Field-Tuning of the electron and hole populations in the ruthenate Bi_3Ru_3O_11

Experiments on the Hall coefficient R_H and heat capactity C reveal an unusual, compensated electronic ground state in the ruthenate Bi_3Ru_3O_11. At low temperature T, R_H decreases linearly with magnetic field |H| for fields larger than the field scale set by the Zeeman energy. The results suggest that the electron and hole populations are tuned by H in opposite directions via coupling of the spins to the field. As T is decreased below 5 K, the curve C(T)/T vs. T^2 shows an anomalous flattening consistent with a rapidly growing Sommerfeld parameter \gamma(T). We discuss shifts of the electron and hole chemical potentials by H to interpret the observed behavior of R_H.Comment: 5 pages, 6 figures, reference adde

SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation

This work has been funded by the Foundation for Applied Medical Research, ISCIII-Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional 'Una manera de hacer Europa' (PI19/00230 to AC, PI19/00098 to LMM, PI17/00411 to RP and DA, PI19/00560 to JMGP; CIBERONC CB16/12/00443 to LMM and CB16/12/00390 to JMGP), AECC and Ramón Areces Foundations (both to LMM), 'Instituto de Investigación Sanitaria del Principado de Asturias to JMGP and BMS (to JA and LMM).Redin, E., Garmendia, I., Lozano, T., Serrano, D., Senent, Y., Redrado, M., Villalba, M., De Andrea, C.E., Exposito, F., Ajona, D., Ortiz-Espinosa, S., Remirez, A., Bertolo, C., Sainz, C., Garcia-Pedrero, J., Pio, R., Lasarte, J., Agorreta, J., Montuenga, L.M., Calvo, A

A model based on the quantification of complement C4c, CYFRA 21-1 and CRP exhibits high specificity for the early diagnosis of lung cancer

Lung cancer screening detects early-stage cancers, but also a large number of benign nodules. Molecular markers can help in the lung cancer screening process by refining inclusion criteria or guiding the management of indeterminate pulmonary nodules. In this study, we developed a diagnostic model based on the quantification in plasma of complement-derived fragment C4c, cytokeratin fragment 21-1 (CYFRA 21-1) and C-reactive protein (CRP). The model was first validated in two independent cohorts, and showed a good diagnostic performance across a range of lung tumor types, emphasizing its high specificity and positive predictive value. We next tested its utility in two clinically relevant contexts: assessment of lung cancer risk and nodule malignancy. The scores derived from the model were associated with a significantly higher risk of having lung cancer in asymptomatic individuals enrolled in a computed tomography (CT)-screening program (OR = 1.89; 95% CI = 1.20–2.97). Our model also served to discriminate between benign and malignant pulmonary nodules (AUC: 0.86; 95% CI = 0.80–0.92) with very good specificity (92%). Moreover, the model performed better in combination with clinical factors, and may be used to reclassify patients with intermediate-risk indeterminate pulmonary nodules into patients who require a more aggressive work-up. In conclusion, we propose a new diagnostic biomarker panel that may dictate which incidental or screening-detected pulmonary nodules require a more active work-up

Estoc: New approach warrants long-term support to the oceanic observational program

Peer Reviewe

Theory of low frequency magnetoelectric coupling in magnetostrictive-piezoelectric bilayers

A theoretical model is presented for low-frequency magnetoelectric (ME) effects in bilayers of magnetostrictive and piezoelectric phases. A novel approach, the introduction of an interface coupling parameter k, is proposed for the consideration of actual boundary conditions at the interface. An averaging method is used to estimate effective material parameters. Expressions for ME voltage coefficients are obtained by solving elastostatic and electrostatic equations. We consider both unclamped and rigidly clamped bilayers and three different field orientations of importance: (i) longitudinal fields in which the poling field, bias field and ac fields are all parallel to each other and perpendicular to the sample plane; (ii) transverse fields for magnetic fields parallel to each other and perpendicular to electric fields, and (iii) in-plane longitudinal fields for all the fields parallel to each other and to the sample plane. The theory predicts a giant ME coupling for bilayers with cobalt ferrite (CFO), nickel ferrite (NFO), or lanthanum strontium manganite (LSMO) for the magnetostrictive phase and barium titanate (BTO) or lead zirconate titanate (PZT) for the piezoelectric phase.Comment: To be published in Physical Review B, August 1, 200

YES1 drives lung cancer growth and progression and predicts sensitivity to dasatinib

Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non–small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy

Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer

Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.M.R. was supported by a fellowship from MICIU (FPU15/00173), R.E. by a donation from Mauge Burgos de la Iglesia’s family. The Proteomics Platforms of Navarrabiomed led by E.S. and J.F.-I. is a member of Proteored, PRB3 and is supported by grant PT17/0019 of the PE I + D + i 2013–2016, funded by ISCIII and ERDF. E.J.-L. was supported by Foundation of Spanish Association Against Cancer (PROYE18012ROSE), by Centro de Investigación Biomédica en Red (CIBERONC; CB16-12-00350), and by Generalitat Valenciana (AICO/2021/333). F.L. was funded by the Gobierno de Navarra (Ref. 34/2021), the Cancer Research Thematic Network of the Instituto de Salud Carlos III (RTICC RD12/0036/0066), PID2021-122638OB-I00 MCIN/AEI/10.13039/501100011033/ FEDER, UE and by FEDER “Una manera de hacer Europa”. I.F. was funded by FIS PI19/00320 and by the Miguel Servet Program CP21/00052. S.V. was supported by Ministerio de Ciencia, Innovación y Universidades, Convocatoria 2019 para incentivar la Incorporación Estable de Doctores (IED2019-001007-I), by FEDER /Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación (SAF2017-89944-R and PID2020‐116344‐RB‐100/MCIN/AEI/10.13039/501100011033, by a Leonardo Grant for Researchers and Cultural Creators 2018 from BBVA Foundation, by a seed grant at the I Convocatoria Proyectos Prueba de Concepto from PRB3-Proteored (Institute of Health Carlos III-ISCIII), by Fundació La Marató de TV3 (474/C/2019), and by Foundation of Spanish Association Against Cancer - Strategic Projects 2020 (PROYE20029VICE). M.P.-S. and S.V. were also funded by Fundación Alberto Palatchi. None of the funding sources were involved in the decision to submit the article for publication.Peer reviewe

Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel