGFR as a promising therapeutic strategy to improve outcomes in patients with OC.

Prognosis signature for predicting the survival and immunotherapy response in esophageal carcinoma based on cellular senescence-related genes.

Background: Cellular senescence occurs throughout life and can play beneficial roles in a variety of physiological processes, including embryonic development, tissue repair, and tumor suppression. However, the relationship between cellular senescence-related genes (CSRGs) and immunotherapy in esophageal carcinoma (ECa) remains poorly defined. Methods: The data set used in the analysis was retrieved from TCGA (Research Resource Identifier (RRID): SCR_003193), GEO (RRID: SCR_005012), and CellAge databases. Data processing, statistical analysis, and diagram formation were conducted in R software (RRID: SCR_001905) and GraphPad Prism (RRID: SCR_002798). Based on CSRGs, we used the TCGA database to construct a prognostic signature for ECa and then validated it in the GEO database. The predictive efficiency of the signature was evaluated using receiver operating characteristic (ROC) curves, Cox regression analysis, nomogram, and calibration curves. According to the median risk score derived from CSRGs, patients with ECa were divided into high- and low-risk groups. Immune infiltration and immunotherapy were also analyzed between the two risk groups. Finally, the hub genes of the differences between the two risk groups were identified by the STRING (RRID: SCR_005223) database and Cytoscape (RRID: SCR_003032) software. Results: A six-gene risk signature (DEK, RUNX1, SMARCA4, SREBF1, TERT, and TOP1) was constructed in the TCGA database. Patients in the high-risk group had a worse overall survival (OS) was disclosed by survival analysis. As expected, the signature presented equally prognostic significance in the GSE53624 cohort. Next, the Area Under ROC Curve (AUC=0.854) and multivariate Cox regression analysis (HR=3.381, 2.073-5.514, P<0.001) also proved that the risk signature has a high predictive ability. Furthermore, we can more accurately predict the prognosis of patients with ECa by nomogram constructed by risk score. The result of the TIDE algorithm showed that ECa patients in the high-risk group had a greater possibility of immune escape. At last, a total of ten hub genes (APOA1, MUC5AC, GC, APOA4, AMBP, FABP1, APOA2, SOX2, MUC8, MUC17) between two risk groups with the highest interaction degrees were identified. By further analysis, four hub genes (APOA4, AMBP, FABP1, and APOA2) were related to the survival differences of ECa. Conclusions: Our study reveals comprehensive clues that a novel signature based on CSRGs may provide reliable prognosis prediction and insight into new therapy for patients with ECa.

Yttrium chloride induces ferroptosis in cardiomyocytes via iron accumulation and triggers cardiac lipid peroxidation and inflammation that cause heart adverse events in mice.

The growing presence of yttrium (Y) in the environment raises concern regarding its safety and toxicity. However, limited toxicological data are available to determine cardiotoxicity of Y and its underlying mechanisms. In the present study, yttrium chloride (YCl3) intervention with different doses was performed in male Kunming mice for the toxicological evaluation of Y in the heart. After 28 days of intragastric administration, 500 mg/kg·bw YCl3 induces iron accumulation in cardiomyocytes, and triggers ferroptosis through the glutathione peroxidase 4 (GPX4)/glutathione (GSH)/system Xc- axis via the inhibition of Nrf2 signaling pathway. This process led to cardiac lipid peroxidation and inflammatory response. Further RNA sequencing transcriptome analysis found that many genes involved in ferroptosis and lipid metabolism-related pathways were enriched. The ferroptosis induced by YCl3 in cardiomyocytes ultimately caused cardiac injury and dysfunction in mice. Our findings assist in the elucidation of the potential subacute cardiotoxicity of Y3+ and its underlying mechanisms.

Expert consensus on the clinical application of totally implantable venous access devices in the upper arm (2022 Edition).

With the widespread adoption of ultrasound guidance, Seldinger puncture techniques, and intracardiac electrical positioning technology for the placement of peripherally inserted central catheters in recent years, an increasing number of medical staff and patients now accept peripheral placement of totally implantable venous access devices (TIVADs) in the upper arm. This approach has the advantage of completely avoiding the risks of hemothorax, pneumothorax, and neck and chest scarring. Medical specialties presently engaged in this study in China include internal medicine, surgery, anesthesiology, and interventional departments. However, command over implantation techniques, treatment of complications, and proper use and maintenance of TIVAD remain uneven among different medical units. Moreover, currently, there are no established quality control standards for implantation techniques or specifications for handling complications. Thus, this expert consensus is proposed to improve the success rate of TIVAD implantation via the upper-arm approach, reduce complication rates, and ensure patient safety. This consensus elaborates on the technical indications and contraindications, procedures and technical points, treatment of complications, and the use and maintenance of upper-arm TIVAD, thus providing a practical reference for medical staff.

Precise diagnosis and targeted therapy of nodal T-follicular helper cell lymphoma (T-FHCL).

Nodal T-follicular helper cell lymphoma (T-FHCL) derived from T-follicular helper (Tfh) cell falls into a heterogeneous category of peripheral T-cell lymphoma (PTCL). Due to the limited number of therapeutic regimens and limited first-line efficacy, T-FHCL has a poor prognosis, and there is an urgent need for effective targeted therapies. With advancements in sequencing technologies, especially single-cell sequencing and next-generation sequencing, more specific genetic aberrations characteristic of T-FHCL can be discovered, allowing for precise molecular diagnosis and specific research on novel agents. Many biomarker-targeting agents, used either alone or in combination, have been tested, and they have generally enhanced the therapeutic outcomes of T-FHCL. Histone deacetylase inhibitors achieve significant clinical benefits in the treatment of T-FHCL, especially in combination therapy. Chimeric antigen receptor T-cell (CAR-T-cell) immunotherapies, hematopoietic stem cell transplantation, and other potential agents merit further study.

Therapeutic efficacy of a MMAE-based anti-DR5 drug conjugate Oba01 in preclinical models of pancreatic cancer.

Pancreatic cancer (PC) is among the most aggressive malignancies associated with a 5-year survival rate of <9%, and the treatment options remain limited. Antibody-drug conjugates (ADCs) are a new class of anticancer agents with superior efficacy and safety profiles. We studied the antitumor activity of Oba01 ADC and the mechanism underlying the targeting of death receptor 5 (DR5) in preclinical PC models. Our data revealed that DR5 was highly expressed on the plasma membrane of PC cells and Oba01 showed potent in vitro antitumor activity in a panel of human DR5-positive PC cell lines. DR5 was readily cleaved by lysosomal proteases after receptor-mediated internalization. Monomethyl auristatin E (MMAE) was then released into the cytosol to induce G2/M-phase growth arrest, cell death via apoptosis induction, and the bystander effect. Furthermore, Oba01 mediated cell death via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. For improved potency, we investigated the synergetic effect of Oba01 in combination with approved drugs. Oba01 combined with gemcitabine showed better antiproliferative activity than either standalone treatment. In cell- and patient-derived xenografts, Oba01 showed excellent tumoricidal activity in mono- or combinational therapy. Thus, Oba01 may provide a novel biotherapeutic approach and a scientific basis for clinical trials in DR5-expressing patients with PC.

Spatial Transcriptomics Analysis Reveals that CCL17 and CCL22 are Robust Indicators of a Suppressive Immune Environment in Angioimmunoblastic T Cell Lymphoma (AITL).

BACKGROUND: T cell lymphoma is a complex and highly aggressive clinicopathological entity with a poor outcome. The angioimmunoblastic T-cell lymphoma (AITL) tumor immune microenvironment is poorly investigated. METHODS: Here, to the best of our knowledge, spatial transcriptomics was applied for the first time to study AITL. RESULTS: Using this method, we observed that AITL was surrounded by cells bearing immune-suppressive markers. CCL17 and CCL22, the dominant ligands for CCR4, were up-regulated, while the expression of natural killer (NK) cell and CD8+ cytotoxic T lymphocyte (CTL) markers decreased. Colocalization of Treg cells with the CD4+ TFH-GC region was also deduced from the bioinformatic analysis. The results obtained with spatial transcriptomics confirm that AITL has a suppressive immune environment. Chemotherapy based on the CHOP regimen (cyclophosphamide, doxorubicin, vincristine plus prednisone) induced complete remission (CR) in this AITL patient. However, the duration of remission (DoR) remains a concern. CONCLUSIONS: This study demonstrates that AITL has an immune suppressive environment and suggests that anti-CCR4 therapy could be a promising treatment for this lethal disease.

A computational method for large-scale identification of esophageal cancer-related genes.

The incidence of esophageal cancer has obvious genetic susceptibility. Identifying esophageal cancer-related genes plays a huge role in the prevention and treatment of esophageal cancer. Through various sequencing methods, researchers have found only a small number of genes associated with esophageal cancer. In order to improve the efficiency of esophageal cancer genetic susceptibility research, this paper proposes a method for large-scale identification of esophageal cancer-related genes by computational methods. In order to improve the efficiency of esophageal cancer genetic susceptibility research, this paper proposes a method for large-scale identification of esophageal cancer-related genes by computational methods. This method fuses graph convolutional network and logical matrix factorization to effectively identify esophageal cancer-related genes through the association between genes. We call this method GCNLMF which achieved AUC as 0.927 and AUPR as 0.86. Compared with other five methods, GCNLMF performed best. We conducted a case study of the top three predicted genes. Although the association of these three genes with esophageal cancer has not been reported in the database, studies by other reseachers have shown that these three genes are significantly associated with esophageal cancer, which illustrates the accuracy of the prediction results of GCNLMF.

Combining clinical examination with exome sequencing for the diagnosis and treatment of Marfan syndrome: a case series of 6 families from China.

BACKGROUND: Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder. Diagnosing MFS can be challenging as the disease's severity and clinical manifestations differ between pathogenic variants, and because a lack of published information currently exists on phenotype-genotype correlations. This report aims to underline the clinical manifestations associated with fibrillin-1 (FBN1) gene mutations by assessing MFS in 6 families from China. METHODS: We diagnosed 6 patients and their relatives with MFS by combining a clinical examination (based on the 2010 revised Ghent nosology criteria) with a targeted next-generation sequencing analysis. The functional analysis of the causal mutations and clinical details of the affected patients were then assessed. RESULTS: We identified 6 pathogenic mutations in FBN1, including 1 novel frameshift, 1 nonsense, and 4 missense mutations. Most uniquely, mitral valve prolapses (MVP) and ectopia lentis (EL) were found in the cysteine-related mutations. Typically, facial symptoms of MFS are observed in frameshift or nonsense mutants, not in cysteine-related ones. Furthermore, the patients with premature terminal codons had a more serious skin condition than patients with missense mutations, partly indicating the important effect FBN1 has on skin. CONCLUSIONS: This study expands the mutation spectrum of MFS and highlights possible genotype-phenotype correlations, thereby improving the early diagnosis and symptomatic treatment of the disease.

17ß-Estradiol Protects Neural Stem/Progenitor Cells Against Ketamine-Induced Injury Through Estrogen Receptor ß Pathway.

Ketamine inhibits neural stem/progenitor cell (NSPC) proliferation and disrupts normal neurogenesis in the developing brain. 17ß-Estradiol alleviates neurogenesis damage and enhances behavioral performance after ketamine administration. However, the receptor pathway of 17ß-estradiol that protects NSPCs from ketamine-induced injury remains unknown. In the present study, we investigated the role of estrogen receptor α (ER-α) and estrogen receptor ß (ER-ß) in 17ß-estradiol's protection against ketamine-exposed NSPCs and explored its potential mechanism. The primary cultured NSPCs were identified by immunofluorescence and then treated with ketamine and varying doses of ER-α agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) or ER-ß agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) for 24 h. NSPC proliferation was analyzed by 5-bromo-2-deoxyuridine incorporation test. The expression of phosphorylated glycogen synthase kinase-3ß (p-GSK-3ß) was quantified by western blotting. It was found that treatment with different concentrations of PPT did not alter the inhibition of ketamine on NSPC proliferation. However, treatment with DPN attenuated the inhibition of ketamine on NSPC proliferation at 24 h after their exposure (P < 0.05). Furthermore, treatment with DPN increased p-GSK-3ß expression in NSPCs exposed to ketamine. These findings indicated that ER-ß mediates probably the protective effects of 17ß-estradiol on ketamine-damaged NSPC proliferation and GSK-3ß is involved in this process.

Wilms' Tumor and Benign Renal Tumor Combined With Hypospadias and Incomplete Orchiocatabasis Appearing Simultaneously in a 10 Months Old Boy.

We herein report a case of left renal Wilms' tumor and right renal hamartoma combined with hypospadias and incomplete orchiocatabasis in a 10-month-old boy. In the literature to date, no case has been reported. The preoperative abdominal computerized tomography (CT) scan was suggestive of bilateral nephroblastomas, and clinical diagnosis was bilateral renal tumors with external genitals malformation, a syndrome? Finally, this case was used by B-ultrasonic guided percutaneous biopsy to help determine the nature of bilateral renal tumors. Afterwards, the boy underwent preoperative chemotherapy, surgery ( a left radical nephrectomy and right wedge excision of the renal tumor) and postoperative chemotherapy. After 3 years of follow-up, there was no evidence of tumor recurrence, the renal function was normal, and the boy's height, weight and intelligence were also within normal range. Owing to no similar cases as a reference, we discussed the preoperative imaging diagnosis, final etiological diagnosis and appropriate treatment of this disease. Long-term follow-up with a sufficient number of cases may be needed to optimize methods of diagnosis and define optimal treatment options for patients with this extremely rare disease.

MiR-141-3p functions as a tumor suppressor through directly targeting ZFR in non-small cell lung cancer.

MicroRNAs are important regulators in the development and progression of non-small cell lung cancer (NSCLC). MiR-141-3p has been reported to function as a suppressor or oncogene in several tumors, but the clinical significance and crucial biological functions of miR-141-3p in NSCLC remains largely unclear. In this study, expression levels of miR-141-3p in tissue samples were measured by quantitative real-time polymerase chain reaction. Kaplan-Meier survival analysis and Cox regression assay were performed to evaluate the prognostic value of miR-141-3p. Cell experiments, including CCK-8, colony formation and transwell assays were carried out to explore its functional role. Luciferase reporter assay was used to confirm its target gene. The results showed that miR-141-3p was significantly down-regulated in NSCLC tissues compared with adjacent normal tissues. The decreased miR-141-3p expression was associated with advanced TNM stage and lymph-node metastasis. Patients with low miR-141-3p expression had poor overall survival compared with those with high expression. Down-regulation of miR-141-3p was demonstrated to be an independent prognostic factor for NSCLC. Moreover, ZFR was confirmed as a target gene of miR-141-3p. Meta-analysis based on Oncomine database showed ZFR was significantly up-regulated in human NSCLC tissues. The in vitro experiments showed that restoration of ZFR rescued the miR-141-3p-mediated inhibitory effects on cell proliferation, migration and invasion in NSCLC cells. In conclusions, miR-141-3p might be a prognostic tumor suppressor involved in the NSCLC progression.

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats.

BACKGROUND/AIMS: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats. METHODS: Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3ß both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult. RESULTS: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3ß both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro. CONCLUSION: We for the first time showed that simvastatin, by upregulating Akt/GSK-3ß signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.

Multidisciplinary effort in treating children with hepatoblastoma in China.

The purpose of this study is to report the first nationwide protocol (Wuhan Protocol) developed by Chinese Children's Cancer Group and the results of multidisciplinary effort in treating hepatoblastoma. In this study, we reported the final analysis, which includes 153 hepatoblastoma patients in 13 hospitals from January 2006 to December 2013. The 6-year overall survival and event-free survival rates were 83.3 ± 3.1% and 71.0 ± 3.7%, respectively, in this cohort. The univariate analysis revealed that female (P = 0.027), under 5 years of age (P = 0.039), complete surgical resection (P = 0.000), no metastases (P = 0.000), and delayed surgery following neoadjuvant chemotherapy (P = 0.000) had better prognosis. In multivariate analysis, male, 5 years of age or above, stage PRETEXT III or IV, and incomplete surgical resection were among the some adverse factors contributing to poor prognosis. The preliminary results from this study showed that patients who underwent treatment following Wuhan Protocol had similar OS and EFS rates compared to those in developed countries. However, the protocol remains to be further optimized in standardizing surgical resection (including liver transplantation), refining risk stratification and risk-based chemotherapy.

Low-grade myxofibrosarcoma following a metal implantation in femur: a case report.

Myxofibrosarcoma is a myxoid variant of malignant fibrous histiocytoma that most commonly involves the extremities of elderly people. However, a primary myxofibrosarcoma with bone invasion in young adults is extremely rare. Herein, we report the case of a 31-year-old male with a gradually enlarging left thigh mass, who had a history of left femur fracture and received an open reduction and internal fixation with titanium alloy plates and screws 33 months previously. Imaging investigations revealed an irregularly shaped soft tissue mass around the left femur shaft and a partial bone defect in the middle one-third of the left femur. Pathological examination of the resected specimen showed a multi-nodular appearance, abundant myxoid matrix and elongated curvilinear capillaries. Immunohistochemical studies revealed that the tumor cells was positive for VIM and MDM2, and was negative for CK, MSA, SMA, DES, S-100 and CD34. Labeling index of Ki-67 was 25%. Based on the morphological finding and immunostaining, it was diagnosed as a low-grade myxofibrosarcoma. The clinical and imaging examinations did not reveal the evidence of a primary cancer elsewhere, and the patient had no personal or family history of malignancy. To our knowledge, this is the first case of a primary myxofibrosarcoma developed following a fracture and metal implantation in young adults. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1745984882113605.

[Research development of amniotic fluid-derived stem cells in regenerative medicine].

OBJECTIVE: To review the latest development of amniotic fluid-derived stem cells (AFSCs) in regenerative medicine, and to discuss issues related to the studies in the field of AFSCs. METHODS: The recent articles about AFSCs were extensively reviewed. The important knowledge of AFSCs was introduced in the field of regenerative medicine, and the basic and clinical researches of AFSCs were summarized and discussed. RESULTS: Currently, it is confirmed that AFSCs have a multi-directional differentiation capacity, therefore, they have a wide application prospect in regenerative medicine, anti-tumor, and other fields. CONCLUSION: AFSCs will become one of the ideal seed cells in the field of regenerative medicine with extensive research value because of the advantages of easy amniotic fluid sampling, little maternal and child trauma, no tumorigenesis, and no ethical restrictions.

[Culture and identification of neural stem cells from mouse embryos].

OBJECTIVE: The purpose of this study was to culture and identify neural stem cells from mouse embryos in vitro using a modified method and provide a basis for further study of the biology of neural stem cells under hypoxia. METHODS: The cells were isolated mechanically from the front cortex of fetal Institute of Cancer Research (ICR) mice on embryonic day 14. They were passaged by mechanical dissociation and enzymatic digestion. The neurospheres were identified by immunofluorescent staining of nestin. Cell differentiation was induced by 1% fetal bovine serum and then the cells were identified by immunohistochemistry of ß-tubulin III and GFAP. RESULTS: The cells obtained from the front cortex of fetal ICR mice had the capacity of forming neurospheres which showed nestin immunoreactive positivity. After being induced by 1% fetal bovine serum, the cells were differentiated into ß-tubulin III-positive cells and GFAP-positive cells. CONCLUSIONS: Using mechanical dissociation of primary cells and mechanical dissociation with enzymatic digestion of primary cells, the NSCs from the front cortex of mouse embryos can be obtained.

Human embryonic neural stem cell transplantation increases subventricular zone cell proliferation and promotes peri-infarct angiogenesis after focal cerebral ischemia.

Neurogenesis and angiogenesis are two important processes that may contribute to the repair of brain injury after stroke. This study was designed to investigate whether transplantation of human embryonic neural stem cells (NSCs) into cortical peri-infarction 24h after ischemia effects cell proliferation in the subventricular zone (SVZ) and angiogenesis in the peri-infarct zone. NSCs were prepared from embryonic human brains at 8 weeks gestation. Focal cerebral ischemia was induced by permanent occlusion of the middle cerebral artery of adult rats. Animals were randomly divided into two groups (n=30, each) at 24h after ischemia: NSC-grafted and medium-grafted groups. Toluidine blue staining and 5'-bromo-2'-deoxyuridine (BrdU) or von Willebrand factor (vWF) immunohistochemistry were performed at 7, 14 and 28 days after transplantation. NSC transplantation increased the number of BrdU-positive cells in the ischemic ipsilateral SVZ compared with the medium control at 7 days (P<0.01). This difference in SVZ cell proliferation persisted at 14 days (P<0.01), but was not significant at 28 days (P>0.05). In addition, angiogenesis, as indicated by BrdU and vWF staining in cortical peri-infarct regions, was augmented by 46% and 65% in NSC-grafted rats versus medium-grafted rats at 7 and 14 days, respectively (P<0.05). However, this increase became non-significant at 28 days (P>0.05). Our results indicate that NSC transplantation enhances endogenous cell proliferation in the SVZ and promotes angiogenesis in the peri-infarct zone, even if it is performed in the acute phase of ischemic injury.