L858R / L718Q and L858R / L792H Mutations of EGFR Inducing Resistance Against Osimertinib by Forming Additional Hydrogen Bonds

ABSTRACT Acquired resistance to first‐line treatments in various cancers both promotes cancer recurrence as well as limits effective treatment. This is true for epidermal growth factor receptor (EGFR) mutations, for which secondary EGFR mutations are one of the principal mechanisms conferring resistance to the covalent inhibitor osimertinib. Thus, it is very important to develop a deeper understanding of the secondary mutational resistance mechanisms associated with EGFR mutations arising in tumors treated with osimertinib to expedite the development of innovative therapeutic drugs to overcome acquired resistance. This work uses all‐atom molecular dynamics (MD) simulations to investigate the conformational variation of two reported EGFR mutants (L858R/L718Q and L858R/L792H) that resist osimertinib. The wild‐type EGFR kinase domain and the L858R mutant are used as the reference. Our MD simulation results revealed that both the L718Q and L792H secondary mutations induce additional hydrogen bonds between the residues in the active pocket and the residues with the water molecules. These additional hydrogen bonds reduce the exposure area of C797, the covalent binding target of osimertinib. The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue‐residue and residue‐solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery.

Pharmacogenomics Education and Knowledge Assessment in Healthcare Curricula: A Scoping Review of the Middle East and North Africa Region

ABSTRACT Pharmacogenomics (PGx) is a crucial part of precision medicine; however, its integration into clinical practice has been slow, primarily due to knowledge gaps regarding pharmacogenomics among healthcare professionals (HCPs). Pharmacogenomics education is considered the most influential barrier to the successful implementation of PGx. In the Middle East and North Africa (MENA) region, several studies have highlighted the lack of PGx education among students and HCPs. This scoping review aims to provide an overview of the existing literature on how PGx is delivered in the curricula and its impact on knowledge acquisition among students and HCPs in the MENA region. A database search of PubMed, Embase, and CINAHL was conducted up to June 2023. Outcomes included PGx education availability, curriculum placement, mode of delivery, and knowledge level. Seven cross‐sectional studies were identified (2014–2023), with 57% from the Gulf region. PGx education is mostly taught to undergraduates (71%) through didactic lectures (100%), with only a few studies reporting a standalone course (29%). Participants demonstrated low (43%) to moderate (43%) knowledge levels, assessed using objective scales or subjective self‐assessment after completion of the course. Reported barriers to implementing PGx education included knowledge gaps, economic constraints, and system sustainability. PGx education in the MENA region is delivered mainly as an integrated course in professional programs including pharmacy and medicine, and the overall knowledge level was low to moderate. Future research could focus on providing more detailed reporting of the PGx educational landscape, developing standardized assessment tools, and evaluating actual knowledge acquisition among different professions.

Safety Monitoring of Colistin Therapy in Critically Ill Neonates With Late‐Onset Sepsis: A Retrospective Observational Study

ABSTRACT This study aimed to evaluate the safety of colistin therapy by monitoring renal function and electrolyte levels in critically ill neonates with late‐onset sepsis (LOS) hospitalized in the neonatal intensive care unit (NICU) between 2015 and 2021. This retrospective case–control study included 58 critically ill neonates treated with colistin for late‐onset sepsis and 22 control neonates with late‐onset sepsis who did not receive colistin. Data were analyzed to compare patient outcomes, microbiological profiles, and side effects of treatment. Statistical analyses were performed using repeated‐measures ANOVA and Bayesian calculations to evaluate serum creatinine levels and biochemical parameters over time. Serum creatinine levels showed similar alterations within the first 7 days of colistin treatment with moderate evidence. However, serum magnesium and sodium levels were lower on the 7th day in the colistin‐treated group compared with the control group. Colistin therapy in critically ill neonates with late‐onset sepsis appears to be a viable treatment option with an acceptable short‐term safety profile. These findings emphasize the importance of routine monitoring of renal function and electrolyte levels during colistin use in neonatal intensive care to minimize potential complications.

Naturally‐occurring nematicides of plant origin: two decades of novel chemistries

Abstract Plant‐parasitic nematodes are among the most destructive plant pathogens, resulting in a global annual economic loss of about 358 billion dollars. Using synthetic nematicides to control plant‐parasitic nematodes has resulted in broad‐spectrum toxicity to the environment. Plant‐derived secondary metabolites have recently emerged as viable options that provide effective, greener, and renewable routes for managing plant‐parasitic nematodes in various cropping systems. However, limited comprehensive information on plant‐derived secondary metabolites sources, chemical structures, and nematicidal activities is available. This study aims to compile and analyze data on plant‐based secondary metabolites with nematicidal properties collected over the last two decades. In this review, we identified 262 plant‐based metabolites with nematicidal activities that were isolated from 35 plant families and 65 plant species. Alkaloids, terpenoids, saponins, flavonoids, coumarins, thiophenes, and annonaceous acetogenins were among the most studied compounds. In addition to the structure–activity relation for specific metabolites with nematicidal potency, various techniques for their extraction and isolation from plant material are discussed. Our findings demonstrate the potential of plants as a feedstock for sourcing nematicidal compounds and discovering new chemistries that could potentially be used for developing the next generation of nematicides. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Derivative spectrophotometric techniques for the simultaneous determination of dinotefuran and acetamiprid in synthetic wastewater

Abstract BACKGROUND The industrialization of the world, and the expansion of urban areas surrounding towns and villages are closely linked to the extensive use of pesticides. Initially, they were widely used to eliminate pests and mitigate their negative effects across various sectors. However, despite their benefits, pesticides are classified among the most hazardous pollutants impacting the environment. Our aim is to simultaneously quantify dinotefuran and acetamiprid in a binary mixture. For this reason, a simple, derivative spectrophotometric method was developed. This method helps to reduce the problem of the overlapping peaks, and facilitates the analysis of single components and mixes containing many components. RESULTS Acetamiprid and dinotefuran have a clear spectrum in the range of 200–400 nm, the lambda max for acetamiprid and dinotefuran was at 246 and 270 nm, respectively. The relations between acetamiprid and dinotefuran in a binary mixture over the concentration range of (0.5–9.0) μg/mL in constant 6 μg/mL of acetamiprid and dinotefuran amount changes at 1st, 2nd, and 3rd zero‐crossing technique fit at (243 nm), (228, 266.9) nm, and (220, 251 279) nm, respectively. Also, another zero‐crossing technique done over the concentration range of (0.5–10) μg/mL in constant 7 μg/mL of dinotefuran and acetamiprid amount changes, for 1st, 2nd, and 3rd zero‐crossing technique fit at (229, 268.95) nm, (253, 285) nm, and (271, 294) nm, respectively. CONCLUSION The amount of acetamiprid and dinotefuran in binary synthetic samples was measured using the recommended method, and the recovery rate for the 1st, 2nd, and 3rd derivatives was 95–96–97–98–99%. Also, the performance of three DS methods (1st, 2nd, and 3rd) with HPLC was measured for the determination of Acetamiprid and Dinotefuran at varying spiked concentrations. The results show that the DS methods provide measurements closely matching those obtained by HPLC, demonstrating their accuracy and reliability as alternative techniques for pesticide analysis. © 2025 Society of Chemical Industry.

Harnessing Open‐Source Solutions: Insights From the First Open Systems Pharmacology ( OSP ) Community Conference

ABSTRACT In 2017, the free and open‐source software Open Systems Pharmacology (OSP) was launched. Since then, OSP has evolved from a small community into a diverse network of stakeholders committed to advancing open‐source solutions for model‐informed drug development (MIDD). In this context, the first OSP Community Conference was hosted by Novartis in Basel, Switzerland, on October 7–8, 2024, which gathered over 100 attendees from more than 40 institutions. This perspective synthesizes key insights from the conference.

Competing Risks Analysis of the Finnish Diabetes Prevention Study

ABSTRACT Clinical studies often observe one interesting event in the presence of other competing events. When both types of events can occur at any time but are only observed at clinical visits (i.e., interval censored), standard survival models may introduce bias in the estimated incidence of the interesting event over time. This can also lead to inflated relative differences between treatment groups. We developed a multi‐state model for competing risks analysis of interval censored data from the Finnish Diabetes Prevention Study. The developed model predicted the participants' clinical outcomes and demonstrated that lifestyle changes significantly decreased the risk of both diabetes and death. The model showed that those who dropped out were at lower risk of developing diabetes, neglecting the assumption of independent censoring. Furthermore, the model identified the most important covariates predicting the future development of diabetes, which should be targeted for therapeutic intervention in likely clinical scenarios. These covariates are baseline BMI, HbA1c, and insulin sensitivity measurements by QUICKI for the onset of developing T2DM, baseline BMI for dropping out, and sex and age as the predictive covariates of death. Trial Registration: ClinicalTrials.gov identifier: NCT00518167

Response to “Enhance Multistate Models With Clinically Meaningful Graphs”

Optimizing Ibrutinib Posology in Chronic Lymphocytic Leukemia Using a Semi‐Mechanistic Pharmacometric Framework

ABSTRACT Ibrutinib, a Bruton's tyrosine kinase (Btk) inhibitor, is a key therapy for chronic lymphocytic leukemia (CLL). In clinical practice, adverse events, such as hypertension, frequently necessitate dose reductions or treatment discontinuation. Emerging evidence suggests that reduced doses may retain clinical efficacy while mitigating toxicity. The synergistic ibrutinib–venetoclax combination remains understudied at low doses, particularly for ibrutinib. This study aimed to explore dose optimization strategies, with/without venetoclax, in treatment‐naïve (TN) and relapsed/refractory (R/R) CLL using mechanism‐based, model‐informed approaches to characterize the relationship between systemic ibrutinib exposure and efficacy and safety biomarkers. We leveraged data from phase 1b/2 and 3 studies, including plasma concentrations, leukocyte and lymphocyte counts, lymph node and spleen size measurements, and blood pressure. A previously developed semi‐mechanistic population pharmacokinetic‐pharmacodynamic (PKPD) framework was re‐evaluated, extended by integrating additional biomarkers and identifying differences between TN and R/R patients, and used to simulate alternative dosing strategies. The model successfully captured the temporal dynamics of all biomarkers simultaneously. We quantified a 76% longer phospho‐Btk half‐life and a 43% shorter peripheral CLL cell half‐life in TN versus R/R patients, with no evidence of ibrutinib resistance in TN patients. Dose reductions based on response depth or toxicity preserved comparable response rates and progression‐free survival to standard dosing. Ibrutinib de‐escalation schedules with venetoclax resulted in a ≤ 5% reduction in peripheral blood measurable residual disease compared to standard dosing at 2 years. This PKPD framework supports dose individualization to improve tolerability without sacrificing treatment outcomes, offering a path toward more personalized, effective CLL management.

Study the Structure, Optical, and Electrochemical Properties of Germanium Oxide/Graphene Nanoplatelet Composite for Energy Storage Applications

Germanium oxide (GeO 2 ) nanoparticles exhibit a high theoretical discharge capacity of 2152 mAh g −1 , making them promising anode materials for lithium‐ion batteries. However, their practical application is hindered by severe volume expansion during charge/discharge cycles, leading to structural degradation and capacity fading. To address this challenge, GeO 2 /graphene nanoplatelet (GNP) composite is synthesized via a modified sonochemical technique. The structural, optical, thermal, and electrochemical properties of GeO 2 and GeO 2 /GNP composites are systematically investigated. The incorporation of GNP improves the structural integrity of GeO 2 by mitigating volume changes, enhancing electronic conductivity, and increasing thermal stability. Optical studies reveal a slight bandgap widening, while Fourier transform infrared spectroscopy analysis confirms strong interfacial interactions between GeO 2 and GNP. Electrochemical evaluation demonstrates that the composite retained a discharge capacity of 181 mAh g −1 after 100 cycles, significantly improving the cyclic stability of GeO 2 anodes. These findings highlight the potential of GeO 2 /GNP composites as high‐performance anode materials for energy storage applications.