The Akt pathway is dysregulated in cancer, leading to proliferation, decreased apoptosis, and metastasis, and hence is a major therapeutic target in cancer treatment. Over the past two decades, substantial advances have been made in the design of potent, selective, and pharmacokinetically optimized Akt inhibitors. This review analyzes recent Akt inhibitors, with particular focus on the structure-activity relationship (SAR) of their heterocyclic core scaffolds and the resulting biological activity. Additional strategies identified in this review that have yielded promising preclinical and clinical candidates include scaffold optimization, conformational restriction, and hybrid design. Special emphasis is given to advanced inhibitors such as capivasertib, ipatasertib, and NTQ1062, which illustrate the influence of pharmacophoric refinement on therapeutic success. In this review, we integrate knowledge of medicinal chemistry and structure to direct the rational design of next generation Akt inhibitors that are safer and more effective for targeted cancer therapy.

Multiple public databases, including TCGA, GEO, and TARGET, were utilized to comprehensively analyze pyridoxal phosphatase (PDXP) expression profiles across 34 cancer types. We further explored the associations of PDXP expression with clinicopathological features, tumor immune microenvironment, genomic heterogeneity, functional signaling pathways, and therapeutic response. In addition, in vitro and in vivo experiments were performed to preliminarily validate the potential mechanism linking PDXP expression to melanoma progression. PDXP exhibited aberrant differential expression in most cancer types and tended to be highly expressed in malignant tumor cells. PDXP expression was correlated with overall survival outcomes in 14 cancer types. In most investigated tumors, PDXP expression was significantly associated with the expression of immunoregulatory and immune checkpoint genes, as well as the general landscape of the tumor immune microenvironment. Correlation analysis of genomic characteristics indicated that PDXP may serve as a potential immune-related biomarker in skin cutaneous melanoma (SKCM). Functional enrichment and signaling pathway analysis showed that elevated PDXP expression in SKCM was correlated with enhanced tumor cell proliferative activity. In vitro and in vivo functional experiments demonstrated that PDXP knockdown significantly suppressed colony formation and migration of melanoma cells, induced G2/M phase cell cycle arrest, and increased cell apoptosis. These findings suggest that PDXP is associated with malignant phenotypes of melanoma cells, which are accompanied by changes in protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling activity. Moreover, we established a prognostic model with moderate predictive performance for melanoma using least absolute shrinkage and selection operator (LASSO)-Cox regression, providing a preliminary prognostic reference for SKCM patients.

Mutations in TP53 occur in approximately half of all common cancer types and play a critical role in tumor progression and metastasis. However, because mutant TP53 can induce both loss- and gain-of-function effects, the development of drugs that directly target TP53 remains challenging. To identify downstream effectors of specific TP53 mutations, we compared gene expression profiles of colorectal (CRC), lung (LC), and stomach cancers (STC) carrying wild-type or mutant TP53. TP53 mutations were frequent (CRC 70.9%, LC 50.1%, STC 45.7%), with TP53-R273H being the most common. Comprehensive analyses comparing patients with TP53 mutations and those with wild-type TP53 identified 24 genes whose expression was significantly increased in TP53-mutated patients, and 20 genes whose expression was decreased across all three tumor types. Among them, PABPC1 showed significantly increased expression in A549 lung cancer cells and MCF7 breast cancer cells with wild-type TP53 transfected with TP53-R273H mutants. Silencing PABPC1 suppressed proliferation of TP53-R273H-mutant colon cancer cells (HT29, SW480). Additionally, patients with CRC harboring the TP53-R273H with high PABPC1 expression had poorer overall survival than those with low PABPC1 expression. These findings indicate that TP53-R273H upregulates PABPC1, suggesting that PABPC1 may function as an oncogene and represent a promising therapeutic target in patients with TP53-R273H mutation.

Cellular senescence, defined by irreversible cell cycle arrest and the senescence-associated secretory phenotype (SASP), has emerged as a critical driver of airway inflammation and hyperresponsiveness in asthma. Despite well-established associations between senescence, aging, and chronic disease, its precise mechanistic role in asthma pathogenesis remains poorly understood. Protein phosphatase 4 (PP4), a serine/threonine phosphatase with broad physiological functions, is significantly downregulated in airway epithelial cells derived from patients with severe asthma, suggesting a potential regulatory role in disease progression.

Bulk RNA sequencing (RNA-seq) was performed to assess transcriptomic changes in PP4-deficient airway epithelial cells. Mechanistic studies examined downstream signaling through PERK phosphorylation, p21-dependent senescence pathways, mitochondrial function, and calcium dynamics. A house dust mite (HDM)-induced murine asthma model was employed to evaluate the therapeutic efficacy of the PERK inhibitor GSK2656157 in vivo. Ex vivo validation was conducted using air-liquid interface (ALI)-cultured human bronchial epithelial cells (HBECs) obtained from patients with severe asthma.

RNA-seq analysis revealed that PP4 deficiency significantly upregulates endoplasmic reticulum (ER) stress-related gene expression in airway epithelial cells. Mechanistically, PP4 loss enhanced PERK phosphorylation, activating the PERK-eIF2α-ATF4-p21 signaling axis, which in turn triggered p21-dependent cellular senescence, mitochondrial dysfunction, and intracellular calcium influx. In the HDM-induced asthma model, pharmacological inhibition of PERK with GSK2656157 attenuated airway epithelial senescence and significantly reduced systemic levels of IgE, IL-5, and IL-13. Consistently, GSK2656157 treatment effectively suppressed p21-mediated senescence and SASP in ALI-cultured HBECs from severe asthmatic donors.

These findings demonstrate that PP4 governs airway epithelial senescence through the PERK-eIF2α-ATF4-p21 signaling axis, mechanistically linking ER stress to SASP-driven airway inflammation in asthma. Targeting PP4-related pathways represents a promising therapeutic strategy for managing senescence-associated pathology in severe asthma.

Invasive meningococcal disease (IMD) remains a major cause of morbidity and mortality in children. Post-pandemic epidemiological patterns of pediatric IMD are not well defined in Türkiye. This study aimed to evaluate the epidemiology, clinical characteristics, outcomes, and serogroup distribution of pediatric IMD in a large multicenter cohort in Türkiye, comparing the during-COVID and post-COVID periods. This retrospective multicenter hospital-based study included children aged 1 month-18 years hospitalized with laboratory-confirmed IMD in 39 hospitals across 23 provinces. Cases were grouped as during-COVID (January 2020-May 2022) and post-COVID (June 2022-December 2025). A total of 166 patients (median age 25 months; 59.6% male) were included; 25 occurred during-COVID and 141 post-COVID. The number of reported cases in participating centers increased after 2022, with seasonal peaks in winter and early spring. Children under 5 years accounted for 62.7% of cases, and infants (< 1 year) were the largest single age group overall (38.6%). The proportion of children under 5 years was lower in the post-COVID period (58.9% vs 84.0%; OR 0.27, 95% CI 0.09-0.84), indicating a relative shift toward older age groups rather than a reduction in disease burden among infants. Pediatric intensive care admission occurred in 69.9% of cases, and overall mortality was 13.3%. Mortality varied markedly by clinical form, from 1.2% in meningitis alone to 21.7% in combined meningitis and meningococcemia and 38.1% in meningococcemia alone (p < 0.001). Only 2.4% of children had received any meningococcal vaccine before their illness. Serogroup data were available for 60.8% of patients, with grouping coverage differing between periods (32.0% vs 66.0%). Among cases with available serogroup data, serogroup B accounted for 69.9% in the post-COVID period and for half of the eight grouped cases during the pandemic. In unadjusted exploratory analysis restricted to cases with serogroup data, mortality was higher in serogroup B than non-B infections (21.7% vs 3.1%; OR 8.61, 95% CI 1.08-68.8); in an exploratory model adjusting for clinical form, age, and period, with ungrouped cases retained as a separate category, serogroup B remained associated with mortality (aOR 7.59, 95% CI 1.55-75.65).

In this multicenter hospital-based cohort, reported pediatric IMD cases increased in the post-pandemic period, with a persistent burden in infants, a relative shift toward older age groups, and predominance of serogroup B among grouped cases. These findings highlight the importance of strengthened surveillance and support further evaluation of meningococcal vaccination strategies, including MenB vaccination.

• Invasive meningococcal disease remains a severe pediatric infection with high morbidity and mortality, despite treatment. • The COVID-19 pandemic and the subsequent easing of restrictions altered IMD epidemiology globally.

• Reported pediatric IMD cases increased in the post-pandemic period, with a relative shift toward older children while the proportion of infants remained unchanged (38.3% vs 40.0%); serogroup B predominated among cases with an available serogroup result, although differential availability of these data precludes conclusions about change over time. • Mortality was determined principally by clinical form, ranging from 1.2% in meningitis alone to 38.1% in meningococcemia alone, and only 2.4% of children had received any meningococcal vaccine before their illness.

Missing data can pose fundamental challenges to statistical inference, with nonignorable missing or missing not at random (MNAR) presenting the most severe methodological difficulties. Despite substantial advances in MNAR inference methods, several limitations remain. These generally include interpretability issues, non-identifiability, unverifiable parametric assumptions, and reliance on external information for which clear practical guidance is often lacking-particularly in sensitivity and Bayesian methods. In this paper, motivated by a real-world COVID-19 dataset from the Centers for Disease Control and Prevention (CDC), we study an MNAR scenario in the presence of a shadow variable that may itself also be subject to MNAR. A shadow variable is associated with the primary variable that is MNAR, but is conditionally independent of that variable's missingness given the primary variable and other covariates. Under the pattern mixture model framework, we propose a nonparametric inference method that can leverage external data to explicitly address the identification and estimation problems in the primary data. The method requires inference only of an observed data density and an odds of missing function, with the latter forming the core of our approach. We further provide two multiple-imputation-based estimation strategies, enhancing transparency and interpretability. The proposed framework can accommodate both covariate MNAR and outcome MNAR settings, as well as different variable types, and extends the existing shadow variable paradigm for MNAR data by relaxing the common assumption that the shadow variable must be fully observed. We evaluate the proposed method through simulation studies and apply it to CDC COVID-19 surveillance data.

Smyrnium olusatrum L. (Apiaceae) is a medicinal plant traditionally used in Mediterranean ethnomedicine to treat gastrointestinal disorders, as well as inflammatory conditions, urinary tract disorders, gynecological ailments, and respiratory diseases. Alkaloids constitute an important class of bioactive constituents in medicinal plants and may contribute to their pharmacological effects; however, their biological activities may also be associated with dose-dependent toxicity. Despite the pharmacological potential of S. olusatrum alkaloids, their toxicological profile remains insufficiently characterized, which may limit their further pharmacological investigation and development.

This study aimed to evaluate the acute and subacute toxicity of the alkaloid-rich fraction isolated from S. olusatrum seeds as part of the preclinical safety assessment to support its further pharmacological investigation.

Acute toxicity was investigated following a single intraperitoneal administration of the alkaloid-rich fraction at doses of 1, 10, 20, 200, and 2000 mg/kg, followed by a 14-day observation period. Subacute toxicity was assessed after daily intraperitoneal (i.p.) administration of 25, 50, 100, and 200 mg/kg for 28 consecutive days. Clinical observations, body and relative organ weights, hematological and biochemical parameters, and histopathological examinations of major organs were performed.

No mortality or treatment-related clinical signs were observed following acute administration, indicating an LD₅₀ greater than 2000 mg/kg (i.p.). Repeated administration for 28 days produced no significant changes in body weight, relative organ weights, hematological indices, or serum biochemical parameters compared with controls. Histopathological examination revealed normal architecture in the kidneys, heart, lungs, and spleen. Mild hepatic histoarchitectural changes, consisting of slight disorganization of hepatocyte cords and sinusoidal dilation, were observed only in male mice at 100 and 200 mg/kg without accompanying biochemical evidence of liver injury. The alkaloid-rich fraction of S. olusatrum seeds exhibited a favorable toxicological profile following acute and repeated i.p. administration in Swiss mice. Under the experimental conditions, the NOAEL was established at 50 mg/kg/day (i.p.) based on the first occurrence of treatment-related hepatic histological changes at 100 mg/kg.

Alkaloid extracts from S. olusatrum seeds showed low acute and subacute toxicity in mice, supporting their further preclinical pharmacological investigation while highlighting the importance of dose optimization and sex-specific hepatic responses.

Autonomic nervous system dysfunction is highly prevalent in hypermobile Ehlers-Danlos syndrome (hEDS) and contributes substantially to multisystem symptoms and reduced quality of life. Neuroimmune dysregulation and chronic low-grade inflammation are increasingly recognized as key mechanisms underlying these manifestations. Transcutaneous auricular vagus nerve stimulation (taVNS) may restore autonomic balance and engage the cholinergic anti-inflammatory pathway.

In this prospective, single-center, open-label pilot study, fourteen consecutive female patients with hEDS and disabling dysautonomia (Composite Autonomic Symptom Score-31 [COMPASS-31] > 20) underwent weekly 60-minute taVNS sessions for eight weeks. Autonomic symptoms were assessed weekly using COMPASS-31. Quality of life was evaluated at baseline and week 8 using the 36-Item Short-Form Health Survey (SF-36).

taVNS was well tolerated, with no serious adverse events. The mean COMPASS-31 total score decreased significantly from 44.6 ± 12.7 at baseline to 28.3 ± 15.4 at week 8 (- 36.5%, p < 0.001). Significant improvements were observed in orthostatic intolerance, gastrointestinal, vasomotor, and secretomotor domains. The SF-36 total score increased by 27.7% (p = 0.07), with statistically significant improvements in physical functioning, physical role, bodily pain, general health, and vitality.

In this pilot study, taVNS was safe and associated with clinically meaningful improvements in dysautonomia in patients with hEDS. These findings support further randomized controlled studies incorporating objective autonomic and neuroimmune biomarkers.

Objective: To investigate the management of pregnant women with positive anti-Ro/Sjögren's syndrome antigen A (SSA) antibody and (or) anti-La/Sjögren's syndrome antigen B (SSB) antibody complicated with fetal arrhythmia. Methods: Clinical data of pregnant women with positive anti-Ro/SSA and (or) anti-La/SSB antibodies complicated with fetal arrhythmia who delivered in Beijing Anzhen Hospital, Capital Medical University from January 2020 to June 2026 were retrospectively collected. Maternal autoantibody profiles, types of fetal arrhythmia and pregnancy outcomes were analyzed. Results: A total of 9 cases of pregnant women with positive anti-Ro/SSA and (or) anti-La/SSB antibodies complicated with fetal arrhythmia were included. All 9 cases were positive for anti-Ro/SSA antibody, including 6 strongly positive, 2 moderately positive and 1 weakly positive; among them, 6 cases were concomitantly positive for anti-La/SSB antibody. Among the 9 fetuses, 4 presented with third-degree atrioventricular block (AVB), 1 with first-degree AVB, 1 with transient bradycardia, 2 with supraventricular tachycardia, and 1 with atrial premature beats. Two cases of fetal third-degree AVB and one case of atrial premature beats failed to restore sinus rhythm after in utero pharmacological treatment, while one fetus with transient bradycardia and one fetus with supraventricular tachycardia achieved rhythm conversion after treatment. Among all 9 cases, 5 resulted in live births, including 4 cesarean deliveries and 1 vaginal delivery. Of these live-born infants, 2 were delivered at term and 3 were preterm. The other 4 pregnancies were terminated by induction of labor. Conclusions: AVB is the most common type of fetal arrhythmia induced by maternal positive anti-Ro/SSA and (or) anti-La/SSB antibodies. The utero pharmacological treatment is unlikely to reverse third-degree AVB in the fetus.

The aim of this study is to evaluate the effects of a unilateral-lower limb exoskeleton rehabilitation training robot on balance and lower limb function after stroke.

In this pilot study, stroke patients with hemiplegic at Tongji University Yangzhi Rehabilitation Hospital (between October 2022 and December 2023) were randomly assigned to either the robot group or the control group. The primary measure was the Berg balance scale (BBS), whereas secondary measures included the 10-m walking time test, 6-min walk test, three-dimensional gait analysis, and pain levels using the Hospital Anxiety and Depression Scale (HADS) and visual analogue scale (VAS).

Among 36 post-stroke hemiplegia patients (25 males; 18 per group), the robot group significantly outperformed the traditional group. The robot group improved BBS scores (5.50 ± 2.09 vs. 3.11 ± 1.50, p < 0.001), 6-min walking distance (15.89 ± 8.64 m vs. 9.73 ± 5.83 m, p = 0.017), and 10-m walking time reduction (8.82 ± 3.22 s vs. 6.83 ± 1.81 s, p = 0.030). Gait parameters also showed greater gains: hip flexion (3.57°±2.30° vs. 1.72°±2.15°, p = 0.018), knee flexion (5.28°±4.89° vs. 2.63°±2.37°, p = 0.046), and ankle dorsiflexion (4.81°±5.57° vs. 1.09°±4.19°, p = 0.030). Depression scores improved more in the robot group (2.89 ± 1.75 vs. 1.61 ± 1.20, p = 0.015). No significant differences occurred in anxiety or pain VAS scores (p > 0.05).

Integrating a unilateral-lower limb exoskeleton rehabilitation robot with traditional therapy significantly enhances lower limb recovery in stroke patients with hemiplegia. Future large-scale randomized controlled trials and follow-up evaluations are needed to validate the current findings.