Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors.

Acridones present numerous pharmacological activities, including inhibition of microtubule affinity-regulating kinase 4 (MARK4) kinase activity. To investigate structure-activity relationships and develop potent MARK4 inhibitors, derivatives of 2-methylacridone were synthesized and tested for their activity against MARK4 kinase. Selective substitutions at the nitrogen atom were accomplished by treating 2-methylacridone with alkyl halides in the presence of K2CO3. In addition, amidation of acridone acetic acid 11 with piperazine or tryptophan methyl ester followed by derivatization with various amines gave a series of new acridone derivatives. Among the tested compounds, six were identified as possessing high inhibitory activity against MARK4. The molecular modeling studies showed that the derivatives bearing piperazine or tryptophan bind well to the ATP-binding site of MARK4. The antiproliferative activity of six active compounds was evaluated against HeLa and U87MG cancer cells. Tryptophan derivatives 23a, 23b, and 23c showed significant cytotoxicity against both cell lines with EC50 values ranging from 2.13 to 4.22 µM, while derivatives bearing piperazine were found to be not cytotoxic. Additionally, compound 23a decreased the proliferation of human MDA-MB-435 and U251 cancer cells in the low micromolar range; however, it also affects the non-cancerous HGF cells. Due to their high binding affinity against MARK4, the synthesized compounds could be potential agents to target MARK4 against cancer and tauopathies.

The Implementation of a Health Care Worker Screening Program Based on the Advanta RT-qPCR Saliva Assay in a Tertiary Care Referral Hospital in Northern Greece.

Health care workers are at increased risk of acquiring SARS-CoV-2 infection due to different exposures in the community and in hospital settings. Interventions implemented to avoid nosocomial outbreaks include preventive testing strategies. In this report, we present results from the mass screening program applied in our hospital to all professionals, irrespective of symptoms or risk of exposure. We processed saliva specimens with real-time reverse transcription polymerase chain reaction. The total number of samples received was 43,726. Positive results were 672 and average positivity rate was 1.21%. The average positivity rate was similar to the positivity rate in the community in Greece and EU. More specifically, 80.5% of the positive participants care for patients in their daily activities, 31% experienced no symptoms before receiving the positive result, 46.1% reported a close contact with a patient or infected coworkers and 32.8% reported a close contact with infected family members. We believe that the identification of asymptomatic carriers has proved the effectiveness of the screening program by preventing the putative nosocomial spread of the virus and the depletion of workforce. In conclusion, in times of high incidence in the community, the periodic testing of health care personnel is wise and relevant for implementation costs.

Evaluation of the Advanta Dx SARS-CoV-2 RT-PCR Assay, a High-Throughput Extraction-Free Diagnostic Test for the Detection of SARS-CoV-2 in Saliva: A Diagnostic Accuracy Study.

Nasopharyngeal swab specimen (NPS) molecular testing is considered the gold standard for SARS-CoV-2 detection. However, saliva is an attractive, noninvasive specimen alternative. The aim of the study was to evaluate the diagnostic accuracy of Advanta Dx SARS-CoV-2 RT-PCR saliva-based assay against paired NPS tested with either NeumoDxTM SARS-CoV-2 assay or Abbott Real Time SARS-CoV-2 assay as the reference method. We prospectively evaluated the method in two settings: a diagnostic outpatient and a healthcare worker screening convenience sample, collected in November-December 2020. SARS-CoV-2 was detected in 27.7% (61/220) of diagnostic samples and in 5% (10/200) of screening samples. Overall, saliva test in diagnostic samples had a sensitivity of 88.5% (77.8-95.3%) and specificity of 98.1% (94.6-99.6%); in screening samples, the sensitivity was 90% (55.5-99.7%) and specificity 100% (98.1-100%). Our data suggests that the Fluidigm Advanta Dx RT-PCR saliva-based assay may be a reliable diagnostic tool for COVID-19 diagnosis in symptomatic individuals and screening asymptomatic healthcare workers.