290 research outputs found
Применение корреляционно-регрессионного и геоинформационного анализа для определения взаимного влияния показателей социальной комфортности элементов городской инфраструктуры на кадастровую стоимость объектов недвижимого имущества
Конкурентний аналіз послуг плавання для немовлят на ринку м. Дніпропетровська згідно моделі "5 сил" М. Портера
Редкие металлы в космической технике
В данной статье рассматривается применение редких металлов в космической технологии. Такжев статье описана классификация редких металлов, уникальные свойства и место каждой группыэлементов в конструировании комических аппаратов.Im vorliegenden Artikel wird die Verwendung von seltenen Metallen in der Raumfahrttechnik betrachtet.Der Artikel beschreibt auch die Klassifizierung von seltenen Metallen, die unikalen Eigenschaften jeder Gruppe undderen Funktion bei der Konstruktion von kosmischen Geräten
Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts
<p>Abstract</p> <p>Background</p> <p>In around 50% of all human cancers the tumor suppressor p53 is mutated. It is generally assumed that in the remaining tumors the wild-type p53 protein is functionally impaired. The two main inhibitors of p53, hMDM2 (MDM2) and hMDMX (MDMX/MDM4) are frequently overexpressed in wild-type p53 tumors. Whereas the main activity of hMDM2 is to degrade p53 protein, its close homolog hMDMX does not degrade p53, but it represses its transcriptional activity. Here we study the role of hMDMX in the neoplastic transformation of human fibroblasts and embryonic retinoblasts, since a high number of retinoblastomas contain elevated hMDMX levels.</p> <p>Methods</p> <p>We made use of an <it>in vitro </it>transformation model using a retroviral system of RNA interference and gene overexpression in primary human fibroblasts and embryonic retinoblasts. Consecutive knockdown of RB and p53, overexpression of SV40-small t, oncogenic HRasV12 and HA-hMDMX resulted in a number of stable cell lines representing different stages of the transformation process, enabling a comparison between loss of p53 and hMDMX overexpression. The cell lines were tested in various assays to assess their oncogenic potential.</p> <p>Results</p> <p>Both p53-knockdown and hMDMX overexpression accelerated proliferation and prevented growth suppression induced by introduction of oncogenic Ras, which was required for anchorage-independent growth and the ability to form tumors <it>in vivo</it>. Furthermore, we found that hMDMX overexpression represses basal p53 activity to some extent. Transformed fibroblasts with very high levels of hMDMX became largely resistant to the p53 reactivating drug Nutlin-3. The Nutlin-3 response of hMDMX transformed retinoblasts was intact and resembled that of retinoblastoma cell lines.</p> <p>Conclusions</p> <p>Our studies show that hMDMX has the essential properties of an oncogene. Its constitutive expression contributes to the oncogenic phenotype of transformed human cells. Its main function appears to be p53 inactivation. Therefore, developing new drugs targeting hMDMX is a valid approach to obtain new treatments for a subset of human tumors expressing wild-type p53.</p
Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers—Results of a dose escalation trial
Background: Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF.
Methods: Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1–2 h infusion of 500–2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed.
Results: Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized.
Conclusions: Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses.
Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476
BMP-7 inhibits TGF-β-induced invasion of breast cancer cells through inhibition of integrin β3 expression
BACKGROUND The transforming growth factor (TGF)-β superfamily comprises cytokines such as TGF-β and Bone Morphogenetic Proteins (BMPs), which have a critical role in a multitude of biological processes. In breast cancer, high levels of TGF-β are associated with poor outcome, whereas inhibition of TGF-β-signaling reduces metastasis. In contrast, BMP-7 inhibits bone metastasis of breast cancer cells. METHODS In this study, we investigated the effect of BMP-7 on TGF-β-induced invasion in a 3 dimensional invasion assay. RESULTS BMP-7 inhibited TGF-β-induced invasion of the metastatic breast cancer cell line MCF10CA1a, but not of its premalignant precursor MCF10AT in a spheroid invasion model. The inhibitory effect appears to be specific for BMP-7, as its closest homolog, BMP-6, did not alter the invasion of MCF10CA1a spheroids. To elucidate the mechanism by which BMP-7 inhibits TGF-β-induced invasion, we analyzed invasion-related genes. BMP-7 inhibited TGF-β-induced expression of integrin α(v)β(3) in the spheroids. Moreover, targeting of integrins by a chemical inhibitor or knockdown of integrin β(3) negatively affected TGF-β-induced invasion. On the other hand, overexpression of integrin β(3) counteracted the inhibitory effect of BMP7 on TGF-β-induced invasion. CONCLUSION Thus, BMP-7 may exert anti-invasive actions by inhibiting TGF-β-induced expression of integrin β(3).Prostatic carcinom
Discovery and Characterization of an Endogenous CXCR4 Antagonist
CXCL12-CXCR4 signaling controls multiple physiological
processes and its dysregulation is associated
with cancers and inflammatory diseases. To
discover as-yet-unknown endogenous ligands of
CXCR4, we screened a blood-derived peptide library
for inhibitors of CXCR4-tropic HIV-1 strains.
This approach identified a 16 amino acid fragment
of serum albumin as an effective and highly specific
CXCR4 antagonist. The endogenous peptide, termed
EPI-X4, is evolutionarily conserved and generated
from the highly abundant albumin precursor by
pH-regulated proteases. EPI-X4 forms an unusual
lasso-like structure and antagonizes CXCL12-induced
tumor cell migration, mobilizes stem cells,
and suppresses inflammatory responses in mice.
Furthermore, the peptide is abundant in the urine
of patients with inflammatory kidney diseases and
may serve as a biomarker. Our results identify EPIX4
as a key regulator of CXCR4 signaling and introduce
proteolysis of an abundant precursor protein
as an alternative concept for chemokine receptor
regulation
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