The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets ...with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source 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.14749. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, 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‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly ...1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 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/bph.15539. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, 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‐2021, and supersedes data presented in the 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.
Genetic testing is being adopted increasingly to identify individuals with germline mutations that predispose to hereditary colorectal cancer syndromes. Deciding who to test and for which syndrome is ...of concern to members of the GI oncology community, molecular geneticists, and genetic counselors. The purpose of this review is to help provide guidelines for testing, given that the results influence syndrome diagnosis and clinical management. Although family history may determine whether testing is appropriate and may direct testing to the most informative family member, evolving clinicopathologic features can identify individual patients who warrant testing. Thus, although the usual absence of clinical premonitory signs in hereditary nonpolyposis colorectal cancer (or Lynch syndrome) adds difficulty to its diagnosis, use of the Amsterdam Criteria and Bethesda Guidelines can prove helpful. In contrast, premonitory stigmata such as pigmentations in Peutz-Jeghers syndrome and the phenotypic features of familial adenomatous polyposis aid significantly in syndrome diagnosis. We conclude that the physician's role in advising DNA testing is no small matter, given that a hereditary cancer syndrome's sequelae may be far reaching. Genetic counselors may be extremely helpful to the practicing gastroenterologist, oncologist, or surgeon; when more specialized knowledge is called for, referral can be made to a medical geneticist and/or a medical genetics clinic.
Hereditary forms of colorectal cancer, as is the case with virtually all forms of hereditary cancer, show extensive phenotypic and genotypic heterogeneity, a phenomenon discussed throughout this ...special issue of Familial Cancer. Clearly, the family physician, oncology specialist, genetic counselor, and cancer geneticist must know fully the complexity of hereditary cancer syndromes, their differential diagnosis, in order to establish a diagnosis, direct highly-targeted surveillance and management, and then be able to communicate effectively with the molecular geneticist so that an at-risk patient’s DNA can be tested in accord with the syndrome of concern. Thus, a family with features of the Lynch syndrome will merit microsatellite instability testing, consideration for immunohistochemistry evaluation, and mismatch repair gene testing, while, in contrast, a patient with FAP will require
APC
testing. However, other germline mutations, yet to be identified, may be important should testing for these mutations prove to be absent and, therein, unrewarding to the patient. Nevertheless, our position is that if the patient’s family history is consistent with one of these syndromes, but a mutation is not found in the family, we still recommend the same surveillance and management strategies for patients from families with an established cancer-causing germline mutation. Our purpose in this paper is to provide a concise coverage of the major hereditary colorectal cancer syndromes, to discuss genetic counseling, molecular genetic evaluation, highly targeted surveillance and management, so that cancer control can be maximized for these high hereditary cancer risk patients.
Lynch syndrome is the most common hereditary syndrome that predisposes patients to colorectal cancer. It accounts for 2%-5% of the total burden of colorectal cancer.2 The estimated number of new ...colorectal cancer cases in Canada in 2008 was 21 500.3 Thus, Lynch syndrome accounted for as many as 1075 cases in Canada in 2008. Each patient with Lynch syndrome may represent a family in which multiple family members can be expected to develop colorectal cancer or an integral extracolonic cancer. Clearly, these families have an important impact on public health policy. In 1966, our team described 2 large families from the midwestern United States with an apparent excess number of members with colorectal cancer that lacked multiple colonic adenomas. 5 This disorder involved a variety of extracolonic cancer sites and was therefore initially referred to as the "cancer family syndrome." It was subsequently renamed hereditary nonpolyposis colorectal cancer syndrome. Since the identification of mismatch repair mutations in this syndrome, it has become known as Lynch syndrome6,7 (Online Mendelian Inheritance in Man database no. 120435).8 The name hereditary nonpolyposis colorectal cancer syndrome is given to disorders that have similar phenotypes but that lack the specific mutations involved in Lynch syndrome (e.g., familial colorectal cancer type X).9,10 Colonoscopic screening has been shown to significantly improve survival among carriers of a mutation associated with Lynch syndrome.31,32 Lindor and colleagues30 reported that the available evidence strongly supports colonoscopic surveillance for patients with Lynch syndrome, and they recommended this procedure every 1-2 years, starting between the ages of 20 and 25. Those with a mutation in MSH6 should start screening at age 30. Features of Lynch syndrome- associated colorectal cancer that are addressed by these recommendations include early age of cancer onset, accelerated carcinogenesis of adenomas into carcinomas, and predilection to cancer of the proximal colon (about 70% of Lynch syndrome- related colorectal cancers occur in the right colon, which is not accessed through sigmoidoscopy).4,7 There is continuing research into improvements in colonoscopic detection of polyps and adenomas, such as chromoscopic colonoscopy33,34 and the use of narrow band imaging.35
The Concise Guide to PHARMACOLOGY 2023/24: Ion channels Alexander, Stephen P. H.; Mathie, Alistair A.; Peters, John A. ...
British journal of pharmacology,
October 2023, 2023-10-00, 20231001, Letnik:
180, Številka:
S2
Journal Article
Recenzirano
Odprti dostop
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 over 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.16178. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, 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‐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.
We identified a highly polarized, steep-spectrum radio source in a deep image with the Australian Square Kilometre Array Pathfinder (ASKAP) telescope at 888 MHz. After considering and rejecting a ...stellar origin for this source, we discovered a new millisecond pulsar (MSP) using observations from the Parkes radio telescope. This pulsar has period 2.77 ms and dispersion measure 228.27 pc cm−3. Although this pulsar does not yet appear to be particularly remarkable, its short spin period, wide profile, and high dispersion measure make it relatively hard to discover through traditional blind periodicity searches. Over the course of several weeks we see changes in the barycentric period of this pulsar that are consistent with orbital motion in a binary system, but the properties of any binary need to be confirmed by further observations. While even a deep ASKAP survey may not identify large numbers of new MSPs compared with the existing population, it would be competitive with existing all-sky surveys and could discover interesting new MSPs at high Galactic latitude without the need for computationally expensive all-sky periodicity searches.
Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this disease during 2009. During this same time, over 15,000 will die from malignancy ascribed to ovarian ...origin. The bulk of these hereditary cases fits the hereditary breast–ovarian cancer syndrome, while virtually all of the remainder will be consonant with the Lynch syndrome, disorders which are autosomal dominantly inherited. Advances in molecular genetics have led to the identification of
BRCA1 and
BRCA2 gene mutations which predispose to the hereditary breast–ovarian cancer syndrome, and mutations in mismatch repair genes, the most common of which are
MSH2 and
MLH1, which predispose to Lynch syndrome. These discoveries enable relatively certain diagnosis, limited only by their variable penetrance, so that identification of mutation carriers through a comprehensive cancer family history might be possible. This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity.
Lynch syndrome is the most common form of hereditary colorectal cancer (CRC). This review covers the cardinal features of Lynch syndrome with particular emphasis upon its diagnostic criteria, ...molecular genetics, natural history, genetic counseling, surveillance and management. Considerable attention has been given to the etiologic role of mismatch repair (MMR) genes as well as low penetrance alleles and modifier genes. The American founder mutation, a deletion of exons 1-6 of MSH2, is discussed in some detail, owing to its high frequency in the US (19 000-30 000 carriers). Genetic counseling is essential prior to patients' undergoing DNA testing and again when receiving their test results. Families with a lower incidence of CRC and extracolonic cancers, in the face of being positive for Amsterdam I criteria but who do not have MMR deficiency by tumor testing, are probably not Lynch syndrome, and thereby should preferably be designated as familial CRC of undetermined type. Patients who are either noncompliant or poorly compliant with colonoscopy, and who are MMR mutation positive, may be candidates for prophylactic colectomy, while MMR mutation-positive women who are noncompliant with gynecologic surveillance may be candidates for prophylactic hysterectomy and bilateral salpingo-oophorectomy.
The identification of germline mutations in families with HNPCC is hampered by genetic heterogeneity and clinical variability. In previous studies,
MSH2 and
MLH1 mutations were found in approximately ...two-thirds of the Amsterdam-criteria–positive families and in much lower percentages of the Amsterdam-criteria–negative families. Therefore, a considerable proportion of HNPCC seems not to be accounted for by the major mismatch repair (MMR) genes. Does the latter result from a lack of sensitivity of mutation detection techniques, or do additional genes underlie the remaining cases? In this study we address these questions by thoroughly investigating a cohort of clinically selected North American families with HNPCC. We analyzed 59 clinically well-defined U.S. families with HNPCC for
MSH2, MLH1, and
MSH6 mutations. To maximize mutation detection, different techniques were employed, including denaturing gradient gel electrophoresis, Southern analysis, microsatellite instability, immunohistochemistry, and monoallelic expression analysis. In 45 (92%) of the 49 Amsterdam-criteria–positive families and in 7 (70%) of the 10 Amsterdam-criteria–negative families, a mutation was detected in one of the three analyzed MMR genes. Forty-nine mutations were in
MSH2 or
MLH1, and only three were in
MSH6. A considerable proportion (27%) of the mutations were genomic rearrangements (12 in
MSH2 and 2 in
MLH1). Notably, a deletion encompassing exons 1–6 of
MSH2 was detected in seven apparently unrelated families (12% of the total cohort) and was subsequently proven to be a founder. Screening of a second U.S. cohort with HNPCC from Ohio allowed the identification of two additional kindreds with the identical founder deletion. In the present study, we show that optimal mutation detection in HNPCC is achieved by combining accurate and expert clinical selection with an extensive mutation detection strategy. Notably, we identified a common North American deletion in
MSH2, accounting for ∼10% of our cohort. Genealogical, molecular, and haplotype studies showed that this deletion represents a North American founder mutation that could be traced back to the 19th century.
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