Between Theory and Practice: Computational/Experimental Integrated Approaches to Understand the Solubility and Lipophilicity of PROTACs.

Emerging drug candidates more often fall in the beyond-rule-of-five chemical space. Among them, proteolysis targeting chimeras (PROTACs) have gained great attention in the past decade. Although physicochemical properties of small molecules accomplishing Lipinski's rule-of-five can now be easily predicted through models generated by large data collections, for PROTACs the knowledge is still limited and heterogeneous, hampering their prediction.

Use of ionic liquids in amidation reactions for proteolysis targeting chimera synthesis.

Selective degradation of disease-causing proteins using proteolysis targeting chimeras (PROTACs) has gained great attention, thanks to its several advantages over traditional therapeutic modalities. Despite the advances made so far, the structural chemical complexity of PROTACs poses challenges in their synthetic approaches. PROTACs are typically prepared through a convergent approach, first synthesizing two fragments separately (target protein and E3 ligase ligands) and then coupling them to produce a fully assembled PROTAC.

Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity.

To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related to oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in the field of antiviral drug discovery is still in its infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum antiviral activity against coronaviruses.

Smooth vs Textured Expanders: Patient Factors and Anatomic Plane Are Greater Factors in Determining First-Stage Breast Reconstruction Outcomes.

Background: Textured implants and expanders are associated with an increased risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). As a result, plastic surgeons are utilizing smooth expanders, but many perceive these produce undesirable outcomes including infection, seroma, and lateral displacement.

Objectives: The aim of this study was to compare clinical outcomes of smooth and textured expanders.

VHL-Modified PROteolysis TArgeting Chimeras (PROTACs) as a Strategy to Evade Metabolic Degradation in Applications.

PROteolysis TArgeting Chimeras (PROTACs) are tripartite molecules consisting of a linker connecting a ligand for a protein of interest to an E3 ligase recruiter, whose rationale relies on proteasome-based protein degradation. PROTACs have expanded as a therapeutic strategy to open new avenues for unmet medical needs. Leveraging our expertise, we undertook a series of experiments aimed at elucidating PROTAC metabolism.

A simulated pedagogical intervention to educate nurse practitioner students about human trafficking.

Human trafficking (HT) affects an estimated 40.3 million people globally with 24.9 million people affected in forced labor and 4.

The Price of Gambling: Examining Gambling Disorders.

Gambling disorders are a serious public health problem. This manuscript will provide a comprehensive overview on this topic. Gambling disorder involves repeated patterns of gambling behaviors, that result in significant distress or impairment in a person's interpersonal relationships, employment, educational/career opportunities, and finances over a period of 12 months.

Applying the 2005 Caprini Score to Plastic Surgery Patients: A Quality Improvement Project.

Background: The Caprini score is a validated scale that calculates a patient's 30-day venous thromboembolism (VTE) risk based on their comorbidities. The American Society of Plastic Surgeons published VTE prophylaxis recommendations in 2011 based on the Caprini score, but these recommendations are vague and up to physician interpretation. The purpose of this study is to evaluate postoperative outcomes after the application of strict guidelines using the Caprini score with specific VTE chemoprophylaxis benchmarks on plastic surgery patients.

MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib.

Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). Recent advances in LC-MS instrumentation have facilitated the structure elucidation of degradants, although a comprehensive data analysis still represents a bottle-neck due to the massive amount of data that can be easily generated.

Bacterial Sequencing Reads in Blood Exome Files from Melanoma and Cervical Cancer Patients are Associated with Cancer Recurrence.

Bacteremia poses great risk for morbidity and mortality for immunocompromised cancer patients. Although the presence of bacteria within solid tumors is gaining greater attention, few studies have analyzed species of bacteria in the blood and their effect on cancer clinical outcomes. Using the Kraken 2 taxonomic profiling tool, we classified bacteria present in blood and primary tumors of cervical cancer and melanoma cases.

Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design.

The field of targeted protein degradation, through the control of the ubiquitin-proteasome system (UPS), is progressing considerably; to exploit this new therapeutic modality, the proteolysis targeting chimera (PROTAC) technology was born. The opportunity to use PROTACs engaging of new E3 ligases that can hijack and control the UPS system could greatly extend the applicability of degrading molecules. To this end, here we show a potential application of the ELIOT (E3 LIgase pocketOme navigaTor) platform, previously published by this group, for a scaffold-repurposing strategy to identify new ligands for a novel E3 ligase, such as TRIM33.

Racial Disparity in Immediate Breast Reconstruction; a Gap That is not Closing.

Immediate breast reconstruction (IBR) is offered as part of the standard-of-care to females undergoing mastectomy. Racial disparity in IBR has been previously reported with a longstanding call for its elimination, though unknown if this goal is achieved. The aim of this study was to examine the current association between race and IBR and to investigate whether racial disparity is diminishing.

PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

Proteolysis targeting chimeras (PROTACs) represent an emerging class of compounds for innovative therapeutic application. Their bifunctional nature induces the formation of a ternary complex (target protein/PROTAC/E3 ligase) which allows target protein ubiquitination and subsequent proteasomal-dependent degradation. To date, despite great efforts being made to improve their biological efficacy PROTACs rational design still represents a challenging task, above all for the modulation of their physicochemical and pharmacokinetics properties.

CROMATIC: ss-Relationship p of Cavies from oronaviruses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 disease, has rapidly imposed an urgent need to identify effective drug candidates. In this context, the high resolution and non-redundant beta-Coronavirus protein cavities database is pivotal to help virtual screening protocols. Furthermore, the cross-relationship among cavities can lead to highlighting multitarget therapy chances.

Discovery of novel SARS-CoV-2 inhibitors targeting the main protease M by virtual screenings and hit optimization.

Two years after its emergence, SARS-CoV-2 still represents a serious and global threat to human health. Antiviral drug development usually takes a long time and, to increase the chances of success, chemical variability of hit compounds represents a valuable source for the discovery of new antivirals. In this work, we applied a platform of variably oriented virtual screening campaigns to seek for novel chemical scaffolds for SARS-CoV-2 main protease (M) inhibitors.

An overview on small molecules acting as broad-spectrum agents for yellow fever infection.

Introduction: Yellow fever virus (YFV) is a mosquito-borne flavivirus, endemic in 47 countries in Africa and South America, which causes febrile symptoms that can evolve in 15% of the patients to serious hemorrhagic conditions, liver injury, and multiorgan failure. Although a highly effective vaccine (YF-17D vaccine) is available, to date, no antiviral drugs have been approved for the prevention and treatment of YFV infections.

Areas Covered: This review article focuses on the description of viral targets that have been considered within YFV and flavivirus drug discovery studies and on the most relevant candidates reported so far that elicit broad-spectrum inhibition against relevant strains and mutants of YFV.

Attitudes toward osteopathic medicine scale: development and psychometrics.

Objective: To develop a valid and reliable instrument for measuring attitudes toward osteopathic medicine.

Methods: Participants included 5,669 first-year students from 33 U.S.

Indomethacin-based PROTACs as pan-coronavirus antiviral agents.

Indomethacin (INM), a well-known non-steroidal anti-inflammatory drug, has recently gained attention for its antiviral activity demonstrated in drug repurposing studies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Although the mechanism of action of INM is not yet fully understood, recent studies have indicated that it acts at an early stage of the coronaviruses (CoVs) replication cycle. In addition, a proteomic study reported that the anti-SARS-CoV-2 activity of INM could be also ascribed to its ability to inhibit human prostaglandin E synthase type 2 (PGES-2), a host protein which interacts with the SARS-CoV-2 NSP7 protein.

A New 3-Stage Approach for Reoperative Hypospadias.

Background: Most hypospadias patients undergo 1 surgical procedure and go on to live normal lives. However, there is a small subset of patients who have remaining functional complications after their repair. Patients presenting with diffuse scarring of the urethral plate and a shortage of penile skin for closure are referred to as "hypospadias cripples.

The effect of Humanitude care methodology on improving empathy: a six-year longitudinal study of medical students in Japan.

Background: Empathy, which involves understanding another person's experiences and concerns, is an important component for developing physicians' overall competence. This longitudinal study was designed to test the hypothesis that medical students' empathy can be enhanced and sustained by Humanitude Care Methodology, which focuses on perception, emotion and speech.

Methods: This six-year longitudinal observational study examined 115 students who entered Okayama University Medical School in 2013.