•Two products will always be found to be different if the sample size is large enough.•Discrimination testing requires the consideration of consumer relevance.•The limitations of the proportion of ...discriminators concept are described·•The idea behind the consumer rejection threshold is outlined.•Setting relevance with a paired preference or a same-different test is described.
In order to ensure consistency in the decision making process over time, a discrimination testing program must take into account all of five elements: The testing protocol, the sample size, the Type I error (α), the Type II error (β) (power=1−β) and a measure of the threshold above which the scientist has established that the difference is meaningful to the consumer (δR). Two putatively different products will always be found to be different provided that the sample size is large enough. This fact underscores the need to set δR. The concept of discriminators is attractive but flawed, as the same underlying sensory difference will result in different proportions of distinguishers depending on the method used. Prescott, Leslie, Kunst, and Kim (2005) proposed the idea of consumer rejection threshold which avoids the pitfalls of the proportion of discriminators concept. However, it is limited to differences that can be linked to a specific compound, such as one responsible for a product defect or off-flavor. In this manuscript two alternative approaches are discussed. The first one uses a special feature of the same-different protocol which permits the estimation of the size of the sensory difference above which consumers would call two products “different”. The second one links the estimate of a standardized measure of sensory difference, d′, to consumer hedonic response between the product pairs and finds the threshold above which a sensory difference results in a meaningful preference result. Experimental research is needed to study the suitability of these approaches. Ultimately, establishing δR is essential to ensure that results from a discrimination testing program are actually relevant to the consumers whose behavior it is trying to predict.
Bioprinting has emerged as a novel technological approach with the potential to address unsolved questions in the field of tissue engineering. We have recently shown that Laser Assisted Bioprinting ...(LAB), due to its unprecedented cell printing resolution and precision, is an attractive tool for the in situ printing of a bone substitute. Here, we show that LAB can be used for the in situ printing of mesenchymal stromal cells, associated with collagen and nano-hydroxyapatite, in order to favor bone regeneration, in a calvaria defect model in mice. Also, by testing different cell printing geometries, we show that different cellular arrangements impact on bone tissue regeneration. This work opens new avenues on the development of novel strategies, using in situ bioprinting, for the building of tissues, from the ground up.
Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are ...often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies.
Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the ...mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.
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•dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β•Knockout of cGAS or STING in dMLH tumor cells renders resistance to checkpoint blockade•Downregulating cGAS-STING in human dMLH1 cancers impairs checkpoint blockade therapy
About 50% of patients with dMMR cancers are objectively responsive to immunotherapy. In addition to neoantigens, Lu et al. find that dMMR-mediated cytosolic DNA sensing by cGAS-STING pathway in tumor cells contributes to such clinical benefits, while impaired expression of cGAS-STING pathway is associated with drug resistance.
Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in ...neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.
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•Pharmacologic modulation of splicing enhances immune checkpoint blockade efficacy•RBM39 degradation and type I PRMT inhibition are well tolerated by immune cells•Splicing perturbation induces splicing-derived neoepitopes that are immunogenic•Rigorous framework for the identification of splicing-derived antigenic peptides
By provoking production of “neoantigens” that are recognized by immune cells, drugs that modulate RNA splicing can enhance cancer immunotherapy.
KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian ...patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens.
Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver ...function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies.
By means of fluctuational electrodynamics, we calculate radiative heat flux between two planar materials respectively made of SiC and SiO2. More specifically, we focus on a first (direct) situation ...where one of the two materials (for example SiC) is at ambient temperature whereas the second material is at a higher one, then we study a second (reverse) situation where the material temperatures are inverted. When the two fluxes corresponding to the two situations are different, the materials are said to exhibit thermal rectification, a property with potential applications in thermal regulation. Rectification variations with temperature and separation distance are reported here. Calculations are performed using material optical data experimentally determined by Fourier transform emission spectrometry of heated materials between ambient temperature (around 300 K) and 1480 K. It is shown that rectification is much more important in the near-field domain, i.e. at separation distances smaller than the thermal wavelength. In addition, we see that the larger is the temperature difference, the larger is rectification. Large rectification is finally interpreted due to a weakening of the SiC surface polariton when temperature increases, a weakening which affects much less SiO
resonances.
•Precise, accurate and sensitive method to quantify two multikinase inhibitors and their 3 active metabolites simultaneously.•Using confirmation/quantification ion ratios criteria to improve ...specificity.•Dynamic range of the concentrations carrying out some pharmacokinetics studies.
A new liquid chromatography-tandem mass spectrometry (LC–MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of regorafenib (REGO), its two metabolites regorafenib-M2 and regorafenib-M5, sorafenib (SORA), and its N-oxide metabolite in human plasma. Separation is achieved on an Hypersil Gold® column using a gradient elution of 10mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3mL/min. After addition of two internal standards and a protein precipitation, the supernatant is diluted two-fold in a 0.1% (v/v) formic acid solution. Two selected reaction monitoring transitions are used, for each analyte, one for quantitation and the second one for confirmation. The standard curves are ranged from 50 to 5 000ng/mL for REGO and its metabolites and 80 to 5 000ng/mL for SORA and its metabolite and were fitted to a 1/x weighted linear regression model. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day CV from 2.4 to 10.2%), accuracy (from 91.0 to 111.7%), recovery as well as stability of the analytes under various conditions. The method is usually used in clinical practice in order to improve the SORA treatment for renal carcinoma, REGO treatment for colorectal cancer and both for hepatocellular carcinoma.
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