A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma

Cancer therapy; Phase I trialsTeràpia del càncer; Assajos de fase ITerapia del cáncer; Ensayos de fase IBackground The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy. Methods We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D). Results In total, 32 recurrent patients were enrolled in the dose-escalation phase (500–16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1–2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years. Conclusions 2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies. Clinical trial registration EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.This study was supported in part by Laminar Pharmaceuticals. Financial support was also provided by the Govern de les Illes Balears i del Fons Social Europeu (ES01/TCAI/53_2016, ES01/TCAI/21_2017, ES01/TCAI/24_2018 and PROCOE/5/2017), the European Commission (H2020 Framework Programmes Project CLINGLIO 755179), Cancer Research UK (C9380/A25138) and the Experimental Cancer Medicine Centre Network (C9380/A25169). VL was supported by a Torres-Quevedo Research contract from the Spanish Ministerio de Economía y Competitividad (PTQ-17-09056), co-funded by the FSE

A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function

$\textbf{PURPOSE}$ Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. $\textbf{METHODS}$ Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m$^{2}$), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m$^{2}$) and C (severe impairment: CrCL <30 mL/min/1.73 m(2)) received cabazitaxel 25 mg/m$^{2}$ (A, B) or 20 mg/m(2) (C, could be escalated to 25 mg/m$^{2}$), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F$_{U}$) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m$^{2}$) versus a control (90 mL/min/1.73 m$^{2}$). $\textbf{RESULTS}$ Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1-20]; Cohort A: 5 [2-13]; Cohort B: 3 [1-15]; and Cohort C: 5 [1-20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80-1.13) and 0.89 (0.61-1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88-1.27) and 1.14 (0.76-1.71); and F U 0.99 (0.94-1.04) and 0.97 (0.87-1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (-0.15 to 0.28); AUC/dose -0.07 (-0.30 to 0.16); and F U 0.02 (-0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports. $\textbf{CONCLUSIONS}$ Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics.This study was supported by Sanofi. Javier Garcia-Corbacho acknowledges clinical fellowship support from SEOM. Experimental Cancer Medicine Centre (ECMC) and NIHR Biomedical Research Centre (BRC) funding is also acknowledged for the Cambridge Cancer Centre

Estudio de adsorbentes para eliminación de nitratos y bromatos en aguas con vista al desarrollo de un sistema continuo de eliminación de oxoaniones

Entre los compuestos que afectan al agua del periurbano bonaerense1 se encuentra el NO3-. Éste es transformado a NO2- en el organismo causando metahemoglobinemia, una deficiencia de oxígeno en la sangre. El BrO3- se genera a partir de Br- por la ozonización del agua para potabilizarla y está clasificado como cancerígeno (IARC)

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Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial

Background: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. Patients and methods: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. Results: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment dur

Validation of a Cost-Efficient Multi-Purpose SNP Panel for Disease Based Research

BACKGROUND: Here we present convergent methodologies using theoretical calculations, empirical assessment on in-house and publicly available datasets as well as in silico simulations, that validate a panel of SNPs for a variety of necessary tasks in human genetics disease research before resources are committed to larger-scale genotyping studies on those samples. While large-scale well-funded human genetic studies routinely have up to a million SNP genotypes, samples in a human genetics laboratory that are not yet part of such studies may be productively utilized in pilot projects or as part of targeted follow-up work though such smaller scale applications require at least some genome-wide genotype data for quality control purposes such as DNA "barcoding" to detect swaps or contamination issues, determining familial relationships between samples and correcting biases due to population effects such as population stratification in pilot studies. PRINCIPAL FINDINGS: Empirical performance in classification of relative types for any two given DNA samples (e.g., full siblings, parental, etc) indicated that for outbred populations the panel performs sufficiently to classify relationship in extended families and therefore also for smaller structures such as trios and for twin zygosity testing. Additionally, familial relationships do not significantly diminish the (mean match) probability of sharing SNP genotypes in pedigrees, further indicating the uniqueness of the "barcode." Simulation using these SNPs for an African American case-control disease association study demonstrated that population stratification, even in complex admixed samples, can be adequately corrected under a range of disease models using the SNP panel. CONCLUSION: The panel has been validated for use in a variety of human disease genetics research tasks including sample barcoding, relationship verification, population substructure detection and statistical correction. Given the ease of genotyping our specific assay contained herein, this panel represents a useful and economical panel for human geneticists

Secondary Chromosomal Attachment Site and Tandem Integration of the Mobilizable Salmonella Genomic Island 1

The Salmonella genomic island 1 is an integrative mobilizable element (IME) originally identified in epidemic multidrug-resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) DT104. SGI1 contains a complex integron, which confers various multidrug resistance phenotypes due to its genetic plasticity. Previous studies have shown that SGI1 integrates site-specifically into the S. enterica, Escherichia coli, or Proteus mirabilis chromosome at the 3′ end of thdF gene (attB site)

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fected individuals. This analysis largely recapitulates the baseline analysis using the categorical trait data (posterior probability of linkage (PPL) = 80%), indicating that our reading impairment phenotype captured poor readers who also have low language ability. Second, we performed epistasis analysis using a functional coding variant in the brain-derived neurotrophic factor (BDNF) gene previously associated with reduced performance on working memory tasks. Modeling epistasis doubled the evidence on 13q21 and raised the PPL to 99.9%, indicating that BDNF and 13q21 susceptibility alleles are jointly part of the genetic architecture of SLI. These analyses provide possible mechanistic insights for further cognitive neuroscience studies based on the models developed herein

Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk loci

Using behavioral and genetic information from the Autism Genetics Resource Exchange (AGRE) data set we developed phenotypes and investigated linkage and association for individuals with and without Autism Spectrum Disorders (ASD) who exhibit expressive language behaviors consistent with a motor speech disorder. Speech and language variables from Autism Diagnostic Interview-Revised (ADI-R) were used to develop a motor speech phenotype associated with non-verbal or unintelligible verbal behaviors (NVMSD:ALL) and a related phenotype restricted to individuals without significant comprehension difficulties (NVMSD:C). Using Affymetrix 5.0 data, the PPL framework was employed to assess the strength of evidence for or against trait-marker linkage and linkage disequilibrium (LD) across the genome. Ingenuity Pathway Analysis (IPA) was then utilized to identify potential genes for further investigation. We identified several linkage peaks based on two related language-speech phenotypes consistent with a potential motor speech disorder: chromosomes 1q24.2, 3q25.31, 4q22.3, 5p12, 5q33.1, 17p12, 17q11.2, and 17q22 for NVMSD:ALL and 4p15.2 and 21q22.2 for NVMSD:C. While no compelling evidence of association was obtained under those peaks, we identified several potential genes of interest using IPA. Conclusion: Several linkage peaks were identified based on two motor speech phenotypes. In the absence of evidence of association under these peaks, we suggest genes for further investigation based on their biological functions. Given that autism spectrum disorders are complex with a wide range of behaviors and a large number of underlying genes, these speech phenotypes may belong to a group of several that should be considered when developing narrow, well-defined, phenotypes in the attempt to reduce genetic heterogeneity