The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. We hypothesize, that performing multi-omic analyses during CPT ...gives the opportunity to home in on molecular mechanisms involved. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken. RNA-Sequencing, steroid profiling and untargeted metabolomics were performed. Each 'omic level was analyzed separately at both single-feature and systems-level (principal component PCA and partial least squares PLS regression analysis) and all 'omic levels were combined using an integrative multi-omics approach, all using the paired-sample design. We showed that PCA was not able to discriminate time points, while PLS did significantly distinguish time points using metabolomics and/or transcriptomic data, but not using conventional physiological measures. Transcriptomic and metabolomic data revealed at feature-, systems- and integrative- level biologically relevant processes involved during CPT, e.g. lipid metabolism and stress response. Multi-omics strategies have a great potential in pain research, both at feature- and systems- level. Therefore, they should be exploited in intervention studies, such as pain provocation tests, to gain knowledge on the biological mechanisms involved in complex traits.
Background & Aims Death receptors expressed on tumor cells can prevent metastasis formation by inducing apoptosis, but they also can promote migration and invasion. The determinants of death receptor ...signaling output are poorly defined. Here we investigated the role of oncogenic K-Ras in determining death receptor function and metastatic potential. Methods Isogenic human and mouse colorectal cancer cell lines differing only in the presence or absence of the K-Ras oncogene were tested in apoptosis and invasion assays using CD95 ligand and tumor necrois factor–related apoptosis-inducing ligand (TRAIL) as stimuli. Metastatic potential was assessed by intrasplenic injections of green fluorescent protein- or luciferase-expressing tumor cells, followed by intravital fluorescence microscopy or bioluminescence imaging, and confocal microscopy and immunohistochemistry. Ras-effector pathway control of CD95 output was assessed by an RNA-interference and inhibitor-based approach. Results CD95 ligand and TRAIL stimulated invasion of colorectal tumor cells and liver metastases in a K-Ras–dependent fashion. Loss of mutant K-Ras switched CD95 and TRAIL receptors back into apoptosis mode and abrogated metastatic potential. Raf1 was essential for the switch in CD95 function, for tumor cell survival in the liver, and for K-Ras–driven formation of liver metastases. K-Ras and Raf1 suppressed Rho kinase (ROCK)/LIM kinase-mediated phosphorylation of the actin-severing protein cofilin. Overexpression of ROCK or LIM kinase allowed CD95L to induce apoptosis in K-Ras–proficient cells and prevented metastasis formation, whereas their suppression protected K-Ras–deficient cells against apoptosis. Conclusions Oncogenic K-Ras and its effector Raf1 convert death receptors into invasion-inducing receptors by suppressing the ROCK/LIM kinase pathway, and this is essential for K-Ras/Raf1–driven metastasis formation.
We search for the rare flavor-changing neutral current process B^{+}→K^{+}τ^{+}τ^{-} using data from the BABAR experiment. The data sample, collected at the center-of-mass energy of the ϒ(4S) ...resonance, corresponds to a total integrated luminosity of 424 fb^{-1} and to 471×10^{6} BBover ¯ pairs. We reconstruct one B meson, produced in the ϒ(4S)→B^{+}B^{-} decay, in one of many hadronic decay modes and search for activity compatible with a B^{+}→K^{+}τ^{+}τ^{-} decay in the rest of the event. Each τ lepton is required to decay leptonically into an electron or muon and neutrinos. Comparing the expected number of background events with the data sample after applying the selection criteria, we do not find evidence for a signal. The resulting upper limit, at the 90% confidence level, is B(B^{+}→K^{+}τ^{+}τ^{-})<2.25×10^{-3}.
ABSTRACT In the summer of 2012, during a Pulsar Search Collaboratory workshop, two high-school students discovered J1930-1852, a pulsar in a double neutron star (DNS) system. Most DNS systems are ...characterized by short orbital periods, rapid spin periods, and eccentric orbits. However, J1930-1852 has the longest spin period ( 185 ms) and orbital period ( 45 days) yet measured among known, recycled pulsars in DNS systems, implying a shorter than average and/or inefficient recycling period before its companion went supernova. We measure the relativistic advance of periastron for J1930-1852, (4) deg yr−1, which implies a total mass ( (4) ) consistent with other DNS systems. The constraints on place limits on the pulsar and companion masses ( and respectively). J1930-1852's spin and orbital parameters challenge current DNS population models and make J1930-1852 an important system for further investigation.
Human papillomavirus (HPV) is a risk factor for the development of benign and malignant mucosal head and neck lesions. P16INK4A is often used as a surrogate marker for HPV‐infection, although there ...is still controversy with respect its reliability. Our aim was to determine if p16INK4A overexpression can accurately predict both high‐risk and low‐risk‐HPV‐presence in (pre)malignant and benign head and neck lesions. P16INK4A immunohistochemistry was performed on paraffin‐embedded tissue sections of 162 oropharyngeal squamous cell carcinomas (OPSCC), 14 tonsillar and 23 laryngeal dysplasias, and 20 tonsillar and 27 laryngeal papillomas. PCR, enzyme‐immunoassay and FISH analysis were used to assess HPV‐presence and type. Of the 162 OPSCC and 14 tonsillar dysplasias, 51 (31%) and 10 (71%) were HPV16‐positive, respectively. All tonsillar papillomas were HPV‐negative and four laryngeal dysplasias and 26 laryngeal papillomas were positive for HPV6 or −11. P16INK4A immunohistochemistry revealed a strong nuclear and cytoplasmic staining in 50 out of 51 HPV16‐positive and 5 out of 111 HPV‐negative OPSCC (p < 0.0001) and in all HPV16‐positive tonsillar dysplasias, whereas highly variable staining patterns were detected in the papillomas and laryngeal dysplasias, irrespective of the HPV‐status. In addition, the latter lesions generally showed a higher nuclear than cytoplasmic p16INK4A immunostaining intensity. In conclusion, our data show that strong nuclear and cytoplasmic p16INK4A overexpression is a reliable surrogate indicator for HPV16 in OPSCC and (adjacent) dysplasias. For HPV6 or −11‐positive and HPV‐negative benign and premalignant lesions of the tonsil and larynx, however, p16INK4A immunostaining is highly variable and cannot be recommended to predict HPV‐presence.
What's new?
Human papillomavirus (HPV) is a risk factor for the development of benign and malignant mucosal head and neck lesions. P16INK4A is often used as a surrogate marker for HPV infection, although there is still controversy with respect to its reliability. The aim of this study was to determine if p16INK4A overexpression can accurately predict both high‐risk and low‐risk‐HPV presence in (pre)malignant and benign head and neck lesions. This results show that p16INK4A overexpression is a reliable surrogate indicator for high‐risk‐HPV16 in oropharyngeal squamous cell carcinomas (OPSCC) and tonsillar dysplasias, but not for low‐risk‐HPV6/11‐positive benign and premalignant tonsillar and laryngeal lesions.
Many scenarios of physics beyond the standard model predict the existence of new gauge singlets, which might be substantially lighter than the weak scale. The experimental constraints on additional ...scalars with masses in the MeV to GeV range could be significantly weakened if they interact predominantly with leptons rather than quarks. At an e+e− collider, such a leptophilic scalar (ϕL) would be produced predominantly through radiation from a τ lepton. We report herein a search for e+e−→τ+τ−ϕL, ϕL→ℓ+ℓ− (ℓ=e, μ) using data collected by the BABAR experiment at SLAC. No significant signal is observed, and we set limits on the ϕL coupling to leptons in the range 0.04<mϕL<7.0 GeV. These bounds significantly improve upon the current constraints, excluding almost entirely the parameter space favored by the observed discrepancy in the muon anomalous magnetic moment below 4 GeV at 90% confidence level.
Ventilator-associated pneumonia (VAP) is the most frequently occurring nosocomial infection associated with increased morbidity and mortality. Although oral decontamination with antibiotics reduces ...incidences of VAP, it is not recommended because of potential selection of antibiotic-resistant pathogens. We hypothesized that oral decontamination with either chlorhexidine (CHX, 2%) or CHX/colistin (CHX/COL, 2%/2%) would reduce and postpone development of VAP, and oral and endotracheal colonization.
To determine the effect of oral decontamination with CHX or CHX/COL on VAP incidence and time to development of VAP.
Consecutive patients needing mechanical ventilation for 48 h or more were enrolled in a randomized, double-blind, placebo-controlled trial with three arms: CHX, CHX/COL, and placebo (PLAC). Trial medication was applied every 6 h into the buccal cavity. Oropharyngeal swabs were obtained daily and quantitatively analyzed for gram-positive and gram-negative microorganisms. Endotracheal colonization was monitored twice weekly.
Of 385 patients included, 130 received PLAC, 127 CHX and 128 CHX/COL. Baseline characteristics were comparable. The daily risk of VAP was reduced in both treatment groups compared with PLAC: 65% (hazard ratio HR=0.352; 95% confidence interval CI, 0.160, 0. 791; p=0.012) for CHX and 55% (HR=0.454; 95% CI, 0.224, 0. 925; p=0.030) for CHX/COL. CHX/COL provided significant reduction in oropharyngeal colonization with both gram-negative and gram-positive microorganisms, whereas CHX mostly affected gram-positive microorganisms. Endotracheal colonization was reduced for CHX/COL patients and to a lesser extent for CHX patients. No differences in duration of mechanical ventilation, intensive care unit stay, or intensive care unit survival could be demonstrated.
Topical oral decontamination with CHX or CHX/COL reduces the incidence of VAP.
Purpose
Next generation sequencing (NGS) is an important tool used in clinical practice to obtain the required molecular information for accurate diagnostics of high-grade adult-type diffuse glioma ...(HGG). Since individual centers use either in-house produced or standardized panels, interlaboratory variation could play a role in the practice of HGG diagnosis and treatment. This study aimed to investigate the current practice in NGS application for both primary and recurrent HGG.
Methods
This nationwide Dutch survey used the expertise of (neuro)pathologists and clinical scientists in molecular pathology (CSMPs) by sending online questionnaires on clinical and technical aspects. Primary outcome was an overview of panel composition in the different centers for diagnostic practice of HGG. Secondary outcomes included practice for recurrent HGG and future perspectives.
Results
Out of twelve neuro-oncology centers, the survey was filled out by eleven (neuro)pathologists and seven CSMPs. The composition of the diagnostic NGS panels differed in each center with numbers of genes ranging from 12 to 523. Differences are more pronounced when tests are performed to find therapeutic targets in the case of recurrent disease: about half of the centers test for gene fusions (60%) and tumor mutational burden (40%).
Conclusion
Current notable interlaboratory variations as illustrated in this study should be reduced in order to refine diagnostics and improve precision oncology. In-house developed tests, standardized panels and routine application of broad gene panels all have their own advantages and disadvantages. Future research would be of interest to study the clinical impact of variation in diagnostic approaches.
Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, ...triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change in GNAI1 and VIPR2 gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.
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