Citations

Breast cancer incidence rises with age and peaks across the menopausal transition, yet why some postmenopausal lobules persist, and why that persistence predicts cancer risk, remains unresolved. Incomplete age-related lobular involution is one of the strongest tissue-level predictors of subsequent breast cancer, but it is still commonly viewed as passive failure of hormonally driven regression. This Review proposes a different framework: persistent lobules are maintained by an active reserve niche that outlasts its reproductive function. By integrating breast epidemiology, mammary stromal biology, cellular senescence, immune surveillance, and comparative reserve systems in skeletal muscle, hematopoiesis, and postmenopausal endometrium, we argue that menopause is a biological control point at which tissue fate diverges. Efficient clearance of senescent cells permits lobular regression to complete, whereas impaired immune surveillance may allow inflammatory paracrine signaling, macrophage reprogramming, and immune evasion to create a self-sustaining senescent-immune niche lock. This framework explains why persistent lobules are biologically active, shifts attention from epithelial quantity to microenvironmental state, and identifies the perimenopausal window as a promising interval for biomarker-guided risk stratification and prevention.

Atezolizumab-bevacizumab and durvalumab-tremelimumab have established immunotherapy as a first-line standard of care in advanced hepatocellular carcinoma (HCC). Yet, objective response rates (ORRs) remain confined to approximately 15-20%, and no validated predictive biomarker exists for patient selection. Unlike melanoma and lung cancer, conventional markers, including programmed death-ligand 1, microsatellite instability-high status, and tumor mutational burden, have not demonstrated reliable predictive value in HCC. Prior narrative reviews comprehensively catalogued the biomarker landscape through 2022 but predate a wave of clinically significant publications. This narrative review synthesizes evidence published between 2020 and 2026, with particular emphasis on 2023–2026 data, within a unified clinical framework not provided by prior reviews. We critically evaluate tissue-based biomarkers, including the AI-derived Atezolizumab-Bevacizumab Response Signature-Pathology model, spatial multiplex immunohistochemistry, and β-catenin mutational profiling; blood-based biomarkers encompassing circulating tumor DNA for minimal residual disease detection and peripheral immune phenotyping; and serum indices including the CRAFITY score and neutrophil-to-lymphocyte ratio. Hepatitis B virus etiology and non-alcoholic steatohepatitis are discussed as biological modifiers of biomarker performance. We propose an original biomarker-guided clinical algorithm, a comparative clinical readiness table, and a disease-continuum biomarker timeline as practical tools for clinicians and trialists. Prospective biomarker-enrichment trials represent the most critical next step toward clinical translation.

Objective To investigate the utility of tumoral and peritumoral [ 18 F]-fluorodeoxyglucose PET-based radiomics models for predicting tumor spread through air spaces (STAS) in non-small-cell lung cancer (NSCLC). Methods A total of 104 patients with NSCLC were retrospectively included and classified as STAS-positive or STAS-negative according to postoperative histopathology. Three radiomics models were developed based on tumoral and peritumoral volumes of interest (VOIs). Peritumoral models were constructed by defining VOIs with 5 and 10 mm expansions from the tumor margin (PR-5 and PR-10). Conventional PET-derived parameters were calculated. Each group was randomly divided into training (70%) and testing (30%) sets. For prediction, five machine learning algorithms were applied. Model performance was assessed by area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, and F1 score. Results Of the 104 patients, 60 (57.7%) were in the STAS-positive group, and 44 (42.3%) were in the STAS-negative group. Statistically significant differences were found in 27 tumoral, 62 PR-5, and 89 PR-10 radiomic features between the groups. Support Vector Machine achieved the best performance for the tumoral model (AUC: 0.70), whereas Logistic Regression was optimal for the PR-5 and PR-10 models, with AUCs of 0.79 and 0.74, respectively. The mean F1 score values for the tumoral, PR-5, and PR-10 models were 0.67, 0.72, and 0.68, respectively. Maximum standardized uptake value (SUV max ), SUV mean , and SUV peak did not differ significantly between groups. Tumor size, total lesion glycolysis, and metabolic tumor volume were significantly higher in the STAS-positive group. Conclusion Our findings suggest that peritumoral PET-based radiomics may help predict STAS status in NSCLC. The PR-5 model demonstrated the highest predictive performance, while conventional SUV-based parameters showed limited predictive value.

Abstract The age-related decline in tissue regenerative capacity drives demand for interventions restoring physiological repair mechanisms. Glycyl-L-histidyl-L-lysine-copper (GHK-Cu) has demonstrated significant regenerative, anti-inflammatory, and antioxidant properties in preclinical models, prompting its increasing integration into aesthetic practice despite a paucity of standardized clinical guidelines. This systematic review evaluates the efficacy, safety, and regenerative mechanisms of GHK-Cu in aesthetic medicine to clarify its clinical utility and inform future research. A systematic search of PubMed, Embase, and Cochrane CENTRAL was conducted from database inception through March 2026, following PRISMA guidelines. Eligible studies included clinical and preclinical models investigating GHK-Cu as a standalone intervention for aesthetic applications. 20 studies (18 preclinical; 2 RCTs) were included. Preclinical data consistently demonstrated that GHK-Cu enhances extracellular matrix synthesis (type I collagen and glycosaminoglycans), modulates metalloproteinase activity, and promotes angiogenesis and cellular proliferation. It also exhibited significant anti-inflammatory effects by suppressing TGF-β and IL-6. Clinically, GHK-Cu improved patient-reported satisfaction after laser resurfacing and significantly reduced wrinkle volume and depth compared with controls. Additionally, advanced delivery systems, including microneedles and liposomes, markedly improved its transdermal bioavailability and efficacy. GHK-Cu demonstrates a reasonable biological basis for use as a regenerative agent in aesthetic medicine, supported by available preclinical data. Nevertheless, the findings reported across studies were constrained by methodological variability and a limited number of well-designed clinical trials. Future research incorporating larger, controlled trials with standardized formulations, dosing regimens, and delivery methods will be necessary to close the translational gap and inform the development of consistent therapeutic protocols in clinical practice.

Abstract Objective Resective surgery achieves seizure freedom in approximately 60%–80% of patients with drug‐resistant temporal lobe epilepsy (TLE), yet the extent to which seizure cessation permits recovery of disrupted functional brain networks remains unclear. Increasing evidence suggests that recurrent seizures alter subcortical–cortical communication involved in arousal and cognition, contributing to chronic interictal deficits, such as in executive function. Prior work demonstrates that the nucleus basalis of Meynert (NBM), the primary source of cortical cholinergic input to the cortex, exhibits aberrant functional connectivity in patients with TLE. We examined NBM connectivity in patients with TLE before and after surgery using patient‐specific NBM segmentations. We sought to investigate whether seizure freedom is associated with recovery of NBM functional connectivity, consistent with previous observations of interictal network dysfunction reversal in other subcortical arousal structures. Methods Resting‐state functional magnetic resonance imaging was analyzed in 75 patients with TLE, including 34 patients postoperatively, and 106 controls. Patient‐specific NBM segmentations were used to compute functional connectivity between the NBM and frontoparietal association cortex (FPAC) and across the whole brain. Subcortical arousal network community structure was assessed using community detection. Postoperative network changes were evaluated relative to seizure outcome. Results Prior to surgery, patients exhibited reduced bilateral NBM connectivity to the FPAC and whole brain compared to controls, indicating widespread cholinergic network disruption beyond the ipsilateral hemisphere. Following surgery, NBM connectivity increased and no longer differed from controls. Seizure‐free patients demonstrated greater postoperative increases in ipsilateral NBM‐FPAC connectivity than non‐seizure‐free patients, which was not explained by time to postoperative scan or volumetric change. Subcortical arousal community structure remained altered postoperatively. Significance Successful TLE surgery is associated with partial restoration of cholinergic arousal network connectivity, supporting the idea that seizure cessation enables recovery of brain networks disrupted by recurrent seizures. These findings position the NBM as a potential biomarker of network recovery following epilepsy surgery.

Background/Objectives: Leptin is a pleiotropic adipokine linking energy metabolism with innate and adaptive immunity. Its relationship with clinical severity across distinct airway disease phenotypes remains insufficiently characterized. This study examined serum leptin concentrations in adults with allergic rhinitis, non-allergic asthma, and allergic asthma associated with allergic rhinitis. Methods: This single-center retrospective observational study analyzed fully anonymized clinical and laboratory data from 88 adults: patients with allergic rhinitis (n = 31), non-allergic asthma (n = 15), or allergic asthma with allergic rhinitis (n = 22) and healthy controls (n = 20). Serum leptin was measured using a quantitative sandwich enzyme-linked immunosorbent assay. Disease severity was classified using the Allergic Rhinitis and its Impact on Asthma and Global Initiative for Asthma frameworks applicable during the study period. Statistical analyses were performed using IBM SPSS Statistics, version 26.0 (IBM Corp., Armonk, NY, USA), and available original statistical outputs were summarized using retained t statistics and two-sided p values. Results: Stage-specific mean serum leptin concentrations were heterogeneous and non-monotonic. Statistically significant relationships between leptin concentration and disease stage were reported for allergic rhinitis (t = 2.844; p = 0.008), non-allergic asthma (t = 4.240; p = 0.001), and allergic asthma with allergic rhinitis (t = 2.700; p = 0.013). In the allergic rhinitis subgroup, 64.5% of participants had normal weight, 32.3% were overweight, and 3.2% had grade II obesity; weight category was not significantly related to rhinitis stage. Conclusions: The retained analyses indicate statistically significant relationships between serum leptin concentration and clinical disease stage across the investigated airway phenotypes. However, the stage-specific descriptive means were heterogeneous and non-monotonic and therefore do not support a uniform progressive increase in leptin with increasing disease severity. Because complete model outputs and covariate-adjusted estimates were unavailable, these findings should be regarded as exploratory and require prospective validation with appropriate adjustment for adiposity and other relevant metabolic confounders.

Abstract Striated muscle weakness and motor neuron (MN) death are associated with aging. These alterations affect both brainstem and spinal motor pools, including hypoglossal MNs innervating the tongue and lumbar MNs innervating the lower/hindlimbs. Both MNs and striated muscles exhibit type‐selective motor unit vulnerability, where larger MNs (likely fast fatigable motor units) and type IIx/b muscles are vulnerable to death and atrophy, respectively. These findings have been cemented in humans to some degree and in Fischer 344 and Wistar rats. However, MN survival in old age has not been evaluated in Sprague–Dawley rats. Here, in 6‐ (young) and 24‐month‐old (old) female and male Sprague–Dawley rats, we performed stereological MN counts on hypoglossal and lumbar MNs using 16 μm Nissl‐stained sections. We observed a 35% loss of hypoglossal and lumbar MNs in old age. Although mean MN somal surface areas were moderately reduced in hypoglossal and unchanged in lumbar MNs with age, frequency histogram analyses revealed a disproportionate loss of larger MN in old age hypoglossal and lumbar pools. These findings reveal reliable and robust observations of MN death in rats. This neurogenic aspect of neuromotor impairment with age may be a key driver of sarcopenia and frailty in the elderly.

Abstract Objective Interictal epileptiform spikes (IESs) are widely used biomarkers of epileptogenic tissue in presurgical epilepsy evaluation. However, their reliability for seizure onset zone (SOZ) localization in high‐density intracranial electroencephalography (iEEG) remains inconsistent. It is underexplored whether this variability reflects methodological differences across detection algorithms or a limitation of IESs as a biomarker. This study evaluates whether IES detection alone provides sufficient spatial specificity for accurate SOZ localization in iEEG. Methods We systematically benchmarked eight established IES detection algorithms using iEEG recordings from 35 patients with drug‐resistant focal epilepsy. To provide a clinically meaningful reference, algorithm performance was evaluated against the clinically defined SOZ. To refine detection outputs and move beyond only IES detection, we applied masking strategies to isolate informative IES subsets based on rate, amplitude, frequency, and co‐occurrence with high‐frequency oscillations (HFOs). Conceptually, masking acts as a spatial refinement strategy that progressively restricts diffuse IES activity to more focal, pathologically relevant event populations. Results Despite substantial variability in detection characteristics, SOZ localization performance (ratio of events originating from SOZ divided by total number of events) converged within a narrow range (.23–.51), suggesting that IESs exhibit an intrinsic ceiling in SOZ localization performance when used alone. Amplitude‐based masking yielded modest improvements, whereas frequency‐based masking reduced performance. In contrast, IES‐HFO co‐occurrence markedly improved localization, particularly when combined with rate‐based masking, achieving a median SOZ localization ratio of .89, exceeding IESs (.37) and HFOs (.63) evaluated independently. Significance These findings demonstrate that IES‐based SOZ localization may require moving beyond detection‐only approaches. The integration of informed, biomarker‐driven masking strategies provides a more robust framework for identifying the activity most relevant to the epileptogenic network and paves the way for future incorporation into the clinical decision‐making pipeline.