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Mesenchymal Stem Cell–Derived Exosomes Mitigate Cutaneous Radiation Injury Through Coordinated Modulation of DNA Repair, Stress, and Inflammatory Gene Programs -
DNA Methylation Dynamics in Development and Disease: Insights from Zebrafish Models -
The Gut–Muscle Axis in Sarcopenia: Mechanisms, Evidence Gaps and Translational Challenges -
3D Virtual Reality Performance Metrics as a Future Fatigue Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) -
Alpha-Ketoglutarate: A Metabolic Regulator of Cellular Homeostasis and Pathophysiology
Journal Description
Biomedicines
Biomedicines
is an international, peer-reviewed, open access journal on biomedicines published monthly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q2 (Pharmacology and Pharmacy) / CiteScore - Q1 (Medicine (miscellaneous))
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 18.2 days after submission; acceptance to publication is undertaken in 2.8 days (median values for papers published in this journal in the first half of 2026).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Companion journals for Biomedicines include: IJTM, BioMed, Anesthesia Research and Emergency Care and Medicine.
Impact Factor:
4.5 (2025);
5-Year Impact Factor:
4.7 (2025)
Latest Articles
Pediatric Lower Gastrointestinal Bleeding: Endoscopic and Histopathologic Spectrum in a 16-Year Tertiary-Center Cohort
Biomedicines 2026, 14(7), 1645; https://doi.org/10.3390/biomedicines14071645 - 21 Jul 2026
Abstract
Objectives: Pediatric lower gastrointestinal bleeding encompasses a broad and age-dependent spectrum of conditions, ranging from benign anorectal disorders to inflammatory bowel disease, colorectal polyps, and less common structural or vascular lesions. Despite advances in diagnostic evaluation, contemporary pediatric data on the distribution
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Objectives: Pediatric lower gastrointestinal bleeding encompasses a broad and age-dependent spectrum of conditions, ranging from benign anorectal disorders to inflammatory bowel disease, colorectal polyps, and less common structural or vascular lesions. Despite advances in diagnostic evaluation, contemporary pediatric data on the distribution of underlying diagnoses, particularly according to age and sex, remain limited. This study aimed to evaluate the endoscopic and histopathologic spectrum of pediatric lower gastrointestinal bleeding and to examine age- and sex-related diagnostic patterns. Methods: This retrospective single-center study included children aged 0–18 years who presented with overt lower gastrointestinal bleeding and underwent colonoscopic evaluation at a tertiary pediatric gastroenterology center between May 2010 and May 2026. Demographic data, colonoscopic and histopathologic findings, final diagnoses, inflammatory bowel disease subtypes, and polyp histopathology were reviewed. Patients were categorized into four age groups: 0–3, 4–6, 7–12, and 13–18 years. Results: A total of 268 children were included. The mean age was 11.4 ± 4.9 years, and 130 patients were female (48.5%). The most common diagnosis was inflammatory bowel disease, identified in 79 patients (29.5%), including 62 with ulcerative colitis and 17 with Crohn’s disease. Normal colonoscopic and histopathologic findings were observed in 65 patients (24.3%), anal fissure in 63 (23.5%), and polypoid lesions in 30 (11.2%). Juvenile polyp was the most common polyp subtype. Diagnostic distribution differed significantly across age groups (p < 0.001). Inflammatory bowel disease was more frequent among adolescents, whereas polypoid lesions were most common in children aged 4–6 years. Exploratory sex-based analyses suggested a female predominance in ulcerative colitis and a male predominance in Crohn’s disease and polypoid lesions. Conclusions: In children undergoing colonoscopic evaluation for lower gastrointestinal bleeding, inflammatory bowel disease, normal findings, anal fissure, and polypoid lesions were the leading diagnostic categories. Age- and sex-related patterns may help guide clinical evaluation and interpretation of colonoscopic and histopathologic findings.
Full article
(This article belongs to the Section Molecular and Translational Medicine)
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Open AccessReview
Unconventional Applications of Semaglutide and Tirzepatide: From Oncology to Human Reproduction
by
Sandro La Vignera and Rosita A. Condorelli
Biomedicines 2026, 14(7), 1644; https://doi.org/10.3390/biomedicines14071644 - 21 Jul 2026
Abstract
Semaglutide and tirzepatide, glucagon-like peptide-1 (GLP-1) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, respectively, have revolutionized the management of type 2 diabetes mellitus and obesity. Beyond their established metabolic indications, emerging preclinical and clinical evidence suggests these incretin-based therapies exert pleiotropic effects
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Semaglutide and tirzepatide, glucagon-like peptide-1 (GLP-1) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, respectively, have revolutionized the management of type 2 diabetes mellitus and obesity. Beyond their established metabolic indications, emerging preclinical and clinical evidence suggests these incretin-based therapies exert pleiotropic effects across multiple organ systems through mechanisms extending beyond glycemic control and weight reduction. This comprehensive review synthesizes current evidence for unconventional applications of semaglutide and tirzepatide across five distinct therapeutic domains: oncology, psychiatry and addiction medicine, orthopedics, aesthetic medicine, and human reproduction. In oncology, both agents demonstrate antitumor activity primarily through immune and metabolic reprogramming rather than direct cytotoxicity, with promising signals in pancreatic, thyroid, breast, and colorectal cancers. In psychiatry, modulation of mesolimbic dopamine reward pathways and GABAergic neurotransmission underlies robust preclinical and observational evidence for reducing alcohol use disorder, substance use, and binge-eating behaviors. Orthopedic applications include clinically meaningful improvements in knee osteoarthritis pain and function, though bone health signals remain mixed. Aesthetic medicine faces the dual challenge of managing GLP-1 receptor agonist-associated facial volume loss while exploring therapeutic potential in inflammatory dermatoses. In reproductive medicine, metabolic improvements translate to benefits in polycystic ovary syndrome and male fertility, though periconception safety concerns persist. Across all domains, evidence derives predominantly from preclinical models, observational cohorts, and pharmacoepidemiologic studies, with randomized controlled trials remaining limited. This review critically evaluates mechanisms, efficacy signals, safety considerations, and research priorities for each application domain, providing a roadmap for translating unconventional uses of semaglutide and tirzepatide into evidence-based clinical practice.
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(This article belongs to the Collection Feature Papers in Obesity, Type 2 Diabetes and Metabolic Syndrome)
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Open AccessReview
Pathology-Anchored Biomarker Research Progress for the Early Diagnosis of Diabetic Kidney Disease: From Pathological Association to Early Validation
by
Qiu Li, Mei Yang, Yingyu Luo and Nannan Zhang
Biomedicines 2026, 14(7), 1643; https://doi.org/10.3390/biomedicines14071643 - 21 Jul 2026
Abstract
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Early diagnosis is therefore critical for improving patient outcomes.However, traditional clinical biomarkers are constrained by diagnostic latency and limited sensitivity, particularly in cases of non-albuminuric DKD. To address these limitations,
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Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Early diagnosis is therefore critical for improving patient outcomes.However, traditional clinical biomarkers are constrained by diagnostic latency and limited sensitivity, particularly in cases of non-albuminuric DKD. To address these limitations, this review systematically explores the technical framework of the pathology-anchored strategy and proposes a two-phase translational approach, consisting of Pathology Anchoring Discovery and Prospective Early Validation. This strategy employs renal biopsy as the pathological gold standard in conjunction with multi-omics technologies to correlate circulating or urinary molecules with specific renal histological lesions, ultimately identifying non-invasive biomarkers with definitive pathological relevance. While numerous biomarkers demonstrate early warning potential in high-risk populations with normal conventional indicators, the pathology-anchored framework serves as a critical bridge linking these clinical biomarkers and distinct pathological changes. This review presents potential insights for early identification, risk stratification, and prognostic assessment of DKD.
Full article
(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications, 3rd Edition)
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Open AccessArticle
Lower Pain Intensity Is Associated with the Use of Recreational Edible Cannabis Products Containing Delta-9-Tetrahydrocannabinol: A Secondary Analysis in Adults Self-Managing Their Chronic Low Back Pain
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Jonathon K. Lisano, Luiza Rosa, Carillon J. Skrzynski, Angela D. Bryan and L. Cinnamon Bidwell
Biomedicines 2026, 14(7), 1642; https://doi.org/10.3390/biomedicines14071642 - 21 Jul 2026
Abstract
Background/Objectives: Current literature regarding the efficacy of cannabis to reduce chronic pain intensity is mixed. Despite growing accessibility throughout the U.S., it is still unclear if the naturalistic use of recreational cannabis edible products is associated with decreases in pain intensity on days
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Background/Objectives: Current literature regarding the efficacy of cannabis to reduce chronic pain intensity is mixed. Despite growing accessibility throughout the U.S., it is still unclear if the naturalistic use of recreational cannabis edible products is associated with decreases in pain intensity on days of use or longitudinally, and if these associations are dependent on the doses of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being consumed. Methods: The trial (NCT03522324) from which these data were pulled was pre-registered in April 2018. Participants (N = 243; 56% female; mean age = 46 ± 12 years) with self-reported chronic low-back pain selected a recreational edible cannabis product to use exclusively, ad libitum, for 14 days. Labeled THC and CBD potency were used to determine product group: CBD-dominant (n = 97), THC + CBD (n = 112), or THC-dominant (n = 34). Participants completed daily surveys indicating current pain intensity (PROMIS; 0–10 scale), use or non-use of their product, and cannabinoid dose (THC and CBD). Results: Linear mixed effects showed a significant use × group interaction (p = 0.002), indicating that pain intensity was significantly lower on days of use in THC-dominant (b = −0.66, 95% CI [−0.94,−0.37]) and THC + CBD (b = −0.41, 95% CI [−0.57,−0.25]) groups compared to days when cannabis was not used. A significant group × time interaction (p = 0.02) indicated that pain intensity significantly decreased from day 1 to day 14 in those using THC + CBD products (b = −0.05, 95% CI [−0.07,−0.03]), with 36.6% of participants in the THC + CBD group experiencing ≥30% reduction in pain intensity from day 1 to day 14. Increasing doses of THC (b = −0.02, 95% CI [−0.04, −0.01]), not CBD (b = 0.003, 95% CI [−0.03, 0.01]), were associated with significantly lower pain intensity on days following product use, with increasing doses of CBD diminishing the impact of THC dose (b = 0.02, 95% CI [0.01, 0.04]). Conclusions: These findings indicate a complex relationship between THC, CBD, and pain intensity associated with the naturalistic use of recreational cannabis edible products. Lower daily pain intensity was associated with the use of products containing THC; however, dose models indicate that this association may be attenuated at higher doses of CBD. Additionally, only products containing relatively equal amounts of THC and CBD were associated with lower pain intensity after 14 days of observation.
Full article
(This article belongs to the Section Molecular and Translational Medicine)
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Open AccessArticle
Modulation of Leptin and Serotonin by Honey and Its Glycoproteins Against High-Fat Diet-Induced Metabolic and Anxiety Phenotypes
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Atia Gohar, Richard L. Atkinson, Muhammad Shakeel, Darakhshan J. Haleem, Kaleem Ullah and Aamir Rasool
Biomedicines 2026, 14(7), 1641; https://doi.org/10.3390/biomedicines14071641 - 21 Jul 2026
Abstract
Background: Obesity-linked anxiety may involve leptin resistance, impairing serotonin (5-hydroxytryptamine; 5-HT) signaling. In addition to drugs, nutraceuticals have been explored for their potential to address this pathophysiology. Herein, natural honey and its glycoproteins were assessed for their roles in modulating the leptin–serotonin
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Background: Obesity-linked anxiety may involve leptin resistance, impairing serotonin (5-hydroxytryptamine; 5-HT) signaling. In addition to drugs, nutraceuticals have been explored for their potential to address this pathophysiology. Herein, natural honey and its glycoproteins were assessed for their roles in modulating the leptin–serotonin axis to alleviate metabolic and anxiety-related disturbances. Methodology: Sixty Wistar rats were allocated to two groups (n = 30 each), one on a normal diet (ND) and the other on a high-fat diet (HFD), for four weeks to induce obesity. Each group was further divided into five sub-groups (n = 6 each) as follows: saline, low honey dose (LHD, 1 g/kg), high honey dose (HHD, 2 g/kg), low protein dose (LPD, 0.25 mg/kg), and high protein dose (HPD, 0.5 mg/kg), while continuing on the ND or HFD. The interventions were administered for four weeks. Body weight and behavioral activities were measured weekly, whereas serum leptin and triglycerides, and brain 5-HT and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured at sacrifice. Statistical analyses were performed using ANOVA, Tukey’s post hoc test, and correlation analyses. Results: The HFD induced leptin-driven metabolic dysfunction and serotonergic disruption, exacerbating anxiety-like behavior and locomotor deficits compared with the ND rats (p < 0.05). HHD produced a dual metabolic–neurochemical improvement by reducing hyperleptinemia, elevating 5-HT, and restoring locomotor activity while reducing anxiety-like behavior. In contrast, HPD increased 5-HIAA without altering 5-HT, reflecting an imbalanced serotonin turnover that yielded only partial anxiolytic effects. Overall, HHD partially reversed HFD-induced pathology through leptin–serotonin crosstalk, whereas HPD provided more targeted neurochemical modulation. Conclusions: Natural honey and its glycoproteins attenuate HFD-induced metabolic dysregulation and anxiety-like behavior by counteracting hyperleptinemia and enhancing serotonin synthesis. These findings highlight the potential of diet-personalized, honey-based interventions for metabolic–CNS comorbidities, warranting validation through clinical trials.
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(This article belongs to the Section Endocrinology and Metabolism Research)
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Porphyromonas Gingivalis Outer Membrane Vesicles Disrupt Trophoblast Mitochondrial FAO and Drive Adverse Pregnancy Outcomes
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Yijia Wang, Siyan Liu, Jiebing Zhang, Ping Ma, Xiaoyuan Li and Yi Liu
Biomedicines 2026, 14(7), 1640; https://doi.org/10.3390/biomedicines14071640 - 21 Jul 2026
Abstract
Background: Periodontitis is increasingly recognised as a significant risk factor for adverse pregnancy outcomes (APOs), yet the mechanisms by which oral pathogens trigger placental dysfunction remain unclear. Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, secretes outer membrane vesicles (Pg-OMVs)
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Background: Periodontitis is increasingly recognised as a significant risk factor for adverse pregnancy outcomes (APOs), yet the mechanisms by which oral pathogens trigger placental dysfunction remain unclear. Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, secretes outer membrane vesicles (Pg-OMVs) that carry virulence factors and can reach distant organs. However, the impact of Pg-OMVs on placental trophoblasts and the accompanying metabolic disturbances is poorly understood. This study investigated the effects of Pg-OMVs on trophoblast function and metabolism. Methods: Pg-OMVs were isolated from Pg cultures. Pregnant mice were exposed to Pg-OMVs in vivo, and placental and uterine weights were recorded. Human trophoblast cells were treated with Pg-OMV in vitro. Untargeted metabolomic profiling of placental tissues was conducted using liquid chromatography–mass spectrometry. Fatty acid β-oxidation (FAO) activity, CD36 expression, and mitochondrial integrity were assessed via enzymatic assays, immunoblotting, transmission electron microscopy, mitochondrial membrane potential measurements, and oxygen consumption rate analysis. Results: Pg-OMVs were internalised by placental trophoblasts, and their presence was associated with significantly reduced placental and uterine weights. Metabolomics revealed a marked accumulation of long-chain acylcarnitines, particularly C20:1 carnitine, indicating impaired FAO. Pg-OMV exposure suppressed FAO activity, downregulated the fatty acid translocase CD36, and induced severe mitochondrial dysfunction, evidenced by cristae loss, decreased mitochondrial membrane potential, and diminished oxygen consumption rates. Conclusions: Pg-OMV compromise placental integrity by disrupting mitochondrial fatty acid β-oxidation, providing a novel mechanistic link between periodontal pathogen-derived vesicles and the pathogenesis of APOs.
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(This article belongs to the Special Issue Innovations in Bone and Craniofacial Tissue Engineering: From Biomaterials and Mechanobiology to Clinical Applications)
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Open AccessEditorial
Role of Factors in Embryo Implantation and Placental Development
by
Micol Massimiani
Biomedicines 2026, 14(7), 1639; https://doi.org/10.3390/biomedicines14071639 - 21 Jul 2026
Abstract
Embryo implantation and placental development are fundamental processes for the establishment and maintenance of a successful pregnancy [...]
Full article
(This article belongs to the Special Issue Role of Factors in Embryo Implantation and Placental Development)
Open AccessArticle
Atezolizumab Plus Bevacizumab Versus Durvalumab Plus Tremelimumab for Advanced Hepatocellular Carcinoma: A Propensity-Score-Matched Analysis
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Sarina Ailawadi, Sepideh Mehravar, Jennifer E. Murphy, Michael H. Storandt and Amit Mahipal
Biomedicines 2026, 14(7), 1638; https://doi.org/10.3390/biomedicines14071638 - 21 Jul 2026
Abstract
Background: Atezolizumab plus bevacizumab (A + B) and durvalumab plus tremelimumab (D + T) are approved first-line systemic therapy options for advanced hepatocellular carcinoma (HCC), with no head-to-head comparison. In this propensity-matched analysis, we compared the survival of patients with advanced HCC
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Background: Atezolizumab plus bevacizumab (A + B) and durvalumab plus tremelimumab (D + T) are approved first-line systemic therapy options for advanced hepatocellular carcinoma (HCC), with no head-to-head comparison. In this propensity-matched analysis, we compared the survival of patients with advanced HCC who received either A + B or D + T therapy. Methods: Patients with advanced HCC who received A + B or D + T treatment in the first-line setting were identified using the TriNetX platform, a health research network that provides access to electronic health record data from 112 healthcare organizations. Propensity-score-matched (PSM) analysis was conducted, and the median overall survival (OS) was estimated using the Kaplan–Meier method. Results: We identified 2819 patients with HCC who were treated with A + B or D + T: 2031 patients received A + B and 788 received D + T. Compared to patients in the A + B cohort, those who received D + T were more likely to be older (median age: 68.4 vs. 66.9 years), have lower platelet counts (186.8 vs. 201.3), higher prevalence of hypoalbuminemia with levels < 2.7 g/dL (35.2% vs. 28.4%), higher prevalence of bilirubin levels between 2.0 and 2.9 mg/dL (28.8% vs. 23.8%), and decreased INR with levels between 0.0 and 1.6 (92.1% vs. 86.3%). After PSM, 1536 patients were included in the survival analyses, with all variables adequately matched. There was no significant difference in the median OS between those receiving A + B or D + T [16.3 vs. 22.5 months, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76–1.0]. Higher rates of immune-mediated colitis were noted in the D + T group. Conclusions: Similar survival rates were observed among patients with advanced HCC who received A + B and D + T in the first-line setting. Our study suggests that both A + B and D + T are valid treatment options, and that therapy can be tailored based on comorbidities, adverse effects, and patient preferences.
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(This article belongs to the Special Issue Cancer Immunotherapy: Molecular Research and Application)
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Open AccessSystematic Review
BDNF Val66met Gene Polymorphism in Primary Acute and Subacute Stroke Functional Recovery: A Systematic Review
by
Juliana Moura Alves Seixas, Cristina Lemos Barbosa Furia, Matheus Gomes de Castro, Larissa Sousa Silva Bonasser, Ligia Canongia de Abreu Cardoso Duarte, Calliandra Maria de Souza Silva and Izabel Cristina Rodrigues da Silva
Biomedicines 2026, 14(7), 1637; https://doi.org/10.3390/biomedicines14071637 - 20 Jul 2026
Abstract
Background/Objectives: Stroke remains a leading global cause of death and disability, resulting from acute focal injury to the central nervous system. The brain-derived neurotrophic factor (BDNF) gene has been extensively investigated for its involvement in post-stroke neuroplasticity and recovery. This systematic review
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Background/Objectives: Stroke remains a leading global cause of death and disability, resulting from acute focal injury to the central nervous system. The brain-derived neurotrophic factor (BDNF) gene has been extensively investigated for its involvement in post-stroke neuroplasticity and recovery. This systematic review examines the influence of the BDNF Val66Met (rs6265) variant on functional recovery during the acute and early subacute phases of primary stroke. Methods: The review followed PRISMA guidelines and was registered in PROSPERO (CRD42024549967). Comprehensive literature searches were performed in PubMed, Web of Science, and the Virtual Health Library in December 2024 to identify observational and interventional studies involving adults with acute or subacute primary stroke that evaluated this polymorphism. Results: Of 475 records identified, 11 studies met the inclusion criteria. Sample sizes ranged from 14 to 829 participants, with follow-up intervals ranging from 2 days to 3 months post-stroke. All studies included ischemic stroke, and seven also included hemorrhagic stroke cases. Outcomes assessed were motor recovery, cortical excitability, swallowing, and language function. Overall, most studies reported poorer recovery among Met allele carriers (Val/Met or Met/Met), particularly in motor outcomes. Evidence for cortical excitability and swallowing also suggested unfavorable effects, while language outcomes were inconclusive. Methodological heterogeneity contributed to inconsistent findings. Conclusions: The Met carriers were the most prevalent and frequently associated with poorer post-stroke outcomes, though results varied. These findings underscore the complex interplay between genetics and post-stroke recovery and indicate the need for more robust, standardized research across diverse populations.
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(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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Open AccessArticle
Somatic Cancer Driver Mutation Analysis in Endometriosis with Tumor-like Presentations: A Case Series Study
by
Lucy Chen, Elizabeth Severino, Dao-Sian Wu, Bhuchitra Singh, James Segars and Ie-Ming Shih
Biomedicines 2026, 14(7), 1636; https://doi.org/10.3390/biomedicines14071636 - 20 Jul 2026
Abstract
Background/Objectives: Endometriosis manifests as ectopic endometrial tissue outside the uterine cavity. This lesion can sometimes appear at unusual anatomical sites or within the intestinal tract, growing and mimicking cancer. Such tumor-like endometriosis lesions are relatively uncommon and biologically intriguing. Methods: This study is
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Background/Objectives: Endometriosis manifests as ectopic endometrial tissue outside the uterine cavity. This lesion can sometimes appear at unusual anatomical sites or within the intestinal tract, growing and mimicking cancer. Such tumor-like endometriosis lesions are relatively uncommon and biologically intriguing. Methods: This study is a retrospective case series of 14 patients presenting with tumor-like endometriosis at a single institution between 2007 and 2023. Laser capture microdissection was used to isolate epithelial cells from endometriotic glands in tissue sections from formalin-fixed, paraffin-embedded blocks, and the microdissected epithelium was analyzed for cancer driver mutations. Results: Unlike conventional endometriosis, these tumor-like lesions were generally sizable and clinically presented in the groin area, aortic wall, omentum, bowel wall, or lymph nodes, all of which raised suspicion for malignancy, despite 11 (78.6%) of the 14 cases having a history of or clinical signs of endometriosis. A total of 11 cancer-driver mutations were identified in 6 of the 14 patients, with four patients harboring multiple mutations. Recurrent mutations included KRAS-activating mutations in four cases and ARID1A-inactivating mutations in two cases. Additional mutations involved PIK3CA, CTNNB1, CHD4, MYD88, and STAG2. Conclusions: This study detected mutations in KRAS, ARID1A, PIK3CA, CTNNB1, and MYD88 in endometriotic lesions, consistent with previous literature, and identified newly reported mutations in CHD4 and STAG2. Not every tumor-like lesion harbored cancer driver mutations.
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(This article belongs to the Section Molecular and Translational Medicine)
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Open AccessArticle
Hexosylceramide Species in the Blood Decline in Both COVID-19 and Non-COVID-19 Sepsis
by
Vlad Pavel, Patricia Mester, Stephan Schmid, Sabrina Krautbauer, Marcus Höring, Gerhard Liebisch, Martina Müller and Christa Buechler
Biomedicines 2026, 14(7), 1635; https://doi.org/10.3390/biomedicines14071635 - 20 Jul 2026
Abstract
Background/Objectives: Hexosylceramides (HexCers) are bioactive lipids whose circulating levels have been associated with severe illness. Blood lipid profiles differ between COVID-19 and non-COVID-19 sepsis and are also affected by liver cirrhosis. To evaluate the impact of SARS-CoV-2 infection and investigate associations with disease
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Background/Objectives: Hexosylceramides (HexCers) are bioactive lipids whose circulating levels have been associated with severe illness. Blood lipid profiles differ between COVID-19 and non-COVID-19 sepsis and are also affected by liver cirrhosis. To evaluate the impact of SARS-CoV-2 infection and investigate associations with disease severity and underlying liver cirrhosis among circulating HexCer species, we analyzed plasma samples from patients with systemic inflammatory response syndrome (SIRS), sepsis, or septic shock. Methods: Plasma levels of five HexCer species were quantified by flow injection analysis tandem mass spectrometry (FIA-MS/MS) in 159 patients with SIRS, sepsis, or septic shock. Among these patients, 24 had COVID-19, and 31 liver cirrhosis. In addition, serum HexCer levels were analyzed in 41 patients with moderate and 61 patients with severe COVID-19. Results: Patients with SIRS, sepsis or septic shock exhibited largely comparable plasma HexCer18:1;O2/22:0, 23:0, and 24:0 concentrations, all of which were significantly lower than those observed in healthy controls. These species and in addition HexCer18:1;O2/16:0 and 24:1 levels were modestly lower in patients with septic shock compared to those with SIRS. No significant differences in any of the five HexCer species were observed between patients with COVID-19 and non-COVID-19 septic shock or between ventilated patients with and without COVID-19, indicating that circulating HexCer levels are associated with disease severity rather than SARS-CoV-2 infection. HexCer18:1;O2/24:1 levels were increased in patients with cirrhosis. No significant differences in HexCer levels were observed between survivors and non-survivors. Conclusions: In COVID-19 and non-COVID-19 patients circulating levels of HexCer18:1;O2/22:0, HexCer18:1;O2/23:0, and HexCer18:1;O2/24:0 decline early during systemic inflammation, whereas reductions in HexCer18:1;O2/16:0 and 24:1 levels become apparent in septic shock. These findings indicate that alterations in circulating HexCer species reflect sepsis severity rather than being specific to COVID-19.
Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases: 2nd Edition)
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Open AccessArticle
BRAF V600E/TERT Promoter Co-Mutation Is Associated with Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Translational Molecular Biomarker Study
by
Madina A. Mussulmanova, Laura A. Pak, Aidana M. Rakhmankulova, Arailym Baurzhan, Lyudmila M. Pivina, Diana A. Pak, Zhandos K. Burkitbayev, Andrey Yu. Orekhov, Azhar S. Baktiyar, Saltanat O. Bolsynbekova and Masahiro Nakashima
Biomedicines 2026, 14(7), 1634; https://doi.org/10.3390/biomedicines14071634 - 20 Jul 2026
Abstract
Background/Objectives: Radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC) is associated with limited treatment options and a less favorable clinical course. Combining molecular alterations with clinicopathological characteristics may improve the early identification of patients at risk of radioiodine refractoriness. This study aimed to evaluate the association
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Background/Objectives: Radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC) is associated with limited treatment options and a less favorable clinical course. Combining molecular alterations with clinicopathological characteristics may improve the early identification of patients at risk of radioiodine refractoriness. This study aimed to evaluate the association between molecular genetic alterations, particularly BRAF and TERT promoter mutations, and RAIR-DTC. Methods: This retrospective single-center study conducted in Kazakhstan included 167 patients with differentiated thyroid carcinoma treated between 2021 and 2023. Patients were classified into radioiodine-sensitive (n = 130) and radioiodine-refractory (n = 37) groups. Clinical, histopathological, and molecular genetic characteristics were analyzed. Results: Radioiodine refractoriness was observed in all 13 patients (100.0%) with concurrent BRAF and TERT promoter mutations, compared with 24 of 154 patients (15.6%) without this co-mutation (OR = 163.46, 95% CI 9.31–2870.79; p < 0.001). The BRAF + TERT co-mutation was also associated with less differentiated histological architecture and a higher T category. In contrast, the BRAF mutation alone showed a substantially weaker association with radioiodine refractoriness, highlighting the incremental value of the combined BRAF + TERT molecular status. Conclusions: The concurrent presence of BRAF and TERT promoter mutations, rather than the BRAF mutation alone, may improve the identification of patients at increased risk of radioiodine refractoriness. Integrating molecular profiling with clinicopathological characteristics may support individualized risk stratification and treatment planning.
Full article
(This article belongs to the Section Cancer Biology and Oncology)
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Open AccessArticle
Sex-Dependent Cardiac Responses to β3-Adrenergic Receptor Activation in a Murine Model of Heart Failure with Preserved Ejection Fraction
by
Sara-Ève Thibodeau, Élisabeth Walsh-Wilkinson, Emylie-Ann Labbé, Diwaba Carmel Teou, Marie-Lune Legros and Jacques Couet
Biomedicines 2026, 14(7), 1633; https://doi.org/10.3390/biomedicines14071633 - 20 Jul 2026
Abstract
Background: Brown adipose tissue (BAT) is increasingly recognized as an endocrine organ that releases bioactive factors (batokines) with cardioprotective properties. Activation of BAT is primarily mediated by the β3-adrenergic receptor (β3-AR). Here, we investigated whether pharmacological activation of β3-AR using mirabegron modulates cardiac
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Background: Brown adipose tissue (BAT) is increasingly recognized as an endocrine organ that releases bioactive factors (batokines) with cardioprotective properties. Activation of BAT is primarily mediated by the β3-adrenergic receptor (β3-AR). Here, we investigated whether pharmacological activation of β3-AR using mirabegron modulates cardiac remodelling in a murine model of heart failure with preserved ejection fraction (HFpEF) induced by metabolic and hypertensive stress (MHS). Methods: Male and female C57BL/6J mice were exposed to MHS (angiotensin II + high-fat diet) for 28 days, with or without mirabegron treatment (2 mg/kg/day). Cardiac structure and function were assessed by echocardiography, and molecular and histological analyses were performed on cardiac and BATs. Results: Mirabegron attenuated several features of cardiac remodelling in males, including cardiac hypertrophy, left atrial enlargement, and left ventricular dilation. These effects were associated with reduced expression of genes related to hypertrophy and fibrosis. In contrast, it was shown that females exhibited a less pronounced response pattern. BAT mass and thermogenic gene expression (Ucp1) increased more markedly in males than in females, suggesting differential BAT responsiveness between sexes. Conclusions: β3-AR activation is associated with sex-dependent cardiac responses in this HFpEF model, with more pronounced protective effects in males. These findings are consistent with a potential contribution of BAT activation to cardiac remodelling, although causality was not directly demonstrated in the present study.
Full article
(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—5th Edition)
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Open AccessArticle
Human Umbilical Cord Mesenchymal Stem Cells Alleviate LPS-Induced Acute Lung Injury in Mice: Association with TLR4/MyD88/NF-κB Pathway Suppression
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Mingyou Yu, Ziyi Zhang, Ying Hu, Jinhui Zhang, Panpan Lu, Jingyu Luo and Jianwei Xu
Biomedicines 2026, 14(7), 1632; https://doi.org/10.3390/biomedicines14071632 - 20 Jul 2026
Abstract
Objective: In a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model, the present study sought to assess the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and characterize their anti-inflammatory mechanistic basis. Methods: Forty mice were randomly divided into four groups:
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Objective: In a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model, the present study sought to assess the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and characterize their anti-inflammatory mechanistic basis. Methods: Forty mice were randomly divided into four groups: control, LPS model, LPS + DEX (positive control), and LPS + hUC-MSCs. Except for the control group, mice received intratracheal instillation of LPS to establish ALI. One hour after LPS administration, animals in the hUC-MSC group were intravenously infused with hUC-MSCs. The positive control group was given an intraperitoneal injection of DEX for 3 consecutive days, starting at 24 h after modeling. On day 4 after cell transplantation or at 24 h after the completion of DEX injection, lung function indicators were detected. Bronchoalveolar lavage fluid (BALF), serum, and lung tissues were subsequently obtained for evaluation of inflammatory cell infiltration, histopathological injury, lung wet-to-dry (W/D) ratio, and cytokine levels. Additionally, the localization of transplanted hUC-MSCs in lungs was examined, and the mRNA and protein expression levels of TLR4, MyD88, and NF-κB p65 were quantified. Results: LPS exposure markedly impaired pulmonary function and induced robust inflammatory responses, evidenced by elevated levels of pro-inflammatory cytokines, increased inflammatory cell counts in BALF and serum, and extensive histological lung damage. Moreover, hUC-MSC injection improved lung function, decreased inflammatory cytokine production and alleviated pulmonary edema, while inhibiting the TLR4/MyD88/NF-κB pathway at transcriptional and protein levels. Conclusions: Intravenous hUC-MSC administration alleviates LPS-induced ALI in mice, an effect associated with suppression of the TLR4/MyD88/NF-κB cascade. These results indicate that this signaling cascade partially mediates the observed anti-inflammatory effects.
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(This article belongs to the Special Issue Human Stem Cells in Disease Modelling and Treatment (2nd Edition))
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Open AccessArticle
Phosphoproteomic Profiling Identifies PAK4 S474 Phosphorylation Affects Docetaxel Chemosensitivity via Modulation of Microtubule Stabilization in Breast Cancer
by
Shiyang Liu, Shuyu Li, Zonghong Lu, Xiaofei Tong, Zhengwei Gui, Meina Sun and Lin Zhang
Biomedicines 2026, 14(7), 1631; https://doi.org/10.3390/biomedicines14071631 - 20 Jul 2026
Abstract
Background/Objectives: Docetaxel is a frontline chemotherapeutic agent for breast cancer; however, therapeutic resistance remains a major clinical challenge. Emerging evidence suggests that chemotherapy-induced adaptive phosphorylation events can promote survival signaling and contribute to drug resistance. However, the phosphoproteomic mechanisms underlying docetaxel-induced adaptive
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Background/Objectives: Docetaxel is a frontline chemotherapeutic agent for breast cancer; however, therapeutic resistance remains a major clinical challenge. Emerging evidence suggests that chemotherapy-induced adaptive phosphorylation events can promote survival signaling and contribute to drug resistance. However, the phosphoproteomic mechanisms underlying docetaxel-induced adaptive responses remain poorly characterized. Methods: We performed integrated quantitative proteomic and phosphoproteomic profiling in breast cancer cells following docetaxel exposure. Candidate kinases associated with phosphorylation remodeling were identified and validated using TCGA-BRCA and CPTAC clinical datasets. The functional significance of PAK4 phosphorylation was validated using phosphomimetic and phospho-deficient mutants, pharmacological inhibition, and assessment of microtubule stabilization. Results: Integrated phosphoproteomic analysis revealed extensive phosphorylation remodeling following docetaxel treatment and identified PAK4 as a candidate kinase associated with the adaptive response. Analysis of the CPTAC phosphoproteomic dataset showed that phosphorylation of PAK4 at S474 was elevated in breast cancer tissues, increased with tumor stage, and was associated with poorer overall survival. In breast cancer cells, docetaxel induced phosphorylation of PAK4 at S474 without altering total PAK4 expression. Functionally, phosphomimetic PAK4 (S474D) reduced docetaxel sensitivity, whereas phospho-deficient PAK4 (S474A) enhanced drug sensitivity. Pharmacological inhibition of PAK4 using LCH-7749944 significantly enhanced the inhibitory effect of docetaxel on cell viability and increased apoptosis in breast cancer cells. Mechanistically, PAK4 inhibition enhanced docetaxel-induced microtubule stabilization, as evidenced by increased α-tubulin acetylation and accumulation of stabilized microtubule structures. Conclusions: Our study demonstrates that docetaxel induces global phosphorylation network reprogramming in breast cancer cells and identifies PAK4 S474 phosphorylation as a key determinant of docetaxel sensitivity. Inhibition of PAK4 enhances microtubule stabilization and improves the efficacy of docetaxel, providing a potential combinatorial strategy to overcome taxane resistance.
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(This article belongs to the Special Issue The Brain–Body Interplay in Pain, Anesthesia, and Oncology)
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Open AccessReview
The Framework of Host Innate and Adaptive Immunological Pathways
by
Wan-Chung Hu
Biomedicines 2026, 14(7), 1630; https://doi.org/10.3390/biomedicines14071630 - 20 Jul 2026
Abstract
Background: Host immune responses can be broadly divided into innate and adaptive immunity. Numerous adaptive immune responses have been identified, including TH1, TH2, TH3, TH9, TH17, and TH22 immunity. Within innate immunity, Vγ9-chain γδ T cells are among the most extensively studied
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Background: Host immune responses can be broadly divided into innate and adaptive immunity. Numerous adaptive immune responses have been identified, including TH1, TH2, TH3, TH9, TH17, and TH22 immunity. Within innate immunity, Vγ9-chain γδ T cells are among the most extensively studied immune-cell populations. Knowledge Gap: However, the precise functional classification of these innate and adaptive immunological pathways in responses to different types of pathogens remains incompletely understood. Purpose of the Review: This review proposes an integrated framework for the detailed functional classification of host innate and adaptive immunological pathways. Proposed Framework: Within innate immunity, γδ T cells can be categorized into several functional groups. The clonal anergy and tolerance pathway is associated with Vγ2-chain γδ T cells. The host innate immunological pathway against viruses is associated with Vγ8-chain γδ T cells, whereas the pathway against intracellular microorganisms is associated with Vγ9-chain γδ T cells. The pathway against extracellular microorganisms is associated with Vγ4-chain γδ T cells, the pathway against helminths with Vγ5-chain γδ T cells, and the pathway against insects with Vγ3-chain γδ T cells. Within adaptive immunity, five eradicable immune reactions and four tolerable immune reactions are described. Among the tolerable immune reactions, TH3 is associated with interleukin-35-producing CD4 T cells, whereas TH4 is associated with interleukin-32-producing CD4 T cells. Significance: A more precise functional classification of innate and adaptive immunological pathways may provide a useful conceptual basis for combating infections and hypersensitivity disorders.
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(This article belongs to the Special Issue New Insights in Immunological Pathways)
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Open AccessArticle
Comparable Euploidy and Aneuploidy Patterns Between Utrogestan-Based Progesterone-Primed Ovarian Stimulation and GnRH Antagonist in PGT-M: A Retrospective Matched Cohort Study
by
Xiaolan Li, Shujing He, Yajie Chang, Pan Chen, Yanfang Wang, Xiaoyan Liang, Zhiqiang Zhang and Jingjie Li
Biomedicines 2026, 14(7), 1629; https://doi.org/10.3390/biomedicines14071629 - 20 Jul 2026
Abstract
Objectives: This study compared controlled ovarian hyperstimulation (COH) outcomes and chromosomal euploidy results between the Utrogestan-based progesterone-primed ovarian stimulation (PPOS) and gonadotropin-releasing hormone antagonist (GnRH-Ant) protocols in preimplantation genetic testing for monogenic disorders (PGT-M) cycles, and assessed the efficacy and safety of the
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Objectives: This study compared controlled ovarian hyperstimulation (COH) outcomes and chromosomal euploidy results between the Utrogestan-based progesterone-primed ovarian stimulation (PPOS) and gonadotropin-releasing hormone antagonist (GnRH-Ant) protocols in preimplantation genetic testing for monogenic disorders (PGT-M) cycles, and assessed the efficacy and safety of the Utrogestan-based PPOS protocol. Methods: In this retrospective single-center cohort study, 176 PGT-M cycles managed with the Utrogestan-based PPOS protocol were compared with 176 GnRH-Ant cycles using 1:1 direct caliper matching without replacement. Embryos were classified as euploid, mosaic, aneuploid, or no-call according to next-generation sequencing results. The primary outcomes were euploidy rate and chromosomal aberration patterns; secondary outcomes included COH outcomes and pregnancy outcomes. Results: Baseline characteristics were comparable after matching. The total gonadotropin (Gn) dose was significantly lower in the Utrogestan-based PPOS group (2100 (1500–3000) vs. 2250 (1800–3000), p = 0.035). PGT analysis revealed comparable rates of euploidy, aneuploidy, mosaicism, and “No-call” between the Utrogestan-based PPOS (n = 586) and GnRH-Ant (n = 605) groups. The unadjusted difference in euploidy rate per MII oocyte between groups (18.98% vs. 16.36%, p = 0.045) was no longer statistically significant after multivariable adjustment (p = 0.194). In addition, patterns of aneuploidy and chromosomal involvement were similar between groups. The Utrogestan-based PPOS group showed numerically higher clinical pregnancy rate (70.67% vs. 63.22%) and live birth rate (62.67% vs. 51.72%), and a lower early abortion rate (5.66% vs. 12.73%), but none of these differences were statistically significant. Conclusions: Compared with the GnRH-Ant protocol, the Utrogestan-based PPOS protocol required a significantly lower total Gn dose while exhibiting comparable euploidy rate, analogous chromosomal abnormality spectrums, and pregnancy outcomes. The Utrogestan-based PPOS protocol may be a feasible alternative ovarian stimulation strategy in PGT-M cycles.
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(This article belongs to the Special Issue Genetic Research into Human Reproduction)
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Open AccessArticle
Circulating Placental Growth Factor as a Prognostic Biomarker in High-Risk Glioblastoma Patients
by
Filippo Gagliardi, Francesca Roncelli, Silvia Snider, Pierfrancesco De Domenico, Daniela Boselli, Simona Di Terlizzi, Chiara Villa and Pietro Mortini
Biomedicines 2026, 14(7), 1628; https://doi.org/10.3390/biomedicines14071628 - 20 Jul 2026
Abstract
Background/Objectives: Angiogenesis in glioblastoma (GBM) is a multifactorial process, and blood–brain barrier disruption enables the detection of circulating mediators. The clinical relevance of circulating placental growth factor (PlGF) in GBM remains unclear. This study aimed to investigate the role of PlGF in GBM
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Background/Objectives: Angiogenesis in glioblastoma (GBM) is a multifactorial process, and blood–brain barrier disruption enables the detection of circulating mediators. The clinical relevance of circulating placental growth factor (PlGF) in GBM remains unclear. This study aimed to investigate the role of PlGF in GBM and its association with disease characteristics and outcomes. Methods: We conducted a prospective observational study on 54 patients with IDH-wildtype GBM. Plasma samples collected at diagnosis and recurrence were analyzed using a multiplex panel of angiogenesis mediators. Associations with clinical, radiological, molecular, and treatment-related variables were assessed, along with survival outcomes. Statistical analysis was performed with R 4.5.0. Results: At baseline, PlGF correlated with multiple angiogenic mediators, including VEGF, IL-6, angiopoietin-1, EGF, FGF, IL-8, and TNF-α. Higher PlGF levels were associated with radiopathological features of tumor biology, including proliferation markers and the FLAIR/contrast enhancement ratio. In high-risk patients (RPA 3–4; n = 33), low baseline PlGF identified a subgroup with significantly longer overall survival (17.6 vs. 8.5 months; log-rank p = 0.031) and retained a protective association in multivariable models. In the overall cohort, this association was weaker and did not reach statistical significance. Exploratory longitudinal analyses suggested an increase in PlGF at recurrence in selected molecular and treatment-defined subgroups, while no association with bevacizumab exposure was observed. Conclusions: Circulating PlGF may reflect tumor biology in GBM and shows prognostic relevance in high-risk patients, where low baseline levels identify a subgroup with improved survival. These findings support PlGF as a candidate circulating biomarker and warrant validation in larger prospective cohorts.
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(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gliomas: 2nd Edition)
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Open AccessArticle
Diagnostic Contribution of SPECT/CT to Dual-Phase 99mTc-MIBI Parathyroid Scintigraphy for Preoperative Localization in Primary Hyperparathyroidism
by
Vuslat Mumcu Çimen and Ebuzer Kalender
Biomedicines 2026, 14(7), 1627; https://doi.org/10.3390/biomedicines14071627 - 20 Jul 2026
Abstract
Background: Accurate preoperative localization of hyperfunctioning parathyroid glands is essential for minimally invasive surgery in primary hyperparathyroidism (PHPT). Although dual-phase 99mTc-MIBI planar scintigraphy is widely used, its diagnostic performance may be limited in small or ectopic lesions. Hybrid SPECT/CT imaging combines functional
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Background: Accurate preoperative localization of hyperfunctioning parathyroid glands is essential for minimally invasive surgery in primary hyperparathyroidism (PHPT). Although dual-phase 99mTc-MIBI planar scintigraphy is widely used, its diagnostic performance may be limited in small or ectopic lesions. Hybrid SPECT/CT imaging combines functional and anatomical information and may improve localization accuracy. The aim of this study is to evaluate the diagnostic contribution of SPECT/CT to dual-phase 99mTc-MIBI planar scintigraphy for preoperative localization in patients with PHPT. Methods: This retrospective study included 128 patients with biochemically confirmed PHPT who underwent dual-phase 99mTc-MIBI planar scintigraphy followed by delayed-phase SPECT/CT imaging before parathyroidectomy between January 2020 and May 2024. Imaging findings were compared with postoperative histopathological results. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. The effects of lesion size, biochemical parameters, and ultrasonographic findings on imaging performance were also evaluated. Results: Histopathology confirmed parathyroid lesions in 122 of 128 patients (95.3%). The sensitivity, specificity, PPV, NPV, and accuracy of planar imaging were 57.4%, 66.7%, 97.2%, 7.1%, and 57.8%, respectively, whereas those of SPECT/CT were 92.6%, 66.7%, 98.3%, 30.8%, and 91.4%, respectively. SPECT/CT findings showed significant concordance with histopathology (p = 0.001), while planar imaging did not (p = 0.247). Among lesions smaller than 1 cm, sensitivities were 37.1% for planar imaging and 91.4% for SPECT/CT. SPECT/CT also provided superior anatomical localization, particularly in ectopic lesions and in patients with concomitant thyroid pathology. Conclusions: SPECT/CT demonstrated substantially higher diagnostic performance than dual-phase planar scintigraphy for preoperative localization in PHPT. Its incremental value was particularly evident in subcentimeter lesions, ectopic parathyroid adenomas, and patients with coexisting thyroid disease.
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(This article belongs to the Section Molecular and Translational Medicine)
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Open AccessArticle
Recovery Patterns After Epineuroclasis and Endoneuroclasis Stretch Injuries in the Rat Median Nerve
by
Christoph A. Schroen, Damien Laudier, Philip Nasser, Paul J. Cagle and Michael R. Hausman
Biomedicines 2026, 14(7), 1626; https://doi.org/10.3390/biomedicines14071626 - 20 Jul 2026
Abstract
Background/Objectives: This study used the neuroclasis nerve injury model to compare the long-term histomorphological, cellular, and inflammatory consequences of epineuroclasis and endoneuroclasis stretch injuries. Methods: Upon IACUC approval, 45 male Sprague-Dawley rats were allocated to 6 injury groups: an epineuroclasis and an endoneuroclasis
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Background/Objectives: This study used the neuroclasis nerve injury model to compare the long-term histomorphological, cellular, and inflammatory consequences of epineuroclasis and endoneuroclasis stretch injuries. Methods: Upon IACUC approval, 45 male Sprague-Dawley rats were allocated to 6 injury groups: an epineuroclasis and an endoneuroclasis group with follow-up at 2 weeks (n = 6 each), 6 weeks (n = 8 each), and 12 weeks (n = 8 and 9). Rats underwent left median nerve stretch to epineuroclasis or endoneuroclasis thresholds using load–deformation curve monitoring. Nerves were harvested at follow-up for qualitative histology and immunohistochemistry (H&E, NF200, S100, CD68, and Glut-1). Results: At 2 weeks, both injury levels demonstrated minimal NF200 staining, consistent with Wallerian degeneration. Epineuroclasis resulted in persistent epineurial rupture with exposed endoneurial tubes at 2, 6, and 12 weeks, indicating no structural restoration of the epineurium. At 12 weeks, axonal regrowth was observed primarily in regions with an intact epineurium and was limited in regions lacking epineurial coverage. Endoneuroclasis was associated with neuroma formation in 16/17 nerves (13/14 in-continuity) at 6 and 12 weeks, characterized by hypervascularity, aberrant fascicle formation, diffuse axonal sprouting, Schwann cell hypercellularity, and sustained macrophage infiltration. Conclusions: Epineurial integrity appears more important for axonal regeneration than previously thought. Persistent epineurial disruption was associated with limited axonal regrowth, whereas endoneurial disorganization was associated with neuroma formation despite macroscopic nerve continuity at time zero. Understanding the regenerative consequences of distinct degrees of connective tissue damage after stretch injury may help guide the development of tools that could diagnose these injuries early and potentially predict recovery after nerve injury.
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(This article belongs to the Special Issue Animal Models for Neurological Disease Research)
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