The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of ...approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Solution‐processed perovskites are promising for hard X‐ray and gamma‐ray detection, but there are limited reports on their performance under extremely intense X‐rays. Here, a solution‐grown ...all‐inorganic perovskite CsPbBr3 single‐crystal semiconductor detector capable of operating at ultrahigh X‐ray flux of 1010 photons s−1 mm−2 is reported. High‐quality solution‐grown CsPbBr3 single crystals are fabricated into detectors with a Schottky diode structure of eutectic gallium indium/CsPbBr3/Au. A high reverse‐bias voltage of 1000 V (435 V mm−1) can be applied with a small and stable dark current of ≈60–70 nA (≈9–10 nA mm−2), which enables a high sensitivity larger than 10 000 µC Gyair−1 cm−2 and a simultaneous low detection limit of 22 nGyair s−1. The CsPbBr3 semiconductor detector shows an excellent photocurrent linearity and reproducibility under 58.61 keV synchrotron X‐rays with flux from 106 to 1010 photons s−1 mm−2. Defect characterization by thermally stimulated current spectroscopy shows a similar low defect density of a synchrotron X‐ray and a lab X‐ray irradiated device. Solid‐state nuclear magnetic resonance spectroscopy suggests that the excellent performance of the solution‐grown CsPbBr3 single crystal may be associated with its good short‐range order, comparable to the spectrometer‐grade melt‐grown CsPbBr3.
The low‐cost solution‐grown CsPbBr3 with low defect density and good short‐range order shows a record‐high X‐ray sensitivity of >10 000 µC Gyair−1 cm−2 and a low detection limit of 22 nGyair s−1. Under ultrahigh flux of synchrotron X‐rays (106 to 1010 photons s−1 mm−2 at 58.61 keV), a good photocurrent linearity and reproducibility are achieved.
Summary
We present a hybridized discontinuous Galerkin (HDG) method for the incompressible Reynolds‐averaged Navier‐Stokes equations coupled with the Spalart‐Allmaras one‐equation turbulence model. ...The method extends upon an HDG method recently introduced by Rhebergen and Wells for the incompressible Navier‐Stokes equations. With a special choice of velocity and pressure spaces for both element and trace degrees of freedom (DOFs), the method returns pointwise divergence‐free mean velocity fields and properly balances momentum and energy. We further examine the use of different polynomial degrees and meshes to see how the order of the scalar eddy viscosity affects the convergence of the mean velocity and pressure fields, specifically for the method of manufactured solutions. As is standard with HDG methods, static condensation can be employed to remove the element DOFs and thus dramatically reduce the global number of DOFs. Numerical results illustrate the effectiveness of the proposed methodology.
We introduce a hybridized discontinuous Galerkin method for the incompressible Reynolds‐averaged Navier‐Stokes equations coupled with the Spalart‐Allmaras one‐equation turbulence model. With a special choice of velocity and pressure spaces for both element and trace degrees of freedom, we arrive at a method that returns pointwise divergence‐free mean velocity field s and properly balances momentum and energy. Numerical results illustrate the effectiveness of the proposed methodology.
Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the standard alternative to total laryngectomy for patients with locally advanced laryngeal cancer. The value of ...adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown.
We randomly assigned patients with locally advanced cancer of the larynx to one of three treatments: induction cisplatin plus fluorouracil followed by radiotherapy, radiotherapy with concurrent administration of cisplatin, or radiotherapy alone. The primary end point was preservation of the larynx.
A total of 547 patients were randomly assigned to one of the three study groups. The median follow-up period was 3.8 years. At two years, the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin (88 percent) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy (75 percent, P=0.005) or radiotherapy alone (70 percent, P<0.001). The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin (78 percent, vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone). Both of the chemotherapy-based regimens suppressed distant metastases and resulted in better disease-free survival than radiotherapy alone. However, overall survival rates were similar in all three groups. The rate of high-grade toxic effects was greater with the chemotherapy-based regimens (81 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin, vs. 61 percent with radiotherapy alone). The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy.
In patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control.
Left ventricular assist device (LVAD) therapy improves myocardial function, but few patients recover sufficiently for explant, which has focused attention on stem cells to augment cardiac recovery.
...To assess efficacy and adverse effects of intramyocardial injections of mesenchymal precursor cells (MPCs) during LVAD implant.
A randomized phase 2 clinical trial involving patients with advanced heart failure, undergoing LVAD implant, at 19 North American centers (July 2015-August 2017). The 1-year follow-up ended August 2018.
Intramyocardial injections of 150 million allogeneic MPCs or cryoprotective medium as a sham treatment in a 2:1 ratio (n = 106 vs n = 53).
The primary efficacy end point was the proportion of successful temporary weans (of 3 planned assessments) from LVAD support within 6 months of randomization. This end point was assessed using a Bayesian analysis with a predefined threshold of a posterior probability of 80% to indicate success. The 1-year primary safety end point was the incidence of intervention-related adverse events (myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization). Secondary end points included readmissions and adverse events at 6 months and 1-year survival.
Of 159 patients (mean age, 56 years; 11.3% women), 155 (97.5%) completed 1-year of follow-up. The posterior probability that MPCs increased the likelihood of successful weaning was 69%; below the predefined threshold for success. The mean proportion of successful temporary weaning from LVAD support over 6 months was 61% in the MPC group and 58% in the control group (rate ratio RR, 1.08; 95% CI, 0.83-1.41; P = .55). No patient experienced a primary safety end point. Of 10 prespecified secondary end points reported, 9 did not reach statistical significance. One-year mortality was not significantly different between the MPC group and the control group (14.2% vs 15.1%; hazard ratio HR, 0.89; 95%, CI, 0.38-2.11; P = .80). The rate of serious adverse events was not significantly different between groups (70.9 vs 78.7 per 100 patient-months; difference, -7.89; 95% CI, -39.95 to 24.17; P = .63) nor was the rate of readmissions (0.68 vs 0.75 per 100 patient-months; difference, -0.07; 95% CI, -0.41 to 0.27; P = .68).
Among patients with advanced heart failure, intramyocardial injections of mesenchymal precursor cells, compared with injections of a cryoprotective medium as sham treatment, did not improve successful temporary weaning from left ventricular assist device support at 6 months. The findings do not support the use of intramyocardial mesenchymal stem cells to promote cardiac recovery as measured by temporary weaning from device support.
clinicaltrials.gov Identifier: NCT02362646.
Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, ...complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.
The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links ...to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13881/full. Other ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
We investigated an antimony chalcohalide compound, SbSeI, as a potential semiconductor material for X-ray and γ-ray detection. SbSeI has a wide band gap of 1.70 eV with a density of 5.80 g/cm3, and ...it crystallizes in the orthorhombic Pnma space group with a one-dimensional chain structure comprised of infinite zigzag chains of dimers Sb2Se4I8 n running along the crystallographic b axis. In this study, we investigate conditions for vertical Bridgman crystal growth using combinations of the peak temperature and temperature gradients as well as translation rate set in a three-zone furnace. SbSeI samples grown at 495 °C peak temperature and 19 °C/cm temperature gradient with 2.5 mm/h translation rate produced a single phase of columnar needlelike crystals aligned along the translational direction of the growth. The ingot sample exhibited an n-type semiconductor with resistivity of ∼108 Ω·cm. Photoconductivity measurements on these specimens allowed us to determine mobility–lifetime (μτ) products for electron and hole carriers that were found to be of similar order of magnitude (∼10–4 cm2/V). Further, the SbSeI ingot with well-aligned, one-dimensional columnar needlelike crystals shows an appreciable response of Ag Kα X-ray.
Semiconductor materials for efficient hard radiation detection are identified by combining a powerful chemical concept called dimensional reduction and precise theoretical electronic structure ...calculations. After more than 50 years of research and development in the field, this constitutes a significant step forward in the search for new detector materials.
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