Anti-SARS-CoV-2 activity of targeted kinase inhibitors: Repurposing clinically available drugs for COVID-19 therapy

Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 variants. Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment. This study supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response.     

Telomeric length variation in human testicular germ cell tumours

Telomeric length was studied in 5 cases of human testicular germ cell rumours by measuring the length of the terminal restriction fragments (TRFs) containing the (TTAGCG)(n) sequence. Mean TRF length in human placenta used as a source of reference DNA for assessing the effect of cellular ageing was 14 kbp. TRF length in two classical seminomas and a mixed embryonal carcinoma/atypical seminoma ranged from 4 to 14 kbp and from 4 to 23 kbp, respectively, with the same mean value of 9 kbp in both tumour types. In a mixed teratoma/embryonal carcinoma, telomeric length ranged from 14 to 27 kbp with a mean of 20 kbp. In the single case of spermatocytic seminoma studied, telomeric length was up to 100 kbp with a distinct sharp band at similar to 50 kbp, representing the longest, homogeneous telomeres found so far.     

Spatial games and the maintenance of cooperation.

The Prisoner's Dilemma (PD) is a widely employed metaphor for problems associated with the evolution of cooperative behavior. We have recently proposed an alternative approach to the PD, by exploring "spatial games" in which players--who are either pure cooperators, C, or pure defectors, D--interact with neighbors in some spatial array; in each generation, players add up the scores from all encounters, and in the next generation a given cell is retained by its previous owner or taken over by a neighbor, depending on who has the largest score. Over a wide range of the relevant parameters, we find that C and D persist together indefinitely (without any of the complex strategies that remember past encounters, and anticipate future ones, which characterize essentially all previous work on the iterated PD). Our earlier work, however, dealt with symmetric spatial lattices in two dimensions, deterministic winning and discrete time. We show here that the essential results remain valid in more realistic situations where the spatial distributions of cells are random in two or three dimensions, and where winning is partly probabilistic (rather than being determined by the largest local total). The essential results also remain valid (pace Huberman and Glance [Huberman, B. A. & Glance, N. S. (1993) Proc. Natl. Acad. Sci. USA 90, 7716-7718]) when interactions occur in continuous rather than discrete time.     

陵水暗罗活性成分研究

从陵水暗罗(polyalthia nemoralis A.etDC)根的乙醇提取物中分离得到五个化合物。经光谱(UV,IR,¹H-NMR,¹³C-NMR,DEPT和MS)解析和化学反应,分别鉴定为暗罗素(zincpolyanemine,PN1),2-巯基吡啶-N-氧化物铜盐(PN₂),β-谷甾醇(PN₃),β-谷甾醇-β-D-吡喃葡萄糖甙(PN₄)和2-巯基吡啶-N-氧化物-2-S-β-D-吡喃葡萄糖甙(PN₅),其中PN₅为新化合物,PN2为新天然产物。PN1和PN2有较强抗疟、防霉杀菌作用。PN5的抗疟、防霉试验尚在进行中。     

The smoking cessation efficacy of varying doses of nicotine patch delivery systems 4 to 5 years post-quit day

BACKGROUND: This study was undertaken to evaluate the long-term smoking cessation efficacy of varying doses of transdermal nicotine delivery systems 4 to 5 years post-quit day. METHODS: A follow-up study was conducted 48 to 62 months after quit day among patients who were enrolled in the Transdermal Nicotine Study Group investigation. The latter study included group smoking cessation counseling and randomized assignment to 21, 14, or 7 mg nicotine patches or placebo patches. Seven of nine smoking cessation research centers participated in the long term follow-up investigation. RESULTS: The self-reported continuous quit rate among patients originally assigned 21 mg (20.2%) was significantly higher than rates for patients assigned 14 mg (10.4%), 7 mg (11.8%), or placebo patches (7.4%). Log rank survival analysis found no difference in relapse rates after 1 year postcessation. Smokers under age 30 years were significantly less likely to be abstinent at long term follow-up compared to smokers > or = 30 years of age (3 vs 13%, respectively). Mean weight gain in confirmed continuous quitters was 10.1 kg in men and 8.0 kg in women. Of the 63 continuous abstainers surveyed, 30 respondents (48%) reported that they no longer craved cigarettes, and no individual reported daily craving for cigarettes. CONCLUSIONS: Nicotine patch therapy with 21 mg/day patches resulted in a significantly higher long-term continuous abstinence rate compared to lower dose patches and placebo. Relapse rates among the various treatment conditions were similar after 1 year postcessation.     

Lack of combined effects of exposure and smoking on respiratory health in aluminium potroom workers

OBJECTIVE: To investigate the combined influence on respiratory health of smoking and exposure in an aluminium potroom. METHODS: In a cross sectional study of 75 potroom workers (23 never smokers, 38 current smokers, 14 ex-smokers) and 56 controls in the same plant (watchmen, craftsmen, office workers, laboratory employees; 18 non-smokers, 21 current smokers, 17 ex-smokers), prevalences of respiratory symptoms and spirometric indices were compared. RESULTS: Smokers in the potroom group had a lower prevalence of respiratory symptoms than never smokers or ex-smokers, which was significant for wheezing (2.6% v 17.4% and 28.6% respectively, both p < 0.01), whereas respiratory symptoms in controls tended to be highest in smokers (NS). No effects of potroom work on the prevalence of respiratory symptoms could be detected. In potroom workers, impairment of lung function due to occupational exposure was found only in non-smokers, with lower results for forced vital capacity (FVC) (98.8% predicted), forced expiratory volume in one second (FEV1) (96.1% predicted) and peak expiratory flow (PEF) (80.2% predicted) compared with controls (114.2, 109.9, and 105.9% predicted; each p < 0.001). Conversely, effects of smoking on lung function were only detectable in non-exposed controls (current smokers v non-smokers: FVC 98.8% v 114.2% predicted; p < 0.01; FEV1 95.5 v 109.9% predicted; p < 0.05). CONCLUSIONS: In a cross sectional survey such as this, the effects of both smoking and occupational exposure on respiratory health may be masked in subjects with both risk factors. This is probably due to strong selection processes which result in least susceptible subjects continuing to smoke and working in an atmosphere with respiratory irritants.

 

     

Respiratory health and fluoride exposure in different parts of the modern primary aluminum industry

Objective: The aim of this cross-sectional study was to investigate possible acute and long-term respiratory health effects of work at different working places in the primary aluminum industry. Method: A cross-sectional study was carried out on 78 potroom workers, 24 foundry workers, and 45 carbon-plant workers (n = 147, exposed group), and 56 control workers (watchmen, craftsmen, office workers, laboratory employees) of a modern German prebake aluminum plant. The survey consisted of pre- and postshift spirometric and urinary fluoride measurements. Results: Potroom workers had significantly lower preshift results with regard to forced vital capacity (FVC, 99.5% versus the 107.2% predicted; P < 0.05) and peak expiratory flow (PEF, 85.2% versus the 98.4% predicted; P < 0.01) as compared with controls. In a multiple regression model a small but significant negative correlation was found between postshift urinary fluoride concentrations and FVC, FEV₁, and PEF. Across-shift spirometric changes were observed only in FVC among carbon-plant workers (103.0 ± 13.3% predicted preshift value versus 101.2 ± 13.6% predicted postshift value; P < 0.05). Conclusions: The results suggest that lung function impairment in the modern primary aluminum industry may be only partly due to fluoride exposure and that working in aluminum carbon plants may cause acute lung function changes. Received: 8 July 1998 / Accepted: 31 October 1998     

Familial form of Fahr syndrome (report of two cases)

Two cases of familial form (in brothers) of extensive, symmetric, idiopathic calcifications of the basal ganglia and cerebellum (Fahr syndrome) are described. In discussion of factors predisposing to appearance of such idiopathic calcifications, particular attention was given to meningoencephalitis suffered in childhood and coexistence of a tumour of the sella of prolactinoma type, in case 1. Attention was also called to progressive, copious clinical and radiological symptology of the discussed cases. It was impossible to suggest a probable type of inheritance (parents of the patients were dead).     

Lipid image in glioblastoma multiforme

Changes in the content and composition of lipids in brain tumours of different degree of malignancy are still the subject of numerous scientific studies. It is known that in developing brain tumours structural and functional changes of its cells, take place, in which lipids play a crucial role. The examination of the lipid spectrum was conducted in a material extracted from tumour adjacent areas (by means of fenestration) as well as from tumours themselves in 11 patients (mean age 56.8 yrs). Based on histological studies all the tumours were qualified as glioblastoma 4th degree of malignancy. Lipids were isolated from the tumours as well as from their adjacent areas. Later on they were separated, using column chromatography and thin-layer chromatography, into three classes: phospholipids, galactolipids and neutral lipids. Separated lipids were subjected to quantitative analysis by spectrophotocolorimetric method. In comparison to adjacent areas, in tumours distinct changes of lipid levels were noticed in all analysed lipid classes. Statistical analysis showed significant decrease of phospholipids (elements stabilizing cell membranes) in tumours in comparison to their adjacent areas (Wilcoxon's test: p < 0.05). At the same time in tumours an increase of level of plasmalogens took place: phosphatidylcholine (PC) (PPC), phosphatidylethanolamine (PE) (PPE) typical elements of malignant tumours, responsible for cross cell membrane transportation processes. This phenomenon was accompanied by changes of levels of PC/PE and PC/SM (sphingomyelin) ratios connected with adhesiveness and other membrane features. Changes in the level of lipids, and phospholipids in particular, in glioblastoma 4th degree of malignancy in comparison to adjacent areas can indicate the pathological processes in cells of these tumours.