Objective:To investigate the evaluation efficacy and predictive prognostic value of alpha-fetoprotein (AFP) response in tyrosine kinase inhibitors (TKIs) in combination with PD-1 inhibitors (α-PD-1) for intermediate-to-advanced hepatocellular carcinoma (HCC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 205 patients with intermediate-to-advanced HCC who were admitted to 9 medical centers, including Mengchao Hepatobiliary Hospital of Fujian Medical University et al, from March 2020 to July 2022 were collected. There were 178 males and 27 females, aged (52±12)years. Based on AFP response at 6-8 weeks after treatment, patients were divided into the AFP response group (AFP level decreased by ≥50% compared to baseline) and the AFP no response group (AFP level decreased by <50% compared to baseline). Observation indicators: (1) AFP response evaluation of anti-tumor efficacy; (2) comparison of patient prognosis; (3) analysis of factors affecting patient prognosis. Measurement data with normal distrubution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range) and M( Q1, Q3). Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. The Kaplan-Meier method was used to draw survival curve and calculate survival rate, and the Log-Rank test was used for survival analysis. The COX proportional risk model was used for univariate analysis and the COX stepwise regression model was used for multivariate analysis. Results:(1) AFP response evaluation of anti-tumor efficacy. Before treatment, all 205 patients were positive of AFP, with a baseline AFP level of 1 560(219,3 400)μg/L. All 205 patients were treated with TKIs in combination with α-PD-1, and the AFP level was 776(66,2 000)μg/L after 6 to 8 weeks of treatment. Of the 205 patients, 88 cases were classified as AFP response and 117 cases were classified as AFP no response. According to the response evaluation criteria in solid tumors version 1.1, the objective response rate (ORR) and disease control rate (DCR) were 42.05%(37/88) and 94.32%(83/88) in patients of the AFP response group and 16.24% (19/117) and 64.10% (75/117) in patients of the AFP no response group, showing significant differences between them ( χ2=16.846, 25.950, P<0.05). According to the modified response evaluation criteria in solid tumors, the ORR and DCR were 69.32% (61/88) and 94.32% (83/88) in patients of the AFP response group and 33.33% (39/117) and 64.10% (75/117) in patients of the AFP no response group, showing significant differences between them ( χ2=26.030, 25.950, P<0.05). (2) Comparison of patient prognosis. All 205 patients were followed up for 12.4(range, 2.4-34.0)months after treatment. The median progression free survival time and total survival time were 5.5 months and 17.8 months, respectively. The 1-year, 2-year progression free survival rates were 20.8% and 7.2%, and the 1-year, 2-year overall survival rates were 68.7% and 31.5%, respectively. The median progression free survival time, 1-year and 2-year progression free survival rates were 9.7 months, 39.6% and 14.2% in patients of the AFP response group and 3.7 months, 7.8% and 2.0% in patients of the AFP no response group, showing a significant difference in progression free survival between them ( χ2=43.154, P<0.05). The median overall survival time, 1-year and 2-year overall survival rates were not reached, 85.2% and 56.3% in patients of the AFP response group and 14.6 months, 56.3% and 14.5% in patients of the AFP no response group, showing a significant difference in overall survival between them ( χ2=33.899, P<0.05). (3) Analysis of factors affecting patient prognosis. Results of multivariate analysis showed that invasion of large blood vessels, extrahepatic metastasis, combined hepatic artery intervention therapy, and AFP response were independent factors influencing progression free survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1 ( hazard ratio=1.474, 1.584, 0.631, 0.367, 95% confidence interval as 1.069-2.033, 1.159-2.167, 0.446-0.893, 0.261-0.516, P<0.05), and Eastern Cooperative Oncology Group score, invasion of large blood vessels, extrahepatic metastasis, and AFP response were independent factors influencing overall survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1 ( hazard ratio= 1.347, 1.914, 1.673, 0.312, 95% confidence interval as 1.041-1.742, 1.293-2.833, 1.141-2.454, 0.197-0.492, P<0.05). Conclusions:AFP response at 6-8 weeks after treatment can effectively evaluate anti-tumor efficacy of TKIs in combination with α-PD-1 for intermediate-to-advanced HCC. AFP response is the independent factor influencing progression free survival and overall survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1.

Depressive disorder ranks as a major bur-den of disease worldwide,yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects.The lateral septum(LS)is thought to control of depression,however,the cellular and circuit substrates are largely unknown.Here,we identified a subpopulation of LS GABAergic adenosine A2A receptors(A2AR)-positive neurons mediating depres-sive symptoms via direct projects to the lateral habenula(LHb)and the dorsomedial hypothalamus(DMH).Activa-tion of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipula-tion of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive pheno-types.Thus,the optogenetic modulation(stimulation or inhibition)of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH,phenocopied depressive behaviors.Moreover,A2AR are upregulated in the LS in two male mouse mod-els of repeated stress-induced depression.This identifica-tion that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant poten-tial of A2AR antagonists,prompting their clinical transla-tion.

Objective To investigate the therapeutic effect of different combinations of acupuncture and robot training on balance function in patients with Parkinson's disease.Methods A total of 60 patients with Parkinson's disease admitted to Wenzhou Traditional Medicine Hospital from October 2020 to October 2022 were randomly divided into two groups.Group A was given robot training after receiving acupuncture of Baihui and Dazhui points.Group B received those treatments simultaneously.And the balance function of patients was evaluated by Berg balance scale(BBS),Morse fall assessment scale(MFS)and timed up and go test(TUGT).Results In the intra-group comparison,TUGT in group A was significantly improved after 4 weeks of treatment(P<0.01);MFS and TUGT in group B were significantly improved compared with those before treatment(P<0.01).After 8 weeks of treatment,BBS and TUGT in group A were significantly improved compared with those before treatment(P<0.01);BBS,MFS and TUGT in group B were significantly improved compared with those before treatment(P<0.01).At the 12th week,BBS,MFS and TUGT in both groups were significantly improved compared with those before treatment(P<0.01).Comparison between groups:BBS,MFS and TUGT in group B were not significantly different from those in group A at 4 weeks of treatment(P>0.05);After 8 weeks of treatment,MFS in group B was significantly improved compared with that in group A(P<0.05),BBS and TUGT were better than that in group A without significant difference(P>0.05).After 12 weeks of treatment,BBS(P<0.01),MFS(P<0.01)and TUGT(P<0.05)in group B were significantly improved compared with group A.Conclusion Acupuncture at Baihui and Dazhui points combined with robot training simultaneously can improve the balance function and anti-falling ability of Parkinson's disease.

Tumor-targeted immunotherapy is a remarkable breakthrough, offering the inimitable advantage of specific tumoricidal effects with reduced immune-associated cytotoxicity. However, existing platforms suffer from low efficacy, inability to induce strong immunogenic cell death (ICD), and restrained capacity of transforming immune-deserted tumors into immune-cultivated ones. Here, an innovative platform, perfluorooctyl bromide (PFOB) nanoemulsions holding MnO₂ nanoparticles (MBP), was developed to orchestrate cancer immunotherapy, serving as a theranostic nanoagent for MRI/CT dual-modality imaging and advanced ICD. By simultaneously depleting the GSH and eliciting the ICD effect via high-intensity focused ultrasound (HIFU) therapy, the MBP nanomedicine can regulate the tumor immune microenvironment by inducing maturation of dendritic cells (DCs) and facilitating the activation of CD8⁺ and CD4⁺ T cells. The synergistic GSH depletion and HIFU ablation also amplify the inhibition of tumor growth and lung metastasis. Together, these findings inaugurate a new strategy of tumor-targeted immunotherapy, realizing a novel therapeutics paradigm with great clinical significance.

Objective To evaluate the value of transpulmonary pressure (Ptp) guided optimal positive end-expiratory pressure (PEEP) selection in patients with early acute respiratory distress syndrome (ARDS).Methods A prospective randomized self-control study was conducted.ARDS patients in the early stage (onset ≤3 days) undergoing intubation and mechanical ventilation admitted to intensive care unit (ICU) of Jiangsu Provincial Subei People's Hospital from December 2013 to December 2015 were enrolled.The PEEP level was regulated to 30 cmH2O (1 cmH2O =0.098 kPa) after recruitment maneuver,and then it was gradually decreased to 0 with lowering by 3 cmH2O every 5 minutes.The optimal PEEP was titrated by Ptp,lowest dead space fraction (VD/VT),highest static lung compliance (Cst),and optimal oxygenation,respectively.Parameters of respiratory mechanics and gas exchange were observed.Results Totally 28 patients with ARDS (including 17 male and 11 female) were included with the average age of (45 ± 12) years old,acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score was 21 ± 9,oxygenation index (PaO2/FiO2) was (165 ± 76) mmHg (1 mmHg =0.133 kPa).① During decremental PEEP titration,Ptp was gradually decreased,and expiratory Ptp (Ptp-e) was more than zero [(1.3±0.3) cmH2O] when PEEP was (9.6 ± 2.3) cmH2O.Cst was initially improved until reaching a peak,and then deteriorated.Cst was highest [(50 ± 8) mL/cmH2O] when PEEP was (11.5 ± 2.4) cmH2O.PaO2/FiO2 reached the maximum [(312 ± 99) mmHg] at PEEP level of (18.0 ± 2.5) cmH2O.Compared with Ptp-e 3.00-5.99 cmH2O,PaO2/FiO2 was significantly decreased when Ptp-e became negative (all P ＜ 0.05).VD/VT was lowest (0.52 ±0.05) when PEEP was (10.1 ± 2.2) cmH2O.When compared with ventilation [inspiratory Ptp (Ptp-i) 0-2.99 cmH2O],it was significantly higher during high (Ptp-i ≥ 15 cmH2O,all P ＜ 0.05).② There were no statistically significant differences in the levels of optimal PEEP,Ptp-i and Ptp-e among Ptp,lowest VD/VT and highest Cst methods (all P ＞ 0.05),but they were significantly less than optimal oxygenation method (all P ＜ 0.05).Compared with baseline and the method of optimal oxygenation,Cst in other three PEEP titration methods including Ptp,lowest VD/VT and highest Cst was improved obviously (mL/cmH2O:46± 7,47±9,50± 8 vs.30± 8,35 ± 10,all P ＜ 0.05).PaO2/FiO2 (mmHg) in the method of Ptp and lowest VD/VT were higher than the baseline (252 ± 86,258 ± 72 vs.165 ± 76,both P ＜ 0.05),but significantly lower than that of optimal oxygenation method (312 ± 99,both P ＜ 0.05),and did not significantly differ from that of highest Cst (268± 85,both P ＞ 0.05).Compared with baseline and the method of optimal oxygenation,VD/Vr improved significantly in ventilated patients on PEEP targeting with Ptp and lowest VD/VT (0.53±0.05,0.52±0.05 vs.0.59±0.05,0.58±0.04,all P ＜ 0.05).Conclusion Titration the optimal PEEP level with the method of Ptp could promote collapse alveolar recruitment,improve oxygenation and lung compliance,decrease dead space ventilation,and will not cause alveolar excessive inflation in patients who undergoing mechanical ventilation with early ARDS.

OBJECTIVETo analyze the characteristics of risky behaviors among different age groups of HIV positive female sex workers, and to explore the strengthening of their management.

METHODSFrom January to June 2014, 22 814 female sex workers were investigated and tested HIV in 117 sentinel surveillance sites in Yunnan Province, and 181 were confirmed to be HIV antibody positive, who accepted questionnaire surveys. According to the age, the participants were divided into the < 35 years old age group and ≥ 35 years old age group. The demographic characteristics, knowledge about HIV/AIDS and related risk behaviors characteristics of the two groups were obtained via questionnaire surveys among 181 HIV positive female sex workers, and in-depth qualitative interviews were conducted from among 12 HIV positive sex workers.

RESULTSHIV antibody positive rate was 0.8% (181), the age of the 181 subjects were (35.83 ± 9.17) years old, 76 cases (42.0%) were < 35 years old, and 105 cases (58.0%) were ≥ 35 years old. The differences of marital status, workplace class, the last work site among two groups were statistically significant (χ(2) = 20.80, 28.32, 7.83; P < 0.001, P < 0.001, P = 0.020, respectively). Among 181 HIV, the proportion of AIDS awareness was 95.6% (173); the proportion of drug use among ≥ 35 years old age group was 51.4% (54), which was higher than that in < 35 years old age group (34.2%, 26/76) (χ(2) = 5.30, P = 0.021). 96.7% (175) received condom promotion or HIV counseling and testing in the past year. The proportion of continuing to engage in sexual services over 5 years after HIV infection was 48.5% (51/105) and the proportion of receiving antiretroviral treatment was 69.5% (73/105) in ≥ 35 years old age group, which were higher than those in the < 35 age group (30.2% (23/76), 52.6% (40/76); χ(2) = 12.26, 5.36; P = 0.002, 0.021, respectively). In-depth interviews among 12 HIV positive female sex workers found that regular clients, not consistent use of condoms were the main cause of no condom use. Economic and livelihood factors are important reasons for continuing to engage in sexual services among HIV positive sex workers.

CONCLUSIONHIV positive sex workers still have high risk behaviors including continuing to engage in commercial sexual service and no condom use after knowing their HIV infection status, and the proportion of using drugs in the ≥ 35 years old group was higher than that in < 35 years old group.

Adult ; China ; Condoms ; Female ; HIV Seropositivity ; Humans ; Marital Status ; Risk Factors ; Risk-Taking ; Safe Sex ; Sex Workers ; statistics & numerical data ; Sexual Behavior ; Substance-Related Disorders ; Surveys and Questionnaires

OBJECTIVE To generate hemophilia A (HA) patient-specific inducible pluripotent stem cells (iPSCs) and induce endothelial differentiation. METHODS Tubular epithelial cells were isolated and cultured from the urine of HA patients. The iPSCs were generated by forced expression of Yamanaka factors (Oct4, Sox2, c-Myc and Klf4) using retroviruses and characterized by cell morphology, pluripotent marker staining and in vivo differentiation through teratoma formation. Induced endothelial differentiation of the iPSCs was achieved with the OP9 cell co-culture method. RESULTS Patient-specific iPSCs were generated from urine cells of the HA patients, which could be identified by cell morphology, pluripotent stem cell surface marker staining and in vivo differentiation of three germ layers. The teratoma experiment has confirmed that such cells could differentiate into endothelial cells expressing the endothelial-specific markers CD144, CD31 and vWF. CONCLUSION HA patient-specific iPSCs could be generated from urine cells and can differentiate into endothelial cells. This has provided a new HA disease modeling approach and may serve as an applicable autologous cell source for gene correction and cell therapy studies for HA.
Cell Differentiation ; Hemophilia A ; pathology ; therapy ; urine ; Humans ; Induced Pluripotent Stem Cells ; cytology ; transplantation ; Urine ; cytology

Objective To investigate the value of extravascular lung water index(EVLWI) in assessment of prognosis of elderly patients with combined septic shock and pulmonary capillary leakage.Methods Totally 34 elderly patients with septic shock and pulmonary capillary leakage in our hospital from Jan.2011 to Dec.2012 were selected.Cardiac index (CI),global end diastolic volume index (GEDI),systemic vascular resistance index (SVRI),pulmonary vascular permeability index (PVPI) and EVLWI were detected by pulse-indicator continuous cardiac output (PiCCO) technology for 3 days.Based on the actual body weight (ABW) and predicted body weight (PBW),the actual extravascular lung water index and predicted extravascular lung water index were calculated.Peak airway pressure (Ppeak),plateau pressure (Pplat),mean airway pressure (Pm),tidal volume (VT),positive end expiratory pressure (PEEP),oxygen concentration (FiO2) and static lung compliance (Cst) were monitored,the arterial partial pressure of oxygen (PaO2) was detected by blood gas analysis,and the PaO2/FiO2 (P/F) and oxygenation index (OI) were calculated.Chest X-ray,lung injury score (LIS) were conducted.The correlations of EVLWI to actual body weight (EVLWIa) and predicted body weight(EVLWIp) with P/F,Cst and LIS were analyzed.The predictive value of EVLWIa and EVLWIp in the prognosis in elderly patients with septic shock and pulmonary capillary leakage was assessed.Results At day 1,non-survivors had higher levels of SOFA score and lactate level than survivors (both P＜0.05).However,these variables including SOFA score,LIS,PVPI,lactate level,fluid balance,norepinephrine level,EVLWIa and EVLWIp were higher and PaO2/FiO2 was lower in non-survivors than in the survivors at day 3 (all P＜0.05).EVLWIa and EVLWIp were positively correlated with LIS (r=0.461 and 0.588,both P＜0.05) and negatively correlated with PaO2/FiO2 (P/F) (r=-0.307 and-0.436,both P＜0.05).EVLWIa and EVLWIp had negatively correlations with Cst,but r=-0.141 and-0.154,both P＞0.05.Multiple logistic regression analysis showed that SOFA,EVLWa and EVLWp were independent predictive risk factors for mortality in elderly patients with septic shock and pulmonary capillary leakage.The areas under the receiver operating characteristic curve (ROC) of SOFA,EVLWIa and EVLWIp for predicting the prognosis were 0.769,0.832 and 0.855 respectively.With 11.96ml/kg as the cutoff point of EVLWIp,the sensitivity and specificity of EVLWIp predicting the survival of patients was 94.4％ and 61.5％ respectively.Conclusions Extravascular lung water can predict the prognosis and reflect the severity of lung injury in elderly patients with septic shock and puhnonary capillary leakage.Compared with EVLWIa,the EVLWIp has a better correlation with lung injury and a higher predictive value for survival.

BACKGROUND:Poly(3-hydroxybutyrate) is approved as its excel ent biocompatibility, biodegradability and piezoelectric properties, but there are also some deficiencies, such as high breakability and poor hydrophilicity. METHODS:Poly(3-hydroxybutyrate) was mixed with different mass percentages of nanohydroxyapatite (0, 10%, 20%and 30%) to prepare new composite fibrous scaffolds through electrospinning process. The microstructure, group composition, crystal ine phase distribution, thermal properties and surface wettability of the scaffolds were detected. RESULTS AND CONCLUSION:Under the scanning electron microscope, with the increase of nano-hydroxyapatite content, more and more nano-hydroxyapatite particles were distributed evenly on the composite fiber surface;the fiber surface was basical y covered with nano-hydroxyapatite particles at the content of 30%, and the roughness of the fiber surface also increased. Results from differential scanning calorimetry and X-ray diffraction showed that the nano-hydroxyapatite reduced the crystal inity of poly(3-hydroxybutyrate) and the crystal tacticity, and this phenomenon became more evident with the increase of nano-hydroxyapatite content. Additional y, the higher the content of nano-hydroxyapatite content, the lower the contact angle and the higher the hydrophily. These findings indicate that the nano-hydroxyapatite/poly(3-hydroxybutyrate) ultrafine-fibrous scaffold using electrospinning technology can effectively improve the surface wettability and crystal inity of the material as wel as the material hydrophily and brittleness, and the higher the content of nano-hydroxyapatite, the more obvious the effect.

Objective To investigate clinical features, diagnosis, and treatment of refractory Mycoplasma pneumoniae pneumonia (MPP) combined with thrombosis. Methods One case with refractory MPP associated with thrombosis was retrospectively analyzed with literature review. Results The patient presented with respiratory symptom at the onset, while melosalgia and decreased respiratory sound in left lung were occurred during anti-infection therapy. Thereafter, thrombosis of lower extremity veins and pulmonary embolism were confirmed by a series of examinations. Serum anti-phospholipid antibody was positive. Finally, the patient was treated with a combination of anticoagulation and immunosuppressive therapies. Conclusions The mechanism of refractory MPP combined with thrombosis may be associated with excessive inflammatory response and endothelial cells injury. The thrombosis complication should be suspected in patient of Mycoplasma pneumonia infection with positive anti-phospholipid antibody and low concentration of protein C and immunosuppressive therapy should be implemented promptly.