As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as ...therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.
All laboratory tests have test performance characteristics (TPCs), whether or not they are explicitly known to the laboratorian or the pathologist. TPCs are thus also an integral characteristic of ...immunohistochemistry (IHC) tests and other in situ, cell-based molecular assays such as DNA or RNA in situ hybridization or aptamer-based testing. Because of their descriptive, in situ, cell-based nature, IHC tests have a limited repertoire of appropriate TPCs. Although only a few TPCs are relevant to IHC, proper selection of informative TPCs is nonetheless essential for the development of and adherence to appropriate quality assurance measures in the IHC laboratory. This paper describes the TPCs that are relevant to IHC testing and emphasizes the role of TPCs in the validation of IHC tests. This is part 2 of the 4-part series "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine."
The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated ...with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the discovery and profiling of a new PPARγ modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγ ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARγ activation with a high eudysmic ratio. The new PPARγ modulator revealed outstanding selectivity over the PPARα and PPARδ subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
Accurate chest X‐ray (CXR) interpretation is an essential skill in clinical practice. Previous studies have shown poor accuracy and confidence rates (CR) of CXR interpretation by junior doctors and ...medical students. We presented 10 chest radiographs via an online questionnaire to Australian medical students and junior doctors, who were asked to identify the radiographic abnormality from a list of 15 options and to rate their confidence for each answer. Of 67 complete responses, junior doctors achieved a mean score of 57.6% and medical students 56.1%, with CR of 67 versus 58% respectively. There was a significant positive relationship between accuracy and CR among junior doctors (Pearson's coefficient + 0.798, P = 0.006) and students (Pearson's coefficient + 0.716, P = 0.020). This study identified similarities in strength and weakness in CXR interpretation between medical students and junior doctors. There was a positive association between test scores and self‐rated confidence scores.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Repeat transarterial chemoembolisation (rTACE) is often required for hepatocellular carcinoma (HCC) to achieve disease control, however, current practice guidelines regarding treatment allocation ...vary significantly. This study aims to identify key factors associated with patient survival following rTACE to facilitate treatment allocation and prognostic discussion.
Patients with HCC undergoing rTACE at six Australian tertiary centers from 2009 to 2014 were included. Variables encompassing clinical, tumour, treatment type and response factors were analysed against the primary outcome of overall survival. Univariate analysis and multivariate Cox regression modelling were used to identify factors pre- and post-TACE therapy significantly associated with survival.
Total of 292 consecutive patients underwent rTACE with mainly Child Pugh A cirrhosis (61%) and BCLC stage A (57%) disease. Median overall survival (OS) was 30 months (IQR 15.2-50.2) from initial TACE. On multivariate analysis greater tumour number (p = 0.02), higher serum bilirubin (p = 0.007) post initial TACE, and hepatic decompensation (p = 0.001) post second TACE were associated with reduced survival. Patients with serum AFP ≥ 200 ng/ml following initial TACE had lower survival (p = 0.001), compared to patients with serum AFP level that remained < 200 ng/ml post-initial TACE, with an overall survival of 19.4 months versus 34.7 months (p = 0.0001) respectively.
Serum AFP level following initial treatment in patients undergoing repeat TACE for HCC is a simple and useful clinical prognostic marker. Moreover, it has the potential to facilitate appropriate patient selection for rTACE particularly when used in conjunction with baseline tumour burden and severity of hepatic dysfunction post-initial TACE.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic cancer is among the most aggressive malignancies with no effective therapeutic options thus far. Immunotherapy has recently emerged as a promising alternative for the treatment of various ...solid tumors. In particular, promising results in clinical trials were observed for therapies targeting immune checkpoint molecules. Efforts have been put into investigating the potential of immunotherapy in treating pancreatic cancer. While most of the clinical trial results are still being awaited, several intrinsic features of pancreatic cancer such as low mutational load and the presence of highly immunosuppressive desmoplasia significantly hamper the efficacy of immunotherapy in this disease. These unique features of pancreatic cancer, however, have advanced our understanding of tumor immunology and might help to tailor the future direction of immunotherapy. In this review, we summarize the current immunotherapeutic strategies and clinical trials targeting checkpoint molecules in pancreatic cancer. Emerging trends towards various combinations with therapies targeting immunosuppressive myeloid cells are also discussed.
Leukotrienes (LTs) and prostaglandin (PG)E2, produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological ...suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC50 = 2.3 and 0.4 μM for isolated 5-LO and 5-LO in intact cells, respectively). Compound 47 prevented the interaction of 5-LO with its activating protein (FLAP) at the nuclear envelope in transfected HEK293 cells as shown by in situ proximity ligation assay. Comprehensive assessment of the LM profile produced by human macrophages revealed the ability of 47 to selectively down-regulate pro-inflammatory LMs (i.e. LTs and PGE2) in M1 but to enhance the formation of pro-resolving LMs (i.e. resolvins and maresins) in M2 macrophages. Moreover, 47 strongly inhibited LT formation and cell infiltration in two in vivo models of acute inflammation (i.e., peritonitis and air pouch sterile inflammation in mice). Together, 47 represents a novel LT biosynthesis inhibitor with an attractive pharmacological profile as anti-inflammatory drug that also promotes the biosynthesis of pro-resolving LM.
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•46 benzensulfonamides were synthesized as potential dual 5-LO/mPGES-1 inhibitors.•Lead cmpd. 47 inhibits 5-LO, LTC4 synthase, mPGES-1 and seemingly FLAP.•Cmpd. 47 reduced inflammatory but elevated pro-resolving mediators in macrophages.•Cmpd. 47 was highly effective in two different models of acute inflammation in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Validation of immunohistochemistry (IHC) assays is a subject that is of great importance to clinical practice as well as basic research and clinical trials. When applied to clinical practice and ...focused on patient safety, validation of IHC assays creates objective evidence that IHC assays used for patient care are "fit-for-purpose." Validation of IHC assays needs to be properly informed by and modeled to assess the purpose of the IHC assay, which will further determine what sphere of validation is required, as well as the scope, type, and tier of technical validation. These concepts will be defined in this review, part 3 of the 4-part series "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine."
Technical progress in immunohistochemistry (IHC) as well as the increased utility of IHC for biomarker testing in precision medicine avails us of the opportunity to reassess clinical IHC as a ...laboratory test and its proper characterization as a special type of immunoassay. IHC, as used in current clinical applications, is a descriptive, qualitative, cell-based, usually nonlinear, in situ protein immunoassay, for which the readout of the results is principally performed by pathologists rather than by the instruments on which the immunoassay is performed. This modus operandi is in contrast to other assays where the instrument also performs the readout of the test result (eg, nephelometry readers, mass spectrometry readers, etc.). The readouts (results) of IHC tests are used either by pathologists for diagnostic purposes or by treating physicians (eg, oncologists) for patient management decisions, the need for further testing, or follow-up. This paper highlights the distinction between the original purpose for which an IHC test is developed and its subsequent clinical uses, as well as the role of pathologists in the analytical and postanalytical phases of IHC testing. This paper is the first of a 4-part series, under the general title of "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine."
The numbers of diagnostic, prognostic, and predictive immunohistochemistry (IHC) tests are increasing; the implementation and validation of new IHC tests, revalidation of existing tests, as well as ...the on-going need for daily quality assurance monitoring present significant challenges to clinical laboratories. There is a need for proper quality tools, specifically tissue tools that will enable laboratories to successfully carry out these processes. This paper clarifies, through the lens of laboratory tissue tools, how validation, verification, and revalidation of IHC tests can be performed in order to develop and maintain high quality "fit-for-purpose" IHC testing in the era of precision medicine. This is the final part of the 4-part series "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine."
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