Triple-negative breast cancer (TNBC) is a highly aggressive malignancy predominantly managed via chemotherapy. Our clinical sample analysis revealed a significant correlation between elevated CD24 expression in TNBC tumor cells and patient survival rates. We developed a novel antibody-drug conjugate (ADC), named HN03, consisting of an antibody with engineered cysteines for site-specific conjugation with a low toxic nitric oxide (NO) precursor as its payload through a novel Pt(IV)-mediated bioorthogonal self-cleavable linker. HN03 specifically targets tumor cells expressing high levels of CD24, concurrently generating cisplatin and releasing NO upon activation. HN03 also exhibited potent in vitro and in vivo antitumor activity. It significantly reduced tumor growth at various doses, prevented tumor metastasis, with markedly lower toxicity than traditional chemotherapy agents. We found that a key mechanism of its action involved inducing apoptosis and endoplasmic reticulum stress, substantially decreasing the number of M2-type macrophages. Overall, HN03 stands out as a promising therapeutic option for TNBC, offering a targeted treatment with reduced side effects and the potential for improved outcomes. Furthermore, using Pt(IV) in the linker and an NO precursor as the payload enhances the versatility of the Antibody-NO donor Conjugate (ANC), offering new avenues for the design of the next generation of ADCs.

OBJECTIVE: To investigate the associations between eight serum per- and polyfluoroalkyl substances (PFASs) and regional fat depots, we analyzed the data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 cycles. METHODS: Multiple linear regression models were developed to explore the associations between serum PFAS concentrations and six fat compositions along with a fat distribution score created by summing the concentrations of the six fat compositions. The associations between structurally grouped PFASs and fat distribution were assessed, and a prediction model was developed to estimate the ability of PFAS exposure to predict obesity risk. RESULTS: Among females aged 39-59 years, trunk fat mass was positively associated with perfluorooctane sulfonate (PFOS). Higher concentrations of PFOS, perfluorohexane sulfonate (PFHxS), perfluorodecanoate (PFDeA), perfluorononanoate (PFNA), and n-perfluorooctanoate (n-PFOA) were linked to greater visceral adipose tissue in this group. In men, exposure to total perfluoroalkane sulfonates (PFSAs) and long-chain PFSAs was associated with reductions in abdominal fat, while higher abdominal fat in women aged 39-59 years was associated with short-chain PFSAs. The prediction model demonstrated high accuracy, with an area under the curve (AUC) of 0.9925 for predicting obesity risk. CONCLUSION PFAS exposure is associated with regional fat distribution, with varying effects based on age, sex, and PFAS structure. The findings highlight the potential role of PFAS exposure in influencing fat depots and obesity risk, with significant implications for public health. The prediction model provides a highly accurate tool for assessing obesity risk related to PFAS exposure.
Humans ; Fluorocarbons/blood* ; Female ; Adult ; Middle Aged ; Male ; Environmental Pollutants/blood* ; Abdominal Fat ; Nutrition Surveys ; Alkanesulfonic Acids/blood* ; Obesity ; Environmental Exposure

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Aim To study the effects of Taohong Siwu Tang(TSD)on serum lipid metabolites in rats with abnormal uterine bleeding(AUB),and to analyze the mechanism of action of TSD in improving lipid metabo-lism disorders in AUB.Methods The rat model of AUB was replicated by the method of incomplete abor-tion with drugs,and the lipid metabolites of serum were detected by applying UPLC-Q-Exactive Orbitrap/MS technology,and combined with the principal com-ponent analysis and orthogonal partial least squares-discriminant analysis to screen for differential lipids,the changes of lipids in serum before and after the in-tervention of TSD were clarified.Results A total of 11 differential lipids were screened,mainly phosphati-dyl inositol,phosphatidic acid,phosphatidyl ethanola-mine,phosphatidyl serine,sterol lipids,ceramide,acrylolipids and fatty acids.The screened differential lipids all tended to regress to normal after the adminis-tration of TSD intervention.Conclusion Improvement of AUB by TSD may be related to lipid metabolism such as phosphatidic acid,phosphatidyl inositol,phos-phatidyl ethanolamine,phosphatidyl serine,and ce-ramide.

Objective To investigate the effect and mechanism of astrocytes on the proliferation of neural stem cells (NSCs) in adult and juvenile hippocampus microenvironment. Methods Hippocampal astrocytes were isolated and cultured from 5 female SD rats at day 1 and week 30 postnatal, respectively; Embryonic hippocampus NSCs was isolated and cultured from 1 SD rat at day 15 of gestation; Conditioned astrocyte culture medium(CM) was collected for NSCs culture; Flow cytometry and CCK-8 were used to detect the proliferation of NSCs cultured in CM. Colony stimulating factor 1 (CSF-1) with differential expression was screened by mass spectrometry after cultured astrocyte CM. Western blotting and ELISA were used to verify the result of mass spectrometry. Immunofluorescence, flow cytometry and CCK-8 were used to detect the proliferation of NSCs treated with different concentrations of CSF-1 recombinant protein (20 μg/ L, 100 μg/ L, 1 mg/ L and 5 mg/ L). Results Compared with the adult group, the CM of hippocampal astrocytes in the young group could promote the proliferation of NSCs(P<0. 01); Compared with the conditioned medium of hippocampal astrocytes in the juvenile group, the expression of CSF-1 in the hippocampus of the elder group was significantly up-regulated(P<0. 01); At 20 μg/ L, CSF-1 promoted the proliferation of NSCs(P<0. 01), and 5 mg/ L CSF-1 inhibited significantly the proliferation of NSCs(P<0. 01). Conclusion The secretion of CSF-1 by astrocytes in hippocampal microenvironment can regulate the proliferation of NSCs with the development of the times.

ObjectiveTo investigate the effect of high-definition transcranial direct current stimulation (HD-tDCS) combined with rehabilitation robot on upper limb and hand dysfunction in patients with subacute stroke. MethodsFrom December, 2019 to December, 2021, 50 inpatients with subacute stroke in Zhejiang Provincial People's Hospital were randomly divided into control group (n = 25) and experimental group (n = 25). Both groups received routine rehabilitation therapy, while the control group added sham HD-tDCS combined with rehabilitation robot, and the experimental group added HD-tDCS combined with rehabilitation robot, for four weeks. The upper limb and hand function was assessed with Action Research Arm Test (ARAT), Fugl-Meyer Assessment-Upper Extremities (FMA-UE) and Motor Assessment Scale (MAS) before and after treatment. ResultsAfter treatment, the scores of ARAT, FMA-UE and MAS increased in the two groups (∣Z∣ > 3.320, t > 6.379, P < 0.01), while the scores of FMA-UE and MAS were higher in the experimental group than in the control group (Z = -2.379, t = 3.181, P < 0.05), as well as the scores of grasping and gross motor of ARAT (∣Z∣ > 2.033, P < 0.05). ConclusionThe combination of HD-tDCS and rehabilitation robot can be more effective on upper limb and hand function in patients with subacute stroke than rehabilitation robot alone.

Objective: To study the effect of diurnal temperature range on the number of elderly inpatients with ischemic stroke in Hunan Province. Method: Demographic and disease data, meteorological data, air quality data, population, economic and health resource data of elderly inpatients with ischemic stroke were collected in 122 districts/counties of Hunan Province from January to December 2019. The relationships between the diurnal temperature range and the number of elderly inpatients with ischemic stroke were analyzed by using the distributed lag non-linear model, including the cumulative lag effect of the diurnal temperature range in different seasons, extremely high diurnal temperature range and extremely low diurnal temperature range. Results: In 2019, 152 875 person-times were admitted to the hospital for ischemic stroke in the elderly in Hunan Province. There was a non-linear relationship between the diurnal temperature range and the number of elderly patients with ischemic stroke, with different lag periods. In spring and winter, with the decrease in diurnal temperature range, the risk of admission of elderly patients with ischemic stroke increased (P_trend<0.001, P_trend=0.002);in summer, with the increase in diurnal temperature range, the risk of admission of elderly patients with ischemic stroke increased (P_trend=0.024);in autumn, the change in the diurnal temperature range would not cause a change in admission risk (P_trend=0.089). Except that the lag effect of the extremely low diurnal temperature range in autumn was not obvious, the lag effect occurred in other seasons under extremely low and extremely high diurnal temperature ranges. Conclusion: The high diurnal temperature range in summer and the low diurnal temperature range in spring and winter will increase the risk of admission of elderly patients with ischemic stroke, and the risk of admission of elderly patients with ischemic stroke will lag under the extremely low and extremely high diurnal temperature ranges in the above three seasons.
Humans ; Aged ; Temperature ; Ischemic Stroke ; Inpatients ; Cold Temperature ; Hot Temperature ; Seasons ; China/epidemiology*

Objective: To compare the effects and safety of dydrogesterone (DG) and medroxyprogesterone acetate (MPA) on the treatment in patients with endometrial hyperplasia without atypia (EH). Methods: This was a single-center, open-label, prospective non-inferior randomized controlled phase Ⅲ trial. From February 2019 to November 2021, patients with EH admitted to the Obstetrics and Gynecology Hospital of Fudan University were recruited. Enrolled patients were stratified according to the pathological types of simple hyperplasia (SH) or complex hyperplasia (CH), and were randomised to receive MPA or DG. Untill May 14, 2022, the median follow-up time after complete response (CR) was 9.3 months (1.1-17.2 months). The primary endpoint was the 6-month CR rate (6m-CR rate). The secondary endpoints included the 3-month CR rate (3m-CR rate), adverse events rate, recurrence rate, and pregnancy rate in one year after CR. Results: (1) A total of 292 patients with EH were enrolled in the study with the median age of 39 years (31-45 years). A total of 135 SH patients were randomly assigned to MPA group (n=67) and DG group (n=68), and 157 CH patients were randomly assigned to MPA group (n=79) and DG group (n=78). (2) Among 292 patients, 205 patients enrolled into the primary endpoint analysis, including 92 SH patients and 113 CH patients, with 100 patients in MPA group and 105 in DG group, respectively. The 6m-CR rate of MPA group and DG group were 90.0% (90/100) and 88.6% (93/105) respectively, and there were no statistical significance (χ²=0.11, P=0.741), with the rate difference (RD) was -1.4% (95%CI:-9.9%-7.0%). Stratified by the pathology types, the 6m-CR rate of SH patients was 93.5% (86/92), and MPA group and DG group were respectively 91.1% (41/45) and 95.7% (45/47); and the 6m-CR rate of CH patients was 85.8% (97/113), and MPA group and DG group were 89.1% (49/55) and 82.8% (48/58) respectively. The 6m-CR rates of the two treatments had no statistical significance either (all P>0.05). A total of 194 EH patients enrolled into the secondary endpoint analysis, including 88 SH patients and 106 CH patients, and 96 patients in MPA group and 98 in DG group, respectively. The 3m-CR rate of SH patients were 87.5% (77/88), while the 3m-CR rates of MPA group and DG group were 90.7% (39/43) and 84.4% (38/45), respectively; the 3m-CR rate of CH patients was 66.0% (70/106), and MPA group and DG group had the same 3m-CR rate of 66.0% (35/53). No statistical significance was found between the two treatments both in SH and CH patients (all P>0.05). (3) The incidence of adverse events between MPA group and DG group had no statistical significance (P>0.05). (4) A total of 93 SH patients achieved CR, and the cumulative recurrence rate in one year after CR were 5.9% and 0 in MPA group and DG group, respectively. While 112 CH patients achieved CR, and the cumulative recurrence rate in one year after CR were 8.8% and 6.5% in MPA group and DG group, respectively. There were no statistical significance between two treatment groups (all P>0.05). Among the 93 SH patients, 10 patients had family planning but no pregnancy happened during the follow-up period. Among the 112 CH patients, 21 were actively preparing for pregnancy, and the pregnancy rate and live-birth rate in one year after CR in MPA group were 7/9 and 2/7, while in DG group were respectively 4/12 and 2/4, and there were no statistical significance in pregnancy rate and live-birth rate between the two treatment groups (all P>0.05). Conclusions: Compared with MPA, DG is of good efficacy and safety in treating EH. DG is a favorable alternative treatment for EH patients.
Female ; Humans ; Adult ; Medroxyprogesterone Acetate/adverse effects* ; Endometrial Hyperplasia/pathology* ; Dydrogesterone/adverse effects* ; Hyperplasia ; Prospective Studies

Tumor blood and lymphatic vessel growth are necessary conditions for tumor growth, progression and metastasis, which are closely related with infiltrating nnate as well as adaptive immune cells. On one hand, immune cells rely on adhesion molecules on vascular endothelial cells to penetrate into tumor tissues and show anti-tumor characteristics. On the other hand, they can regulate tumor angiogenesis and lymphangiogenesis by secreting chemokines and cytokines, playing an important role in the process of tumor blood metastasis. In addition, the role of immune cells in promoting tumor blood metastasis highlights the shortcomings of t anti-angiogenic therapy. Therefore, targeting immune cells and tumor angiogenesis improve the effect of therapeutic. Based on these, this article summarizes the effects of immune cells on blood and lymphatic vessels n tumor metastasis, as well as related anti-vascular and immune therapies, in order o provide deas for subsequent research.

Immune checkpoint inhibitor ( ICI) activates the host' s anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. Anti-angiogenesis drugs commonly used to block tumor angiogenesis can inhibit the growth of tumors, but they cannot improve the survival of patients with limitations in application such as drug resistance. Tumor immune response is closely related to angiogenesis. In turn, tumor angiogenesis highly depends on immunosuppressive microenvironment. Recent studies have indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment, and the efficacy of combination therapy was superior to that of monotherapy. The reciprocal regulation between tumor vascular normalization and immune reprogramming forms a reinforcing loop that reconditions the tumor immune microenvironment to induce durable antitumor immunity. This review clarifies the latest understanding of ICI combined anti-angiogenesis therapy and provides ideas for subsequent research.