Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors

Leukemia inhibitory factor; Safety; Solid tumorsFactor inhibidor de la leucemia; Seguridad; Tumores sólidosFactor inhibidor de la leucèmia; Seguretat; Tumors sòlidsBackground Activation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors. Materials and methods Using accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers. Results Forty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action. Conclusions MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors.This work was supported by Northern Biologics (no grant number). Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Carole Mongin-Bulewski, PhD, of Ashfield MedComms (Manchester, UK), an Ashfield Health company, and was funded by AstraZeneca (no grant number)

Aluminium incorporation in AlGaN/GaN heterostructures: a comparative study by ion beam analysis and X-ray diffraction

The Al content in AlxGa1 − xN/GaN heterostructures has been determined by X-ray diffraction (XRD) and contrasted with absolute measurements from ion beam analysis (IBA) methods. For this purpose, samples with 0.1bxb0.3 grown by metal organic chemical vapour deposition on sapphire substrates have been studied. XRD and IBA corroborate the good epitaxial growth of the AlGaN layer, which slightly deteriorates with the incorporation of Al for xN0.2. The assessment of Al incorporation by XRD is quite reliable regarding the average value along the sample thickness. However, XRD analysis tends to overestimate the Al fraction at low contents, which is attributed to the presence of strain within the layer. For the highest Al incorporation, IBA detects a certain Al in-depth compositional profile that should be considered for better XRD data analysis

Effects of N2 Plasma Pretreatment on the SiN Passivation of AlGaN/GaN HEMT

The impact of in situ low-power plasma pretreatment, prior to silicon-nitride (SiN) deposition, was investigated in AlGaN/GaN high-electron mobility transistors (HEMTs). These studies reveal that the use of plasma in HEMT passivation reduces current-collapse and gate-lag effects. Such treatment is also beneficial to improve gate leakage, and from RF measurements, no degradation of was observed. These beneficial effects of the plasma pretreatment seem to be due to a significant reduction in interface charge density, as shown in this letter using GaN MIS devices, where a decrease of 60% was observed

Eyespot resistance gene Pch-1 in H-93 wheat lines. Evidence of linkage to markers of chromosome group 7 and resolution from the endopeptídase locus Ep-Dlb

Gene Pch1, which confers resistance to eyespot disease (Pseudocercosporella herpotrichoides Fron), has been located on chromosome 7D in the H-93 wheat-Aegilops ventricosa transfer lines using isozyme markers and DNA probes corresponding to group 7 chromosomes. Previous experiments had failed to ascertain this location. The lack of segregation of the resistance trait in progeny from reciprocal crosses between lines H-93-70 and VPM1 indicates that their respective resistance factors are allelic. Line H-93-51 carries the endopeptidase allele Ep-D1b but is susceptible to eyespot, which indicates that resistance to eyespot is not a product of the Ep-D locus, as had been proposed in a previous hypohesi

Eyespot resistance gene Pch-1 from Aegilops ventricosa is associated with a different chromosome in wheat line H-93-70 than the resistance factor in "Roazon" wheat

The hexaploid wheat line H-93-70 carries a gene (Pch-1) that has been transferred from the wild grass Aegilops ventricosa and confers a high degree of resistance to eyespot diesease, caused by the fungus Pseudocercosporella herpotrichoides. Crosses of the resistant line H-93-70 with the susceptible wheat Pané 247 and with a 7D/7Ag wheat/Agropyron substitution line were carried out and F2 kernels were obtained. The kernels were cut transversally and the halves carrying the embryos were used for the resistance test, while the distal halves were used for genetic typing. Biochemical markers were used to discriminate whether the transferred Pch-1 gene was located in chromosome 7D, as is the case for a resistance factor present in Roazon wheat. In the crosses involving Pané 247, resistance was not associated with the 7D locus Pln, which determines sterol ester pattern (dominant allele in H-93-70). In the crosses with the 7D/7Ag substitution line, resistance was neither associated with protein NGE-11 (7D marker), nor alternatively inherited with respect to protein C-7 (7Ag marker). It is concluded that gene Pch-1 represents a different locus and is not an allele of the resistance factor in Roazon whea

Biochemical and cytological characterization of wheat/Aegilops ventricosa addition and transfer lines carrying chromosome 4MV

The gene encoding a variant of alcohol dehydrogenase, Adh-, has been found to be associated with the chromosome of the Mv genome which is present in type 9 wheat/Aegilops ventricosa addition line, to which the genes for protein CM-4 and for a phosphatase variant, Aph-v, had been previously assigned. Transfer line H-93-33, which has 42 chromosomes and has been derived from the cross (Triticum turgidum x Ae. ventricosa) x T. aestivum, carries genes encoding all three biochemical markers. Linkage between these genes has been demonstrated by analysis of individual kernels of the F2 (H-93-33 x T. aestivum cv. Almatense H-10-15). A study of the hybrids of line H-93-33 with T. aestivum H-10-15 and with the 4DS ditelosomic line has confirmed that, as suspected, the linkage group corresponds to chromosome 4Mv from Ae. ventricosa. Additionally, it has been found that the previously reported resistance of line H-93-33 to powdery mildew (Erysiphe graminis) is also linked to the biochemical markers; this indicates that either the gene responsible for it is different from that in lines H-93-8 and H-93-35, or that a translocation between two different Mv chromosomes has occurred in line H-93-33

tumor infiltrating lymphocytes tils and pdl1 expression as prescreening enrichment biomarkers of clinical benefit to immune checkpoint inhibitors ci in early clinical trials ect

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Revista de Vertebrados de la Estación Biológica de Doñana

La reproducción de Hyla meridionalis en el suroeste de EspañaAlimentación y relaciones tróficas entre larvas de Triturus marmoratus, T. alpestris y T. helveticus (Amphibia: CaudataOrganization of behaviour in isolated lizards (Gallotia galloti galloti) as revealed by multivariate analyseComposición y estructura de las comunidades de aves a lo largo de un gradiente altitudinal en tres medios arbustivos del macizo de Ayllón(Sistema Central)La comunidad de aves de un acebuchar del sur de España durante el periodo invernal y de cria.Alimentación del buho chico (Asio otus) en la isla de Tenerife y análisis comparativo con la dieta de Tyto albaAlimentación del zorzal charlo (Turdus viscivoros) en la sierra de Cazorla, SE de España.La migración en España del verderón común (Carduelis chloris, L.) según los resultados de anillamientoIdentificación de los principales quirópteros ibéricos a partir de sus dientes aislados. Valor sistemático de los caracteres morfológicos y métricos dentariosRitmo de actividad en Gazella dorcasSobre la sistemática y biología de Eliomys quercinus en la Cordillera Cantábrica.Primeras citas de Barbus microcephalus Almaça, 1967 (Ostariophysi: Cyprinidae) en EspañaSobre la presencia de Lampetra planeri BLOCH, 1784 en España.Sobre el status taxonómico del género Valencia Myers, 1928 en el suroeste de IberiaNuevas localidades de Chondrostroma polypis Steindachner, 1865 (Ostariophysi, Cyprinidae) en España.Sobre la distribución Gobio gobio (L., 1758)(OSTAOPHYSI, CIPRINIDAE) en EspañaNotas sobre la alimentación de larvas de anfibios: 2. Salamandra salamandra de CazorlaNuevos datos sobre la permanencia de caracteres larvarios en individuos adultos de una población de tritón pirenaico (Euproctus asper) en el valle de AránLa variación del diseño natural como método de reconocimiento individual en Triturus boscaiPresencia de Triturus boscai en la provincia de Córdoba.Datos sobre la alimentación de Athene cunicularia en la Reserva de fauna altoandina de Ulla-Ulla, Bolivia.Falco peregrinus cassini en BoliviaAlgunos datos sobre quirópteros de Galicia.Notas sobre la alimentación de la nutria (Lutra lutra) en el embalse de Matavacas, HuelvaPeer reviewe

PD-1 blockade in recurrent or metastatic cervical cancer: Data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer

Objectives: To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. Methods: In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA). Results: Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens (N = 155), PD-L1 protein expression in tumor and immune cells was negative (<1%) more commonly in adenocarcinoma than in squamous tumors. PD-L1 mRNA levels were lower in adenocarcinoma than squamous cell tumors (1.2 vs 5.0 mean transcripts per million, respectively) in TCGA. Conclusions: Cemiplimab has activity in cervical squamous cell carcinoma. The phase I results, combined with results from other anti-PD-1 trials in cervical cancer and our biomarker analyses have informed the design of the ongoing phase III trial, with the primary overall survival hierarchical analyses being done first in patients with squamous histology