Neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), cerebral ischemia, and multiple sclerosis (MS), impose an escalating global health burden and remain largely incurable. These disorders arise from multifactorial and interconnected pathological processes, such as chronic neuroinflammation, oxidative stress, protein misfolding and aggregation, demyelination, and neurovascular dysfunction. Despite substantial advances in elucidating disease-associated molecular mechanisms, current therapeutic strategies are predominantly symptomatic and fail to effectively halt or reverse disease progression. This limitation highlights the urgent need to identify endogenous regulatory molecules capable of coordinating neuronal survival, synaptic maintenance, inflammatory control, and tissue repair within the central nervous system (CNS). Pleiotrophin (PTN) is a heparin-binding, growth-associated cytokine that has emerged as a key regulator of neural development, plasticity, and regeneration. Structurally, PTN contains multiple high-affinity heparin-binding domains that facilitate interactions with extracellular matrix components and cell surface proteoglycans, enabling spatially restricted and context-dependent signaling. Through these molecular properties, PTN functions as a multifunctional organizer of neural growth, plasticity, and tissue remodeling across developmental and adult stages. Its diverse biological effects are executed through a multi-receptor signaling system that integrates extracellular cues with intracellular programs governing cellular survival, migration, and differentiation. Notably, PTN displays a highly dynamic and cell type-specific expression pattern in the central nervous system, being enriched in neural progenitor cells during development and later restricted to discrete neuronal populations, neural stem cells, and non-neuronal niche cells—including astrocytes, pericytes, and vascular endothelial cells—which serve as critical sources of PTN under physiological and pathological conditions. PTN expression is tightly regulated during development and exhibits pronounced plasticity in response to pathological stimuli. Under physiological conditions, PTN is transiently expressed during critical windows of neural growth and synaptogenesis, supporting neuron-glia interactions and myelin formation. In contrast, in pathological contexts such as amyloid β-protein (Aβ) accumulation in AD, dopaminergic neuron degeneration in PD, demyelination in MS, and ischemic brain injury, PTN expression is frequently dysregulated, suggesting an active role in disease-associated remodeling rather than a passive bystander effect. Importantly, accumulating evidence indicates that PTN exerts a dual and context-dependent influence on neurological disorders. On the one hand, aberrant PTN signaling may contribute to maladaptive responses, including sustained glial activation, dysregulated neuroinflammation, extracellular matrix remodeling, and enhanced Aβ deposition. On the other hand, PTN displays robust neuroprotective and reparative functions by promoting neuronal survival, enhancing oligodendrocyte maturation and remyelination, and stimulating post-injury angiogenesis, thereby facilitating tissue repair and functional recovery. At the mechanistic level, PTN signaling is characterized by extensive cross-talk among receptor-dependent pathways. Activation of anaplastic lymphoma kinase (ALK) triggers canonical PI3K-AKT-mTOR and MAPK cascades that support neuronal survival and axonal integrity. PTN binding to protein tyrosine phosphatase receptor type Z1 (PTPRZ1) induces conformational inhibition of its phosphatase activity, resulting in increased phosphorylation of downstream effectors such as β-catenin, Fyn, and Src, which regulate neuronal migration and synaptic stabilization. Syndecan-3 (SDC3) functions as both a co-receptor and an independent signaling mediator by capturing extracellular PTN, amplifying ALK- and PTPRZ1-dependent signaling, and directly modulating cytoskeletal dynamics through PKC and ERK pathways. In parallel, PTN interaction with αVβ3 integrin contributes to remodeling of the neurovascular niche, linking angiogenesis with neurogenesis and neural repair. From a translational perspective, therapeutic strategies targeting PTN can be broadly classified into 3 categories: direct enhancement of PTN signaling through exogenous protein supplementation or gene therapy-mediated upregulation, pharmacological modulation of PTN-associated receptor pathways and downstream signaling nodes, and exploitation of PTN as a dynamic biomarker to inform disease stratification and therapeutic responsiveness. These complementary approaches underscore the growing interest in PTN-centered interventions across a spectrum of neurological disorders. In summary, PTN functions not merely as a classical trophic factor but as a central signaling hub integrating inflammatory regulation, neural regeneration, and vascular remodeling within the CNS. This review aims to synthesize current insights into PTN’s molecular architecture, multi-receptor signaling mechanisms, and disease-specific functions, and to highlight emerging therapeutic strategies targeting PTN. By conceptualizing PTN as a dynamic modulator of neuronal resilience rather than a static biomarker, we propose that precise modulation of PTN signaling may offer promising avenues for therapeutic development in neurodegenerative and neuroinflammatory diseases.

Objective To explore the predictive value of peripheral blood cells in the efficacy of neoadjuvant immunotherapy combined with chemotherapy for esophageal squamous cell carcinoma. Methods A retrospective study was conducted on patients with esophageal squamous cell carcinoma (clinical stages Ⅱ-Ⅳa) who underwent neoadjuvant immunotherapy combined with chemotherapy at the Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College from April 2020 to November 2023. According to whether the pathology was completely relieved after treatment, patients were divided into a pathological complete remission group and a pathological incomplete remission group. The College of American Pathologists criteria were used to evaluate the tumor pathological regression grade (TRG) after neoadjuvant therapy (TRG=0, 1 defined as a good efficacy group, TRG=2, 3 defined as a poor efficacy group). Results A total of 92 patients with esophageal squamous cell carcinoma were collected, including 72 males and 20 females. The average age was (65.86±7.66) years. The complete remission of pathology was closely related to the number of lymphocytes in the blood before treatment (P=0.019). The area under the curve (AUC) for predicting complete remission of esophageal squamous cell carcinoma after neoadjuvant immunotherapy combined with chemotherapy was 0.678, the maximum Youden index was 0.328, and the optimal cutoff value was 1.845. The incidence of postoperative pulmonary infection in the pathological incomplete remission group was higher than that in the pathological complete remission group (25.0% vs. 5.6%, P=0.030). Using the optimal cutoff value, there were statistically significant differences in pathological N stage and pathological TNM stage between patients with lymphocyte counts <1.845×109/L and ≥1.845×109/L (P<0.05). Treatment response (by TRG) was significantly associated with the pretreatment red blood cell count (P=0.009). The AUC for predicting a good TRG response was 0.669, with a maximum Youden index of 0.385 and an optimal cutoff value of 4.235. Between the good and poor response groups, there were statistically significant differences in postoperative pathological T stage (P<0.001), N stage (P=0.041), and TNM stage (P＜0.001). When stratified by the optimal cutoff value, there were statistically significant differences in age (P＜0.001) and the prevalence of hypertension (P=0.022) between patients with red blood cell counts <4.235×1012/L and ≥4.235×1012/L. Conclusion A pretreatment absolute lymphocyte count ≥1.845×109/L and a red blood cell count <4.235×1012/L are good predictors for pathological complete response and a good pathological response, respectively, following neoadjuvant immunotherapy combined with chemotherapy in patients with esophageal squamous cell carcinoma.

Objective To investigate the factors influencing international normalized ratio (INR)>3.0 in patients undergoing warfarin anticoagulation therapy after mechanical heart valve replacement. Methods A retrospective analysis was performed on the clinical data of patients who underwent mechanical heart valve replacement surgery and received warfarin anticoagulation therapy at West China Hospital of Sichuan University from January 1, 2011 to June 30, 2022. Based on the discharge INR values, patients were divided into two groups: an INR≤3.0 group and an INR>3.0 group. The factors associated with INR>3.0 at the time of discharge were analyzed. Results A total of 8901 patients were enrolled, including 3409 males and 5492 females, with a median age of 49.3 (43.5, 55.6) years. The gender, body mass index (BMI), New York Heart Association (NYHA) cardiac function grading, INR, glutamic oxaloacetic transaminase, and preoperative prothrombin time (PT) were statistically different between the two groups (P<0.05). Multivariate logistic regression analysis revealed that lower BMI, preoperative PT>15 s, and mitral valve replacement were independent risk factors for INR>3.0 at discharge (P<0.05). Conclusion BMI, preoperative PT, and surgical site are factors influencing INR>3.0 at discharge in patients undergoing warfarin anticoagulation therapy after mechanical heart valve replacement. Special attention should be given to patients with lower BMI, longer preoperative PT, and mitral valve replacement to avoid excessive anticoagulation therapy.

Neurofibromatosis type 1 (NF1) presents with a diverse range of symptoms that can affect the skin, bones, eyes, central nervous system, and other organs. This article reports the diagnosis and treatment process of a patient with NF1 complicated by bilateral severe-to-profound sensorineural hearing loss. Genetic testing revealed a heterozygous variant of NF1 NM_ 000267.3: c.4054_ 4058del(p.Ser1352LeufsTer20, supporting the diagnosis of NF1. After thorough evaluation, a right cochlear implantation was performed, yielding satisfactory postoperative results. This case suggests that NF1 patients may exhibit phenotypic heterogeneity and atypicality, providing a reference for clinicians in the diagnosis and treatment of such patients.

BACKGROUND: The effects of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment on coronavirus disease 2019 (COVID-19) patients have been preliminarily characterized. However, real-world data on the safety and efficacy of intravenous transfusions of MSCs in hospitalized COVID-19 patients at the convalescent stage remain to be reported. METHODS: This was a single-arm, multicenter, real-word study in which a contemporaneous external control was included as the control group. Besides, severe and critical COVID-19 patients were considered together as the severe group, given the small number of critical patients. For a total of 110 patients, 21 moderate patients and 31 severe patients were enrolled in the MSC treatment group, while 26 moderate patients and 32 severe patients were enrolled in the control group. All patients received standard treatment. The MSC treatment patients additionally received intravenous infusions of MSCs at a dose of 4 × 10 7 cells on days 0, 3, and 6, respectively. The clinical outcomes, including adverse events (AEs), lung lesion proportion on chest computed tomography, pulmonary function, 6-min walking distance (6-MWD), clinical symptoms, and laboratory parameters, were measured on days 28, 90, 180, 270, and 360 during the follow-up visits. RESULTS: In patients with moderate COVID-19, MSC treatment improved pulmonary function parameters, including forced expiratory volume in the first second (FEV1) and maximum forced vital capacity (VCmax) on days 28 (FEV1, 2.75 [2.35, 3.23] vs . 2.11 [1.96, 2.35], P  = 0.008; VCmax, 2.92 [2.55, 3.60] vs . 2.47 [2.18, 2.68], P  = 0.041), 90 (FEV1, 2.93 [2.63, 3.27] vs . 2.38 [2.24, 2.63], P  = 0.017; VCmax, 3.52 [3.02, 3.80] vs . 2.59 [2.45, 3.15], P  = 0.017), and 360 (FEV1, 2.91 [2.75, 3.18] vs . 2.30 [2.16, 2.70], P  = 0.019; VCmax,3.61 [3.35, 3.97] vs . 2.69 [2.56, 3.23], P  = 0.036) compared with the controls. In addition, in severe patients, MSC treatment notably reduced the proportion of ground-glass lesions in the whole lung volume on day 90 ( P  = 0.045) compared with the controls. No difference in the incidence of AEs was observed between the two groups. Similarly, no significant differences were found in the 6-MWD, D-dimer levels, or interleukin-6 concentrations between the MSC and control groups. CONCLUSIONS: Our results demonstrate the safety and potential of MSC treatment for improved lung lesions and pulmonary function in convalescent COVID-19 patients. However, comprehensive and long-term studies are required to confirm the efficacy of MSC treatment. TRIAL REGISTRATION Chinese Clinical Trial Registry, ChiCTR2000031430.
Humans ; COVID-19/therapy* ; Female ; Male ; Mesenchymal Stem Cell Transplantation/adverse effects* ; Middle Aged ; Adult ; Umbilical Cord/cytology* ; Mesenchymal Stem Cells/cytology* ; SARS-CoV-2 ; Aged ; Treatment Outcome

The study aims to examine the effects and potential mechanisms of disulfiram (DSF) on cardiac hypertrophic injury, focusing on the role of transforming growth factor-β-activated kinase 1 (TAK1)-mediated pan-apoptosis (PANoptosis). H9C2 cardiomyocytes were treated with angiotensin II (Ang II, 1 µmol/L) to establish an in vitro model of myocardial hypertrophy. DSF (40 µmol/L) was used to treat cardiomyocyte hypertrophic injury models, either along or in combination with the TAK1 inhibitor, 5z-7-oxozeaenol (5z-7, 0.1 µmol/L). We assessed cell damage using propidium iodide (PI) staining, measured cell viability with CCK8 assay, quantified inflammatory factor levels in cell culture media via ELISA, detected TAK1 and RIPK1 binding rates using immunoprecipitation, and analyzed the protein expression levels of key proteins in the TAK1-mediated PANoptosis pathway using Western blot. In addition, the surface area of cardiomyocytes was measured with Phalloidin staining. The results showed that Ang II significantly reduced the cellular viability of H9C2 cardiomyocytes and the binding rate of TAK1 and RIPK1, significantly increased the surface area of H9C2 cardiomyocytes, PI staining positive rate, levels of inflammatory factors [interleukin-1β (IL-1β), IL-18, and tumor necrosis factor α (TNF-α)] in cell culture media and p-TAK1/TAK1 ratio, and significantly up-regulated key proteins in the PANoptosis pathway [pyroptosis-related proteins NLRP3, Caspase-1 (p20), and GSDMD-N (p30), apoptosis-related proteins Caspase-3 (p17), Caspase-7 (p20), and Caspase-8 (p18), as well as necroptosis-related proteins p-MLKL, RIPK1, and RIPK3]. DSF significantly reversed the above changes induced by Ang II. Both 5z-7 and exogenous IL-1β weakened these cardioprotective effects of DSF. These results suggest that DSF may alleviate cardiac hypertrophic injury by inhibiting TAK1-mediated PANoptosis.
Animals ; MAP Kinase Kinase Kinases/physiology* ; Rats ; Myocytes, Cardiac/pathology* ; Disulfiram/pharmacology* ; Cardiomegaly ; Apoptosis/drug effects* ; Cell Line ; Angiotensin II ; Necroptosis/drug effects* ; Interleukin-1beta/metabolism* ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism* ; Lactones ; Resorcinols ; Zearalenone/administration & dosage*

Progressive pulmonary fibrosis (PPF) is a progressive and lethal condition with few effective treatment options. Improvements in quality of life for patients with PPF remain limited even while receiving treatment with approved antifibrotic drugs. Traditional Chinese medicine (TCM) has the potential to improve cough, dyspnea and fatigue symptoms of patients with PPF. TCM treatments are typically diverse and individualized, requiring urgent development of efficient and precise design strategies to identify effective treatment options. We designed an innovative Bayesian adaptive two-stage trial, hoping to provide new ideas for the rapid evaluation of the effectiveness of TCM in PPF. An open-label, two-stage, adaptive Bayesian randomized controlled trial will be conducted in China. Based on Bayesian methods, the trial will employ response-adaptive randomization to allocate patients to study groups based on data collected over the course of the trial. The adaptive Bayesian trial design will employ a Bayesian hierarchical model with "stopping" and "continuation" criteria once a predetermined posterior probability of superiority or futility and a decision threshold are reached. The trial can be implemented more efficiently by sharing the master protocol and organizational management mechanisms of the sub-trial we have implemented. The primary patient-reported outcome is a change in the Leicester Cough Questionnaire score, reflecting an improvement in cough-specific quality of life. The adaptive Bayesian trial design may be a promising method to facilitate the rapid clinical evaluation of TCM effectiveness for PPF, and will provide an example for how to evaluate TCM effectiveness in rare and refractory diseases. However, due to the complexity of the trial implementation, sufficient simulation analysis by professional statistical analysts is required to construct a Bayesian response-adaptive randomization procedure for timely response. Moreover, detailed standard operating procedures need to be developed to ensure the feasibility of the trial implementation. Please cite this article as: Zhang C, Nie YS, Zhang CT, Yang HJ, Zhang HR, Xiao W, Cui GF, Li J, Li SJ, Huang QS, Yan SY. An adaptive Bayesian randomized controlled trial of traditional Chinese medicine in progressive pulmonary fibrosis: Rationale and study design. J Integr Med. 2025; 23(2): 138-145.
Female ; Humans ; Male ; Bayes Theorem ; Disease Progression ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional/methods* ; Pulmonary Fibrosis/therapy* ; Quality of Life ; Randomized Controlled Trials as Topic ; Research Design ; Adaptive Clinical Trials as Topic

OBJECTIVE: To identify the key features of facial and tongue images associated with anemia in female populations, establish anemia risk-screening models, and evaluate their performance. METHODS: A total of 533 female participants (anemic and healthy) were recruited from Shuguang Hospital. Facial and tongue images were collected using the TFDA-1 tongue and face diagnosis instrument. Color and texture features from various parts of facial and tongue images were extracted using Face Diagnosis Analysis System (FDAS) and Tongue Diagnosis Analysis System version 2.0 (TDAS v2.0). Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for feature selection. Ten machine learning models and one deep learning model (ResNet50V2 + Conv1D) were developed and evaluated. RESULTS: Anemic women showed lower a-values, higher L- and b-values across all age groups. Texture features analysis showed that women aged 30-39 with anemia had higher angular second moment (ASM)and lower entropy (ENT) values in facial images, while those aged 40-49 had lower contrast (CON), ENT, and MEAN values in tongue images but higher ASM. Anemic women exhibited age-related trends similar to healthy women, with decreasing L-values and increasing a-, b-, and ASM-values. LASSO identified 19 key features from 62. Among classifiers, the Artificial Neural Network (ANN) model achieved the best performance [area under the curve (AUC): 0.849, accuracy: 0.781]. The ResNet50V2 model achieved comparable results [AUC: 0.846, accuracy: 0.818]. CONCLUSION Differences in facial and tongue images suggest that color and texture features can serve as potential TCM phenotype and auxiliary diagnostic indicators for female anemia.
Humans ; Female ; Tongue/diagnostic imaging* ; Adult ; Anemia/diagnosis* ; Middle Aged ; Face/diagnostic imaging* ; Young Adult ; Machine Learning

Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors (NETs). Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue (denoted as ¹⁷⁷Lu-EB-TATE) is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs. This study aimed to enhance the in vivo stability, pharmacokinetics, and pharmacodynamics of ¹⁷⁷Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain, resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical, ¹⁷⁷Lu-LNC1010, for PRRT. In preclinical studies, ¹⁷⁷Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts. Thereafter, we presented the first-in-human dose escalation study of ¹⁷⁷Lu-LNC1010 in patients with advanced/metastatic NETs. ¹⁷⁷Lu-LNC1010 was well-tolerated by all patients, with minor adverse effects, and exhibited significant uptake and prolonged retention in tumor lesions, with higher tumor radiation doses than those of ¹⁷⁷Lu-EB-TATE. Preliminary PRRT efficacy results showed an 83% disease control rate and a 42% overall response rate after two ¹⁷⁷Lu-LNC1010 treatment cycles. These encouraging findings warrant further investigations through multicenter, prospective, and randomized controlled trials.