Esophageal cancer remains one of the hardest cancers to treat with rising incidence rates, low overall survival and high levels of treatment resistance. The lack of clinically available biomarkers ...hinder diagnosis and treatment stratification. While large scale sequencing approaches have uncovered a number of molecular makers, little has translated in the routine treatment of esophageal cancer patients.
We evaluate the treatment response towards a panel of 215 FDA-approved and 163 epigenetic compounds of 4 established and 2 patient-derived esophageal cancer cell lines. Cell viability was evaluated after 72h of treatment using cell titer glow. The drug sensitivity testing results for gemcitabine and cisplatin were validated using clonogenic assays.
The tested cell lines display different drug sensitivity profiles, although we found compounds that display efficacy in all of the tested established or patient-derived cell lines. Clonogenic assays confirmed the validity of the drug sensitivity testing results. Using the epigenetic library, we observed high sensitivity towards a number of epigenetic modifiers.
Ex vivo drug sensitivity testing may present a viable option for the treatment stratification of esophageal cancer patients and holds the potential to greatly improve patient outcome while reducing treatment toxicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A
bstract
We present a scheme to construct grand unified models based on the superconformal algebra and the inclusion of matter fields in the adjoint representation of supersymmetry. As an ...illustration, we implemented the Georgi-Glashow SU(5) model. The model predicts the existence of a dark (
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Lempel-Ziv complexity (LZ) and derived LZ algorithms have been extensively used to solve information theoretic problems such as coding and lossless data compression. In recent years, LZ has been ...widely used in biomedical applications to estimate the complexity of discrete-time signals. Despite its popularity as a complexity measure for biosignal analysis, the question of LZ interpretability and its relationship to other signal parameters and to other metrics has not been previously addressed. We have carried out an investigation aimed at gaining a better understanding of the LZ complexity itself, especially regarding its interpretability as a biomedical signal analysis technique. Our results indicate that LZ is particularly useful as a scalar metric to estimate the bandwidth of random processes and the harmonic variability in quasi-periodic signals
A fast, simple and robust method has been developed for the simultaneous determination of 23 pharmaceuticals (including some major metabolites) in bivalve mollusks. The analytes belong to eight ...different therapeutic groups: antibiotics, psychiatric drugs, analgesics/anti-inflammatories, tranquilizer, calcium channel blockers, diuretic, and prostatic hyperplasia. The method is based on pressurized liquid extraction (PLE) followed by solid phase extraction clean-up (SPE), and ultra performance liquid chromatography–triple quadrupole mass spectrometry (UHPL–MS/MS) for the identification and quantification of the target analytes. It has been developed and validated in three different species of bivalves: Crassostrea gigas (Pacific oyster), Mytilus galloprovincialis (Mediterranean mussel), and Chamelea gallina (striped venus clam). The majority of the compounds were extracted with a recovery between 40 and 115%. The developed analytical method allowed the determination of the compounds in the lower ng/g concentration levels. The relative standard deviation was under 12% for the intra-day and 20% inter-day analyses, respectively. Finally, the method was applied to oyster, clam and mussel samples collected from the Ebro delta, Spain. The most ubiquitous compounds detected were the psychiatric drug venlanfaxine and the antibiotic azithromycin, with the highest concentrations found in mussel (2.7ng/g dw) and oyster (3.0ng/g dw), respectively. To the best of our knowledge, this is the first time that azithromycin has been reported in environmental samples of marine biota.
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•Analytical method for the simultaneous determination of pharmaceuticals and some major metabolites in mollusks.•Fast, simple, robust, and easy to implement for routine analysis.•Fifteen compounds detected over the MDL in oyster samples from shellfish farm in the Spanish Mediterranean.•The antibiotic azithromycin has been detected for the first time in environmental samples of marine biota.
Background
Oropharyngeal dysphagia (OD) is a prevalent disease with poor prognosis among older people and has no pharmacological treatment. Polymodal sensory receptors like the TRP or ASIC family ...receptors are potential targets to treat OD. TRPM8 agonists and acidic solutions can improve the swallow response in patients with OD, but little is known about the expression of TRPM8, ASIC1, and ASIC3 in the human oropharynx. The aim of this study was to assess the expression and localization of TRPM8, ASIC1, and ASIC3 in human samples of the oropharynx to lay the basis for new pharmacological treatments for OD.
Methods
Pathology‐free samples from oropharyngeal regions innervated by cranial nerves V, IX, and X were obtained during major ENT surgery and processed to obtain mRNA (20 patients) or to be used in immunohistochemical assays (12 patients). TRPM8, ASIC1, and ASIC3 expression and localization were studied with RT‐qPCR and fluorescent immunohistochemistry.
Key Results
ASIC3 was expressed in the 3 regions studied with similar levels and was localized on sensory fibers innervating the mucosa below the basal lamina of all studied regions. TRPM8 was also co‐localized on the sensory fibers innervating the mucosa below the basal lamina of all studied regions. In contrast, ASIC1 was only found in the nerves innervating the tongue muscular fibers.
Conclusions & Inferences
TRPM8 and ASIC3 are found on submucosal sensory nerves in the human oropharynx. Our study lays the basis to use oropharyngeal TRPM8 and ASIC3 receptors as therapeutic targets to develop new active pharmacological treatments for OD patients.
Previous studies have proved the therapeutic effect of TRPM8 and ASIC agonists on neurogenic OD patients, but little is known about the expression and localization of these receptors in the oropharynx.
This study explores the expression and localization of TRPM8, ASIC1, and ASIC3 in human oropharyngeal samples with RT‐qPCR and fluorescent immunohistochemistry.
ASIC3 expression is found throughout the oropharynx. TRPM8 and ASIC3 are immunolocalized on the sensory nerves innervating the oropharyngeal mucosa. ASIC1 is only found on sensory nerves innervating the tongue muscles.
Oropharyngeal TRPM8 and ASIC receptors are promising therapeutic targets to develop active treatments for OD patients.
Experience shapes the development and connectivity of adult-born granule cells (GCs) through mechanisms that are poorly understood. We examined the remodeling of dentate gyrus microcircuits in mice ...in an enriched environment (EE). Short exposure to EE during early development of new GCs accelerated their functional integration. This effext was mimicked by in vivo chemogenetic activation of a limited population of mature GCs. Slice recordings showed that mature GCs recruit parvalbumin γ-aminobutyric acidreleasing interneurons (PV-INs) that feed back onto developing GCs. Accordingly, chemogenetic stimulation of PV-INs or direct depolarization of developing GCs accelerated GC integration, whereas inactivation of PV-INs prevented the effects of EE. Our results reveal a mechanism for dynamic remodelling in which experience activates dentate networks that "prime" young GCs through a disynaptic feedback loop mediated by PV-INs.
Optical interferometry of a thin film array of titanium dioxide (TiO2) nanotubes allows the label-free sensing of rabbit immunoglobulin G (IgG). A protein A capture probe is used, which is ...immobilized on the inner pore walls of the nanotubes by electrostatic adsorption. Control experiments using IgG from chicken (which does not bind to protein A) confirms the specificity of the protein A-modified TiO2 nanotube array sensor. The aqueous stability of the TiO2 nanotube array was examined and compared with porous silica (SiO2), a more extensively studied thin film optical biosensor. The TiO2 nanotube array is stable in the pH range 2 to 12, whereas the porous SiO2 sensor displays significant degradation at pH > 8.
► We grow Scenedesmus obliquus in urban wastewater in batch and continuous operation. ► Biomass in continuous operation can be predicted based on batch growth kinetics. ► Optimum operation residence ...times are based on specific growth rate from batch. ► Optimum hydraulic retention time depends on the objective of the culture.
A laboratory-scale flat panel photobioreactor was operated for the continuous growth of Scenedesmus obliquus and consequent removal of nutrients in wastewater. This study develops a simple model by which biomass values in continuous operation can be predicted from kinetic growth parameters obtained from a shorter batch experiment. Based on this study, biomass concentrations and productivities in continuous operation can be successfully predicted as a function of the specific hydraulic retention time (HRT) assumed. Considerable biomass production and nutrient uptake from wastewater were achieved in the experiment. Optimum operating conditions for the reactor depend on the particular objective: the maximization of biomass production and carbon dioxide biofixation involves a HRT of 2μ−1 (specific growth rate), whereas efficient nutrient removal involves a HRT as close as possible to μ−1 (as long as discharges comply fully with the parameters set); alternatively biomass intended for biodiesel or biogas production would involve a HRT>2μ−1.
Fishes were collected at 16 sites within the three major river drainages (Delaware, Susquehanna, and Ohio) of Pennsylvania. Three species were evaluated for biomarkers of estrogenic/antiandrogenic ...exposure, including plasma vitellogenin and testicular oocytes in male fishes. Smallmouth bass Micropterus dolomieu, white sucker Catostomus commersonii, and redhorse sucker Moxostoma species were collected in the summer, a period of low flow and low reproductive activity. Smallmouth bass were the only species in which testicular oocytes were observed; however, measurable concentrations of plasma vitellogenin were found in male bass and white sucker. The percentage of male bass with testicular oocytes ranged from 10 to 100 %, with the highest prevalence and severity in bass collected in the Susquehanna drainage. The percentage of males with plasma vitellogenin ranged from 0 to 100 % in both bass and sucker. Biological findings were compared with chemical analyses of discrete water samples collected at the time of fish collections. Estrone concentrations correlated with testicular oocytes prevalence and severity and with the percentage of male bass with vitellogenin. No correlations were noted with the percentage of male sucker with vitellogenin and water chemical concentrations. The prevalence and severity of testicular oocytes in bass also correlated with the percent of agricultural land use in the watershed above a site. Two sites within the Susquehanna drainage and one in the Delaware were immediately downstream of wastewater treatment plants to compare results with upstream fish. The percentage of male bass with testicular oocytes was not consistently higher downstream; however, severity did tend to increase downstream.
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