Introduction:The search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome-wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2-73), a selective sigma-1 receptor (SIGMAR1) agonist, was studied in a 57-week Phase 2a trial (NCT02244541).The study was extended for a further 208 weeks (NCT02756858) after meeting its primary safety endpoint. Methods: Safety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment.Results: Biomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE:P < .041), genomic variants SIGMAR1 p.Gln2Pro (ΔMMSE:P < .039; ΔADCS-ADL:P < .063) and COMT p.Leu146fs (ΔMMSE:P < .039; ΔADCS-ADL:P < .063), and baseline MMSE score (slope MMSE:P < .015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models.

Background Gastric cancer (GC) is the third leading cause of cancer death. Early detection is a key factor to reduce its mortality. Methods We retrospectively collected pre- and postoperative serum samples as well as tumour tissues and adjacent normal tissues from 100 GC patients. Serum samples from non-cancerous patients were served as controls ( n = 50). A high-throughput protein detection technology, multiplex proximity extension assays (PEA), was applied to measure levels of over 300 proteins. Alteration of each protein was analysed by univariate analysis. Elastic-net logistic regression was performed to select serum proteins into the diagnostic model. Findings We identified 19 serum proteins (CEACAM5, CA9, MSLN, CCL20, SCF, TGF-alpha, MMP-1, MMP-10, IGF-1, CDCP1, PPIA, DDAH-1, HMOX-1, FLI1, IL-7, ZBTB-17, APBB1IP, KAZALD-1, and ADAMTS-15) that together distinguish GC cases from controls with a diagnostic sensitivity of 93%, specificity of 100%, and area under receiver operating characteristic curve (AUC) of 0·99 (95% CI: 0·98–1). Moreover, the 19-serum protein signature provided an increased diagnostic capacity in patients at TNM I-II stage (sensitivity 89%, specificity 100%, AUC 0·99) and in patients with high microsatellite instability (MSI) (91%, 98%, and 0·99) compared to individual proteins. These promising results will inspire a large-scale independent cohort study to be pursued for validating the proposed protein signature. Interpretation Based on targeted proteomics and elastic-net logistic regression, we identified a 19-serum protein signature which could contribute to clinical GC diagnosis, especially for patients at early stage and those with high MSI. Fund This study was supported by a European H2020-Marie Skłodowska-Curie Innovative Training Networks grant (316,929, GastricGlycoExplorer). Funder had no influence on trial design, data evaluation, and interpretation.

Microsatellite instability (MSI) is a distinct molecular subtype of gastric cancer. In recent years, the clinical consequences of MSI and the therapeutic opportunities to target this peculiar cancer subtype became evident. However, despite the importance of MSI for the stratification of patients, the time and resources required for diagnosis still present an obstacle. In an attempt to identify a new marker for MSI in gastric cancer, we evaluated the expression of five cancer-associated glycan epitopes in a cohort of 13 MSI and 17 microsatellite stable (MSS) cases. Our analysis revealed a highly significant (p < 0.001) association between the expression of the Thomsen-Friedenreich (TF) antigen and MSI status. Hence, we present here the identification of the first single marker for MSI in gastric cancer, excelling with a specificity of 94% (16/17), sensitivity of 69.2% (9/13), negative predictive value of 80% (16/20), and positive predictive value of 90% (9/10). The TF antigen, detected by simple antibody-based assays, is highly specific for carcinoma being undetectable in gastric healthy and premalignant epithelia. This finding lays the basis for new studies and holds promise in improving the rapid identification of MSI in the clinical setting.

The potential carcinogenicity of beryllium has been a topic of study since the mid-1940s. Since then, numerous scientific and regulatory bodies have assigned beryllium to various categories with respect to its carcinogenicity. Past epidemiologic and animal studies, however, have been marked with notable methodological shortcomings. Because it has been about 16 yr since IARC evaluated beryllium and approximately 50 relevant papers on the topic have been published since that time, we conducted a weight-of-evidence analysis of the historical as well as recent animal and human literature. We also assessed whether recently published studies improved upon methodological shortcomings or shed light upon uncertainties in prior studies. Thirty-three animal studies, principally designed to evaluate the cancer hazard or related mechanisms, and seventeen epidemiologic studies were considered in this assessment. Based on this analysis, the evidence for carcinogenicity of beryllium is not as clear as suggested by previous evaluations, because of the inadequacy of the available smoking history information, the lack of well-characterized historical occupational exposures and shortcomings in the animal studies. We concluded that the increase in potential risk of lung cancer was observed among those exposed to very high levels of beryllium and that beryllium's carcinogenic potential in humans at exposure levels that exist in modern industrial settings should be considered either inadequate or marginally suggestive.

Abstract. Fatal adverse reactions to vaccination are uncommon and poorly documented. To our knowledge, this is the first case report of fatal adverse reaction to an inadvertent intravenous vaccination in three calves vaccinated against respiratory (Somnustar Ph) and clostridial (Tasvax 8) diseases. All three calves had severe acute interstitial pneumonia with multifocal pulmonary hemorrhages that resulted in fatal respiratory failure. Qualitatively, the pulmonary lesions in these calves were similar to those in septicemic/endotoxemic calves; however, the severity and extensity of pulmonary hemorrhages were of a higher degree than those usually observed in clinical septicemia/endotoxemia. In addition, approximately 30% of the arterioles and small arteries were surrounded by hemorrhages, which occasionally extended around adjacent bronchioles. A unilateral perijugular hematoma with recent transmural perforation of jugular vein found in all three calves was believed to have been caused by the injection needle during vaccination, and the fatal pulmonary changes were believed to have been secondary to the intravenous injection of vaccine.

Background: Gastric cancer (GC) is the third leading cause of cancer death. Early detection is a key factor to reduce its mortality. Methods: We retrospectively collected pre-and postoperative serum samples as well as tumour tissues and adjacent normal tissues from 100 GC patients. Serum samples from non-cancerous patients were served as controls (n = 50). A high-throughput protein detection technology, multiplex proximity extension assays (PEA), was applied to measure levels of over 300 proteins. Alteration of each protein was analysed by univariate analysis. Elastic-net logistic regression was performed to select serum proteins into the diagnostic model. Findings: We identified 19 serum proteins (CEACAM5, CA9, MSLN, CCL20, SCF, TGF-alpha, MMP-1, MMP-10, IGF-1, CDCP1, PPIA, DDAH-1, HMOX-1, FLI1, IL-7, ZBTB-17, APBB1IP, KAZALD-1, and ADAMTS-15) that together distinguish GC cases from controls with a diagnostic sensitivity of 93%, specificity of 100%, and area under receiver operating characteristic curve (AUC) of 0·99 (95% CI: 0·98-1). Moreover, the 19-serum protein signature provided an increased diagnostic capacity in patients at TNM I-II stage (sensitivity 89%, specificity 100%, AUC 0·99) and in patients with high microsatellite instability (MSI) (91%, 98%, and 0·99) compared to individual proteins. These promising results will inspire a large-scale independent cohort study to be pursued for validating the proposed protein signature. Interpretation: Based on targeted proteomics and elastic-net logistic regression, we identified a 19-serum protein signature which could contribute to clinical GC diagnosis, especially for patients at early stage and those with high MSI. Fund: This study was supported by a European H2020-Marie Skłodowska-Curie Innovative Training Networks grant (316,929, GastricGlycoExplorer). Funder had no influence on trial design, data evaluation, and interpretation.EBioMedicine 44 (2019) 322-333Abbreviations: ADAMTS-15, A disintegrin and metalloproteinase with thrombospondin motifs 15; APBB1IP, Amyloid beta A4 precursor protein-binding family B member 1-interacting protein; CA9, Carbonic anhydrase 9; CCL20, C-C motif chemokine 20; CDCP1, CUB domain-containing protein 1; CEACAM5, Carcinoembryonic antigen-related cell adhesion molecule 5; DDAH1, dimethylarginine dimethylaminohydrolase 1; FLI-1, Friend leukemia integration 1 transcription factor; GCNT1, beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-Nacetylglucosaminyltransferase; HMOX1, Heme oxygenase 1; IGF1, Insulin-like growth factor I; IL-7, Interleukin-7; KAZALD1, Kazal-type serine protease inhibitor domain containing protein 1; MSLN, Mesothelin; MMP-1, Matrix metalloproteinase-1; MMP-10, Matrix metalloproteinase-10; PPIA, Peptidyl-prolyl cis-trans isomerase A; SCF, Stem cell factor/KIT ligand; TGF alpha, Transforming growth factor alpha; ZBTB-17, Zinc finger and BTB domain-containing protein 17.

Background and Objectives A clinical trial was conducted to measure and analyse the pharmacokinetic parameters of a lipid formulation of risperidone, VAL401. The VAL401 formulation is designed to repurpose risperidone from an antipsychotic to an adenocarcinoma treatment, with the lipid formulation altering the cellular uptake of risperidone, thus enabling anticancer biology to be exhibited in preclinical testing. Methods This first human trial of VAL401 measured the concentrations of risperidone and its primary metabolite, 9-hydroxyrisperidone, in the blood of patients after treatment with a single 2-mg dose of VAL401. Results The trial provided information on differences in the pharmacokinetic profile of risperidone in VAL401 that may be caused by the formulation and/or the nature of the cancer patient population. VAL401 provided the following key pharmacokinetic parameters for the risperidone plasma concentration after a single 2-mg dose of VAL401, with results normalised to a dosage of 1 mg for comparison with literature values: T max , 2 h; C max , 8 ng/ml; half-life, 3.5 h; area under the plasma concentration–time curve from time zero to infinity (AUC 0–∞ ), 58.2 ng h 2 /mL. Conclusions Further comparisons of the pharmacokinetic parameters of risperidone and 9-hydroxyrisperidone in plasma of patients administered VAL401 and the corresponding parameters obtained from published data for conventionally formulated risperidone provide evidence for altered biological processing of VAL401 as compared to risperidone. The absolute values obtained provide support for future studies of VAL401 as a cancer treatment, as the C max demonstrates sufficient exposure to reach the concentrations seen during preclinical anticancer testing, yet the overall exposure to the active moiety supports the use of the safety and tolerability data from conventional risperidone during future clinical trials. Electronic supplementary material The online version of this article (10.1007/s13318-018-00538-4) contains supplementary material, which is available to authorized users.

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