Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors ...using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR antagonists or genetic targeting of A2AR using shRNA. In 2 syngeneic HER2+ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8+ CAR T cells and increased activation of both CD8+ and CD4+ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types.
Heavy and hyper doping of ZnO by a combination of gallium (Ga) ion implantation using a focused ion beam (FIB) system and post‐implantation laser annealing is demonstrated. Ion implantation allows ...for the incorporation of impurities with nearly arbitrary concentrations, and the laser‐annealing process enables dopant activation close to or beyond the solid‐solubility limit of Ga in ZnO. Heavily doped ZnO:Ga with free‐carrier concentrations of ≈1021 cm−3, resulting in a plasma wavelength of 1.02 μm, which is substantially shorter than the telecommunication wavelength of 1.55 μm is demonstrated. Thus, this approach enables the control of the plasma frequency of ZnO from the far infrared down to 1.02 μm, thus, providing a promising plasmonic material for applications in this regime.
The optical properties of ZnO are tunable by Gallium ion implantation and laser annealing. The highest achieved free‐carrier concentration in ZnO:Ga is Ne ≈ 1.23 ± 0.41 ×1021 cm−3. Heavily doped ZnO:Ga by a focused ion beam (FIB) opens a wide field for lateral arrangements of doped and un‐doped regions, which are a promising for photonic or plasmonic applications.
Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with ...myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOA
mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.
We demonstrate spatial modification of the optical properties of thin-film metal oxides, zinc oxide (ZnO) and vanadium dioxide (VO
) as representatives, using a commercial focused ion beam (FIB) ...system. Using a Ga
FIB and thermal annealing, we demonstrated variable doping of a wide-bandgap semiconductor, ZnO, achieving carrier concentrations from 10
cm
to 10
cm
. Using the same FIB without subsequent thermal annealing, we defect-engineered a correlated semiconductor, VO
, locally modifying its insulator-to-metal transition (IMT) temperature by up to ∼25 °C. Such area-selective modification of metal oxides by direct writing using a FIB provides a simple, mask-less route to the fabrication of optical structures, especially when multiple or continuous levels of doping or defect density are required.
Approximately 20% of acute myeloid leukemia (AML) patients carry mutations in IDH1 or IDH2 that result in over-production of the oncometabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors ...that block 2-HG synthesis can induce complete morphological remission; however, almost all patients eventually acquire drug resistance and relapse. Using a multi-allelic mouse model of IDH1-mutant AML, we demonstrate that the clinical IDH1 inhibitor AG-120 (ivosidenib) exerts cell-type-dependent effects on leukemic cells, promoting delayed disease regression. Although single-agent AG-120 treatment does not fully eradicate the disease, it increases cycling of rare leukemia stem cells and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitizes IDH1-mutant AML to azacitidine, with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide a mechanistic rationale for the observed combinatorial effect of AG-120 and azacitidine in patients.
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•Inhibition of mutant IDH1 promotes exhaustion of the leukemic hierarchy•Resistance to the IDH1 inhibitor AG-120 can arise through transcriptional reprogramming•The differentiation state of AML cells affects their response to IDH1 inhibition•The response of LSCs to AG-120 sensitizes them to azacitidine
IDH1-mutant acute myeloid leukemia cells accumulate the oncometabolite D-2-hydroxyglutarate (2-HG). Gruber et al. demonstrate that pharmacological 2-HG blockade sensitizes rare leukemia stem cells to the cytosine analogue azacitidine by promoting cycling and upregulating pyrimidine salvage.
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•Monohexadecylboron-capped Zn, Co, Fe and Mn(II) tris-pyrazoloximates were obtained.•Condensation of pyrazoloxime with n-hexadecylboronic acid on M2+ was used.•H atoms of pyrazolyl ...groups form a pseudomacrobicycle via their H-bonding with Cl−•This ligand pseudoencapsulates the corresponding central metal(II) ion.
Self-assembly of monohexadecylboron-capped zinc, cobalt, iron and manganese(II) tris-pyrazoloximate pseudoclathrochelates was performed using one-pot template condensation of 2-acetylpyrazole oxime with n-hexadecylboronic acid as a capping Lewis-acidic agent on the corresponding metal ion as a matrix. Hydrogen atoms of three terminal pyrazolyl NH groups of three pyrazoloxime synthons form a pseudomacrobicyclic ligand through their hydrogen bonding with a chloride counterion Cl− … (HN)3, thus allowing an encapsulation of the corresponding metal ion. The complexes obtained were characterized using elemental analysis, MALDI-TOF mass spectrometry, IR, UV-Vis-NIR, 57Fe Mössbauer (for the iron complex), 1H and 13C NMR spectroscopy, as well as by SQUID magnetometry. The structure of the complexes synthesized was also confirmed by single crystal X-ray diffraction analysis of the zinc(II) pseudoclathrochelate. Its pseudocaged zinc(II) ion is located almost in the center of ZnN6-coordination polyhedron, which adopts a trigonal prismatic geometry with a very low distortion angle. As follows from variable-temperature magnetometry data, the χT values for manganese and iron(II) pseudoclathrochelates in the temperature range 50–300 К are close to theoretical pure high-spin values without of orbital contribution. 1H and 13C NMR chemical shifts of their pyrazoloximate nuclei reach to some hundreds of ppm, while those chemical shifts of the normal hexadecyl chain's nuclei, on the distance of more than five chemical bonds from the pseudoencapsulated paramagnetic metal ion, are close to those for the diamagnetic zinc(II) pseudoclathrochelate. This is indicative of the contact nature of thus induced paramagnetic shifts, as well as a weak pseudocontact contribution.
The relevance of the work is caused by the need to improve the methods for monitoring the characteristics of groundwater and their changes in the seismically active regions of the Altai Republic. ...Groundwater is an indicator of seismic processes and they react to changes in the stress-strain state of rocks in the zones of foci of upcoming tectonic earthquakes. The aim of the work is to identify short-term changes in the helium content and generalized hydrogeochemical indicators in the previously identified highly dynamic groundwater monitoring facilities of the Altai Republic in relation to the search for precursors of strong seismic events. Research methods. The work is based on the results of daily monitoring of groundwater in the Altai Republic, which was carried out in January–March 2021 at two observation points for temperature conditions and the qualitative composition of groundwater – well and a column – f the Territorial Center «Altaigeomonitoring». Results. The purpose of the work is to study the change in helium content in groundwater and its hydrogeochemical characteristics at several points of the geological environment monitoring in order to search for precursors of strong seismic events. For this study, we used two groundwater observation points located in Gorno-Altaisk (street water fountain) and in the village Stariy Beltir (borehole) distant from each other of more than 200 km. These monitoring points were chosen due to the fact that a significant change in the characteristics of groundwater was recorded there during the preparation and course of seismic events in the region. The work gives a characteristic of the seismic setting of the Altai-Sayan region during the monitoring period. In order to identify the dynamics of helium content and hydrogeochemical characteristics of groundwater, we started studying these characteristics in the period of January 14 – March 22, 2021. It is shown that the Stariy Beltir monitoring point, located in the fault zone near the epicentral zone of the Chuya earthquake (2003), is characterized by a high sensitivity of changes not only in the hydrogeochemical characteristics of groundwater, but also by a high response of helium content dynamics to earthquakes. It was revealed that the Mongolian earthquake (2021) did not affect the hydrogeochemical composition of the studied monitoring points located on the territory of Gorny Altai, at the same time, the seismic events closest to them are reflected in the presented groundwater monitoring points. The chosen monitoring points in some cases do not overlap each other and react mainly to the nearest earthquakes, including weak ones. The most dynamic response to earthquakes was noted in helium, pH, Eh, and temperature.
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