Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Aromatic interactions with phenylalanine 691 and cysteine 828: a concept for FMS-like tyrosine kinase-3 inhibition. Application to the discovery of a new class of potential antileukemia agents.

FLT3 kinase inhibitors are currently under investigation as a new treatment for acute myeloid leukemia. We report here a molecular concept invoking interactions between an aromatic ring and the side chains of Phe691 and Cys828, two residues of the ATP pocket, to obtain potent and specific inhibitors of this kinase. The hypothesis has been validated by the successful design of a new inhibitor prototype showing promising antiproliferative activity in cellular assays

Pharmacokinetics of a Novel HIV-1 Protease Inhibitor Incorporated into Biodegradable or Enteric Nanoparticles following Intravenous and Oral Administration to Mice

CGP 57813 is a peptidomimetic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease. This lipophilic compound was successfully entrapped into poly(D,L-lactic acid) (PLA) and pH sensitive methacrylic acid copolymers nanoparticles. The intravenous administration to mice of PLA nanoparticles loaded with CGP 57813 resulted in a 2-fold increase of the area under the plasma concentration-time curve, compared to a control solution. An increase in the elimination half-life (from 13 to 61 min) and in the apparent volume of distribution (1.7-3.6 L/kg) was observed for the nanoparticle incorporated compound vs control solution. Following oral administration, only nanoparticles made of the methacrylic acid copolymer soluble at low pH provided sufficient plasma levels of CGP 57813. In vitro, these nanoparticles dissolved completely within 5 min at pH 5.8. PLA nanoparticles, which are insoluble in the gastrointestinal tract, did not provide significant plasma concentrations of CGP 57813. From these observations, one can conclude that the passage of intact PLA nanoparticles across the gastrointestinal mucosa appears to be very low.</p

Novel beta-lactam derivatives: potent and selective inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

A series of beta-lactam derivatives has been designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of beta-subunit selective 20S proteasome inhibitors exhibit IC50 values in the low-nanomolar range and show good selectivity over the trypsin-like and post-glutamyl-peptide hydrolytic activities of the enzyme

Non-Covalent Inhibitors of the 20S Proteasome

Peptidomimetics have been commonly used as lead compounds to design inhibitors with high affinity and specificity for a particular enzyme. The discovery that a 2-aminobenzylstatine derivative originally designed to target an aspartyl protease was able to inhibit specifically and non-covalently the chymotrypsin-like activity of the 20S proteasome represented a unique starting point for our medicinal chemistry endeavor for this target. Utilizing a structure-based design approach, we have been able to improve the potency of this new class of proteasome inhibitors without affecting its in vitro selectivity profile

Antileukemic Effects of Novel First- and Second-Generation FLT3 Inhibitors: Structure-Affinity Comparison

Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in late-stage clinical trials. However, the identification of PKC412-resistant leukemic blast cells in the bone marrow of AML patients has propelled the development of novel and structurally distinct FLT3 inhibitors that have the potential to override drug resistance and more efficiently prevent disease progression or recurrence. Here, we present the novel first-generation “type II” FLT3 inhibitors, AFG206, AFG210, and AHL196, and the second-generation “type II” derivatives and AST487 analogs, AUZ454 and ATH686. All agents potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell cycle inhibition. Cross-resistance between “type I” inhibitors, PKC412 and AAE871, was demonstrated. While cross-resistance was also observed between “type I” and first-generation “type II” FLT3 inhibitors, the high potency of the second-generation “type II” inhibitors was sufficient to potently kill “type I” inhibitor-resistant mutant FLT3-expressing cells. The increased potency observed for the second-generation “type II” inhibitors was observed to be due to an improved interaction with the ATP pocket of FLT3, specifically associated with introduction of a piperazine moiety and placement of an amino group in position 2 of the pyrimidine ring. Thus, we present 2 structurally novel classes of FLT3 inhibitors characterized by high selectivity and potency toward mutant FLT3 as a molecular target. In addition, presentation of the antileukemic effects of “type II” inhibitors, such as AUZ454 and ATH686, highlights a new class of highly potent FLT3 inhibitors able to override drug resistance that less potent “type I” inhibitors and “type II” first-generation FLT3 inhibitors cannot