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T Ponnapakkam R Katikaneni H Suda S Miyata O Matsushita J Sakon RC Gensure 《Calcified tissue international》2012,91(3):196-203
Parathyroid hormone (PTH) is the most effective osteoporosis treatment, but it is only effective if administered by daily injections. We fused PTH(1-33) to a collagen binding domain (PTH-CBD) to extend its activity, and have shown an anabolic bone effect with monthly dosing. We tested the duration of action of this compound with different routes of administration. Normal young C57BL/6J mice received a single intraperitoneal injection of PTH-CBD (320?μg/kg). PTH-CBD treated mice showed a 22.2?% increase in bone mineral density (BMD) at 6?months and 12.8?% increase at 12?months. When administered by subcutaneous injection, PTH-CBD again caused increases in BMD, 15.2?% at 6?months and 14.3?% at 12?months. Radiolabeled PTH-CBD was concentrated in bone and skin after either route of administration. We further investigated skin effects of PTH-CBD, and histological analysis revealed an apparent increase in anagen VI hair follicles. A single dose of PTH-CBD caused sustained increases in BMD by >10?% for 1?year in normal mice, regardless of the route of administration, thus showing promise as a potential osteoporosis therapy. 相似文献
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Azar Dokht Khosravi Abdolrazagh Hashemi Shahraki Soolmaz Khandan Dezfuli Mohammad Hashemzadeh Hamed Goodarzi Parviz Mohajeri 《The Kaohsiung journal of medical sciences》2017,33(11):550-557
Tuberculosis (TB) is considered as one of the most important infectious diseases in the world, and recent rise and spread of multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains, have made the matter worsened. Due to the importance of TB prevalence in Iran, this study was designed to investigate the genetic diversity among MDR strains of MTB by MIRU-VNTR typing scheme. A total of 88 drug resistant M. tuberculosis isolates belong to pulmonary TB cases were collected from several TB reference centers of Iran. Drug susceptibility testing for Isoniazid and Rifampin was performed using the agar proportion method and MDR isolates were underwent genotyping by using 12-locus- based MIRU-VNTR typing. On performing proportion method, 22 isolates were identified as MDR. By typing of MDR isolates using 12-loci MIRU-VNTR technique, high diversity were demonstrated in MDR strains and these were classified into 20 distinct MIRU-VNTR genotypes. MIRU loci 10 and 26 were the most discriminatory loci with 8 and 7 alleles respectively; while MIRU loci 2, 20, 24 and 39 were found to be the least discriminatory with 1–2 alleles each. We noticed a mixed infection in isolate 53, as this isolate comprised simultaneous two alleles in MIRU loci 40, 10, 16 and 39. In conclusion, this result represents MIRU-VNTR typing as a useful tool for studying genetic diversity of MDR-MTB in regional settings, and will help the health sectors to construct a preventive program for MDR-TB. Additionally, it can detect mixed infection which can facilitate management of treatment. 相似文献
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Kira Gritsman Haluk Yuzugullu Thanh Von Howard Yan Linda Clayton Christine Fritsch Sauveur-Michel Maira Gregory Hollingworth Christine Choi Tulasi Khandan Mahnaz Paktinat Rachel O. Okabe Thomas M. Roberts Jean J. Zhao 《The Journal of clinical investigation》2014,124(4):1794-1809
The genes encoding RAS family members are frequently mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). RAS proteins are difficult to target pharmacologically; therefore, targeting the downstream PI3K and RAF/MEK/ERK pathways represents a promising approach to treat RAS-addicted tumors. The p110α isoform of PI3K (encoded by Pik3ca) is an essential effector of oncogenic KRAS in murine lung tumors, but it is unknown whether p110α contributes to leukemia. To specifically examine the role of p110α in murine hematopoiesis and in leukemia, we conditionally deleted p110α in HSCs using the Cre-loxP system. Postnatal deletion of p110α resulted in mild anemia without affecting HSC self-renewal; however, deletion of p110α in mice with KRASG12D-associated JMML markedly delayed their death. Furthermore, the p110α-selective inhibitor BYL719 inhibited growth factor–independent KRASG12D BM colony formation and sensitized cells to a low dose of the MEK inhibitor MEK162. Furthermore, combined inhibition of p110α and MEK effectively reduced proliferation of RAS-mutated AML cell lines and disease in an AML murine xenograft model. Together, our data indicate that RAS-mutated myeloid leukemias are dependent on the PI3K isoform p110α, and combined pharmacologic inhibition of p110α and MEK could be an effective therapeutic strategy for JMML and AML. 相似文献
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Julie Gray-Bablin Juan Zalvide M.Pat Fox ChrisJ. Knickerbocker JamesA. DeCaprio Khandan Keyomarsi 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(26):15215-15220
Cyclin E is an important regulator of cell cycle progression that together with cyclin-dependent kinase (cdk) 2 is crucial for the G1/S transition during the mammalian cell cycle. Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in populations of breast cancer cells and tissues that also overexpress p16. In these tumor cells and tissues, we show that the expression of p16 and pRb is not mutually exclusive. Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin D1/cdk complexes inactive. However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time course similar to phosphorylation of glutathione S-transferase retinoblastoma by cyclin E immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop, providing yet another mechanism by which tumors can gain a growth advantage. 相似文献
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Thymosin beta 15A (TMSB15A) is a predictor of chemotherapy response in triple-negative breast cancer
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Urs von Holzen Abujiang Pataer Uma Raju Dora Bocangel Stephan A Vorburger Yanna Liu Xiaolin Lu Jack A Roth Bharat B Aggarwal Glen N Barber Khandan Keyomarsi Kelly K Hunt Stephen G Swisher 《Clinical cancer research》2007,13(20):6032-6039
PURPOSE: Activation of the double-stranded RNA-activated protein kinase (PKR) leads to the induction of various pathways including the down-regulation of translation through phosphorylation of the eukaryotic translation initiation factor 2alpha (eIF-2alpha). There have been no reports to date about the role of PKR in radiation sensitivity. EXPERIMENTAL DESIGN: A clonogenic survival assay was used to investigate the sensitivity of PKR mouse embryo fibroblasts (MEF) to radiation therapy. 2-Aminopurine (2-AP), a chemical inhibitor of PKR, was used to inhibit PKR activation. Nuclear factor-kappaB (NF-kappaB) activation was assessed by electrophoretic mobility shift assay (EMSA). Expression of PKR and downstream targets was examined by Western blot analysis and immunofluorescence. RESULTS: Ionizing radiation leads to dose- and time-dependent increases in PKR expression and function that contributes to increased cellular radiation resistance as shown by clonogenic survival and terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) apoptosis assays. Specific inhibition of PKR with the chemical inhibitor 2-AP restores radiation sensitivity. Plasmid transfection of the PKR wild-type (wt) gene into PKR(-/-) MEFs leads to increased radiation resistance. The protective effect of PKR to radiation may be mediated in part through NF-kappaB and Akt because both NF-kappaB and Akt are activated after ionizing radiation in PKR+/+ but not PKR-/- cells. CONCLUSIONS: We suggest a novel role for PKR as a mediator of radiation resistance modulated in part through the protective effects of NF-kappaB and Akt activation. The modification of PKR activity may be a novel strategy in the future to overcome radiation resistance. 相似文献
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Tuberculosis (TB) and breast cancer are common diseases in developing countries. Their coexistence in the breast and axillary lymph nodes is, however, rare. It can lead to overstaging of the breast cancer. Treatment compliance may also be difficult when two major illnesses exist. Five cases of coexistent breast cancer and TB are presented with regard to presentation and outcome, with a review of the literature. 相似文献