Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody ...targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC.
Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% 95% confidence interval (CI) 7.6% to 22.5%, with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class.
Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.
•Retifanlimab (PD-1 inhibitor) monotherapy demonstrated encouraging results in patients with platinum-refractory SCAC.•Clinically meaningful antitumor activity was reported with ORR of 13.8% and stable disease in 35.1%, for a DCR of 48.9%.•Observed responses in advanced SCAC were durable (median 9.5 months).•Acceptable safety profile consistent with that reported for the PD-(L)1 inhibitor class.•Promising results warrant further investigation of retifanlimab in advanced SCAC as well as earlier stages of disease.
•A new surface imprinting method by template immobilizing strategy.•Michael addition of EGDMA and amino functional groups on the magnetic surface.•High adsorption capacity, proper selectivity and ...fast kinetic binding were achieved.•Magnetic sorbent was utilized for selective determination of 4-nitrophenol.
In order to resolve the low adsorption capacity of the surface molecularly imprinting methods, an approach was developed for the preparation of magnetic imprinted polymers by pre-grafting the amino functional material, 3-aminopropyltriethoxysilane (APTES), on the surface of the silica coated magnetic substrate. APTES was used for amino functionalization of the silica coated Fe3O4 nanoparticles. Amino groups were used for immobilization of the template molecules on the magnetic surface and additionally to react with the terminal vinyl groups of cross-linker, ethylene glycol dimethacrylate (EGDMA), by the Michael addition reaction. In this way, the imprinting sites of the analytes formed on the substrate were increased. The sorbent was synthesized in the presence of 4-nitrophenol (4-NP) and EGDMA as the template and cross-linker, respectively. Different parameters affecting the adsorption, such as pH, desorption solvent type and adsorption time were evaluated and optimized. The prepared magnetic molecularly imprinted polymer (MMIP) showed high adsorption capacity and proper selectivity for the template molecule. The kinetic adsorption curve indicated that 90min was sufficient to achieve the adsorption equilibrium for MMIP. The maximum adsorption capacity was 129.1mgg−1. The experiments exhibited a linear range of 10–3000μgL−1 for 4-NP with the correlation coefficient (R2) of 0.997. The results of the real sample analysis confirmed the applicability of the proposed MMIP for quantitative analysis of 4-NP in the aqueous samples.
•A novel nanocomposite was utilized by gold coating of magnetic MCM-41.•The present sorbent was coupled with dispersive liquid–liquid microextraction procedure.•The proposed method was developed for ...trace analysis of some polycyclic aromatic hydrocarbons.
An efficient magnetic sorbent was introduced for solid phase extraction by incorporation of the gold nanoparticles into the hexagonal lattice of magnetic MCM-41. For the effective incorporation of the gold nanoparticles, magnetic MCM-41 was functionalized with 3-aminopropyltriethoxysilane (APTES), which then interacted with Au atoms through the amine groups. Furthermore, to achieve high pre-concentration factors (PFs), the method was coupled with dispersive liquid–liquid microextraction (DLLME) procedure. Polycyclic aromatic hydrocarbons (PAHs) were used as the model compounds to evaluate the extraction performance of the proposed method. The π-system of PAH compounds and immobilized Au atoms on the surface of the sorbent can cause the electron donor–acceptor interactions. The parameters affecting extraction recovery such as types of the disperser and extraction solvents, pH of the sample solution, and the extraction time were optimized. Under the optimized conditions, the high PFs were obtained in the range 5519–6271 for the target analytes. The kinetic adsorption illustrated that 5min was sufficient to achieve adsorption equilibrium for PAHs. The evaluations also showed a linearity range 0.01–50μgL−1 with the detection limit in the range 0.002–0.004μgL−1 for the PAHs. The applicability of the method for the analysis of PAHs in real samples was justified by the extraction of PAHs from seawater samples. The results indicated good recovery efficiencies ranging from 91.4 to 104.2%.
► Combination of molecularly imprinted polymer and magnetic nanoparticles. ► Vinyl-modified silica nanoparticles were prepared for grafting polymerization. ► MIP of 4-NP was synthesized by ...copolymerization of MAA and EGDMA.
In this study, an analytical procedure for the selective extraction and detection of 4-nitrophenol (4-NP) was investigated by using of molecularly imprinted polymer on the surface of magnetic nanoparticles (MNPs). The magnetic nanoparticles were modified by tetraethyl orthosilicate (TEOS) and 3-methacryloxypropyl trimethoxysilane (MPTS) before imprinting. The magnetic molecularly imprinted polymer (MMIP) was polymerized at the surface of modified MNPs by using of methacrylic acid (MAA) as functional monomer, 4-NP as template and ethylene glycol dimethacrylate (EGDMA) as cross-linker. Experimental design by the Taguchi method was used for the optimization of synthesis procedure of imprinted polymer. The resulting MMIP showed high adsorption capacity, proper selectivity and fast kinetic binding for the template molecule. It was characterized by Fourier transform infrared (FT-IR) analysis, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) methods. The maximum adsorption capacity of MMIP was obtained as 57.8mgg−1 and it took about 2h to achieve the equilibrium state. The adsorption curve of MMIP was also fitted with the Freundlich isotherm equation. The assay exhibited a linear range of 25–1000μgL−1 for 4-NP with the correlation coefficient (R2) of 0.995. The method was also examined for the analysis of 4-NPs in seawater. For recovery evaluation, the seawater samples were spiked at two concentration levels of 50 and 100μgL−1 of 4-NPs and the recovery values were in the range of 79.3–99.8%. The relative standard deviations (RSD) for the recoveries were less than 5.2%.
When asked to describe possible elicitors of fear, American children generate more stories about imaginary creatures than realistic ones; Palestinian children generate more realistic than imaginary ...causes (Kayyal et al., 2015). The current study reversed this task to investigate whether these patterns persist when American (n = 72) and Palestinian (n = 72) children (3–8 years, sex- and age-matched) freely labeled a story protagonist's emotion and generated a behavioral consequence. For each story, children heard a brief description about a protagonist who encountered an imaginary (e.g., monster) or realistic (e.g., snake) fear-eliciting creature. Americans labeled the protagonist's emotion for imaginary fear stories as scared significantly more often than for realistic ones; Palestinians labeled the protagonist's emotion for both types as scared with equal probability. Children in both groups associated escape-related behaviors (e.g., running away) with both imaginary and realistic fear elicitors, but they associated inquisitive behaviors (e.g., going to look) exclusively with imaginary fear elicitors. Thus, culture plays a role in what children identify as scary but not in the behavioral responses they associate with different fear elicitors.
The main aim of the work was to develop an efficient strategy for preparing molecularly imprinted polymers (MIPs) on the surface of graphene oxide (GO) sheets. Amine functionalization of GO was ...accomplished by a facile and efficient procedure with 3-aminopropyltriethoxysilane (APTES). Then, the template was immobilized onto amino-functionalized GO in order to improve the recognition ability of MIP-based sensors. Also, prior to polymerization, ethylene glycol dimethacrylate was grafted onto the APTES coated graphene oxide sheets by the Michael addition reaction. In this way, many homogeneous imprinting sites were formed on the GO sheets. The resulting composite was placed on a glassy carbon electrode (GCE) which then was used for determination of bisphenol A (BPA) by electrochemical technique. The composite of amino-functionalized GO and MIP (GO/APTES–MIP) was characterized by scanning electron microscopy, Fourier transform infrared spectroscopy and energy dispersive X-ray spectroscopy. The electrochemical behaviors of the sensors were investigated by cyclic voltammetry and differential pulse voltammetry (DPV) techniques. Compared with non-imprinted polymer, the DPV current response of MIP sensor is about 4.6 times larger. Under the optimized conditions, GO/APTES–MIP sensor displays two linear ranges (from 0.006 to 0.1 μM and 0.2 to 20 μM) for determination of BPA, and the detection limit is 0.003 μM (at an S/N ratio of 3). The MIP-based sensor was applied to the in-situ determination of BPA in milk and mineralised water without any pre-treatment and matrix interfering effects.
Graphical Abstract
Ethylene glycol dimethacrylate was grafted onto the amino-functionalized graphene oxide sheets. The template was already immobilized onto surface to improve the recognition ability of MIP-based sensor. The resulting composite was placed on a glassy carbon electrode for determination of bisphenol A by electrochemical technique.
Conditioned taste aversion (CTA) is an associative learning paradigm, wherein consumption of an appetitive tastant (e.g., saccharin) is paired to the administration of a malaise-inducing agent, such ...as intraperitoneal injection of LiCl. Aversive taste learning and retrieval require neuronal activity within the anterior insula (aIC) and the basolateral amygdala (BLA). Here, we labeled neurons of the aIC projecting to the BLA in adult male mice using a retro-AAV construct and assessed their necessity in aversive and appetitive taste learning. By restricting the expression of chemogenetic receptors in aIC-to-BLA neurons, we demonstrate that activity within the aIC-to-BLA projection is necessary for both aversive taste memory acquisition and retrieval, but not for its maintenance, nor its extinction. Moreover, inhibition of the projection did not affect incidental taste learning per se, but effectively suppressed aversive taste memory retrieval when applied either during or before the encoding of the unconditioned stimulus for CTA (i.e., malaise). Remarkably, activation of the projection after novel taste consumption, without experiencing any internal discomfort, was sufficient to form an artificial aversive taste memory, resulting in strong aversive behavior upon retrieval. Our results indicate that aIC-to-BLA projecting neurons are an essential component in the ability of the brain to associate taste sensory stimuli with body states of negative valence and guide the expression of valence-specific behavior upon taste memory retrieval.
In the present study we subjected mice to the conditioned taste aversion paradigm, where animals learn to associate novel taste with malaise (i.e., assign it negative valence). We show that activation of neurons in the anterior insular cortex (aIC) that project into the basolateral amygdala (BLA) in response to conditioned taste aversion is necessary to form a memory for a taste of negative valence. Moreover, artificial activation of this pathway (without any feeling of pain) after the sampling of a taste can also lead to such associative memory. Thus, activation of aIC-to-BLA projecting neurons is necessary and sufficient to form and retrieve aversive taste memory.
To survive in an ever-changing environment, animals must detect and learn salient information. The anterior insular cortex (aIC) and medial prefrontal cortex (mPFC) are heavily implicated in salience ...and novelty processing, and specifically, the processing of taste sensory information. Here, we examined the role of aIC-mPFC reciprocal connectivity in novel taste neophobia and memory formation, in mice. Using pERK and neuronal intrinsic properties as markers for neuronal activation, and retrograde AAV (rAAV) constructs for connectivity, we demonstrate a correlation between aIC-mPFC activity and novel taste experience. Furthermore, by expressing inhibitory chemogenetic receptors in these projections, we show that aIC-to-mPFC activity is necessary for both taste neophobia and its attenuation. However, activity within mPFC-to-aIC projections is essential only for the neophobic reaction but not for the learning process. These results provide an insight into the cortical circuitry needed to detect, react to- and learn salient stimuli, a process critically involved in psychiatric disorders.
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