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.
1
,
2
However, resistance develops in a majority of patients, resulting in a median progression-free survival of 6 to 7 months.
3
,
4
Most reported resistance mechanisms reactivate the MAPK pathway.
5
–
7
In addition, BRAF-inhibitor–induced paradoxical activation of the MAPK pathway
8
–
10
can result in secondary cancers, including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant tumors.
11
–
13
Independently, single-agent trametinib, a MEK inhibitor, improves the overall survival of patients . . .
Biocatalysis in both the homogeneous and heterogeneous versions is an independent interdisciplinary direction in scientific and practical research of single-stage conversions of feed reagents ...(substrates) to valuable marketable products involving, in most cases, a single enzyme as a catalyst. Single-enzyme biocatalytic processes exhibiting all specific features of enzymatic catalysis are a fairly competitive alternative to conventional chemical production. This review provides information on the results achieved by domestic research teams/laboratories that have been involved in extensive and efficient studies in the field of biocatalysis over the past decades and have practical developments protected by RF patents, which, under favorable circumstances, can be offered to commercial enterprises/companies for testing and use on a laboratory and/or pilot-scale with the prospects of industrial scale-up. In the review, special attention is given to targeted systematic studies of lipolytic enzymes (lipases), which have a unique ability to catalyze reactions in a medium of organic solvents, primarily esterification and transesterification reactions, which lead to the formation of valuable products of organic synthesis, such as esters. Lipases are active components of heterogeneous biocatalysts (BCs) synthesized by fixing (immobilizing) these enzymes on the surface of solid adsorbing supports. The review briefly describes the results of studies of domestic research teams and gives complete lists of their reports providing information on the methods of immobilization of target enzymes, the catalytic properties of the developed BCs (enzyme activity, substrate specificity, operational stability) and describing the conditions for biocatalytic processes involving heterogeneous BCs, such as the synthesis of acrylamide and various esters. Taking into account the average activity (
А
), which is similar to the activity measured at the half-inactivation time (
t
1/2
), and the operational stability of BCs characterized by the
t
1/2
value, a fairly rough assessment of the productivity of BCs is conducted by calculating the amount of valuable product produced (in tons) per kilogram of BC.
Structural quality and stability of nanocrystals are fundamental problems that bear important consequences for the performances of small-scale devices. Indeed, at the nanoscale, their functional ...properties are largely influenced by elastic strain and depend critically on the presence of crystal defects. It is thus of prime importance to be able to monitor, by noninvasive means, the stability of the microstructure of nano-objects against external stimuli such as mechanical load. Here we demonstrate the potential of Bragg coherent diffraction imaging for such measurements, by imaging in 3D the evolution of the microstructure of a nanocrystal exposed to in situ mechanical loading. Not only could we observe the evolution of the internal strain field after successive loadings, but we also evidenced a transient microstructure hosting a stable dislocation loop. The latter is fully characterized from its characteristic displacement field. The mechanical behavior of this small crystal is clearly at odds with what happens in bulk materials where many dislocations interact. Moreover, this original in situ experiment opens interesting possibilities for the investigation of plastic deformation at the nanoscale.
Summary
Pyoderma gangrenosum (PG) is a rare, debilitating, inflammatory skin disease associated with a variety of systemic diseases. Because of its rarity, PG is treated with miscellaneous ...immunosuppressive agents as there is no US Food and Drug Administration‐approved standardized treatment approach. We present four patients with PG treated with tofacitinib in the context of the six existing cases in the literature. Tofacitinib appeared to be beneficial in the small sample of patients (n = 10) who failed an average of four other systemic therapies. The majority of patients had classic PG located on the legs (80%, 8/10), while 20% of cases (2/10) were peristomal. The most common comorbidity was inflammatory bowel disease (78%, 7/9). There were no negative treatment results and 40% (4/10) of patients had complete healing of their ulcers, while the other 60% (6/10) had marked clinical improvement. From our observation, tofacitinib appears to be a promising steroid‐sparing adjuvant treatment in patients with refractory PG who have failed on other systemic therapies.
The ceramics СaСu3Тi4–xAlxО12–0.5x–yFy were prepared using solid-state reactions technique and pre-synthesized CaTiO3. It was found that the resistances of both the grain boundary RGB and the ...interface between sample and electrode RSE increase at the combined introduction of Al3+ and F– ions. At 1100 °С, a decrease in dielectric properties after 12 h of sintering time due to copper losses was observed. The samples with x/y = 0.04/0.04 sintered for 10 h at 1 kHz are characterized by the following dielectric parameters: ε′ ≈ 72,000 and tan δ ≈ 0.047. In the sample x/y = 0.04/0, the lowest dielectric loss (tan δ ≈ 0.044) were found.
Display omitted
•CCTO with improved dielectric properties were produced using Al/F-dopants.•CaTiO3 as a starting reagent and CaF2 as F source is promising.•High permittivity (ε ≈ 7.2 × 104) and low dielectric loss (tan δ ≈ 0.046) was achieved.•Combined introduction of Al and F results in synergetic abnormal grain growth.
“Gaia hypothesis”, or “Science of curse” Kovalenko, A. G.
Vestnik Rossijskogo universiteta družby narodov. Seriâ Sociologiâ,
06/2023, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The article is a review of the book by A. Etkind, which is based on the data of sociology, history, economics, political science and statistics: the author describes the relationship between raw ...materials and humankind to suggest a way out of the dramatic collision ( The Nature of Evil. Raw Materials and the State . Moscow: New Literary Review, 2023. 504 p.). The second edition of the book confirms the relevance of its agenda in the contemporary situation. The chronological framework of the book covers the history from antiquity to the present day: the author shows how the key raw materials changed from timber and grain in the past to oil and gas in the present, and how such changes affected not only tastes and lifestyle but also political systems and economic vectors, which, in turn, had the opposite effect on the choice of raw materials. The author argues that the desire to possess raw materials and the intensity of their extraction and processing determined the geopolitical interests of the states, led to wars and, ultimately, to new state borders. The author introduces the concept “addictivity of raw materials” in the life of the individual and societies, which implies an unjustified dependence on a certain type of raw materials (sugar, tobacco, opium or oil), and this dependence led to global disproportions and changed the ‘natural’ historical process.
The rates of ultrafast intersystem crossing in acceptor-bridge-donor molecules centered on Pt(
ii
) acetylides are investigated. Specifically, a Pt(
ii
)
trans
-acetylide triad ...NAP-&z.tbd;-Pt-&z.tbd;-Ph-CH
2
-PTZ
1
, with acceptor 4-ethynyl-
N
-octyl-1,8-naphthalimide (NAP) and donor phenothiazine (PTZ), is examined in detail. We have previously shown that optical excitation in
1
leads to a manifold of singlet charge-transfer states, S*, which evolve
via
a triplet charge-transfer manifold into a triplet state
3
NAP centered on the acceptor ligand and partly to a charge-separated state
3
CSS (NAP
−
-Pt-PTZ
+
). A complex cascade of electron transfer processes was observed, but intersystem crossing (ISC) rates were not explicitly resolved due to lack of spin selectivity of most ultrafast spectroscopies. Here we revisit the question of ISC with a combination and complementary analysis of (i) transient absorption, (ii) ultrafast broadband fluorescence upconversion, FLUP, which is only sensitive to emissive states, and (iii) femtosecond stimulated Raman spectroscopy, FSR. Raman resonance conditions allow us to observe S* and
3
NAP exclusively by FSR, through vibrations which are pertinent only to these two states. This combination of methods enabled us to extract the intersystem crossing rates that were not previously accessible. Multiple timescales (1.6 ps to ∼20 ps) are associated with the rise of triplet species, which can now be assigned conclusively to multiple ISC pathways from a manifold of hot charge-transfer singlet states. The analysis is consistent with previous transient infrared spectroscopy data. A similar rate of ISC, up to 20 ps, is observed in the
trans
-acetylide NAP-&z.tbd;-Pt-&z.tbd;-Ph
2
which maintains two acetylide groups across the platinum center but lacks a donor unit, whilst removal of one acetylide group in mono-acetylide NAP-&z.tbd;-Pt-Cl
3
leads to >10-fold deceleration of the intersystem crossing process. Our work provides insight on the intersystem crossing dynamics of the organo-metallic complexes, and identifies a general method based on complementary ultrafast spectroscopies to disentangle complex spin, electronic and vibrational processes following photoexcitation.
A combination of ultrafast broadband fluorescence upconversion spectroscopy and femtosecond stimulated Raman spectroscopy resolves the rates of intersystem crossing in donor-bridge-acceptor complexes.
Purpose. Development of a two-dimensional field mathematical model of a magnetic gearbox operating as part of a low-power wind turbine for the purpose of evaluating its parameters and characteristics ...and optimizing geometric parameters from the point of view of electromagnetic torque pulsations. Methodology. To carry out the research, the methods of the general theory of electromechanical energy converters, numerical methods of mathematical modeling based on the finite element method, numerical solution of nonlinear differential equations, and methods of spectral analysis to estimate pulsations of the electromagnetic torque were used in the work. Findings. The paper developed a two-dimensional numerical field mathematical model of a magnetic gearbox for an autonomous wind turbine. The model was developed to evaluate the parameters and characteristics of the magnetic gear, as well as to evaluate the influence of the design parameters on the magnitude of the electromagnetic torque and the magnitude of the pulsations of the electromagnetic torque. The effect of the configuration of permanent magnets, the parameters of the ferromagnetic inserts of the magnetic flux modulator and the size of the air gap was investigated in the paper. The obtained results show that there is an optimal configuration of permanent magnets and ferromagnetic elements of the magnetic flux modulator in which the maximum electromagnetic torque and minimum pulsations are achieved. Changing the parameters of the magnetic system affects the dynamics of the magnetic gear, its reliability and efficiency, therefore configuration optimization is an important task in the design, development and implementation of such systems. Originality. A two-dimensional field mathematical model of the magnetic gear has been developed, which makes it possible to estimate the change in its parameters and characteristics when the geometric dimensions change. This allows investigating the influence of various parameters of the magnetic system, such as the height of the permanent magnets and the width of the ferromagnetic inserts, on the electromagnetic torque. This makes it possible to obtain the optimal configuration of the system to achieve the optimal value of the torque and minimal pulsations and to determine the regularity of the change of the electromagnetic torque and other parameters of the gearbox under different operating modes in the future. Practical value. The simulation results indicate the prospects of industrial implementation of magnetic gaers as part of a wind power plant, and the obtained research results indicate the possibility of optimizing the design of magnetic gears in order to increase their reliability and efficiency.
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.
We experimentally demonstrated that chronic social stress during the development of a depression-like state enhances lung metastasis and modifies the expression of many carcinogenesis- and ...apoptosis-related genes in the hypothalamus of mice, including genes involved in lung cancer pathogenesis in humans. Analysis of the expression of genes encoding the major clinical markers of lung cancer in the hypothalamus of mice with depression-like behavior revealed increased expression of the
Eno2
gene encoding neuron-specific enolase, a blood marker of lung cancer progression in humans. It was shown that the expression of this gene in the hypothalamus correlated with the expression of many carcinogenesis- and apoptosis-related genes. The discovered phenomenon may have a fundamental significance and requires further studies.
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