4 research outputs found
HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer
No full textOvarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests that resistant clones exist within a larger drug-sensitive cell population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically derived, intrapatient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 downregulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of histone deacetylase (HDAC) 4, FOLR2, PIK3R1, or STAT1 (P <0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum-sensitive cells but not in HDAC4 overexpressing platinum-resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum-induced STAT1 activation, and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors [n = 7 of 16 (44%); P = 0.04]. Therefore, clinical selection of HDAC4-overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer
Minimum flexural reinforcement for T-beams made of higher strength concrete
No full text Design codes specify minimum flexural reinforcement for reinforced concrete beams. With the extensive use of higher strength concrete, the empirical expressions of the past for minimum flexural reinforcement, in which the concrete strength is not considered, had to be revised. Six reinforced concrete T-beams, having small ratios of flexural reinforcement, were tested to study the behaviour at the positive moment region and to evaluate the code requirements on minimum flexural reinforcement. A criterion was set and evaluations of different minimum reinforcement requirements were made using this criterion and the test data.Key words: beams, crack control, ductility, flexural strength, high strength concrete, minimum flexural reinforcement, reserve strength. </jats:p
Epithelial-stromal cell interactions and ECM mechanics drive the formation of airway-mimetic tubular morphology in lung organoids
No full textComplex human airway cellular organisation where extracellular matrix (ECM), epithelial and stromal lineages interact present challenges for organ study in vitro. Current in vitro lung models, that focus on the lung epithelium do not represent complex airway morphology and cell-ECM interactions seen in vivo.
Models including stromal populations often separate them via a semipermeable barrier precluding cell-cell interaction or the effect of ECM mechanics. We investigated the effect of stromal cells on basal epithelial cell-derived bronchosphere structure and function through a triple culture of human bronchial epithelial, lung fibroblast and airway smooth muscle cells. Epithelial-stromal cross-talk resulted in epithelial cell-driven branching tubules with stromal cells surrounding epithelial cells termed bronchotubules. Agarose-matrigel scaffold (Agrigel) formed a mechanically tuneable ECM, with adjustable viscoelasticity and stiffness enabling long-term tubule survival. Bronchotubule models may enable research into how epithelial-stromal cell and cell-ECM communication drive tissue patterning, repair and development of disease
