Biomedical subjects

Michael Yang

Publications and source records attributed to Michael Yang.

7 recordsLinked to original sources

PubMed2026

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗

PubMed2006

De novo isodicentric X chromosome: 46,X,idic(X)(q24), and summary of literature.

We describe a 12-year-old patient, the second live born prenatally ascertained patient in the literature, with a de novo isodicentric X chromosome, karyotype 46,X,idic(X)(q24), with normal growth and development and lack of dysmorphic features. Molecular and cytogenetic studies were performed to further characterize the isodicentric chromosome X behavior. Literature on isodicentric X chromosomes with various breakpoints on Xq is reviewed and summarized.

Child↗

PubMed2005

Self-assembled three dimensional radio frequency (RF) shielded containers for cell encapsulation.

This paper describes the construction of three dimensional (3D) encapsulation devices in large numbers, using a novel self-assembling strategy characterized by high mechanical stability, controlled porosity, extreme miniaturization, high reproducibility and the possibility of integrating sensing and actuating electromechanical modules. We demonstrated encapsulation of microbeads and cells within the containers, thereby demonstrating one possible application in cell encapsulation therapy. Magnetic resonance (MR) images of the containers in fluidic media suggest radio frequency (RF) shielding and a susceptibility effect, providing characteristic hypointensity within the container, thereby allowing the containers to be easily detected. This demonstration is the first step toward the design of 3D, micropatterned, non-invasively trackable, encapsulation devices.

Animals↗

PubMed2004

Novel adenoviral vectors coding for GFP-tagged wtCFTR and deltaF508-CFTR: characterization of expression and electrophysiological properties in A549 cells.

E1/E3-deleted adenoviral vectors expressing an N-terminal green fluorescent protein (GFP) reporter gene fused to either wtCFTR (H5.040CMVEGFP-wtCFTR) or deltaF508-CFTR (H5.040CMVEGFP-deltaF508CFTR) were generated. To characterize the expression and activity, A549 cells were infected with vectors expressing GFP-tagged and non-tagged forms of CFTR and deltaF508CFTR. CFTR activity was assayed in cell-attached and excised patches. For H5.040CMVEGFP-wtCFTR, forskolin-dependent outward current was observed in cell-attached patches from 56 of 67 GFP-positive cells. Single-channel conductances, open probability, mean open and mean closed time values for GFP-CFTR and CFTR were not significantly different. After excision, GFP-CFTR activity required ATP and exhibited a linear I-V relationship. For H5.040CMVEGFP-deltaF508CFTR, media were supplemented with 5 mM butyrate 16 h after infection. Forskolin-dependent outward current was observed in cell-attached patches from 21 of 30 butyrate-treated GFP-positive cells and 0 of 8 GFP-positive cells without butyrate. Single-channel conductances, open probability, mean open and mean closed time values for GFP-deltaF508CFTR and deltaF508CFTR were not significantly different. However, the increase in open probability with genistein was significantly smaller for GFP-deltaF508CFTR than for deltaF508CFTR. In excised patches, GFP-deltaF508CFTR activity required ATP and exhibited a linear I-V relationship. Despite the consistent detection of GFP-CFTR and GFP-deltaF508CFTR channels in the plasma membrane by patch clamping, GFP fluorescence was observed only in intracellular regions and was not altered by butyrate. The data show that high levels of functional GFP-tagged CFTR channels can be expressed with these adenoviral vector constructs.

Adenocarcinoma↗

PubMed2003

Arginine-based molecular transporters: the synthesis and chemical evaluation of releasable taxol-transporter conjugates.

[structure: see text] A flexible and efficient procedure has been developed for the conjugation of taxol to various arginine-based molecular transporters via the taxol C2' O-chloroacetyl derivative. The resultant taxol-transporter conjugates are highly water soluble and release free taxol with half-lives of minutes to hours depending on the pH and the linker structure.

Acetylation↗

PubMed2003

Induction of HL-60 cell differentiation by the p38 mitogen-activated protein kinase inhibitor SB203580 is mediated through the extracellular signal-regulated kinase signaling pathway.

The pyridinyl imidazole p38 kinase inhibitor, SB203580, was initially used to block inflammatory cytokine synthesis. Here we report that SB203580 by itself could induce human promyeloid leukemic HL-60 cells to differentiate mainly along the granulocytic lineage, as evidenced by cellular morphological changes, and the concurrent expression of cell surface markers CD11b and CD14. This differentiation induction was time and dose dependent. After 12 h exposure to 10 microM SB203580, 12.5% of the cells became CD11b as compared to only 2.6% in untreated control cells. By 96 h, CD11b cells increased to 72.3%, and among them, 26% were CD14. Morphologically, the cells were smaller in size with lower nuclear/cytoplasmic ratio. The nucleus was indented and nucleoli markedly reduced. However, 10 microM SB203580 had little effect on HL-60 cell growth and survival during the first 72 h, but by 96 h the percentage of cells in G1 phase was markedly increased. These effects of SB203580 were not attributable to its inhibition of p38 kinase activity. Instead, the essential kinases in the extracellular signal-regulated kinase (ERK) pathway such as phospho-Raf-1, phospho-MEK1/2, phospho-ERK1/2 and phospho-p90RSK were all elevated dramatically shortly after cells were exposed to SB203580 and lasted for 24 h before declining. Pre-incubation of cells with 20 microM of PD98059 1 h before addition of SB203580 could completely block the expression of differentiation markers. Our results suggest that SB203580-induced differentiation in HL-60 cells was mediated by activation of MEK/ERK signaling. In conclusion, our data have shown that SB203580 possessed biological activities other than inhibition of p38 and these activities could make it a potential candidate as an inducing agent for cell differentiation in the therapeutic treatment of leukemia.

Cell Differentiation↗

PubMed2003

Numerous microRNPs in neuronal cells containing novel microRNAs.

Spinal muscular atrophy (SMA) is a common neurodegenerative disease that is caused by deletions or loss-of-function mutations in the Survival of Motor Neuron (SMN) protein. SMN is part of a large complex that functions in the assembly/restructuring of ribonucleoprotein (RNP) complexes. We recently showed in HeLa cells that two components of the SMN complex, Gemin3 and Gemin4, together with the argonaute protein eIF2C2, also associate with microRNAs (miRNAs) as part of a novel class of RNPs termed miRNPs. Here we report on miRNPs isolated from neuronal cell lines of mouse and human, and describe 53 novel miRNAs. Several of these miRNAs are conserved in divergent organisms, including rat, zebrafish, pufferfish, and the nematode Caenorhabditis elegans. The chromosomal locations of most of the novel miRNAs were identified and indicate some phylogenetic conservation of the likely precursor structures. Interestingly the gene locus of one miRNA, miR-175, is a candidate region for two neurologic diseases: early-onset parkinsonism (Waisman syndrome) and X-linked mental retardation (MRX3). Also, several miRNAs identified as part of miRNPs in these cells appear to constitute two distinct subfamilies. These subfamilies comprise multiple copies of miRNAs on different chromosomes, suggesting an important function in the regulation of gene expression.

Animals↗