Collinsnielsen6977

COVID-19 is a respiratory disease caused by SARS-CoV-2, an enveloped positive sense RNA virus. The SARS-CoV-2 spike glycoprotein, human angiotensin-converting enzyme 2 (ACE2) and human transmembrane protease serine 2 (TMPRSS2) are essential for the host cell-mediated viral entry. Targeting these proteins represent viable options to stop the first stage of infection and transmission. Hence, 97 alkaloids from African medicinal plants with reported antiviral activity were evaluated for this purpose via in silico studies. These alkaloids were docked for their interactions with SARS-CoV-2 spike glycoprotein, ACE2, and TMPRSS2. Top 20 alkaloids with highest binding affinities were further screened for their interactions with spike glycoprotein of SARS-CoV and MERS-CoV, and with ACE2-SARS-CoV-2 receptor-binding domain complex (ACE2-RBD). The energy profiling, molecular dynamics simulation (MDS), binding free energy base on Molecular Mechanics/Generalized Born Surface Area (MMGBSA), clustering of MDS trajectories, and virtual physicochemical and pharmacokinetic screening of the best docked alkaloids were performed. Results revealed that more than 15 alkaloids interacted better than the reference compounds. 10-Hydroxyusambarensine and Cryptospirolepine were docked in a similar binding pattern to the S1-specificy pocket of TMPRSS2 as camostat (reference inhibitor). The strong binding affinities, stability of the alkaloid-protein complexes and amino acid interactions displayed by cryptospirolepine, 10-hydroxyusambarensine, and cryptoquindoline with important binding hotspots of the proteins suggest these alkaloids have the potential of altering the capacity of SARS-CoV-2 membrane mediated host cell entry. Further in vitro and in vivo evaluation of these "drug-like" alkaloids as potential inhibitors of coronavirus cell entry is proposed. Communicated by Ramaswamy H. Sarma.Human topoisomerase II alpha (TopoIIα) is a crucial enzyme involved in maintaining genomic integrity during the process of DNA replication and mitotic division. It is a vital therapeutic target for designing novel anticancer agents in targeted cancer therapy. Sulfones, members of organosulfur compounds, have been reported to possess various biological activities such as antimicrobial, anti-inflammatory, anti-HIV, anticancer, and antimalarial properties. In the present study, a series of sulfones was selected to evaluate their inhibitory activity against TopoIIα using computational approaches. Molecular docking results revealed that several sulfone analogs bind efficiently to the ATPase domain of TopoIIα. Among them, sulfones 18a, 60a, *4 b, *8 b, *3c, and 8c exhibit higher binding affinity than the known TopoII inhibitor, salvicine. Molecular dynamics simulations and free energy calculations based on MM/PB(GB)SA method demonstrated that sulfone *8 b strongly interacts with amino acid residues in the ATP-binding pocket (E87, N91, D94, I125, I141, F142, S149, G161, and A167), driven mainly by an electrostatic attraction and a strong H-bond formation at G161 residue. Altogether, the obtained results predicted that sulfones could have a high potential to be a lead molecule for targeting TopoIIα. Communicated by Ramaswamy H. Sarma.

Metastatic triple-negative breast cancers (mTNBC) are characterized by aggressive behavior and worse clinical outcomes than other breast cancer subtypes, as well as poor response to cytotoxic chemotherapies. The use of antibody-drug conjugates (ADCs) has been investigated as a potential treatment strategy, particularly in heavily pretreated disease.

This article reviews the preclinical and clinical data supporting the use of the ADCs sacituzumab govitecan (SG), ladiratuzumab vedotin (LV), and trastuzumab deruxtecan (T-DXd) in mTNBC, and highlights ongoing clinical trials and future clinical applications.

SG, LV, and T-DXd have demonstrated their potential to meaningfully improve clinical outcomes in patients with pretreated mTNBC, as demonstrated by notable response rates in phase I/II and, for SG, phase III clinical trials. Investigation of their use in combination with other agents, including PARP inhibitors and checkpoint inhibitors, is ongoing in the metastatic setting, and their application in early-stage TNBCs are under investigation. ADCs are therefore expected to redefine treatment paradigms in TNBC.

SG, LV, and T-DXd have demonstrated their potential to meaningfully improve clinical outcomes in patients with pretreated mTNBC, as demonstrated by notable response rates in phase I/II and, for SG, phase III clinical trials. Investigation of their use in combination with other agents, including PARP inhibitors and checkpoint inhibitors, is ongoing in the metastatic setting, and their application in early-stage TNBCs are under investigation. ADCs are therefore expected to redefine treatment paradigms in TNBC.The COVID-19 pandemic has presented new challenges in how Primary Care clinicians care for community patients. Our organization quickly allocated 1 of our community clinic sites into a dedicated COVID Clinic caring for the COVID positive or any patient with COVID like symptoms to minimize contact with the well patients. A prerequisite for all patients to be seen in the COVID Care Clinic was a virtual visit staffed with Advanced Practice Providers that would further determine if the patient needed to seek emergency medical care or be seen in the COVID Clinic. From March 23, 2020 through May 15, 2020, 852 patients with COVID symptoms were seen in this clinic rather than the emergency department. This article describes a collaborative effort to care for a community during the COVID-19 pandemic. This unique setting allowed us to focus an appropriate level of care to a high risk population in a safe and effective manner in the ongoing effort to flatten the epidemiological curve.Regulations for new drug approvals require stringent safety testing and efficacy trial programs. The approval process for generic drugs, however, is significantly streamlined. Bioavailability data can substitute for new rounds of efficacy trials, thereby both decreasing time to approval and reducing the costs required for new studies. This regulatory choice has not been available when generic drugs are offered in a controlled release format such as a subcutaneous depot, transdermal patch or implant. The purpose of this review is to suggest that the approval of generic drugs in inert controlled release envelopes should be eligible for similar regulatory relief. Proof for this concept is provided by the example of the numerous controlled release buprenorphine products. Buprenorphine is a generic opioid used since the 1980s in tablet form to treat pain and to treat opioid addiction. Long-acting, inert delivery vehicles for the drug have become available for the same indications. Zunsemetinib cost Safety and bioavailability profiles of the long-acting products are the same or improved over the parent product.