41 research outputs found
Effect of band-filling and structural distortions on the Curie temperature of Fe-Mo double perovkites
By means of high resolution neutron powder diffraction at low temperature we
have characterized the structural details of
() and () series of compounds. This study reveals a similar variation of the mean
bond-angle \FeOMo in both series. In contrast, the mean bond-distance \FeMoO\
increases with La but not with Ca substitution. Both series also present a
different evolution of the Curie temperature (), which raises in the La
series and slightly decreases in the Ca one. We thus conclude that the
enhancement of in the La series is due to the electron filling of the
conduction band and a concomitant rising of the density of states at the Fermi
level.Comment: Revtex, 4 Journal pages, 2 figures, 1 tabl
Genetic determinants of cellular addiction to DNA polymerase theta
Polymerase theta (Pol Ξ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol Ξ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol Ξ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol Ξ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol Ξ inhibition represents a promising therapeutic strategy
Structural response to O*-O' and magnetic transitions in orthorhombic perovskites
We present a temperature dependent single crystal x-ray diffraction study of
twinned orthorhombic perovskites La1-xCaxMnO3, for x=0.16 and x=0.25. These
data show the evolution of the crystal structure from the ferromagnetic
insulating state to the ferromagnetic metallic state. The data are modelled in
space group Pnma with twin relations based on a distribution of the b axis over
three perpendicular cubic axes. The twin model allows full structure
determination in the presence of up to six twin fractions using the single
crystal x-ray diffraction data.Comment: 13 pages, including 13 figures and 2 table
Exchange coupling in CaMnO and LaMnO: configuration interaction and the coupling mechanism
The equilibrium structure and exchange constants of CaMnO and LaMnO
have been investigated using total energy unrestricted Hartree-Fock (UHF) and
localised orbital configuration interaction (CI) calculations on the bulk
compounds and MnO and MnO clusters. The
predicted structure and exchange constants for CaMnO are in reasonable
agreement with estimates based on its N\'eel temperature. A series of
calculations on LaMnO in the cubic perovskite structure shows that a
Hamiltonian with independent orbital ordering and exchange terms accounts for
the total energies of cubic LaMnO with various spin and orbital orderings.
Computed exchange constants depend on orbital ordering. UHF calculations tend
to underestimate exchange constants in LaMnO, but have the correct sign
when compared with values obtained by neutron scattering; exchange constants
obtained from CI calculations are in good agreement with neutron scattering
data provided the Madelung potential of the cluster is appropriate. Cluster CI
calculations reveal a strong dependence of exchange constants on Mn d e
orbital populations in both compounds. CI wave functions are analysed in order
to determine which exchange processes are important in exchange coupling in
CaMnO and LaMnO.Comment: 25 pages and 9 postscript figure
Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience.
BACKGROUND: Uveal melanoma exhibits a high incidence of metastases; and, to date, there is no systemic therapy that clearly improves outcomes. The anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.
METHODS: To assess ipilimumab in this setting, the authors performed a multicenter, retrospective analysis of 4 hospitals in the United States and Europe. Clinical characteristics, toxicities, and radiographic disease burden, as determined by central, blinded radiology review, were evaluated.
RESULTS: Thirty-nine patients with uveal melanoma were identified, including 34 patients who received 3 mg/kg ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response criteria and modified World Health Organization criteria were used to assess the response rate (RR) and the combined response plus stable disease (SD) rate after 12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6 months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1 complete response and 1 late partial response (at 100 weeks after initial SD) for an immune-related RR of 5.1%. Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab. The median overall survival from the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4 months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level, and an absolute lymphocyte count â„ 1000 cells/ÎŒL at week 7 were associated significantly with survival.
CONCLUSIONS: In this multicenter, retrospective analysis of 4 hospitals in the United States and Europe of patients with uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed
Correlations of structural, magnetic, and dielectric properties of undoped and doped CaCu3Ti4O12
The present work reports synthesis, as well as a detailed and careful
characterization of structural, magnetic, and dielectric properties of
differently tempered undoped and doped CaCu3Ti4O12 (CCTO) ceramics. For this
purpose, neutron and x-ray powder diffraction, SQUID measurements, and
dielectric spectroscopy have been performed. Mn-, Fe-, and Ni-doped CCTO
ceramics were investigated in great detail to document the influence of
low-level doping with 3d metals on the antiferromagnetic structure and
dielectric properties. In the light of possible magnetoelectric coupling in
these doped ceramics, the dielectric measurements were also carried out in
external magnetic fields up to 7 T, showing a minor but significant dependence
of the dielectric constant on the applied magnetic field. Undoped CCTO is
well-known for its colossal dielectric constant in a broad frequency and
temperature range. With the present extended characterization of doped as well
as undoped CCTO, we want to address the question why doping with only 1% Mn or
0.5% Fe decreases the room-temperature dielectric constant of CCTO by a factor
of ~100 with a concomitant reduction of the conductivity, whereas 0.5% Ni
doping changes the dielectric properties only slightly. In addition,
diffraction experiments and magnetic investigations were undertaken to check
for possible correlations of the magnitude of the colossal dielectric constants
with structural details or with magnetic properties like the magnetic ordering,
the Curie-Weiss temperatures, or the paramagnetic moment. It is revealed, that
while the magnetic ordering temperature and the effective moment of all
investigated CCTO ceramics are rather similar, there is a dramatic influence of
doping and tempering time on the Curie-Weiss constant.Comment: 10 pages, 11 figure
Evolution of the use of corticosteroids for the treatment of hospitalised COVID-19 patients in Spain between March and November 2020: SEMI-COVID national registry
Objectives: Since the results of the RECOVERY trial, WHO recommendations about the use of corticosteroids (CTs) in COVID-19 have changed. The aim of the study is to analyse the evolutive use of CTs in Spain during the pandemic to assess the potential influence of new recommendations. Material and methods: A retrospective, descriptive, and observational study was conducted on adults hospitalised due to COVID-19 in Spain who were included in the SEMI-COVID- 19 Registry from March to November 2020. Results: CTs were used in 6053 (36.21%) of the included patients. The patients were older (mean (SD)) (69.6 (14.6) vs. 66.0 (16.8) years; p < 0.001), with hypertension (57.0% vs. 47.7%; p < 0.001), obesity (26.4% vs. 19.3%; p < 0.0001), and multimorbidity prevalence (20.6% vs. 16.1%; p < 0.001). These patients had higher values (mean (95% CI)) of C-reactive protein (CRP) (86 (32.7-160) vs. 49.3 (16-109) mg/dL; p < 0.001), ferritin (791 (393-1534) vs. 470 (236- 996) ”g/dL; p < 0.001), D dimer (750 (430-1400) vs. 617 (345-1180) ”g/dL; p < 0.001), and lower Sp02/Fi02 (266 (91.1) vs. 301 (101); p < 0.001). Since June 2020, there was an increment in the use of CTs (March vs. September; p < 0.001). Overall, 20% did not receive steroids, and 40% received less than 200 mg accumulated prednisone equivalent dose (APED). Severe patients are treated with higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%. Conclusions: Patients with greater comorbidity, severity, and inflammatory markers were those treated with CTs. In severe patients, there is a trend towards the use of higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%
Treatment implications of the emerging molecular classification system for melanoma.
Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease
Plasma membrane fluidity and hydraulic conductance in wheat roots: interactions between root temperature and nitrate or phosphate deprivation
Uveal melanoma
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UMs are usually initiated by a mutation in GNAQ or GNA11, unlike cutaneous melanomas, which usually harbour a BRAF or NRAS mutation. The annual incidence in Europe and the USA is 6 per million population per year. Risk factors include fair skin, light-coloured eyes, congenital ocular melanocytosis, ocular melanocytoma and the BAP1-tumour predisposition syndrome. Ocular treatment aims at preserving the eye and useful vision and, if possible, preventing metastases. Enucleation has largely been superseded by various forms of radiotherapy, phototherapy and local tumour resection, often administered in combination. Ocular outcomes are best with small tumours not extending close to the optic disc and/or fovea. Almost 50% of patients develop metastatic disease, which usually involves the liver, and is usually fatal within 1 year. Although UM metastases are less responsive than cutaneous melanoma to chemotherapy or immune checkpoint inhibitors, encouraging results have been reported with partial hepatectomy for solitary metastases, with percutaneous hepatic perfusion with melphalan or with tebentafusp. Better insight into tumour immunology and metabolism may lead to new treatments.Ophthalmic researc