BACKGROUND: This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate. RESULTS: A total of 409 patients, 65.0% ( n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% ( n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 10 9 /L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 10 9 /L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs. CONCLUSIONS A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Lung Neoplasms/metabolism* ; Aged ; B7-H1 Antigen/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; Adult ; Aged, 80 and over ; Immune Checkpoint Inhibitors/therapeutic use*

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Mesangial cell proliferation is an early pathological indicator of diabetic nephropathy (DN). Growing evidence highlights the pivotal role of paired-related homeobox 1 (Prrx1), a key regulator of cellular proliferation and tissue differentiation, in various disease pathogenesis. Notably, Prrx1 is highly expressed in mesangial cells under DN conditions. Both in vitro and in vivo studies have demonstrated that Prrx1 overexpression promotes mesangial cell proliferation and contributes to renal fibrosis in db/m mice. Conversely, Prrx1 knockdown markedly suppresses hyperglycemia-induced mesangial cell proliferation and mitigates renal fibrosis in db/db mice. Mechanistically, Prrx1 directly interacts with the Yes-associated protein 1 (YAP) promoter, leading to the upregulation of YAP expression. This upregulation promotes mesangial cell proliferation and exacerbates renal fibrosis. These findings emphasize the crucial role of Prrx1 upregulation in high glucose-induced mesangial cell proliferation, ultimately leading to renal fibrosis in DN. Therefore, targeting Prrx1 to downregulate its expression presents a promising therapeutic strategy for treating renal fibrosis associated with DN.

Objective To discuss the effectiveness and safety of transarterial chemoembolization(TACE)combined with regorafenib and programmed death receptor-1(PD-1)in the second-line sequential treatment of advanced hepatocellular carcinoma(HCC).Methods The clinical data of a total of 83 patients with advanced HCC,who received TACE combined with regorafenib and PD-1(triple-therapy group)or TACE combined with regorafenib(dual-therapy group)at the Affiliated Hospital of Nantong University and Nantong Municipal Third People's Hospital of China between October 2020 and May 2022,were retrospectively analyzed.The clinical data were collected and evaluated.Modified response evaluation criteria in solid tumors(mRECIST)was used to evaluate the curative effect.The progression-free survival(PFS),overall survival(OS)and treatment-related adverse events(TRAEs)were compared between the two groups.The Kaplan-Meier method was used to draw PFS and OS curves,the Log-rank test was used to compare the relevant data between the two groups,and the COX regression model was drawn to determine the factors influencing PFS and OS.Results There were no statistically significant differences in the baseline data between the two groups(P≥0.05).In the triple-therapy group and the dual-therapy group,the objective response rate(ORR)was 31.1％and 18.4％respectively(P=0.024),and the disease control rate(DCR)was 77.8％and 57.8％respectively(P=0.038).The OS and PFS in the triple-therapy group were higher than those in the dual-therapy group(16.80 months vs 13.20 months,and 9.10 months vs.7.40 months,respectively).No statistically significant difference in the incidence of adverse drug reactions existed between the two groups(P 0.05).Conclusion In the second-line sequential treatment of advanced HCC,TACE combined with regorafenib and PD-1 is more effective than TACE combined with regorafenib,therefore,it can be used as a preferred second-line treatment for advanced HCC.

【Objective】 To clarify the hematological characteristics and current situation of chronic mountain sickness among Tibetan residents in extreme high altitude area (more than 5 000 m above the sea level) of Ali district based on the analysis of physical examination and blood test results. 【Methods】 Totally 250 Tibetan residents were selected by convenient sampling for blood oxygen saturation (SpO2), heart rate, and blood routine examination. Chronic mountain sickness was determined according to the hemoglobin (Hb) level and SpO2. 【Results】 The red blood cell (RBC), Hb and hematocrit (HCT) of the Tibetan residents at 5 200-meter altitude were all higher than the normal physiological reference range of China. Mean red blood cell volume (MCV), mean red blood cell hemoglobin content (MCH), mean red blood cell hemoglobin concentration (MCHC), white blood cell (WBC) and platelet (PLT) were in the upper limit of the reference value. The RBC, Hb, HCT and MCHC of male Tibetan residents were higher than those of females, while PLT was lower than that of females, with significant differences. There were no statistical differences in MCV, MCH or WBC among different genders of Tibetan residents. The SpO2 of the Tibetan residents was about 85% of the normal value, and the males had higher SpO2 than the females in the same age group, and the difference was statistically significant, but the heart rate did not differ significantly. The prevalence rate of chronic mountain sickness in this area was as high as 16.4%, and the prevalence rate of heavy manual workers was significantly higher than that of light manual workers, with significant differences. 【Conclusion】 The high-altitude anoxic environment causes the changes in red blood cells, hemoglobin, and oxygen saturation of local residents, and the prevalence of chronic mountain sickness increases significantly. Labor intensity is one of the risk factors for chronic mountain sickness in high-altitude areas.

BACKGROUND: Low dose computed tomography (LDCT) for lung cancer screening is widely employed in China as a result of increasing cancer screening awareness. Although some pulmonary lesions detected by LDCT are cancerous, most of the pulmonary nodules are benign. It is important to make effective preoperative differentiation of pulmonary lesions and to obviate the need for surgery in some patients with benign disease. METHODS: From January 1, 2017 to December 31, 2018, patients in our institution with surgical pathology confirmed benign pulmonary lesions in which malignancy could not be excluded in preoperative assessment were enrolled in this study. Retrospective analysis of clinical data was conducted. RESULTS: 297 cases were collected in this study. Prevalence of benign disease in patients underwent resection for focal pulmonary lesions is 9.8% in our institution. In 197 patients (66.3%), pulmonary lesions were detected by LDCT screening. A total of 323 assessable pulmonary lesions were detected by chest CT. The average diameter of pulmonary lesions was (17.9±12.1) mm, and 91.0% of which were greater than or equal to 8 mm. Solid nodules accounted for 65.6% of these lesions. Imaging characteristics suggesting malignancy were common, including spicule sign (71/323, 22.0%), lobulation (94/323, 29.1%), pleural indentation (81/323, 25.1%), vascular convergence sign (130/323, 40.2%) and vacuole sign (23/323, 7.1%). 292 patients (98.3%) underwent video-assisted thoracoscopic surgery (VATS). Pulmonary wedge resection was performed in 232 cases (78.1%), segmental resection in 13 cases (4.4%) and lobotomy in 51 cases (17.2%). Surgical complications occurred in 4 patients (1.3%). The most frequent findings on surgical pathology analysis were: infectious lesions in 98 cases (33.0%), inflammatory nodules in 96 cases (32.3%), and hamartoma in 64 cases (21.5%). CONCLUSIONS Solid nodules accounted for most of these benign pulmonary lesions in which malignancy could not be excluded preoperatively, and imaging characteristics suggesting malignancy were common. VATS is an important biopsy method to identify etiology and pathology for lesions. The most frequent benign pulmonary diseases that are suspected to be malignant and underwent surgical resection are: infectious lesions, inflammatory nodules and hamartoma.

Objective To explore the intervention effect of the combination of medicine and education on teachers and parents of children with attention deficit hyperactivity disorder (ADHD).Methods The students in Grade 1 to 3 of 6 public primary school (6～11 years old) were enrolled by stratified sampling method and randomly divided into the experimental group and the control group.All the students were screened for ADHD,and the children diagnosed with ADHD and their parents and teachers were enrolled into study as the research object.The children in the control group were given oral short-effect methylphenidate hydrochloride tablets and their parents underwent routine health education,while the parents and teachers in the experimental group were given both the routine health education and systematic training.Before and after training,the awareness rates of ADHD knowledge among parents and teachers were observed,and the clinical effects of two groups were compared.Results The control group included 71 children with ADHD,71 pairs of parents and 31 teachers,while the experimental group included 68 children with ADHD,68 pairs of parents and 34 teachers.The difference of general data between the two groups has no statistical significance (P＞0.05).Before intervention,there was no significant difference in awareness rate of ADHD knowledge among teachers and parents in the two groups (P＞0.05).After the intervention,the awareness rate of ADHD knowledge in teachers of the control group did not change obviously,while which in parents of the control group and the parents and teachers in the experimental group were significantly improved,and the improvement effect in the experimental group was significantly better than that of the control group (P＜0.05).The scores of the SNAP-Ⅳ scale in both groups were significantly decreased,and the scores of the experimental group were significantly lower than those in the control group.The significant rate and total effective rates of the experimental group were significantly higher than those in the control group (P＜0.05).Conclusion The intervention effect of combination of medicine and education on teachers and parents of children with ADHD is definite,which is worthy of further research.

The isolated type of orofacial cleft, termed non-syndromic cleft lip with or without cleft palate (NSCL/P), is the second most common birth defect in China, with Asians having the highest incidence in the world. NSCL/P involves multiple genes and complex interactions between genetic and environmental factors, imposing difficulty for the genetic assessment of the unborn fetus carrying multiple NSCL/P-susceptible variants. Although genome-wide association studies (GWAS) have uncovered dozens of single nucleotide polymorphism (SNP) loci in different ethnic populations, the genetic diagnostic effectiveness of these SNPs requires further experimental validation in Chinese populations before a diagnostic panel or a predictive model covering multiple SNPs can be built. In this study, we collected blood samples from control and NSCL/P infants in Han and Uyghur Chinese populations to validate the diagnostic effectiveness of 43 candidate SNPs previously detected using GWAS. We then built predictive models with the validated SNPs using different machine learning algorithms and evaluated their prediction performance. Our results showed that logistic regression had the best performance for risk assessment according to the area under curve. Notably, defective variants in MTHFR and RBP4, two genes involved in folic acid and vitamin A biosynthesis, were found to have high contributions to NSCL/P incidence based on feature importance evaluation with logistic regression. This is consistent with the notion that folic acid and vitamin A are both essential nutritional supplements for pregnant women to reduce the risk of conceiving an NSCL/P baby. Moreover, we observed a lower predictive power in Uyghur than in Han cases, likely due to differences in genetic background between these two ethnic populations. Thus, our study highlights the urgency to generate the HapMap for Uyghur population and perform resequencing-based screening of Uyghur-specific NSCL/P markers.
Asian Continental Ancestry Group ; genetics ; China ; ethnology ; Cleft Lip ; genetics ; Cleft Palate ; genetics ; Genome-Wide Association Study ; Humans ; Infant ; Logistic Models ; Machine Learning ; Methylenetetrahydrofolate Reductase (NADPH2) ; genetics ; Polymorphism, Single Nucleotide ; Retinol-Binding Proteins, Plasma ; genetics ; Risk Assessment

Objective To observe the effects of mild hypothermia on the myocardial mitochondrial injury induced by oxidative stress after restoration of spontaneous circulation (ROSC) in rat of cardiac arrest model.Methods Eighteen male Wistar rats were randomly (raudom number) divided into normal temperature group and mild hypothermia group after ROSC.Ultrasound was used to measure the left ventricular ejection fraction (EF),shortening fraction (FS) and stroke volume (SV).The levels of glutathione (GSH),malondialdehyde (MDA) and adenosine triphosphate (ATP) in myocardium were detected.The ultramicroscopic structure of myocardial mitochondria was observed under transmission electron microscope at 4 h after ROSC.Results There were no significant differences in basic life support (BLS) time,dosage of epinephrine and number of defibrillation attempt between two groups (P ＞ 0.05).The concentrations of GSH and ATP in myocardium of rats in hypothermia group were significantly higher than those in normal temperature group,while the level of MDA was significantly lower in hypothermia group than that in normal temperature group.Echocardiographic findings showed that hypothermia could significantly improve the EF,FS and SV after ROSC.The hypothermia decreased the myocardial mitochondria injury rather than normothermia [mitochondrial injury score:(0.21-±0.04) vs.(0.42 ±0.08),P ＜ 0.05].Conclusions In this model,mild hypothermia can decrease myocardial oxidative stress injury,improving the cardiac function after ROSC.

Objective To explore the effects of estrogen on oxidative stress of the lung tissue induced by acute paraquat (PQ) poisoning. Methods Thirty-two male adult New Zealand rabbits were randomly divided into model group and estrogen intervention group, 16 rabbits in each group. The model of lung injury induced by PQ poisoning was reproduced by feeding 16 mg/kg of 20% PQ through gastric tube. The rabbits in estrogen intervention group received intravenous infusion of 5 mg/kg estrogen after PQ challenge for 7 days, and the rabbits in model group received an equal volume of normal saline. Three rabbits in each group were sacrificed at 1, 2 and 3 days respectively after exposure. The lung tissue was harvested, the levels of reactive oxygen species (ROS) was determined by 2',7'-dichlorofluorescin diacetate (DCFH-DA), malondialdehyde (MDA) was determined by thiobarbituric acid (TBA), the mRNA expression of manganese-containing superoxide dismutase (MnSOD) was determined by reverse transcription-polymerase chain reaction (RT-PCR), and adenosine triphosphatase (ATP) content in mitochondrion was determined by enzyme linked immunosorbent assay (ELISA). The pathological changes in lung were observed under light microscopy using hematoxylin and eosin (HE) staining, and the lung injury was evaluated with lung injury score. Results The contents of ROS and MDA in lung within 3 days after PQ poisoning were gradually increased, and MnSOD mRNA expression and ATP content were gradually decreased. Estrogen intervention could significantly reduce the production of ROS and MDA after PQ poisoning [3-day ROS (fluorescence intensity): 161.05±30.04 vs. 188.30±31.80, 3-day MDA (mmol/L): 98.71±0.92 vs. 122.12±1.24], up-regulate MnSOD mRNA expression (integral A value: 3.05±0.90 vs. 1.22±0.24), and increase ATP content in mitochondrion (ng/L: 3.75±0.92 vs. 2.28±0.29) with statistically significant differences (all P < 0.01). In lung tissue after PQ poisoning, congestion, edema, focal pulmonary consolidation, pulmonary interstitial and alveolar space were infiltrated by a large number of neutrophil, alveolar interval were thickened obviously and the above phenomenon were most serious at 3 days after poisoning as shown under optical microscope. Estrogen intervention could significantly improve lung injury as compared with that of model group, and the lung injury score at 3 days was significantly lower than that of model group (11.8±0.7 vs. 13.5±1.0, P < 0.01). Conclusions The oxidative stress indicators in the lung tissue after PQ poisoning were obviously abnormal, the pathological damage was serious with time dependence. The administration of estrogen can reduce acute lung injury after PQ poisoning by reducing the oxidative stress.