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14 pages, 266 KB  
Case Report
Diagnostic Overshadowing in Functional Neurological Disorder Leading to a Diagnosis of Acute Motor and Sensory Axonal Neuropathy: A Case Report
by Alicia Roldan, Julieanne Shulman, Rohini Singh, Eli Dayon, Andrew Abdou, Josette Hartnett and Erika L. Trovato
J. Clin. Med. 2026, 15(9), 3501; https://doi.org/10.3390/jcm15093501 (registering DOI) - 3 May 2026
Abstract
Background: Features intersecting neurological and psychiatric disorders impose differential diagnostic challenges, especially in younger, healthy patients. Cognitive biases, such as diagnostic overshadowing, can lead to errors for patients with neurologic deficits in the presence of psychiatric comorbidities. Methods: This case report [...] Read more.
Background: Features intersecting neurological and psychiatric disorders impose differential diagnostic challenges, especially in younger, healthy patients. Cognitive biases, such as diagnostic overshadowing, can lead to errors for patients with neurologic deficits in the presence of psychiatric comorbidities. Methods: This case report describes a 22-year-old female patient admitted for acute inpatient rehabilitation with an initial primary diagnosis of Functional Neurologic Disorder (FND), who subsequently underwent additional neurologic work-up following clinical and functional inconsistencies. Results: Physical exam findings, lack of response to therapeutic modalities, and electromyography/nerve conduction study findings led to a full neurological work-up consistent with Acute Motor and Sensory Axonal Neuropathy (AMSAN), treated with intravenous immunoglobulin. Conclusions: Systemic peripheral neuropathies must be addressed during differential diagnosis in suspected FND, a potential gap in current practice. This report emphasizes the essential role of physiatry and the value of an unbiased, patient-centered approach, integrating clinical knowledge and compassion to ensure accurate diagnosis and appropriate treatment. Full article
(This article belongs to the Special Issue Recent Progress in Rehabilitation Medicine—3rd Edition)
16 pages, 699 KB  
Article
Sustainable Probiotic Whey Protein Edible Films for Soft Cheese Quality and Shelf-Life Enhancement
by Charikleia Tsanasidou, Agathi Giannouli, Loulouda A. Bosnea, Antonia Terpou and Vasiliki G. Kontogianni
Foods 2026, 15(9), 1570; https://doi.org/10.3390/foods15091570 (registering DOI) - 2 May 2026
Abstract
Soft spread cheese is highly perishable, and conventional packaging offers limited protection against surface spoilage. Here, we present a sustainable, multifunctional solution: edible films made from whey protein concentrate (WPC), a valuable by-product of the cheese industry, incorporated with the probiotic Lactobacillus acidophilus [...] Read more.
Soft spread cheese is highly perishable, and conventional packaging offers limited protection against surface spoilage. Here, we present a sustainable, multifunctional solution: edible films made from whey protein concentrate (WPC), a valuable by-product of the cheese industry, incorporated with the probiotic Lactobacillus acidophilus LA5 (LA5). The objective of this study was to evaluate these films as active coatings for soft cheese, specifically assessing their physicochemical properties, probiotic viability during storage and simulated gastric transit, and their impact on cheese microbial stability and sensory quality over 60 days. Applied as active coatings on soft cheese stored at 4 °C for 60 days, these films were evaluated for their physicochemical properties, probiotic viability, microbial stability, and sensory acceptance. The incorporation of LA5 did not significantly alter film thickness (control: 0.20 ± 0.03 mm; test: 0.18 ± 0.02 mm), moisture content (control: 33.42 ± 0.54%; test: 32.34 ± 1.28%), or water solubility (control: 21.44 ± 1.14%; test: 22.89 ± 0.75%) (p > 0.05). However, mechanical properties were markedly modified: tensile strength decreased from 35.42 ± 5.38 MPa (control) to 6.04 ± 0.55 MPa (test), while elongation at break increased from 4.87 ± 0.93% to 68.23 ± 3.46% (p < 0.05), indicating a transition from rigidity to flexibility upon probiotic incorporation. The probiotic strain exhibited exceptional resilience, retaining 100% viability during simulated gastric exposure at both day 0 and day 30 of storage. During cheese storage, LA5 counts in test film-coated samples remained above the recommended therapeutic threshold (106 cfu/g), starting at 7.44 ± 0.15 log(cfu/g) on day 0 and maintaining 6.56 ± 0.20 log(cfu/g) after 60 days. Critically, yeast and mold spoilage were delayed in probiotic-coated cheese, with detectable growth appearing only at day 60 (1.64 ± 1.34 log(cfu/g)), whereas uncoated cheese showed spoilage as early as day 28 (1.33 ± 1.62 log(cfu/g)). Sensory evaluation revealed no significant differences (p > 0.05) between the coated and uncoated samples for color, appearance, texture, flavor, or overall acceptability. By valorizing a dairy by-product into an active, probiotic-loaded edible film, this approach offers a sustainable, waste-reducing strategy that enhances cheese preservation while delivering added functional value—bridging the gap between food packaging and nutrition. Sensory evaluation (n = 8, preliminary) indicated no significant differences between coated and uncoated samples, but these results require confirmation with a larger, validated panel. Full article
(This article belongs to the Special Issue Sustainable Uses and Applications of By-Products of the Food Industry)
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18 pages, 2189 KB  
Article
Endothelium-Dependent Nitric Oxide-Mediated Vasorelaxant Effects of BPC 157 in Human Internal Mammary Artery
by Alperen Kutay Yildirim, Ahmet Onur Dastan, Meric Demeli Ertus, Mesher Ensarioglu, Kubilay Karabacak and Bilge Pehlivanoglu
J. Clin. Med. 2026, 15(9), 3488; https://doi.org/10.3390/jcm15093488 (registering DOI) - 2 May 2026
Abstract
Background/Objectives: Body Protection Compound-157 (BPC 157) is a stable gastric pentadecapeptide with cytoprotective, pro-angiogenic, and nitric oxide (NO)-modulating properties that has gained increasing attention for its therapeutic potential. Although vasodilatory effects have been demonstrated in animal models, functional evidence in human arterial tissue [...] Read more.
Background/Objectives: Body Protection Compound-157 (BPC 157) is a stable gastric pentadecapeptide with cytoprotective, pro-angiogenic, and nitric oxide (NO)-modulating properties that has gained increasing attention for its therapeutic potential. Although vasodilatory effects have been demonstrated in animal models, functional evidence in human arterial tissue remains limited. This study investigated the effects of BPC 157 on vascular tone in human internal mammary artery (IMA) rings and evaluated the contribution of endothelial NO signaling. Methods: Residual IMA segments obtained from elective coronary artery bypass graft surgeries (n = 12) were dissected into endothelium-intact and endothelium-denuded rings. Following equilibration, the rings were challenged by phenylephrine (PheE; 3 × 10−6 M) to induce contraction. Cumulative concentration–response curves of BPC 157 (0.01–1 mg/mL) for five consecutive doses were constructed. The involvement of NO was assessed by BPC 157 dose–response curves in the nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME; 10−6 M) pre-incubated rings. Maximum force of contraction, area under the curve, maximum response (Emax), and negative logarithm of the half-maximal effective concentration (pEC50) values were analyzed. Results: BPC 157 produced a concentration-dependent reduction in PheE-induced contraction in both groups, with significantly greater relaxation in endothelium-intact rings (p < 0.05). L-NAME increased contractile responsiveness in intact rings and attenuated BPC 157-induced relaxation. Under NOS inhibition, differences between groups progressively diminished and concentration–response curves converged at higher concentrations. Emax analysis demonstrated that endothelial integrity markedly enhanced maximal vasorelaxation, whereas this advantage was largely abolished after NOS inhibition. Conclusions: BPC 157 induces concentration-dependent vasorelaxation in human arterial tissue, predominantly mediated via an endothelium-dependent NO pathway. Endothelial integrity primarily enhances maximal efficacy, while residual effects indicate additional mechanisms. These findings provide early mechanistic evidence for the vascular activity of BPC 157, although further molecular and in vivo studies are required to clarify its clinical relevance. Full article
(This article belongs to the Section Vascular Medicine)
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11 pages, 465 KB  
Article
Assessment and Appraisal of Drug Innovativeness in Italy: Ultimate Evidence on Key Drivers and Consistency
by Alvise Verde, Federica Turati, Clara Trimarchi, Carlotta Galeone and Claudio Jommi
J. Mark. Access Health Policy 2026, 14(2), 28; https://doi.org/10.3390/jmahp14020028 (registering DOI) - 2 May 2026
Abstract
This study aims to update and integrate empirical evidence on the key drivers and consistency of the appraisals of drug innovativeness in Italy by the Italian Medicines Agency (AIFA), and discuss if this evidence is supportive of the reform and requirements implemented in [...] Read more.
This study aims to update and integrate empirical evidence on the key drivers and consistency of the appraisals of drug innovativeness in Italy by the Italian Medicines Agency (AIFA), and discuss if this evidence is supportive of the reform and requirements implemented in 2025. Appraisals from July 2017 to December 2024 were retrieved from the AIFA website. The association between the innovativeness appraisal, the innovativeness domains (unmet need/added therapeutic value/quality of evidence) and disease/drug/evidence-specific variables was assessed using odds ratios (ORs) from binary/multinomial logistic regression models. Innovativeness status was strongly associated with added therapeutic value (OR > 70). Medicines for rare diseases were more likely to receive conditional innovativeness (OR = 2.95). Full innovativeness was more frequently recognized for indications including paediatric patients (OR = 3.60). References to severe diseases and patient-reported outcomes (PROs) had a higher, not statistically significant, likelihood of innovativeness, whereas reference to indirect treatment comparisons had a lower likelihood (OR = 0.18). The appraisal process showed high internal consistency, but its regulation needs more specific guidance. The innovativeness regulation was reformed in July 2025, including specific recommendations on the criteria to identify the alternative treatments; the role and robustness of indirect comparisons; and the role and requirements for PROs. Our evidence provides an empirical rationale for this reform. Full article
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20 pages, 17336 KB  
Review
Disulfidptosis vs. Ferroptosis: A Comprehensive Review of SLC7A11-Mediated Metal Dyshomeostasis and Cell Death
by Iogann Tolbatov and Alessandro Marrone
Biomolecules 2026, 16(5), 671; https://doi.org/10.3390/biom16050671 - 1 May 2026
Abstract
This systematic review examines the emerging interplay between ferroptosis and disulfidptosis, two distinct forms of regulated cell death (RCD) centered on the SLC7A11 (also known as xCT)-mediated metabolic paradox. Traditionally recognized as a potent anti-ferroptotic factor, SLC7A11 imports cystine for glutathione synthesis to [...] Read more.
This systematic review examines the emerging interplay between ferroptosis and disulfidptosis, two distinct forms of regulated cell death (RCD) centered on the SLC7A11 (also known as xCT)-mediated metabolic paradox. Traditionally recognized as a potent anti-ferroptotic factor, SLC7A11 imports cystine for glutathione synthesis to neutralize iron-dependent lipid peroxidation. However, the discovery of disulfidptosis identifies SLC7A11 as a metabolic liability, representing a paradigm shift in our understanding of cellular antioxidant defense. This discovery reveals a transformative vulnerability in SLC7A11-overexpressing cells, shifting the focus from conventional survival mechanisms to the consequences of catastrophic structural collapse. Beyond metabolic exhaustion, this review highlights the role of metal dyshomeostasis as a primary driver, spanning from iron-catalyzed ferroptosis to copper-mediated metabolic interference. This conceptual framework redefines the SLC7A11 axis as a targetable “double-edged sword” in therapy-resistant malignancies. Clinical synthesis of multi-omic gene signatures, such as the disulfidptosis- and ferroptosis-related gene prognostic score (DRGPS) and the ferroptosis- and disulfidptosis-related gene (FDRG) scores, demonstrates their robust value in prognostic stratification and in predicting immunotherapy response across malignancies, including lung adenocarcinoma and hepatocellular carcinoma. Furthermore, we evaluate the capacity of disulfidptosis to prime immunogenic cell death (ICD) and remodel the immunosuppressive tumor microenvironment to bypass chemoresistance. By integrating mechanistic insights with clinical data, this review provides a comprehensive framework for targeting the SLC7A11 axis as a transformative therapeutic vulnerability in precision oncology. Full article
(This article belongs to the Special Issue Feature Papers in Section “Cellular Biochemistry”, 2nd Edition)
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15 pages, 721 KB  
Article
Management of Bone-Only Progressive Disease in Metastatic Breast Cancer—A Retrospective Single-Center Analysis
by Christine Deutschmann, Paola Clauser, Florian Heinzl, Daphne Gschwantler-Kaulich, Christian F. Singer, Carmen Leser, Sabine Danzinger, Valentina Patrzek, Laura Anzengruber, Katharina Krepper and Georg Pfeiler
J. Clin. Med. 2026, 15(9), 3456; https://doi.org/10.3390/jcm15093456 - 1 May 2026
Abstract
Background/Objectives: The optimal management of bone-only progressive disease (PD) in metastatic breast cancer remains unclear for several reasons. Radiologic diagnosis of bone PD is complicated by the lack of standardized response assessment criteria, unspecific morphologic changes of the bone, and flare-up phenomena. Furthermore, [...] Read more.
Background/Objectives: The optimal management of bone-only progressive disease (PD) in metastatic breast cancer remains unclear for several reasons. Radiologic diagnosis of bone PD is complicated by the lack of standardized response assessment criteria, unspecific morphologic changes of the bone, and flare-up phenomena. Furthermore, bone-only disease and oligoprogression have been associated with favorable prognosis challenging a change of systemic treatment with the consequence of limited treatment options in the future. Additionally, bone-only metastatic disease is frequently excluded from clinical trials resulting in scarce data. This study aimed to assess the therapeutic management and outcome of bone-only PD in metastatic breast cancer patients in a real-world academic setting. Methods: A retrospective analysis of all breast cancer patients with bone metastases (BMs) and at least one event of radiologic evidence of bone-only PD and/or the occurrence of a skeletal-related event (SRE) who were treated at the Department of Obstetrics and Gynecology of the Medical University of Vienna, Austria, between 1 January 2015 and 14 December 2021 was performed. In cases of multiple bone-only PD events in one patient only the first event was considered for analysis. All cases with PD in organs other than the bone were excluded. The primary outcome of the study was to assess therapeutic measures of bone-only PD. Secondary outcomes were the time from bone-only PD to next bone PD (TTF BD) and overall survival (OS; time from bone-only PD to death). Predictors of TTF BD and OS were assessed as exploratory outcomes. Results: Out of a total of 308 breast cancer patients with BMs, 57 had at least one event of bone-only PD. In 59.3% of bone-only PD cases the systemic treatment was continued with a numerically higher rate if multiple metastatic sites were present (71.4% vs. 46.4%). In most bone-only PD events the bone-targeted agent (BTA) was continued (94.5%), independent of the total number of metastatic sites. In 24.1% radiotherapy (RT) was administered with similar rates between patients with bone-only and multiple metastatic sites. The median TTF BD was 6.3 months. In multivariate analysis no predictor for TTF BD could be identified including change of systemic treatment, RT, previous BTA treatment duration, number of previous treatment lines for the metastatic disease, number of metastatic sites and previous or current SRE. Median OS was 21.8 months. Number of previous treatment lines for the metastatic setting was significantly associated with OS with shorter OS in the more advanced disease stage (p-value = 0.0208). Conclusions: Systemic and BTA treatment were continued in the majority of bone-only PD cases. In 24.1% RT was administered. No association between change of systemic therapy and improved oncologic outcome was found. The study’s results are hypothesis-generating in terms of whether change of systemic treatment should be performed restrictively to avoid limited treatment options in the future. Similarly, radiotherapy did not ameliorate prognosis. Full article
(This article belongs to the Section Oncology)
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13 pages, 647 KB  
Article
Comparative Analysis of Anticoagulation Stability in Critically Ill Patients Receiving Argatroban for Suspected or Confirmed Heparin-Induced Thrombocytopenia Compared with Unfractionated Heparin: A Retrospective Cohort Study
by Imran Khan, Elizabeth Lamarche, Bernadett Kovacs, Ariel Hendin, Andy Pan, Caitlin Richler, Christine Landry, Sydney Morin, Kaouther Derouiche and Pierre Thabet
Hematol. Rep. 2026, 18(3), 31; https://doi.org/10.3390/hematolrep18030031 - 30 Apr 2026
Viewed by 1
Abstract
Background: Achieving and maintaining therapeutic anticoagulation with unfractionated heparin in critically ill patients is challenging due to biologic variability, heparin resistance, and limitations of activated partial thromboplastin time (aPTT) monitoring. Argatroban, a direct thrombin inhibitor, provides antithrombin-independent anticoagulation with more predictable pharmacokinetics, but [...] Read more.
Background: Achieving and maintaining therapeutic anticoagulation with unfractionated heparin in critically ill patients is challenging due to biologic variability, heparin resistance, and limitations of activated partial thromboplastin time (aPTT) monitoring. Argatroban, a direct thrombin inhibitor, provides antithrombin-independent anticoagulation with more predictable pharmacokinetics, but real-world data describing its anticoagulation stability in the intensive care unit (ICU) remain limited. Objective: This study aimed to compare anticoagulation stability between continuous intravenous argatroban and unfractionated heparin in critically ill patients using time in therapeutic range (TTR) based on aPTT as the primary performance metric. Methods: A retrospective cohort study was conducted in the ICU and step-down unit of Hôpital Montfort (Ottawa, ON, Canada) between January 2016 and December 2024. Adult patients receiving continuous intravenous argatroban or unfractionated heparin for systemic anticoagulation were included. All aPTT values obtained during active infusion were extracted, and TTR was calculated using linear interpolation between consecutive measurements. Continuous variables were summarized as medians with interquartile ranges and compared using the Wilcoxon rank-sum test; categorical TTR strata were compared using Fisher’s exact test. Results: Sixty-eight patients met the inclusion criteria, contributing 9 argatroban and 61 heparin infusion courses. Argatroban demonstrated a higher median TTR than heparin (83.3% [IQR 82.0–90.7] vs. 47.5% [32.9–62.4]; p < 0.001), with a moderate-to-large effect size (r = 0.51). Median aPTT values were similar between groups, but argatroban showed narrower dispersion and fewer prolonged subtherapeutic periods. A majority of heparin courses (56.5%) spent <50% of time within range, whereas no argatroban courses fell into this category. Conversely, 33.3% of argatroban courses achieved ≥90% TTR compared with none in the heparin group. Conclusions: In this real-world ICU cohort where argatroban was used for suspected or confirmed HIT, argatroban was associated with higher TTR than unfractionated heparin. These findings support the use of time-dependent metrics to evaluate anticoagulation quality and warrant prospective studies in more homogeneous populations. Full article
15 pages, 356 KB  
Article
Association of Initial Chest CT Findings, CT Severity Score and Clinical Parameters with ICU Admission in Hospitalized COVID-19 Patients
by Aleksandra Milenkovic, Simon Nikolic, Jelena Aritonovic Pribakovic, Branislava Radovic, Aleksandra Ilic, Milica Stevanovic, Sara Kovacevic, Kristina Bulatovic, Jelena Milovanovic, Arijeta Kostic and Aleksandra Janicevic
Viruses 2026, 18(5), 528; https://doi.org/10.3390/v18050528 - 30 Apr 2026
Viewed by 31
Abstract
The aim of this study was to evaluate the association between baseline clinical and CT characteristics and to identify factors associated with intensive care unit (ICU) admission in hospitalized COVID-19 patients. This retrospective study included 176 adult patients with laboratory-confirmed SARS-CoV-2 infection hospitalized [...] Read more.
The aim of this study was to evaluate the association between baseline clinical and CT characteristics and to identify factors associated with intensive care unit (ICU) admission in hospitalized COVID-19 patients. This retrospective study included 176 adult patients with laboratory-confirmed SARS-CoV-2 infection hospitalized at the COVID Hospital of the Clinical Hospital Center Kosovska Mitrovica during 2021–2022 (Delta and Omicron variants). Patients were divided into two groups according to intensive care unit requirement: those treated in a general inpatient ward (No ICU) and those requiring ICU admission (ICU group). Demographic and clinical characteristics, lifestyle factors, CT findings, CT severity score (CTSS) values, and therapeutic interventions were compared between groups. Of the total cohort, 113 patients (64%) were hospitalized in a general inpatient ward, while 63 (36%) required intensive care unit admission. Independent predictors of ICU admission identified in the multivariate logistic regression analysis were obesity (B = 2.96, p < 0.001), dyspnea (B = 1.51, p = 0.041), higher CT severity score (B = 0.68, p < 0.001), and lower glucose levels (B = −0.27, p = 0.014). Furthermore, for each one-point increase in the CTSS, the odds of ICU admission nearly doubled (OR = 1.97). Total CT score values above the cut-off point (15.0) demonstrated significant reliability in discriminating the need for ICU transfer in patients with COVID-19. These findings suggest that combined clinical and radiological assessment at hospital admission may facilitate early identification of patients at high risk of requiring ICU care, with the CT severity score representing the strongest radiological predictor. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology, 3rd Edition)
27 pages, 1698 KB  
Systematic Review
Diagnostic and Prognostic Significance of Chemokines in Head and Neck Cancers: A Systematic Review and Meta-Analysis
by Raneem Alsheikh, Deemah Assami, Dima Nasrallah, Ahmed Arabi, Ahmad Hamdan, Mohamed Ragab Elhadary, Ibrahim Elmakaty and Mohammed Imad Malki
Cancers 2026, 18(9), 1437; https://doi.org/10.3390/cancers18091437 - 30 Apr 2026
Viewed by 26
Abstract
Background: Head and neck cancers (HNCs) represent a global health burden, with high morbidity and mortality largely driven by late-stage diagnosis and heterogeneous clinical outcomes. Reliable biomarkers are needed to improve early detection, prognostic stratification, and therapeutic decision-making. This study evaluates the diagnostic [...] Read more.
Background: Head and neck cancers (HNCs) represent a global health burden, with high morbidity and mortality largely driven by late-stage diagnosis and heterogeneous clinical outcomes. Reliable biomarkers are needed to improve early detection, prognostic stratification, and therapeutic decision-making. This study evaluates the diagnostic and prognostic value of chemokines in HNCs and identifies candidates with clinical relevance. Methods: A comprehensive literature search was conducted on 28 March 2026 across PubMed, Embase, Scopus, Web of Science, and EBSCO. Observational studies involving patients or biological samples with confirmed HNCs were included if they evaluated chemokines as diagnostic or prognostic biomarkers. Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) for prognostic studies and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool for diagnostic studies. Meta-analyses were performed for chemokines evaluated in ≥3 studies using the inverse-variance heterogeneity model. Results: Forty-four studies encompassing 7294 participants were included. Prognostic findings were heterogeneous across biomarkers. MIP-3α demonstrated consistently significant associations with poorer survival outcomes. In contrast, IL-8, CXCL10, and CXCR4 showed inconsistent or predominantly non-significant associations with overall survival (OS), disease-free survival (DFS), and locoregional control (LRC). For diagnostic performance, IL-8, in saliva, demonstrated relatively high sensitivity and specificity for oral squamous cell carcinoma. Chemerin showed high diagnostic accuracy, although evidence remains limited. Conclusions: Certain chemokines show potential as diagnostic and prognostic biomarkers in HNCs. However, heterogeneity across tumor types, samples, and methodologies limits evidence. Larger, well-designed studies are needed to validate their clinical utility in risk stratification and personalized management of HNCs. Full article
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24 pages, 2981 KB  
Article
Cudratricusxanthone A Exhibits Antitumor Activities Against NSCLC Harboring EGFR L792H and G796R Triple Mutations via Regulating EGFR-ERK/AKT/STAT3 Signaling
by Yinghao Wang, Jiamin Xian, Zhuoyi Wang, Jingmeng Wang, Ruohan Zhang, Jun Sheng, Jing Wang and Peiyuan Sun
Molecules 2026, 31(9), 1504; https://doi.org/10.3390/molecules31091504 - 30 Apr 2026
Viewed by 5
Abstract
Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that [...] Read more.
Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that directly interferes with osimertinib binding, yet effective targeted therapeutic strategies for these specific mutations remain lacking. Cudratricusxanthone A (CTXA), a natural xanthone derivative isolated from Cudrania tricuspidata Bur., has demonstrated various pharmacological activities, but its effects against EGFR triple-mutant NSCLC have not been systematically investigated. Methods: Stable Ba/F3 and NIH/3T3 cell lines expressing EGFR L858R/T790M/L792H or L858R/T790M/G796R triple mutations were generated via electroporation. The antiproliferative effects of CTXA were evaluated by MTT/MTS assays, colony formation, and wound healing assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression of EGFR signaling pathway components (p-EGFR, p-ERK, p-AKT, p-STAT3) and cell cycle regulators (Cyclin D1, CDK4) were examined by Western blotting. Molecular docking and 200 ns molecular dynamics simulations were performed to investigate the stability and binding modes of CTXA to the mutant EGFR kinase domains. Results: The successfully established triple-mutant cell lines exhibited high EGFR expression, IL-3-independent growth, and significant resistance to osimertinib. CTXA inhibited the proliferation of all triple-mutant cell lines in a time- and concentration-dependent manner, with 48 h IC50 values ranging from 0.362 to 2.488 μM. Mechanistically, CTXA suppressed EGFR autophosphorylation and downregulated downstream p-ERK, p-AKT, and p-STAT3. CTXA induced G1 phase cell cycle arrest by downregulating Cyclin D1 and CDK4, significantly promoted apoptosis, and inhibited cell migration. Molecular docking revealed that while osimertinib binding was blocked by steric hindrance from His-792 or Arg-796, CTXA adapted to the mutated ATP-binding pockets through multiple hydrogen bonds and extensive hydrophobic interactions. Molecular dynamics simulations confirmed the stable binding of CTXA to both mutant EGFR proteins over the 200 ns simulations. Conclusions: This study demonstrates for the first time that the natural compound CTXA possesses antitumor efficacy against EGFR L858R/T790M/L792H and L858R/T790M/G796R mutants by regulating EGFR-ERK/AKT/STAT3 signaling. Our findings position CTXA as a promising lead compound for tackling this challenging form of acquired resistance and highlight the value of natural products in multi-target antitumor drug discovery. Full article
33 pages, 1983 KB  
Review
Danger or Salvation? The Role of DAMPs in Cancer Therapy
by Anna A. Vedunova, Evgenii L. Guryev, Sergey V. Gudkov, Tatiana A. Mishchenko and Maria V. Vedunova
Cancers 2026, 18(9), 1442; https://doi.org/10.3390/cancers18091442 - 30 Apr 2026
Viewed by 34
Abstract
Background: Modern oncology views immune system dysfunction as a key factor in carcinogenesis. The induction of immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immunity, represents a promising therapeutic strategy. Damage-associated molecular patterns (DAMPs) play a central [...] Read more.
Background: Modern oncology views immune system dysfunction as a key factor in carcinogenesis. The induction of immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immunity, represents a promising therapeutic strategy. Damage-associated molecular patterns (DAMPs) play a central role in this process. This review aims to summarize current knowledge of DAMPs, their release mechanisms during ICD, their classification, and their prognostic and therapeutic significance in antitumor immunity. Methods: We systematically reviewed and synthesized literature published in Pubmed and Google Scholar on ICD and DAMPs, focusing on distinct forms of DAMPs which were categorized based on recognition mechanisms (five classes) and cellular origin (extracellular, mitochondrial, nuclear, and cytosolic). Key molecules, their receptors, downstream signaling pathways, and clinical associations were analyzed. Results: The spatiotemporally coordinated release of the pattern of DAMPs promotes dendritic cell maturation, antigen presentation, activation of cytotoxic T lymphocytes, and elimination of tumor cells. DAMPs can exhibit a dual role: they are able to induce sterile inflammation essential for antitumor immunity, but may also contribute to metastasis and chronic inflammation. Among all DAMPs, high-mobility group box 1 (HMGB1, a nuclear DAMP) and calreticulin (CRT, a cytosolic protein) demonstrate the greatest prognostic value. Other DAMPs (e.g., extracellular matrix components, uric acid) act as signal amplifiers during various forms of cell death. Conclusions: Understanding the spatiotemporal dynamics of DAMP release is critical for activating immune responses against malignant cells. Monitoring DAMPs may improve patient stratification, predict therapeutic responses, and enable personalized immunotherapeutic strategies. Further investigation of ICD mechanisms and DAMP release represents a fundamental basis for developing novel anticancer therapies. Full article
(This article belongs to the Special Issue Cancer Cell Death and Immune Response)
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14 pages, 1392 KB  
Article
Optimized LL-37-Derived Peptides Exhibit Antitubercular Activity, Induce Membrane Disruption, and P-Type ATPase Transcriptional Responses in Mycobacterium tuberculosis
by Paola A. Santos, Milena Maya-Hoyos, Luz Mary Salazar, Claudia Andrea Cruz, Alver Cruz-Cacais, Mayerly Giraldo-Avila, Juliana Gómez-Manchego, Lineth Valentina Triana and Carlos Y. Soto
Biomolecules 2026, 16(5), 665; https://doi.org/10.3390/biom16050665 - 30 Apr 2026
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Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major cause of morbidity and mortality worldwide, particularly due to the emergence of drug-resistant strains. Membrane-active antimicrobial peptides (AMPs) represent attractive therapeutic candidates because they target bacterial envelope integrity and disrupt essential [...] Read more.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major cause of morbidity and mortality worldwide, particularly due to the emergence of drug-resistant strains. Membrane-active antimicrobial peptides (AMPs) represent attractive therapeutic candidates because they target bacterial envelope integrity and disrupt essential cellular processes. We evaluated two rationally designed LL-37-derived peptides: a truncated C-terminally amidated analog (LL37-1) and a modified variant incorporating N-terminal acetylation and a single D-amino acid substitution (D-LL37). Dose–response analysis demonstrated that D-LL37 exhibited greater antimycobacterial potency, with lower inhibitory concentrations of 90% (IC90) and 50% (IC50) values (18.40 ± 0.39 μM and 10.11 ± 0.60 μM, respectively) compared with LL37-1 (25.44 ± 0.36 μM and 15.45 ± 1.40 μM). Fluorescence-based permeability assays revealed partial membrane disruption (36% and 44% at IC90 for LL37-1 and D-LL37, respectively), which was supported by ultrastructural alterations observed by scanning electron microscopy, including bacillary shortening, rough surface formation, cell clusters, and the presence of cellular debris, all of which are consistent with membrane damage. RT-qPCR analysis demonstrated significant upregulation of the P-type ATPase genes ctpF, ctpA, and ctpH following D-LL37 exposure. Collectively, these findings indicate that optimized LL-37-derived peptides exert antitubercular activity associated with envelope perturbation and coordinated activation of ion transport-related stress responses. Full article
(This article belongs to the Section Natural and Bio-derived Molecules)
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33 pages, 26000 KB  
Article
Ethnobotany and Medicinal Potential of Wild Edible Fruit Species in Kut Chum District, Yasothon Province, Thailand
by Tammanoon Jitpromma, Piyaporn Saensouk, Santi Watthana and Surapon Saensouk
Biology 2026, 15(9), 711; https://doi.org/10.3390/biology15090711 - 30 Apr 2026
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Abstract
Wild edible fruits play an important role in supporting food security, nutrition, and traditional knowledge systems in rural communities, yet their diversity and uses remain insufficiently documented in many parts of Thailand. This study aimed to investigate the diversity, utilization, and ethnobotanical significance [...] Read more.
Wild edible fruits play an important role in supporting food security, nutrition, and traditional knowledge systems in rural communities, yet their diversity and uses remain insufficiently documented in many parts of Thailand. This study aimed to investigate the diversity, utilization, and ethnobotanical significance of wild edible fruit species in Kut Chum District, Yasothon Province. Ethnobotanical data were collected through semi-structured interviews and field surveys with local informants, and quantitative indices, including the Cultural Importance Index (CI), Fidelity Level (%FL), and Informant Consensus Factor (ICF), were applied to evaluate species significance and medicinal agreement. A total of 71 species belonging to 33 families were recorded, with most species consumed as fresh fruits and a subset used for medicinal purposes. Several species, such as Irvingia malayana Oliv. ex A.W.Benn., Phyllanthus emblica L., and Syzygium cumini (L.) Skeels exhibited high cultural importance, reflecting their key roles in local diets. High ICF values across therapeutic categories indicated strong consensus in ethnomedicinal knowledge. Additionally, 44 species not used medicinally in the study area were reported as medicinal in other regions, highlighting spatial variation in knowledge systems. These findings emphasize the importance of wild edible fruits as multifunctional resources contributing to food and nutritional security. Integrating culturally important species into conservation and sustainable use strategies may support biodiversity preservation and the continuity of traditional ecological knowledge. Full article
(This article belongs to the Section Conservation Biology and Biodiversity)
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21 pages, 1883 KB  
Review
Cardiac PET in the Last Five Years: Established Tracers, Novel Radiopharmaceuticals, and Translational Challenges
by Agostino Chiaravalloti, Luca Verdesca, Marco Alfonso Perrone, Antonio Chiaravalloti and Daniele Di Biagio
Appl. Sci. 2026, 16(9), 4355; https://doi.org/10.3390/app16094355 - 29 Apr 2026
Viewed by 89
Abstract
Cardiac positron emission tomography (PET) has undergone substantial development in recent years, moving beyond conventional perfusion imaging toward a multiparametric and increasingly quantitative assessment of cardiovascular disease. This article provides a critical narrative overview of the recent cardiac PET literature, with particular emphasis [...] Read more.
Cardiac positron emission tomography (PET) has undergone substantial development in recent years, moving beyond conventional perfusion imaging toward a multiparametric and increasingly quantitative assessment of cardiovascular disease. This article provides a critical narrative overview of the recent cardiac PET literature, with particular emphasis on studies published over the last five years, and discusses both established tracers and emerging radiopharmaceuticals in contemporary cardiology. Among established applications, 18F-FDG remains relevant for myocardial viability assessment and selected inflammatory indications, although its prognostic and therapeutic implications are less uniform than earlier narratives suggested. For myocardial perfusion imaging, 13N-ammonia and 82Rb PET provide robust assessment of myocardial blood flow and myocardial flow reserve, but their clinical interpretation remains strongly influenced by acquisition protocols, software reproducibility, and methodological standardization. The review also addresses newer tracers, including 68Ga-FAPI for fibroblast activation, 18F-flurpiridaz for high-performance perfusion imaging, 18F-FDOPA for cardiac sympathetic dysfunction, and amyloid-binding PET radiopharmaceuticals for cardiac amyloidosis. Overall, recent evidence supports cardiac PET as a powerful platform for physiologic and molecular imaging, but not as a uniform or methodologically neutral technology. Its current value lies in selective, question-driven clinical use, whereas broader implementation will depend on tracer-specific validation, harmonized quantitative workflows, and clear demonstration of incremental benefit over existing imaging strategies. Full article
(This article belongs to the Section Biomedical Engineering)
28 pages, 1009 KB  
Review
Agro-Industrial Plant Biomass as a Sustainable Source of Anticancer Polyphenols: Molecular Mechanisms and Future Perspectives
by Sorur Yazdanpanah, Fabrizia Sepe, Silvia Romano, Anna Valentino, Orsolina Petillo, Gianfranco Peluso, Raffaele Conte and Anna Calarco
Curr. Issues Mol. Biol. 2026, 48(5), 459; https://doi.org/10.3390/cimb48050459 - 29 Apr 2026
Viewed by 90
Abstract
The increasing global burden of cancer, together with the need for more sustainable resource management, has stimulated growing interest in the valorization of agro-industrial plant residues as sources of bioactive compounds with therapeutic potential. This review highlights the potential of plant by-products—including citrus [...] Read more.
The increasing global burden of cancer, together with the need for more sustainable resource management, has stimulated growing interest in the valorization of agro-industrial plant residues as sources of bioactive compounds with therapeutic potential. This review highlights the potential of plant by-products—including citrus peels, olive leaves, date palm residues, and tea and coffee processing wastes—as sustainable reservoirs of polyphenols and other phytochemicals with significant anticancer activity. Key compounds such as hesperidin and naringenin from citrus peels, oleuropein and hydroxytyrosol from olive leaves, quercetin and syringic acid from date palm residues, and chlorogenic acid and epigallocatechin gallate from tea and coffee by-products have demonstrated promising antitumor effects in both in vitro and in vivo studies. These molecules exert their activity through multiple mechanisms, including the inhibition of cancer cell proliferation, induction of apoptosis, regulation of the cell cycle, and modulation of major oncogenic signaling pathways such as PI3K/AKT, MAPK, NF-κB, and EGFR. For instance, hydroxytyrosol induces apoptosis and cell cycle arrest while inhibiting the PI3K/AKT and MAPK pathways. Quercetin limits metastasis and glycolysis and suppresses VEGF, PKM2, and AKT signaling. Ferulic acid suppresses tumor growth by inhibiting the PI3K/AKT and JAK2/STAT6 pathways, thereby promoting apoptosis (in vitro and in vivo). In addition to their pharmacological potential, the recovery of these compounds from plant waste supports circular economy strategies by reducing environmental impact and promoting the development of value-added products. Future research should focus on optimizing extraction methods, improving bioavailability and stability, and validating safety and efficacy through well-designed preclinical and clinical studies. Full article
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