Lung cancer remains the leading cause of cancer-related incidence and mortality worldwide. Among its histological subtypes, non-small cell lung cancer (NSCLC) accounts for the majority of cases, representing the predominant pathological type. Notably, in the elderly population, NSCLC continues to be a major contributor to cancer-related deaths. With the global ageing population, immunosenescence has emerged as a key factor influencing the occurrence, progression, and the efficacy of immunotherapy of NSCLC. Immunosenescence refers to the age-related decline in immune system function, which manifests as alterations in both the quantity and functionality of immune cells. These include thymic involution, T cell exhaustion, epigenetic modifications, weakened immune responses, and a chronic low-grade inflammatory state. This review comprehensively analyzes the role of immunosenescence in elderly patients with advanced NSCLC and proposes potential therapeutic strategies to intervene in the immunosenescence process. By targeting immunosenescence, these strategies aim to inhibit the progression of NSCLC and improve the effectiveness of immunotherapy.
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Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Immunotherapy ; Lung Neoplasms/genetics* ; Immunosenescence ; Aged

OBJECTIVES: To elucidate the anti-aging effect of β-sitosterol (BS), an important component in the fruits of Alpinia oxyphylla Miq., in C. elegans and its regulatory effect on ETS-5 gene to modulate ferroptosis. METHODS: C. elegans treated with 10 µg/mL BS were monitored for survival time and changes in body length, motility, and reproductive function. The effect of ETS-5 gene knockdown on survival time of C. elegans was observed, and the changes in fat accumulation and lipid redox homeostasis in the transfected C. elegans were assessed using Oil Red O staining and by detecting MDA levels and the GSH/GSSG ratio. The mRNA expression levels of ferroptosis-related genes (FTN-1, GPX-1 and AAT-9) were detected using qPCR. The effects of BS treatment and ETS-5 knockdown on AAT-9 enzyme activity in C. elegans were examined. The effect of BS on nuclear localization of FEV (the human homolog of ETS-5) was validated in cultured human umbilical venous endothelial cells (HUVECs). RESULTS: Both BS treatment and ETS-5 knockdown significantly prolonged the lifespan, promoted lipid accumulation and reduced lipid peroxidation in C. elegans. ETS-5 knockdown resulted in upregulated expressions of the ferroptosis repressors GPX-1, AAT-9 and FTN-1 and increased the GSH/GSSG ratio in C. elegans. CONCLUSIONS BS inhibits ferroptosis in C. elegans by suppressing the expression of ETS-5 transcription factor and hence the activity of AAT-9 enzyme, a key gene for ferroptosis, which in turn prolongs the lifespan of C. elegans.
Animals ; Caenorhabditis elegans/physiology* ; Ferroptosis/drug effects* ; Alpinia/chemistry* ; Sitosterols/pharmacology* ; Longevity/drug effects* ; Fruit/chemistry* ; Humans

Objective·To construct and verify the mouse model that can mimic the vitamin A deficiency(VAD)-like craniofacial skeletal deformity and do not cause embryonic death.Methods·Based on the Cre-LoxP system,the OsxCre;Rosa26dn/dn mice expressing osteoblast-specific dominant-negative retinoid acid receptor α(dnRARα)mutation were obtained by hybridization through OsxCre and Rosa26dnRARa/ddnRARa mice,to achieve the conditional inhibition of retinoic acid signaling to simulate VAD disease.Femur bone mesenchymal stem cells(BMSCs)and parietal bone cells of OsxCre;Rosa26dn/dn mice and their control littermates were isolated and underwent osteogenic induction,to assess the expression of retinoid acid receptor α(RARα)protein through Western blotting.Osteoblasts induced from parietal bone cells of OsxCre;Rosa26dn/dn mice and their control littermates were isolated and the effect of retinoic acid signaling inhibition was verified through dual luciferase gene reporter assay.Meanwhile,Ad-eGFP or Ad-Cre adenovirus-infected femur BMSCs and parietal bone cells of Rosa26dn/dnmice underwent osteogenic induction to assess the expression of dominant-negative mutant protein and the inhibition of the retinoic acid signaling pathway in vitro by Western blotting and dual luciferase gene reporter assay.Moreover,the skulls of 6-week-old OsxCre;Rosa26dn/dn mice were collected,and Micro-CT scanning and three-dimensional(3D)reconstruction were performed to verify the craniofacial skeletal deformities of the mouse model.Results·Western blotting results demonstrated that the level of RARα protein increased in the femur and parietal osteoblasts of OsxCre;Rosa26dn/dn mice compared to that of their control littermates,and also increased in the Ad-Cre-infected femur and parietal osteoblasts of Rosa26dn/dn mice compared to that in the Ad-eGFP-infected group(P＜0.05).Dualluciferase gene reporter assay results indicated that the activity of retinoid acid response element(RARE)was inhibited in the osteoblasts of OsxCre;Rosa26dn/dn mice compared to their control littermates,and was also inhibited in the Ad-Cre-infected group compared to the Ad-eGFP-infected group(P＜0.05).Micro-CT and 3D reconstruction suggested that the skull of 6-week-old OsxCre;Rosa26dn/dn mice exhibited VAD-like craniofacial skeletal deformities,including smaller size of the skull and osteogenesis imperfecta compared to their control littermates.Conclusion·An osteoblast-specific dnRARα expressing mouse model that can mimic VAD-like craniofacial skeletal deformity is successfully constructed,therefore providing a new model for exploring the pathogenesis and therapeutic targets of VAD-like craniofacial skeletal deformity in the future.

Objective:To analyze the clinical characteristics and prognosis of patients with stiff-person syndrome (SPS) associated with glutamic acid decarboxylase (GAD) antibodies.Methods:A retrospective analysis was conducted on demographic characteristics, clinical manifestations, auxiliary examination results, treatment, and prognosis of patients with GAD antibody-related SPS treated at Peking Union Medical College Hospital from January 2015 to July 2023.Results:A total of 33 patients were included, comprising 26 females (78.8%) and 7 males (21.2%), with an onset age of (42±12) years and a disease duration of 24.0 (10.5, 37.5) months. Two cases (6.1%) were diagnosed with tumors, including 1 case with invasive thymoma and 1 case with small cell lung cancer. The majority of patients (87.9%, 29/33) presented with stiffness of trunk and proximal limb muscles, 42.4% (14/33) of patients exhibited episodic spasm, and 54.5% (18/33) of patients were triggered by stimuli such as sound and light. Babinski or Chaddock reflexes were elicited in 33.3% (11/33) of patients. Some patients (36.4%, 16/33) had concurrent limbic encephalitis/epilepsy or cerebellar ataxia (referred to as complex SPS). The median cerebrospinal fluid (CSF) white blood cell count was 2×10 6/L [quartile: 1×10 6/L, 6×10 6/L; range: (0-30)×10 6/L], with mild elevation in 28.0% (7/25) of patients. Multi-channel surface electromyography in 14 out of 21 cases (66.7%) suggested synchronous contraction of agonist and antagonist muscles in a relaxed state. The modified Rankin Scale (mRS) score during the acute phase was 4 (3, 4). All patients received treatment with benzodiazepines or baclofen. Thirty patients (90.9%, 30/33) received first-line immunotherapy, 3 patients (9.1%, 3/33) received second-line immunotherapy with rituximab, and 14 (42.4%, 14/33) received mycophenolate mofetil as long-term immunotherapy. The follow-up period was 16 (10, 42) months, with a median best mRS score of 2; 66.7% (22/33) of patients had a favorable functional prognosis (mRS score≤2), and the recurrence rate was 30.0% (9/30). At the last follow-up, the median mRS score was 2, and 53.3% (16/30) of patients had a favorable functional prognosis. Prognosis was not significantly correlated with gender, age, clinical type, or CSF white blood cell level (all P>0.05). Conclusions:SPS is one of the main clinical phenotypes of GAD antibody-related neuroimmune diseases, commonly observed in middle-aged women, and exhibits a chronic progressive course. Only a minority of patients have concomitant tumors. The diagnosis relies on typical symptoms, GAD antibody testing, and electromyography examination. The initial immune therapy yields good results, but the prognosis for recurrent patients is poor.

Since the first case of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019, the virus has spread rapidly around the world and has become a global public health problem. In the process of this virus epidemic, compared with the general population, cancer patients are considered to be highly susceptible people, especially the lung cancer patients. Some studies have shown that angiotensin converting enzyme 2 (ACE2) may be the pathway for SARS-CoV-2 to infect the host. At the same time, ACE2 is often abnormally expressed in non-small cell lung cancer. Therefore, understanding the respective mechanisms of ACE2 in COVID-19 and non-small cell lung cancer has extremely important reference value for the study of vaccines and therapeutic drugs, and also provides meaningful guidance for the protection of patients with lung cancer during the epidemic. This article reviews the possible invasive mechanism of ACE2 in SARS-CoV-2 and its abnormal expression in non-small cell lung cancer.

Objective    To systematically evaluate the efficacy and safety of jejunostomy tube versus nasojejunal tube for enteral nutrition after radical resection of esophageal cancer. Methods    PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, Wanfang, VIP and CBM databases were searched to collect the clinical effects of jejunostomy tube versus nasojejunal nutrition tube after radical resection of esophageal cancer from inception to October 2021. Meta-analysis was performed using RevMan 5.4 software. Results    Twenty-six articles were included, including 17 randomized controlled studies and 9 cohort studies, with a total of 35 808 patients. Meta-analysis results showed that: in the jejunostomy tube group, the postoperative exhaust time (MD=–4.27, 95%CI –5.87 to –2.66, P=0.001), the incidence of pulmonary infection (OR=1.39, 95%CI 1.06 to 1.82, P=0.02), incidence of tube removal (OR=0.11, 95%CI 0.04 to 0.30, P=0.001), incidence of tube blockage (OR=0.47, 95%CI 0.23 to 0.97, P=0.04), incidence of nasopharyngeal discomfort (OR=0.04, 95%CI 0.01 to 0.13, P=0.001), the incidence of nasopharyngeal mucosal damage (OR=0.13, 95%CI 0.04 to 0.42, P=0.008), the incidence of nausea and vomiting (OR=0.20, 95%CI 0.08 to 0.47, P=0.003) were significantly shorter or lower than those of the nasojejunal tube group. The postoperative serum albumin level (MD=5.75, 95%CI 5.34 to 6.16, P=0.001) was significantly better than that of the nasojejunal tube group. However, the intraoperative operation time of the jejunostomy tube group (MD=13.65, 95%CI 2.32 to 24.98, P=0.02) and the indent time of the postoperative nutrition tube (MD=17.81, 95%CI 12.71 to 22.91, P=0.001) were longer than those of the nasojejunal nutrition tube. At the same time, the incidence of postoperative intestinal obstruction (OR=6.08, 95%CI 2.55 to 14.50, P=0.001) was significantly higher than that of the nasojejunal tube group. There were no statistical differences in the length of postoperative hospital stay or the occurrence of anastomotic fistula between the two groups (P>0.05). Conclusion    In the process of enteral nutrition after radical resection of esophageal cancer, jejunostomy tube has better clinical treatment effect and is more comfortable during catheterization, but the incidence of intestinal obstruction is higher than that of traditional nasojejunal tube.

BACKGROUND: Pancreatic β-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions. Deficits in β-cell compensatory capacity result in hyperglycemia and type 2 diabetes (T2D). However, the mechanism in the regulation of β-cell compensative capacity remains elusive. Nuclear factor-Y (NF-Y) is critical for pancreatic islets' homeostasis under physiological conditions, but its role in β-cell compensatory response to insulin resistance in obesity is unclear. METHODS: In this study, using obese ( ob/ob ) mice with an absence of NF-Y subunit A (NF-YA) in β-cells ( ob , Nf-ya βKO) as well as rat insulinoma cell line (INS1)-based models, we determined whether NF-Y-mediated apoptosis makes an essential contribution to β-cell compensation upon metabolic stress. RESULTS: Obese animals had markedly augmented NF-Y expression in pancreatic islets. Deletion of β-cell Nf-ya in obese mice worsened glucose intolerance and resulted in β-cell dysfunction, which was attributable to augmented β-cell apoptosis and reactive oxygen species (ROS). Furthermore, primary pancreatic islets from Nf-ya βKO mice were sensitive to palmitate-induced β-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response, which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase (JNK) and cleaved caspase-3. These detrimental effects were completely relieved by ROS scavenger. Ultimately, forced overexpression of NF-Y in INS1 β-cell line could rescue palmitate-induced β-cell apoptosis, dysfunction, and mitochondrial impairment. CONCLUSION Pancreatic NF-Y might be an essential regulator of β-cell compensation under metabolic stress.
Rats ; Mice ; Animals ; Reactive Oxygen Species/metabolism* ; Diabetes Mellitus, Type 2/metabolism* ; Insulin Resistance ; Insulin ; Insulin-Secreting Cells/metabolism* ; Apoptosis ; Stress, Physiological ; Transcription Factors/metabolism* ; Palmitates/pharmacology* ; Obesity/metabolism*

  Objective  To evaluate the clinical and paraclinical features of Chinese patients with anti- LGI1 encephalitis.  Methods  Patients with memory deficits, psychiatric symptoms, seizures or altered level of consciousness, suspicious of encephalitis, at presentation to Peking Union Medical College Hospital were recruited between July 2013 and January 2018, and tested for anti-LGI1 antibodies in their serum and/or cerebrospinal fluid(CSF) samples. Patients with anti-LGI1 antibodies were enrolled. The demographic characteristics, clinical manifestations, laboratory examination results, neuroimaging features, immunotherapy, follow-up practices and outcomes for included patients were registered and analyzed.  Results  The study enrolled 120 patients, of whom 66.7% were male. The median age was 61 years (interquartile range [IQR]: 49-66 years). Seizures(65.0%) were the most common initial symptoms. Most patients developed seizures (95.0%), including faciobrachial dystonic seizures (54.2%), memory deficits (92.5%), and psychiatric symptoms (69.1%). Brain MRI and ¹⁸F-FDG PET / CT showed that the lesions were mainly located in unilateral or bilateral medial temporal lobes, and (or) basal ganglia. Of the patients, 95.0% received intravenous immunoglobulin (IVIg) or corticosteroids, 47.5% received mycophenolate mofetil as long-term immunotherapy, and no one received second-line immunotherapy. The median follow-up was 34.2 months(IQR: 22.0-45.6 months). 91.2% had a good outcome (modified Rankin Scale score≤2 points). Residual mild memory deficits were present in 47.8% of the patients. Nine deaths were documented. Relapses occurred in 24.8% of the patients in the first year. In total, 24 (20%)cases were young patients(onset age ≤45 years).There were fewer males among the younger patients(37.5% vs. 74.0%, P < 0.01). Besides, there were fewer younger patients with psychiatric symptoms(50.0% vs. 74.0%, P=0.02), hyponatremia(33.3% vs. 68.8%, P < 0.01), and abnormalities on brain ¹⁸F-FDG PET/CT(20.8% vs. 47.9%, P=0.02). The relapse-free survival rate was significantly higher in the young patients.  Conclusions  Elderly males were predominant in patients with anti-LGI1 encephalitis. Most patients developed symptoms of limbic encephalitis and/or FDBS during the disease course. Several patients were young adults and lacked typical symptoms. Neuroimaging features were consistent with the involvement of limbic system or basal ganglia. Patients with anti-LGI1 encephalitis respond well to immunotherapy, irrespective of the age.

With the gradual improvement of medical informatization and the vigorous development of medical and health big data，the exploration and practice of real -world research are becoming more and more mature ，and real -world data have become an important source of evidence for post marketing re -evaluation of drugs . As an important high -quality real -world medical data ， electronic medical record data is an indispensable data source for post marketing re -evaluation of drugs . Most of the existing guidelines and norms of real -world research are designed from the perspective of prospective research ，and do not propose specific measures and methods in the implementation of retrospective research ，especially for the operation suggestions on the technical level of using conventionally collected electronic medical record data . In combination with the operational process framework formulated by the existing guidelines and norms ，this paper creatively adds the operating procedures for dataE- validation，data integration ，data verification ，and throughout quality control ，data management and storage of retrospectiveelectronic medical record data ，and describes the data analysis methods and key points involved in carrying out multi -center retrospective real -world research using electronic medical record data ，taking the post marketing safety research of drugs as an example. Finally，the full process operation procedure applicable to the use of multi -center retrospective electronic medical record data is established .

Objective:To investigate the diagnostic value of quantitative parameters of synthetic MRI in patients with prostate cancer (PCa).Methods:From April 2018 to April 2019, 25 PCa patients confirmed by whole-mount pathology were prospectively enrolled in Beijing Hospital. All patients underwent prostate MRI examinations including DWI and synthetic MRI. Four kinds of tissue types were identified in pathology, including PCa, stromal hyperplasia (SH), glandular hyperplasia (GH) and prostatitis. According to the pathological results, quantitative parameters including ADC, T 1, T 2 and proton density (PD) values were measured on DWI and synthetic MRI. One-way analysis of variance or Kruskal-Wallis H test was performed to compare the difference of each parameter among PCa, SH or GH in the transitional zone (TZ). The difference of each parameter between PCa and prostatitis in the peripheral zone (PZ) was evaluated by using independent sample t test or Mann-Whitney U test. The diagnostic performance of each parameter in discriminating PCa from other benign conditions was evaluated by using ROC curve. Area under the curve (AUC) of each parameter was compared by using DeLong test. Results:The overall differences of T 1, T 2 PD and ADC values were statistically significant among PCa and other benign conditions. The T 1, T 2 and ADC values of PCa in the TZ were lower than those in the SH ( P=0.041, 0.030,<0.001) and GH (all P<0.001). The PD value of PCa in the TZ was lower than that in the GH ( P=0.040). The differences of T 1, T 2, PD and ADC values between PCa and prostatitis in the PZ were significant ( P<0.05). The AUC of ADC value (0.943) was higher than that of T 1 (0.691, P=0.001), PD (0.555, P=0.002) and T 2 (0.754, P=0.016) values in differentiating PCa from SH. For discriminating PCa and GH, T 1, T 2 and ADC showed similar AUC ( P>0.05), which were higher than AUC of PD value ( P=0.001). For discriminating PCa and prostatitis, T 1, T 2, PD and ADC values showed similar AUC ( P>0.05). Conclusions:Quantitative parameters of synthetic MRI were practical tools for discriminating PCa from other benign pathologies.