The ontogeny of human laughter

Human adult laughter is characterized by vocal bursts produced predominantly during exhalation, yet apes laugh while exhaling and inhaling. The current study investigated our hypothesis that laughter of human infants changes from laughter similar to that of apes to increasingly resemble that of human adults over early development. We further hypothesized that the more laughter is produced on the exhale, the more positively it is perceived. To test these predictions, novice (n = 102) and expert (phonetician, n = 15) listeners judged the extent to which human infant laughter (n = 44) was produced during inhalation or exhalation, and the extent to which they found the laughs pleasant and contagious. Support was found for both hypotheses, which were further confirmed in two pre-registered replication studies. Likely through social learning and the anatomical development of the vocal production system, infants' initial ape-like laughter transforms into laughter similar to that of adult humans over the course of ontogeny

A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival

Chondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeuticapproaches. Kinase inhibitors have been investigated and shown successful for several different cancer types. Inthis study we aimed at identifying kinase inhibitors that inhibit the survival of chondrosarcoma cells and therebyserve as new potential therapeutic strategies to treat chondrosarcoma patients.An siRNA screen targeting 779 different kinases was conducted in JJ012 chondrosarcoma cells in parallelwith a compound screen consisting of 273 kinase inhibitors in JJ012, SW1353 and CH2879 chondrosarcoma celllines. AURKA, CHK1 and PLK1 were identified as most promising targets and validated further in a morecomprehensive panel of chondrosarcoma cell lines. Dose response curves were performed using tyrosine kinaseinhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycleanalysis. Apoptosis was measured at 24 h after treatment using a caspase 3/7 assay. Finally, chondrosarcomapatient samples (N = =34) were used to examine the correlation between AURKA, CHK1 and PLK1 RNAexpression and documented patient survival.Dose dependent decreases in viability were observed in chondrosarcoma cell lines after treatment with MK-5108, LY2603618 and volasertib, with cell lines showing highest sensitivity to PLK1 inhibition. In additionincreased sensitivity to conventional chemotherapy was observed after CHK1 inhibition in a subset of the celllines. Interestingly, whereas AURKA and CHK1 were both expressed in chondrosarcoma patient samples, PLK1expression was found to be low compared to normal cartilage. Analysis of patient samples revealed that highCHK1 RNA expression correlated with a worse overall survival.AURKA, CHK1 and PLK1 are identified as important survival genes in chondrosarcoma cell lines. Althoughfurther research is needed to validate these findings, inhibiting CHK1 seems to be the most promising potentialtherapeutic target for patients with chondrosarcoma.Toxicolog

Comparative Proteomic Analysis of Serum from Patients with Systemic Sclerosis and Sclerodermatous GVHD. Evidence of Defective Function of Factor H

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by immunological and vascular abnormalities. Until now, the cause of SSc remains unclear. Sclerodermatous graft-versus-host disease (ScGVHD) is one of the most severe complications following bone marrow transplantation (BMT) for haematological disorders. Since the first cases, the similarity of ScGVHD to SSc has been reported. However, both diseases could have different etiopathogeneses. The objective of this study was to identify new serum biomarkers involved in SSc and ScGVHD. METHODOLOGY: Serum was obtained from patients with SSc and ScGVHD, patients without ScGVHD who received BMT for haematological disorders and healthy controls. Bi-dimensional electrophoresis (2D) was carried out to generate maps of serum proteins from patients and controls. The 2D maps underwent image analysis and differently expressed proteins were identified. Immuno-blot analysis and ELISA assay were used to validate the proteomic data. Hemolytic assay with sheep erythrocytes was performed to evaluate the capacity of Factor H (FH) to control complement activation on the cellular surface. FH binding to endothelial cells (ECs) was also analysed in order to assess possible dysfunctions of this protein. PRINCIPAL FINDINGS: Fourteen differentially expressed proteins were identified. We detected pneumococcal antibody cross-reacting with double stranded DNA in serum of all bone marrow transplanted patients with ScGVHD. We documented higher levels of FH in serum of SSc and ScGVHD patients compared healthy controls and increased sheep erythrocytes lysis after incubation with serum of diffuse SSc patients. In addition, we observed that FH binding to ECs was reduced when we used serum from these patients. CONCLUSIONS: The comparative proteomic analysis of serum from SSc and ScGVHD patients highlighted proteins involved in either promoting or maintaining an inflammatory state. We also found a defective function of Factor H, possibly associated with ECs damage

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1(R132H) mutations. Patients harbouring IDH1(R132H) mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1(R132H) have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1(R132H) mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.MTG6Molecular tumour pathology - and tumour genetic

The ontogeny of human laughter

Human adult laughter is characterized by vocal bursts produced predominantly during exhalation, yet apes laugh while exhaling and inhaling. The current study investigated our hypothesis that laughter of human infants changes from laughter similar to that of apes to increasingly resemble that of human adults over early development. We further hypothesized that the more laughter is produced on the exhale, the more positively it is perceived. To test these predictions, novice (n = 102) and expert (phonetician, n = 15) listeners judged the extent to which human infant laughter (n = 44) was produced during inhalation or exhalation, and the extent to which they found the laughs pleasant and contagious. Support was found for both hypotheses, which were further confirmed in two pre-registered replication studies. Likely through social learning and the anatomical development of the vocal production system, infants' initial ape-like laughter transforms into laughter similar to that of adult humans over the course of ontogeny

Quantitative multiple fragment monitoring with enhanced in-source fragmentation/annotation mass spectrometry

Analytical techniques with high sensitivity and selectivity are essential to the quantitative analysis of clinical samples. Liquid chromatography coupled to tandem mass spectrometry is the gold standard in clinical chemistry. However, tandem mass spectrometers come at high capital expenditure and maintenance costs. We recently showed that it is possible to generate very similar results using a much simpler single mass spectrometry detector by performing enhanced in-source fragmentation/annotation (EISA) combined with correlated ion monitoring. Here we provide a step-by-step protocol for optimizing the analytical conditions for EISA, so anyone properly trained in liquid chromatography-mass spectrometry can follow and apply this technique for any given analyte. We exemplify the approach by using 2-hydroxyglutarate (2-HG) which is a clinically relevant metabolite whose d-enantiomer is considered an 'oncometabolite', characteristic of cancers associated with mutated isocitrate dehydrogenases 1 or 2 (IDH1/2). We include procedures for determining quantitative robustness, and show results of these relating to the analysis of dl-2-hydroxyglutarate in cells, as well as in serum samples from patients with acute myeloid leukemia that contain the IDH1/2 mutation. This EISA-mass spectrometry protocol is a broadly applicable and low-cost approach for the quantification of small molecules that has been developed to work well for both single-quadrupole and time-of-flight mass analyzers.The tandem mass spectrometers used in clinical chemistry are expensive. This protocol describes how to generate similar results using a single mass spectrometry detector by optimizing in-source fragmentation and data analysis via correlated ion monitoring

A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer

Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify novel therapeutic targets to prevent this antiestrogen resistance, we performed kinase inhibitor screens with 273 different inhibitors in MCF7 cells overexpressing IGF1R or EGFR. Kinase inhibitors that antagonized antiestrogen resistance but are not directly involved in IGF1R or EGFR signaling were prioritized for further analyses. Various ALK (anaplastic lymphoma receptor tyrosine kinase) inhibitors inhibited cell proliferation in IGF1R expressing cells under normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; the ALK inhibitors did not affect EGFR signaling. On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 219 patients with metastasized ER + breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome