Intratracheal bleomycin in rats is associated with respiratory distress of uncertain etiology. We investigated the expression of surfactant components in this model of lung injury. Maximum respiratory distress, determined by respiratory rate, occurred at 7 days, and surfactant dysfunction was confirmed by increased surface tension of the large-aggregate fraction of bronchoalveolar lavage (BAL). In injured animals, phospholipid content and composition were similar to those of controls, mature surfactant protein (SP) B was decreased 90%, and SP-A and SP-D contents were increased. In lung tissue, SP-B and SP-C mRNAs were decreased by 2 days and maximally at 4--7 days and recovered between 14 and 21 days after injury. Immunostaining of SP-B and proSP-C was decreased in type II epithelial cells but strong in macrophages. By electron microscopy, injured lungs had type II cells lacking lamellar bodies and macrophages with phagocytosed lamellar bodies. Surface activity of BAL phospholipids of injured animals was restored by addition of exogenous SP-B. We conclude that respiratory distress after bleomycin in rats results from surfactant dysfunction in part secondary to selective downregulation of SP-B and SP-C.
The frequency of epithelial cell adhesion molecule (EpCAM) expression was investigated in non-small cell lung cancer (NSCLC) cells and human tissues, and its clinicopathological significance in adenocarcinoma of the lung was evaluated.EpCAM expression was analysed by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry in human NSCLC cells. EpCAM protein expression was evaluated in 234 adenocarcinoma tissues using immunohistochemistry.A high expression level of EpCAM was observed in human NSCLC cells by flow cytometry and RT-PCR. EpCAM overexpression was detected in 120/234 (51.3%) surgically resected adenocarcinoma tissues. EpCAM overexpression occurred significantly more frequently in adenocarcinoma than in bronchioloalveolar carcinoma (p=0.02). The overall survival did not differ significantly between EpCAM-overexpressing and EpCAM-negative patients (p=0.40).These findings suggest EpCAM plays a role in the carcinogenesis of adenocarcinoma of the lung and might provide a promising molecule for targeted therapy in NSCLC.
MARLENE STRAYER,1 RASHMIN C. SAVANI,1 LINDA W. GONZALES,1 AISHA ZAMAN,1 ZHENG CUI,1 EDINA VESZELOVSZKY,1 EMILY WOOD,1 YE-SHIH HO,2 AND PHILIP L. BALLARD1 1Division of Neonatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and 2Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan 482021
Objective To evaluate the clinical efficacy of Oculyzer-guided customized LASIK for eccentric cutting induced by keratorefractive surgery.Methods Twenty-one eyes of 16 patients with eccentric cutting induced by keratorefractive surgery were enrolled in this retrospective study and were treated with Oculyzer-guided customized LASIK.The uncorrected visual acuity (UCVA),the value of optical eccentric cutting,index of surface variance (ISV),index of vertical asymmetry (IVA) and corneal topography were analyzed and compared between before and after operation.Results The UCVA was improved significantly in all patients.The value of optical eccentric cutting changed significantly from 1.4 ～ 2.6 mm (average 2.05 ± 0.55mm) before operation to 0.06 ～0.28 mm (average 0.18±0.12 mm) at 3 months after operation.The ISV and IVA decreased significantly compared with that of pre-operation.The eccentric cutting was corrected in all eyes after operation,and the visual quality was improved.Conclusion Oculyzer-guided customized LASIK is a safe and effective surgery for eccentric cutting induced by keratorefractive surgery.
Key words:
Cutting, eccentric; Keratomileusis, laser in situ; Oculyzer-guide; Correction
Surfactant protein B (SP-B) is a developmentally and hormonally regulated lung protein that is required for normal surfactant function. We generated transgenic mice carrying the human SP-B promoter (−1,039/+431 bp) linked to chloramphenicol acetyltransferase (CAT). CAT activity was high in lung and immunoreactive protein localized to alveolar type II and bronchiolar epithelial cells. In addition, thyroid, trachea, and intestine demonstrated CAT activity, and each of these tissues also expressed low levels of SP-B mRNA. Developmental expression of CAT activity and SP-B mRNA in fetal lung were similar and both increased during explant culture. SP-B mRNA but not CAT activity decreased during culture of adult lung, and both were reduced by transforming growth factor (TGF)-β 1 . Treatment of adult mice with intratracheal bleomycin caused similar time-dependent decreases in lung SP-B mRNA and CAT activity. These findings indicate that the human SP-B promoter fragment directs tissue- and lung cell-specific transgene expression and contains cis-acting elements involved in regulated expression during development, fetal lung explant culture, and responsiveness to TGF-β and bleomycin-induced lung injury.
With the advent of tyrosine kinase inhibitors (TKIs), the treatment prospects of chronic myeloid leukemia (CML) have changed markedly. This innovation can lengthen the long-term survival of patients suffering from CML. However, long-term exposure to TKIs is accompanied by various adverse events (AEs). The latter affect the quality of life and compliance of patients with CML, and may lead to serious disease progression (and even death). Recently, increasing numbers of patients with CML have begun to pursue a dose optimization strategy. Dose optimization may be considered at all stages of the entire treatment, which includes dose reduction and discontinuation of TKIs therapy. In general, reduction of the TKI dose is considered to be an important measure to reduce AEs and improve quality of life on the premise of maintaining molecular responses. Furthermore, discontinuation of TKIs therapy has been demonstrated to be feasible and safe for about half of patients with a stable optimal response and a longer duration of TKI treatment. This review focuses mainly on the latest research of dose optimization of imatinib, dasatinib, and nilotinib in CML clinical trials and real-life settings. We consider dose reduction in newly diagnosed patients, or in optimal response, or for improving AEs, either as a prelude to treatment-free remission (TFR) or as maintenance therapy in those patients unable to discontinue TKIs therapy. In addition, we also focus on discontinuation of TKIs therapy and second attempts to achieve TFR.
Alveogenesis, an essential component of normal lung development, occurs in the immediate postnatal period in rodents. Exposure to hypoxia in newborn rats results in an inhibition of secondary septation, simplification of the distal lung architecture and increased expression of Transforming Growth Factor-Beta (TGFβ). We hypothesized that TGFβ was causally related to hypoxia-mediated inhibition of distal lung development. Transgenic mice expressing a TGFβ-responsive promoter driving GFP as a reporter were placed either in room air or in 12% oxygen for 20 hours a day from birth to 15 days. Alveolar development was assessed by lung histology and radial alveolar counts (RAC) at PN 1, 5, 10 and 15. Mice exposed to hypoxia showed larger distal airspaces from PN5 with significantly lower RAC that persisted to PN15 as compared to room air controls (PN5 RAC: Normoxia 6.16 ± 0.24 vs. Hypoxia 5.24 ± 0.04, P = 0.025, n = 5/group). Somatic growth was delayed at PN5 and 10 in mice maintained in hypoxia, but this difference had resolved by PN15. Immunofluorescence staining for GFP expression showed that active TGFβ was increased in both the alveolar and bronchiolar airspaces in the hypoxia group from PN5 and maximally at PN15. Treatment with anti-TGFβ antibody prevented approximately 50% of the inhibition of secondary septation seen with chronic hypoxia (RAC PN15: Normoxia 8.85 ± 0.18, Hypoxia: 6.80 ± 0.13, Hypoxia + Anti-TGFβ: 7.68 ± 0.03, P < 0.001, n=7–14/group). We conclude that the inhibition of alveolar development due to hypoxia is, at least in part, mediated by TGFβ. We speculate that strategies to block TGFβ may enhance alveolar septation in conditions such as Bronchopulmonary Dysplasia that are associated with an arrest of distal lung development.
Abstract Background Glioblastoma multiforme (GBM) is a highly aggressive brain tumor, characterized by its poor prognosis. Glycolipid metabolism is strongly associated with GBM development and malignant behavior. However, the precise functions of snoRNAs and ADARs in glycolipid metabolism within GBM cells remain elusive. The objective of the present study is to delve into the underlying mechanisms through which snoRNAs and ADARs exert regulatory effects on glycolipid metabolism in GBM cells. Methods RNA immunoprecipitation and RNA pull-down experiments were conducted to verify the homodimerization of ADAR2 by SNORD113-3, and Sanger sequencing and Western blot experiments were used to detect the A-to-I RNA editing of PHKA2 mRNA by ADAR2. Furthermore, the phosphorylation of EBF1 was measured by in vitro kinase assay. Finally, in vivo studies using nude mice confirmed that SNORD113-3 and ADAR2 overexpression, along with PHKA2 knockdown, could suppress the formation of subcutaneous xenograft tumors and improve the outcome of tumor-bearing nude mice. Results We found that PHKA2 in GBM significantly promoted glycolipid metabolism, while SNORD113-3, ADAR2, and EBF1 significantly inhibited glycolipid metabolism. SNORD113-3 promotes ADAR2 protein expression by promoting ADAR2 homodimer formation. ADAR2 mediates the A-to-I RNA editing of PHKA2 mRNA. Mass spectrometry analysis and in vitro kinase testing revealed that PHKA2 phosphorylates EBF1 on Y256, reducing the stability and expression of EBF1. Furthermore, direct binding of EBF1 to PKM2 and ACLY promoters was observed, suggesting the inhibition of their expression by EBF1. These findings suggest the existence of a SNORD113-3/ADAR2/PHKA2/EBF1 pathway that collectively regulates the metabolism of glycolipid and the growth of GBM cells. Finally, in vivo studies using nude mice confirmed that knockdown of PHKA2, along with overexpression of SNORD113-3 and ADAR2, could obviously suppress GBM subcutaneous xenograft tumor formation and improve the outcome of those tumor-bearing nude mice. Conclusions Herein, we clarified the underlying mechanism involving the SNORD113-3/ADAR2/PHKA2/EBF1 pathway in the regulation of GBM cell growth and glycolipid metabolism. Our results provide a framework for the development of innovative therapeutic interventions to improve the prognosis of patients with GBM.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
'/%3e%3cuse xlink:href='%23a' transform='rotate(144 450 300)'/%3e%3cuse xlink:href='%23a' transform='rotate(216 450 300)'/%3e%3cuse xlink:href='%23a' transform='rotate(288 450 300)'/%3e%3c/svg%3e)
'%3e%3cg id='b'%3e%3cpath id='a' stroke='%23000' stroke-width='2' d='M-6-25H6m-12 3H6m-12 3H6'/%3e%3cuse xlink:href='%23a' y='44'/%3e%3c/g%3e%3cpath stroke='%23fff' d='M0 17v10'/%3e%3ccircle r='12' fill='%23cd2e3a'/%3e%3cpath fill='%230047a0' d='M0-12A6 6 0 0 0 0 0a6 6 0 0 1 0 12 12 12 0 0 1 0-24z'/%3e%3c/g%3e%3cg transform='rotate(-123.69)'%3e%3cuse xlink:href='%23b'/%3e%3cpath stroke='%23fff' d='M0-23.5v3M0 17v3.5m0 3v3'/%3e%3c/g%3e%3c/svg%3e)