• Tran Stephansen posted an update 6 months, 4 weeks ago

    Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N-carbamates of N-deacetyl-4-(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti-proliferative activity than COL (IC50  = 8.6 nM) towards primary ALL cells in cell viability assays (IC50 range of 1.1-6.4 nM), and several were more potent towards primary IDCG3 (IC50 range of 0.1 to 10.3 nM) or MC (IC50 range of 2.3-9.1 nM) compared to COL (IC50 of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non-small-cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer. © 2020 Wiley Periodicals, Inc.The mechanobiology of receptor-ligand interactions and force-induced enzymatic turnover can be revealed by simultaneous measurements of force response and fluorescence. Investigations at physiologically relevant high labeled substrate concentrations require total internal reflection fluorescence microscopy or zero mode waveguides (ZMWs), which are difficult to combine with atomic force microscopy (AFM). A fully automatized workflow is established to manipulate single molecules inside ZMWs autonomously with noninvasive cantilever tip localization. A protein model system comprising a receptor-ligand pair of streptavidin blocked with a biotin-tagged ligand is introduced. The ligand is pulled out of streptavidin by an AFM cantilever leaving the receptor vacant for reoccupation by freely diffusing fluorescently labeled biotin, which can be detected in single-molecule fluorescence concurrently to study rebinding rates. This work illustrates the potential of the seamless fusion of these two powerful single-molecule techniques. © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. Immunology inhibitor KGaA, Weinheim.BACKGROUND Hospital admissions for preventable reasons can indicate gaps in access to or quality of primary care. This paper seeks to document the numbers and causes of these admissions in England for people with intellectual disabilities (ID) compared with those without. METHODS Observational cohort study of number and duration of emergency admitted patient episodes for ACS conditions, overall and by cause, using the Clinical Practice Research Datalink GOLD primary care database and the linked Hospital Episode Statistics Admitted Patient Care dataset. RESULTS The study covered 5.2% of the population of England from April 2010 to March 2014 giving a total population base of 59 280 person-years for people with ID and 11 103 910 for people without identified ID. The rate of emergency admissions for ACS conditions for people with ID was 77.5 per 1000 person-years. As a crude comparison, this was 3.0 times the rate for those without ID, but standardising for the distinn pneumonitis. Influenza pneumonia was also a common cause for people without ID. Episodes for convulsions and epilepsy and aspiration pneumonitis were specifically associated with people with ID. CONCLUSIONS Rates of hospital admissions for ACS conditions provide an important indicator of health literacy, basic self-care (or support by carers) and the accessibility of primary care. High rates are seen for some conditions specifically associated with premature death in people with ID. Local monitoring of these figures could be used to indicate the effectiveness of local primary health services in providing support to people with ID. © 2020 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.Elbow incongruity is a form of elbow dysplasia that causes osteoarthritis, pain, and lameness, and it is common in chondrodystrophic dog breeds. The objective of this retrospective secondary analysis study was to evaluate the intra- and interobserver repeatability of a novel radiographic incongruity grading system for assessing elbow incongruity in three chondrodystrophic dog breeds-the dachshund, Skye Terrier, and Glen of Imaal Terrier. We conducted an observer agreement study that included 220 mediolateral antebrachial radiographs from 110 dogs with the elbow in 90° flexion. The radiographs were independently assessed by three observers at three time points, using a four-stepped grading scale. The proportion of agreement and Kappa coefficient were calculated. Both the intra- and interobserver proportions of agreement were substantial when three grades were required to be identical (.705-.777 and .609, respectively), and almost perfect for two identical grades (.991-1.000 and .991, respectively). Some differences in repeatability between breeds were noted; specifically, the intraobserver repeatability was higher in the dachshund, and the interobserver repeatability was lower in the Glen of Imaal Terrier. Our study showed that the radiographic imaging protocol and incongruity grading system have high repeatability when assessing elbow incongruity in chondrodystrophic dog breeds. © 2020 American College of Veterinary Radiology.OBJECTIVE To document a case of transient AB blood type indicated by immunochromatography in a type B cat following administration of an incompatible type A transfusion. CASE SUMMARY A 7-month-old neutered male domestic longhair cat was evaluted for anemia, pigmenturia, and intravascular hemolysis 1 day after receiving a feline whole blood transfusion. Neither blood donor nor patient had been blood-typed or crossmatched. The cat presented in shock with a severe non-regenerative anemia, hyperlactatemia, hyperbilirubinemia, hemoglobinemia, hemoglobinuria, and a positive saline slide agglutination test. Immunochromatographic blood typing tests initially indicated the cat had type AB blood, but crossmatch tests with blood from type A and type B donors suggested that the cat was type B. The cat was transfused with type B packed red blood cells without apparent complications and clinically improved. The cat’s blood type reverted to type B once all the previously transfused type A cells were cleared from circulation.

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