Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide. Coupled with the substantial workload, the clinical management of lung cancer is challenged by the critical need to efficiently and accurately process increasingly complex medical information. In recent years, large language models (LLMs) technology has undergone explosive development, demonstrating unique advantages in handling complex medical data by leveraging its powerful natural language processing capabilities, and its application value in the field of lung cancer diagnosis and treatment is continuously increasing. The paper systematically analyzes that the exceptional potential of LLMs in lung cancer auxiliary diagnosis, tumor feature extraction, automatic staging, progression/outcome analysis, treatment recommendations, medical documentation generation, and patient education. However, they face critical technical and ethical challenges including inconsistent performance in complex integrated decision-making (e.g., TNM staging, personalized treatment suggestions) and "black box" opacity issues, along with dilemmas such as training data biases, model hallucinations, data privacy concerns, and cross-lingual adaptation challenges ("data colonization"). Future directions should prioritize constructing high-quality multimodal corpora specific to lung cancer, developing interpretable and compliant specialized models, and achieving seamless integration with existing clinical workflows. Through dual drivers of technological innovation and ethical standardization, LLMs should be prudently advanced for holistic lung cancer management processes, ultimately promoting efficient, standardized, and personalized diagnosis and treatment practices.

Immunotherapy, including immune checkpoint inhibitors, tumor vaccine therapy, oncolytic virotherapy, and adoptive cell therapy, has made remarkably breakthroughs in the field of oncology. Immune checkpoint inhibitors, which block programmed death receptor 1 or programmed death ligand 1, have been included in the first-line clinical treatment for advanced solid tumors, such as non-small cell lung cancer and malignant melanoma. However, primary or secondary drug resistance in tumors severely limits the survival benefits for patients. Immune-related adverse reactions, such as pneumonia, hypothyroidism, hypophysitis, and myocarditis, also greatly affect the quality of life of patients. Fuzheng Jiedu Huayu is an important concept guiding the prevention and treatment of tumors with traditional Chinese medicine (TCM). It is also a curative principle and therapeutic TCM method to reduce the toxicity and enhance the efficacy of immunotherapy. This article summarizes the research progress of immunotherapy and discusses how TCM reduces the toxicity and enhances the efficacy of immunotherapy, hoping to provide a reference for the integrated treatment of tumors with TCM and immunotherapy.

Voice biomarkers， as an emerging smart medical technology， are now being used in applications such as assisting in the diagnosis and treatment of diseases， facilitating accurate and personalized medical services for patients. However， it also raises many ethical issues， including informed consent， privacy protection， accuracy and reliability， data security， legal risks， and other issues. This paper systematically sorted out the ethical issues in the applications of voice biomarkers in the medical field， summarized these issues， such as informed consent， privacy protection， accuracy and reliability， data security， and legal risks， as well as explored the corresponding coping strategies. These countermeasures encompassed utilizing new media platforms to raise public awareness of voice biomarkers， strengthening supervision and management to promote the privacy protection of voice biomarkers， reducing algorithm biases to promote the general benefits of voice biomarkers to the public， establishing multidisciplinary teams to protect the data security of voice biomarkers， and encouraging medical professionals and researchers to participate in policy research， with a view to providing references for promoting and regulating the applications of voice biomarkers in the medical field.

Objective:To investigate the effect of age factor on glymphatic function in patients with Parkinson′s disease (PD) and its potential correlation with overall cognitive performance based on diffusion tensor imaging analysis along the perivascular space(DTI-ALPS) index.Methods:The study was cross-sectional. Clinical and imaging data of 77 PD patients (PD group) who attended the Provincial Hospital of Shandong First Medical University from October 2021 to June 2024 were retrospectively analyzed. In the same period, 30 healthy volunteers matched by age and gender were collected as the normal control (NC) group. All subjects underwent MRI scanning and DTI-ALPS index was calculated based on diffusion tensor imaging. Cognitive functions of 46 patients in the PD group were assessed using the mini-mental state examination (MMSE) and montreal cognitive assessment (MoCA) scores. Independent samples t-tests were used to compare the differences in DTI-ALPS index between the PD and NC groups. After adjusting for confounders, the relationship between DTI-ALPS and age was explored using partial correlation analyses, multiple linear regression models. A mediation model was further developed to explore the mediating effect of DTI-ALPS index between age and cognitive function scores. Results:The DTI-ALPS indices of PD and NC groups were 1.66±0.20 and 1.44±0.17, respectively, and the differences were statistically significant ( t=5.27, P<0.001). The age of patients in the PD group was negatively correlated with the DTI-ALPS index ( r=-0.54, P<0.001), and age (β=-0.467, P<0.001) was an independent influencer of DTI-ALPS index. The DTI-ALPS index was positively correlated with MMSE scores ( r=0.53, P<0.001) and positively correlated with MoCA scores ( r=0.56, P<0.001). The mediation model showed that the DTI-ALPS index fully mediated between age and MMSE scores and partially mediated between age and MoCA scores, with an effect share of 33.25%. Conclusion:Age is an independent risk factor for impaired glymphatic pathway in PD patients, and it may induce cognitive decline in PD patients by exacerbating glymphatic pathway impairment.

Objective:To explore brain MRI features of methylmalonic acidemia (MMA).Methods:This observational study retrospectively analyzed the clinical and imaging data of 123 patients with MMA diagnosed at Shandong Provincial Hospital Affiliated to Shandong First Medical University and Qilu Hospital of Shandong University from January 2010 to November 2022. The 123 patients were divided into 7 stages according to age of onset, neonatal period (0 to<1 month), infancy (1 month to<1 year), early childhood (1 to<4 years), preschool (4 to<7 years), school age (7 to<13 years), adolescent (13 to 17 years) and adult (>17 years). All patients underwent brain MRI scanning. The imaging performances were evaluated, including the number, location, morphology of the lesions.Results:Of the 123 patients, 40 were in the neonatal period, 29 in infancy, 13 in early childhood, 9 in preschool, 6 in school age, 13 in adolescence, and 13 in adulthood. The first symptoms of patients in the neonatal period were mainly digestive system abnormalities, such as difficulty in breastfeeding (37.5%, 15/40) and vomiting (25.0%, 10/40), with neurological symptoms gradually becoming the main manifestations from infancy. Seventy-three cases (59.3%) showed significant abnormalities on cranial MRI, including 17 cases with 33 foci in the neonatal period, 23 cases with 53 foci in infancy, 11 cases with 16 foci in early childhood, 2 cases with 2 foci in preschool, 3 cases with 7 foci in school age, 7 cases with 9 foci in adolescence, and 10 cases with 16 foci in adulthood. In neonatal period, the main manifestations were myelin dysplasia (18%,6/33), dilatation of the lateral ventricular system (18%,6/33), and pallidal bulb infarct foci (18%,6/33); in infancy, the main manifestations were hypoplasia or thinning of the corpus callosum (30%,16/53); in early childhood, the main manifestations were pallidal bulb infarct foci (38%,6/16); and the two MRI abnormalities in preschool were pallidum and thalamic infarct foci; in school age, the main manifestations were infarct foci in the chiasmatic nucleus (29%,2/7) and in the caudate nucleus (29%,2/7); in adolescence, the main manifestation was dilatation of the lateral ventricular system (33%,3/9); and in adulthood, the main manifestation was dilatation of the lateral ventricular system (19%,3/16).Conclusion:By staging the age of onset, it is found that the imaging manifestations of MMA patients show significant differences with age, suggesting that there is a dynamic nature of MMA damage to brain structures at different developmental stages.

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Gliomas are the most common primary neuroepithelial tumors of the central nervous system in adults, of which glioblastoma is the deadliest subtype. Apart from the intrinsically indestructible characteristics of glioma (stem) cells, accumulating evidence suggests that the tumor microenvironment also plays a vital role in the refractoriness of glioblastoma. The primary functions of platelets are to stop bleeding and regulate thrombosis under physiological conditions. Furthermore, platelets are also active elements that participate in a variety of processes of tumor development, including tumor growth, invasion, and chemoresistance. Glioma cells recruit and activate resting platelets to become tumor-educated platelets (TEPs), which in turn can promote the proliferation, invasion, stemness, and chemoresistance of glioma cells. TEPs can be used to obtain genetic information about gliomas, which is helpful for early diagnosis and monitoring of therapeutic effects. Platelet membranes are intriguing biomimetic materials for developing efficacious drug carriers to enhance antiglioma activity. Herein, we review the recent research referring to the contribution of platelets to the malignant characteristics of gliomas and focusing on the molecular mechanisms mediating the interaction between TEPs and glioma (stem) cells, as well as present the challenges and opportunities in targeting platelets for glioma therapy.
Humans ; Glioma/metabolism* ; Blood Platelets/physiology* ; Brain Neoplasms/pathology* ; Tumor Microenvironment