Comprehensive understanding of glioblastoma molecular phenotypes:classification,characteristics,and transition

Among central nervous system-associated malignancies,glioblastoma(GBM)is the most common and has the highest mortality rate.The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide.In precision medicine,research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity,as well as the refractory nature of GBM toward therapy.Deep understanding of the different molecular expression patterns of GBM subtypes is critical.Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes.The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors.These subtypes also exhibit high plasticity in their regulatory pathways,oncogene expression,tumor microenvironment alterations,and differential responses to standard therapy.Herein,we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype.Furthermore,we review the mesenchymal transition mechanisms of GBM under various regulators.

Molecular phenotypes reveal heterogeneous engraftments of patient-derived hepatocellular carcinoma xenografts

Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.

Intertumoral heterogeneity of molecular phenotype and analysis of prognosis in multifocal and multicentric breast cancer

Objective This study was designed to investigate the prognostic implications of the intertumoral heterogeneity of molecular phenotype in multifocal and multicentric breast cancer(MMBC).Methods The clinical and follow-up data of 146 patients with MMBC from Jan.2009to Dec.2009 treated in Tumor Hospital Affiliated to Zhengzhou University were retrospectively analyzed.

Phenotypic and Molecular Characterization of Staphylococcaceae and Enterobacteriaceae Species Isolated from Smoked, Dried, and Braised Fish Marketed in Ouagadougou

Background: To preserve its nutritional properties, fish must have good sanitary quality. The objective of this study was to investigate some pathogens contaminating smoked, dried, and braised fish marketed in Ouagadougou. Methodology: Potential pathogens of Enterobacteriaceae and Staphylococcus were screened in eight (8) species of processed fish. The investigation of the germs was carried out following the normative methods of microbiology. The identities of the strains were determined by API 20 E (BioMerieux S.A., France) and API STAPH (BioMerieux S.A., France) kits for Enterobacteriaceae and Staphylococcus species respectively. The uidA gene profile in Escherichia coli isolates was determined by simplex PCR. The identity of Staphylococcus aureus was confirmed by amplification of specific 23S rDNA regions and nuc gene profile with PCR. Results: A total of 235 fish samples were analyzed. A diversity of Enterobacteriaceae and Staphylococcus was detected. Twenty species of Enterobacteriaceae were identified among which, the most frequent were Escherichia coli, Salmonella sp, Raoultella ornithinolytica and Serratia odorifera, respectively in 22.6%, 4.3%, 28.9%, 17.4% of the samples analyzed. However, eleven species of Staphylococcus were identified among which, Staphylococcus xylosus, Staphylococcus aureus, Staphylococcus lugdunensis, and Staphylococcus sciuri were the most frequent with respective percentages of 47.7%, 23.4%, 12.8% and 10.6% of samples. For all the samples, the species frequently isolated were: Raoultella ornithinolytica, Escherichia coli, Serratia odorifera, Staphylococcus aureus, Staphylococcus xylosus, and Staphylococcus lugdunensis. The uidA gene specific to Escherichia coli was detected in 82.85% of strains (29/35). Amplification of the specific 23S rDNA region using staur primers was observed in 98% (49/50) of the isolated Staphylococcus aureus strains and the nuc gene was detected in 86% of Staphylococcus aureus strains. Conclusion: The isolated bacteria are potential pathogens involved in foodborne illnesses and intoxications. Effective sanitary safety systems must be implemented to guarantee the sanitary quality of fish supplied to consumers.

Simultaneously quantifying hundreds of acylcarnitines in multiple biological matrices within ten minutes using ultrahigh-performance liquid-chromatography and tandem mass spectrometry

Acylcarnitines are metabolic intermediates of fatty acids and branched-chain amino acids having vital biofunctions and pathophysiological significances. Here, we developed a high-throughput method for quantifying hundreds of acylcarnitines in one run using ultrahigh performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). This enabled simultaneous quantification of 1136 acylcarnitines (C0–C26) within 10-min with good sensitivity (limit of detection < 0.7 fmol), linearity (correlation coefficient > 0.992), accuracy (relative error < 20%), precision (coefficient of variation (CV), CV < 15%), stability (CV < 15%), and inter-technician consistency (CV < 20%, n = 6). We also established a quantitative structure-retention relationship (goodness of fit > 0.998) for predicting retention time (tR) of acylcarnitines with no standards and built a database of their multiple reaction monitoring parameters (tR, ion-pairs, and collision energy). Furthermore, we quantified 514 acylcarnitines in human plasma and urine, mouse kidney, liver, heart, lung, and muscle. This provides a rapid method for quantifying acylcarnitines in multiple biological matrices.

Expression of Ether à go-go 1 and its molecular mechamism of regulating the malignant phenotype of osteosarcoma

Objective To explore the expression of etheràgo-go1(Eag1)in human osteosarcoma and its molecular mechanisms of regulating the malignant phenotype of osteosarcoma.Methods The expression levels of Eag1 in osteosarcoma cell lines and human osteosarcoma tissues were detected by reverse transcription polymerase chain reaction(RT-PCR),western blot analysis and immunohistochemistry.The small interfering RNA(siRNA)was

Analyses of functional conservation and divergence reveal requirement of b HLH010/089/091 for pollen development at elevated temperature in Arabidopsis

The Arabidopsis b HLH010/089/091(basic helix-loop-helix)genes are functionally redundant and are required for both anther development and normal expression of DYT1-activated anther-related genes.These three genes are conserved in Brassicaceae,suggesting that each of them is under selection pressure;however,little is known about the possible functional differences among these b HLH genes and between the b HLH and DYT1 genes.Here,we compared novel anther transcriptomic data sets from b HLH010/089/091 single and double mutants,with an anther transcriptomic data set from the wild type(WT)and a previously obtained anther transcriptomic data set from the bhlh010 bhlh089 bhlh091 triple mutant.The results revealed molecular phenotypes that support the functional redundancy and divergence of b HLH010,b HLH089,and b HLH091,as well as the functional overlap and difference between them and DYT1.DNA-binding analyses revealed that DYT1 and b HLH089 specifically recognize the TCATGTGC box to activate the expression of target genes,including ATA20,EXL4,and MEE48.In addition,among genes whose expression was affected in the bhlh010 bhlh089 double and bhlh010 bhlh089 bhlh091 triple mutants,genes that are involved in the stress response and cell signaling were enriched,which included256 genes whose expression was preferentially induced by heat during early flower development.Moreover,the bhlh double mutants exhibited defective pollen development when the plants were grown under elevated temperature,suggesting that b HLH genes are important for anther gene expression under such conditions.These results are consistent with the observation that the heat-induced expression of several genes is less in the bhlh mutants than that in the WT.Therefore,our results provide important insights into the molecular mechanism underlying the activation of direct targets by DYT1-b HLH089 heterodimers and demonstrate the protective roles of b HLH010/089/091 in maintaining fertility upon heat stress.

Proteomic analysis of F_(1)hybrids and intermediate variants in a Littorina saxatilis hybrid zone

Proteomic analysis was carried out on the Crab(upper-shore)and Wave(lower-shore)ecotypes of Littorina saxatilis from a hybrid zone at Silleiro Cape,Spain.Proteome profiles of individual snails were obtained.Protein expression in F_(1)hybrid snails bred in the laboratory and snails with intermediate shell phenotypes collected from the mid-shore were compared with Crab and Wave ecotypes using analytical approaches used to study dominance.Multivariate analysis over many protein spots showed that the F_(1)snails are distinct from both ecotypes but closer to the Wave ecotype.The intermediate snails are highly variable,some closer to the Crab and others to the Wave ecotype.Considered on a protein by protein basis,some proteins are significantly closer in expression to the Crab and others to the Wave ecotype for both F_(1)and intermediate snails.Furthermore,a significant majority of proteins were closer in expression to the Wave ecotype for the F_(1),consistent with the multivariate analysis.No such significant majority toward either the Crab or Wave ecotype was observed for the intermediate snails.The closer similarity of F_(1)and Wave ecotype expression patterns could be the result of similar selective pressures in the similar mid-shore and low-shore environments.For a significantly larger number of proteins,intermediate snails were closer in expression to the ecotype having the lower expression,for both Crab and Wave ecotypes.This is somewhat unexpected as lower expression might be expected to be an indication of impairment of function and lower fitness.Proteomic analysis could be important for the identification of candidate proteins useful for gaining improved understanding of adaptation and barriers to gene flow in hybrid zones.

Factors affecting the prognosis of children with medulloblastoma: A single institution retrospective analysis of 40 cases

Few studies have investigated the factors associated with the prognosis of children with medulloblastoma. This retrospective observational study evaluated the association of molecular subtype, clinical characteristics, and pathological types with the outcomes of children with medulloblastoma. This study included 40 patients with medulloblastoma who underwent surgical resection at the Affiliated Children's Hospital of Fudan University between January 2004 and June 2014. The primary outcome was overall survival(OS). Risk factors associated with survival, disease progression, and recurrence were analyzed by univariate Cox regression analysis; the identified significant risk factors were further analyzed by Kaplan-Meier survival curves. Immunohistochemistry analysis of Yes-associated protein 1(YAP1) and GRB2-associated protein 1(GAB1) was used for medulloblastoma subtype identification; 20% of tumors were the WNT subtype, and 32.5% were the SHH subtype, with the remainder being non-SHH/WNT.Factors associated with OS included M stage, calcification, cerebrospinal fluid fistula,postoperative treatment(radiotherapy, chemotherapy, or both), postoperative Karnofsky Performance Scale score, and molecular subtype(P < 0.044). Patients with the WNT subtype had better survival outcomes(hazard ratio [HR] = 0.16, 95% confidence interval[CI]: 0.05–0.58). Number of symptoms, M stage, and postoperative radiotherapy were associated with disease progression(P ≤ 0.033). The risk of recurrence increased with advanced M stage(HR = 30.71; 95% CI: 3.92–240.44, P = 0.001). Patients receiving both chemotherapy and radiotherapy were less likely to have a recurrence(P = 0.040).Molecular subtyping of medulloblastoma was more predictive of survival than histopathology in patients undergoing adjuvant therapy.