Coulomb drag Narozhny, B. N.; Levchenko, A.
Reviews of modern physics,
05/2016, Letnik:
88, Številka:
2
Journal Article
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Coulomb drag is a transport phenomenon whereby long-range Coulomb interaction between charge carriers in two closely spaced but electrically isolated conductors induces a voltage (or, in a closed ...circuit, a current) in one of the conductors when an electrical current is passed through the other. The magnitude of the effect depends on the exact nature of the charge carriers and the microscopic, many-body structure of the electronic systems in the two conductors. Drag measurements have become part of the standard toolbox in condensed matter physics that can be used to study fundamental properties of diverse physical systems including semiconductor heterostructures, graphene, quantum wires, quantum dots, and optical cavities.
In long-term follow-up of more than 500 patients with melanoma containing a
BRAF
V600E or V600K mutation, a combination of dabrafenib plus trametinib was associated with progression-free survival in ...19% of the patients and overall survival in 34% at 5 years. A complete response to dabrafenib plus trametinib was the strongest predictor of long-term survival.
A solid tumor is an organ composed of cancer and host cells embedded in an extracellular matrix and nourished by blood vessels. A prerequisite to understanding tumor pathophysiology is the ability to ...distinguish and monitor each component in dynamic studies. Standard fluorophores hamper simultaneous intravital imaging of these components. Here, we used multiphoton microscopy techniques and transgenic mice that expressed green fluorescent protein, and combined them with the use of quantum dot preparations. We show that these fluorescent semiconductor nanocrystals can be customized to concurrently image and differentiate tumor vessels from both the perivascular cells and the matrix. Moreover, we used them to measure the ability of particles of different sizes to access the tumor. Finally, we successfully monitored the recruitment of quantum dot-labeled bone marrow-derived precursor cells to the tumor vasculature. These examples show the versatility of quantum dots for studying tumor pathophysiology and creating avenues for treatment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The addition of a MEK inhibitor to a BRAF inhibitor improved response rates by nearly 16 percentage points (from 51% to 67%) and improved progression-free survival by 0.5 months (from 8.8 to 9.3 ...months).
Targeted inhibition of the RAF–MEK–ERK (MAPK) pathway with BRAF inhibitors dabrafenib or vemurafenib, as compared with chemotherapy, improves the progression-free and overall survival of patients who have metastatic melanoma with
BRAF
V600 mutations.
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However, resistance develops in a majority of patients, resulting in a median progression-free survival of 6 to 7 months.
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Most reported resistance mechanisms reactivate the MAPK pathway.
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In addition, BRAF-inhibitor–induced paradoxical activation of the MAPK pathway
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can result in secondary cancers, including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant tumors.
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Independently, single-agent trametinib, a MEK inhibitor, improves the overall survival of patients . . .
Cell-penetrating peptides (CPPs) have been used to overcome the lipophilic barrier of the cellular membranes and deliver large molecules and even small particles inside the cell for their biological ...actions. CPPs are being used to deliver inside cell a large variety of cargoes such as proteins, DNA, antibodies, contrast (imaging) agents, toxins, and nanoparticular drug carriers including liposomes. In this paper, we have reviewed the delivery of different molecules and particles mediated by TAT, Antp, VP22, and other CPPs as well as potential applications of these delivery systems in different areas of vaccine development, cancer immunotherapy, gene delivery, and cellular imaging.
Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in ...BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after≥36-month follow-up for all living patients.
This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150mg twice daily) plus trametinib (2mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.
Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n= 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and<3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.
These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
We calculate exact two-dimensional analytic expressions for the electric and magnetic fields and their potentials generated by a linear beam of relativistic charged particles between infinite ideally ...conducting planes and ferromagnetic poles. We use the method of summing an infinite sequence of fields of linear image charges and image currents to obtain solutions and also calculate the density distribution of the electric charge on the conductor surface induced by the charged particle beam. We obtain new formulas for the linear approximation of the fields near the beam and discuss the mathematical features of the exact solutions and the applicability constraints for the linear approximations.
Summary Background Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF ...Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov , number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2–not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2–23·7) in the dabrafenib only group (hazard ratio HR 0·71, 95% CI 0·55–0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0–13·9) in the dabrafenib and trametinib group and 8·8 months (5·9–9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53–0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. Interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. Funding GlaxoSmithKline.
Abstract
We derive analytical expressions for external fields of a relativistic bunch of charged particles with a circular and an elliptical cross section under different boundary conditions and ...interaction of the fields with an accelerator structural elements. The particle density in the bunch is assumed to be uniform as well as non-uniform. At distances far apart from the bunch, in free space the field reduces to the relativistic modified Coulomb form for a pointlike charge and at small distances the expressions reproduce the external fields of a continuous beam. In an ultra-relativistic limit the longitudinal components of the internal and external electric fields of the bunch are strongly suppressed by the Lorentz factor. If the bunch is surrounded by conducting surfaces, the bunch self-fields are modified. Image fields generated by a bunch between two parallel conducting plates are studied in detail. Exact summation of the electric, $E_y$, and magnetic, $B_x$, image field components allows the infinite series to be represented in terms of elementary trigonometric functions. The new expressions for modified fields are applied to study image forces acting on the bunch constituents and the bunch as a whole. The coherent and incoherent tune shifts for an arbitrary bunch displacement from the midplane are calculated in the framework of an improved linear theory, for both infinite and finite parallel flat surfaces. Moreover, the developed method allows us to generalize the Laslett image coefficients $\epsilon_1$, $\epsilon_2$, $\xi_1$, $\xi_2$ to the case of an arbitrary bunch offset and reveal relationships between these coefficients. Appendix C provides a brief historical background of the development of the method of electrical images.
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