Chemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient ...eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model.
CD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment.
A significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups (P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay (P < .05; R2 = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay.
Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.
Pericytes and vascular smooth muscle cells (VSMCs), which are recruited to developing blood vessels by platelet-derived growth factor BB, support endothelial cell survival and vascular stability. ...Here, we report that imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor β (PDGFRβ), impaired growth of lymphoma in both human xenograft and murine allograft models. Lymphoma cells themselves neither expressed PDGFRβ nor were growth inhibited by imatinib. Tumor growth inhibition was associated with decreased microvascular density and increased vascular leakage. In vivo, imatinib induced apoptosis of tumor-associated PDGFRβ+ pericytes and loss of perivascular integrity. In vitro, imatinib inhibited PDGFRβ+ VSMC proliferation and PDGF-BB signaling, whereas small interfering RNA knockdown of PDGFRβ in pericytes protected them against imatinib-mediated growth inhibition. Fluorescence-activated cell sorter analysis of tumor tissue revealed depletion of pericytes, endothelial cells, and their progenitors following imatinib treatment. Compared with imatinib, treatment with an anti-PDGFRβ monoclonal antibody partially inhibited lymphoma growth. Last, microarray analysis (Gene Expression Omnibus database accession number GSE30752) of PDGFRβ+ VSMCs following imatinib treatment showed down-regulation of genes implicated in vascular cell proliferation, survival, and assembly, including those representing multiple pathways downstream of PDGFRβ. Taken together, these data indicate that PDGFRβ+ pericytes may represent a novel, nonendothelial, antiangiogenic target for lymphoma therapy.
• Blockade of PDGFRβ impairs lymphoma growth by depleting vascular mural cells.• Pericytes may represent a novel, antiangiogenic target for lymphoma therapy.
The purpose of the present work was to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo acute myelogenous leukemia by sequencing the entire ...coding region. EZH2 mutations were identified in 13/714 (1.8%) of AML patients were found to be more common in males (P = 0.033). The presence of EZH2 mutations was significantly associated with lower blast percentage (21-30%) in bone marrow (P<0.0001) and -7/del(7q) (P = 0.025). There were no differences in the incidence of mutation in 13 genes, ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. No difference in complete remission, event-free survival, or overall survival was observed between patients with and without EZH2 mutation (P>0.05). Overall, these results showed EZH2 mutation in de novo acute myeloid leukemia as a recurrent genetic abnormality to be associated with lower blast percentage in BM and -7/del(7q).
With a median age of 65 years, mantle cell lymphoma affects predominantly older patients with comorbidities. Initial treatment of older patients is not standardized but traditionally includes ...chemoimmunotherapy regimens that are not curative. Incorporation of maintenance strategy after induction and introduction of novel agents have expanded access to effective treatment options and improved survival outcome. Ongoing randomized studies comparing induction regimens and maintenance strategies are expected to further define the role of novel agents and combinations in the initial treatment of older patients with mantle cell lymphoma.
Due to the outstanding properties, magnetic particles have been widely used as magnetic carriers and adsorbents in a diverse range of fields, such as biomedical diagnostics, food safety, and ...environmental monitoring, etc. Sorting different magnetic particles from each other based on size simultaneously can be very useful in multiple targets separation. To the best of our knowledge, this research firstly proposes the arc comb structure microfluidic (ACSM) chip for multi-magnetic particles separation based on size by magnetophoresis. And the parameters affecting particle trajectory and separation efficiencies, such as flow velocity, velocity ratio of the two inlets, the remanent flux density of the magnets, and dynamic viscosity of the buffer solution, were investigated by numerical simulations in this study. Particle magnetophoresis spectrum width
and general separation ratio
are put forward to characterize the particles separation efficiency. Under the recommended simulation condition, six kinds of magnetic beads were separated with a general separation ratio
of 0.83 using the newly designed chip. And the separation ratio
of the 0.5, 1.8, 2.5, 3, 3.5 and 4.5 µm magnetic particle is 100.00%, 98.18%, 66.36%, 97.25%, 97.27% and 96.36%, respectively. This numerical simulation study provides a theoretical basis for multiple magnetic particles' separation before experimental trials and also facilitates the utilization and development of microfluidic chips in the future.
A generic model of grid-connected doubly-fed induction generator (DFIG)-type wind turbines represented by differential-algebraic equations (DAE) is proposed for short-term transient-stability ...analysis. From the view of analytical research, vital simplifications are made to the complex physical model of DFIGs, whereas characteristic dynamics are still preserved. When the connection between the wind turbine and grid is weak, transient voltage collapse caused by singularity-induced instability (SII) is observed and analyzed adopting the generic model. In addition, it is shown that collapse might also occur when state variables of the dynamical system get out of control when the connection between the wind turbine and grid is stiff, where fast drop of dc-bus voltage occurs. Critical indices for evaluating transient-stability performances of the DFIG are proposed and parameter sensitivity analysis is carried out. Physical meanings of SII in generators/units with power-electronic interface in vector-oriented control frame are generalized. Novel interaction between the grid and these nonconventional generators/units is highlighted.
In mantle cell lymphoma (MCL), cyclin D1 combines with CDK4/6 to phosphorylate Rb, releasing a break on the G1 to S phase cell cycle. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 ...capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. The proteasome inhibitor bortezomib is approved by the US Food and Drug Administration for treatment of mantle cell lymphoma. Palbociclib-induced pG1 appears to sensitize MCL cells to killing by low-dose bortezomib, potentially improving its activity and tolerability. We conducted a phase 1 trial of palbociclib plus bortezomib in patients with previously treated MCL (NCT01111188). Patients received palbociclib at 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) on days 1-12 of each 21-day cycle in addition to intravenous bortezomib 1.0 mg/m
2
(dose levels 1, 2, 3) or 1.3 mg/m
2
(dose level 4) on days 8, 11, 15 and 18. A total of 19 patients with a median age of 64 and an average of 2 prior therapies were enrolled. Two subjects experienced dose limiting toxicity (DLT): thrombocytopenia (dose level 1) and neutropenia (dose level 3). Although no DLTs were seen at dose level 4, all patients required dose delays during cycle 2 due to cytopenias, and the study team decided to stop the trial. Four of 19 patients achieved a clinical response, including one patient with a complete response. Three patients received treatment for more than one year, including one patient receiving single-agent palbociclib for more than 6 years. The combination of palbociclib 125 mg on days 1-12 plus bortezomib 1.0 mg/m
2
on days 8, 11, 15, and 18 of a 21-day cycle is feasible and active in previously treated MCL, with the primary toxicity being myelosuppression. The regimen may be worthy of further evaluation in patients with non-blastoid MCL following failure of other newer agents.
By varying the composition of Ln3+ ion, the emission wavelength could be tuned from ligand-centered blue light emissions (La3+), to Ln-centered green (Tb3+) and the red (Eu3+), the mixed-lanthanide ...La0.59Eu0.12Tb0.29 exhibiting white light emission.
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A series of two-dimensional layered lanthanide phosphonates, based on 4′-((hydroxy(methoxy)phosphoryl)methyl)-1,1′-biphenyl-2-carboxylic acid (H3L′ = HOOC-C6H4-C6H4-CH2-PO(OH)OCH3), Ln(HL)(H2L)(H2O) (H3L = HOOC-C6H4-C6H4-CH2-PO(OH)2), Ln = La (1), Ce (2), Eu (3), Gd (4), Tb (5), La0.59Eu0.12Tb0.29 (6) have been obtained by pH-dependent hydrothermal synthesis promoted by ultrasonic. Coordination polymers 1–6 are characterized by single-crystal X-ray diffraction analysis, elemental analysis, infrared spectroscopy, powder X-ray diffraction and thermogravimetry measurements. Their photoluminescence properties are investigated and found that the emission wavelength of 6 could be turned by varying the composition of Ln ions from ligand-centered blue light emission (La3+), to Ln-centered green (Tb3+) and red (Eu3+) light emission, exhibiting white light emission. The magnetic properties of 4 and 5 are also studied.
Background
Several studies have shown that scorpion venom peptide BmK AGAP has an analgesic activity. Our previous study also demonstrated that intraplantar injection of BmK AGAP ameliorates ...formalin-induced spontaneous nociceptive behavior. However, the effect of intrathecal injection of BmK AGAP on nociceptive processing is poorly understood.
Methods
We investigated the effects of intrathecal injection of BmK AGAP on spinal nociceptive processing induced by chronic constrictive injury or formalin. Thermal hyperalgesia and mechanical allodynia were measured using radiant heat and the von Frey filaments test. Formalin-induced spontaneous nociceptive behavior was also investigated. C-Fos expression was assessed by immunohistochemistry. Phosphorylated mitogen-activated protein kinase (p-MAPK) expression was monitored by Western blot assay.
Results
Intrathecal injection of BmK AGAP reduced chronic constrictive injury-induced neuropathic pain behavior and pain from formalin-induced inflammation, accompanied by decreased expression of spinal p-MAPKs and c-Fos protein. The results of combining low doses of different MAPK inhibitor (U0126, SP600125, or SB203580; 0.1 µg for each inhibitor) with a low dose of BmK AGAP (0.2 µg) suggested that BmK AGAP could potentiate the effects of MAPK inhibitors on inflammation-associated pain.
Conclusion
Our results demonstrate that intrathecal injection of BmK AGAP produces a sensory-specific analgesic effect via a p-MAPK-dependent mechanism.
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