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Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.

ObjectiveWhether exercise-induced venous-to-systemic shunt (EIS) during cardiopulmonary exercise testing (CPET) has different manifestations or characteristics in idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients remains unknown. We explored the differences in hemodynamics, echocardiography, and prognosis between IPAH and CTEPH patients with and without EIS.MethodsWe conducted a retrospective cross-sectional cohort study and included 161 PH patients at Shanghai Pulmonary Hospital. Demographic, echocardiography, pulmonary hemodynamic, and CPET variables were compared between patients with and without EIS stratified by IPAH and CTEPH. EIS was determined by CPET. Binary logistic regression analyses were performed to explore independent influencing factors of EIS. Cox survival analysis was used to quantify the impact of EIS on the prognosis of patients.ResultsExercise-induced venous-to-systemic shunt was found in approximately 17.4% of 86 IPAH patients and 20% of 75 CTEPH patients. All-cause mortality occurred in 43 (26.7%) patients during a median follow-up of 6.5 years. Compared with those without EIS, patients with EIS had higher peak end-tidal O2 and lower VO2/VE and tricuspid annular plane systolic excursion (TAPSE). Among the IPAH patients, EIS was associated with lower cardiac output, cardiac index, mixed venous oxygen saturation, VO2/VE, and TAPSE and higher VE/VCO2 and right ventricular end-diastolic transverse diameter. Logistic regression analysis indicated that VO2/VE was an independent factor influencing whether IPAH patients developed EIS during CPET. Cox logistic regression indicated that female IPAH patients or IPAH patients with higher VO2/VE and EIS had a better prognosis. Female IPAH patients had better 10-year survival. In IPAH patients without EIS, patients with higher VO2/VE had better 10-year survival. However, compared with CTEPH patients without EIS, those with EIS had similar echocardiographic, hemodynamic, CPET parameter results and 10-year survival.ConclusionExercise-induced venous-to-systemic shunt exhibits different profiles among IPAH and CTEPH patients. Among IPAH patients, those with EIS had worse peak end-tidal O2, VO2/VE, and TAPSE than those without EIS. VO2/VE was an independent factor of EIS among IPAH patients. IPAH patients with EIS, female sex or higher VO2/VE had better survival. However, the association between EIS and PAH severity or prognosis in CTEPH patients needs to be further explored.

Economists believe that economic fluctuations can be smoothed by stabilization mechanisms, such as price adjustment, embedded in the economy. While price adjustment can be seen as a stabilization mechanism, are there mechanisms that can destabilize an economy? We find that as early as 1939, Harrod discussed a destabilization mechanism, the firm's investment adjustment, illustrated in his knife-edge puzzle. We build a macro-dynamic model with investment and price as the core macroeconomic variables. Our analysis shows that the interaction between the stabilization mechanism (price adjustment) and the destabilization mechanism (investment adjustment) generates fluctuations and cycles. However, due to price stickiness, the price adjustment mechanism may not be enough to stabilize the economy. In this case, a government stabilization policy is necessary for further stabilization. As this paper also addresses the microfoundations of Keynesian quantity theory, including the choice of output and investment in optimization, it can be related to traditional Keynesian economics, with a new perspective to understand business cycles.

Background: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer’s disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro. Objective: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. Methods: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. Results: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. Conclusion: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway.

Introduction The two‐pore domain potassium channel TREK‐1 is a member of background K+ channels that are thought to provide baseline regulation of membrane excitability. Recent studies have highlighted the putative role of TREK‐1 in the action of antidepressants, and its antagonists might be potentially effective antidepressants. However, the mechanisms underlying the actions of TREK‐1 are not yet fully understood. Methods The expression of TREK‐1 was examined in a mouse model of chronic unpredictable mild stress (CUMS) using immunoblotting. Neuron‐specific genetic manipulation of TREK‐1 was performed through adeno‐associated virus. Behavioral tests were performed to evaluate depression‐related behaviors. Electrophysiological recordings were used to evaluate synaptic plasticity. Golgi staining was used to examine neuroplasticity. Results TREK‐1 expression was increased in the mouse hippocampus after CUMS. Knockdown of TREK‐1 in hippocampal neurons significantly attenuated depressive‐like behaviors and prevented the decrease of CUMS‐induced synaptic proteins in mice. Further examination indicated that neuron‐specific knockdown of TREK‐1 in the hippocampus prevented stress‐induced impairment of glutamatergic synaptic transmission in the CA1 region. Moreover, chronic TREK‐1 inhibition protected against CUMS‐induced depressive‐like behaviors and impairment of synaptogenesis in the hippocampus. Conclusion Our results indicate a role for TREK‐1 in the modulation of synaptic plasticity in a mouse model of depression. These findings will provide insight into the pathological mechanism of depression and further evidence for a novel target for antidepressant treatment., TREK‐1 channel in the hippocampus is essential for depressive‐like behaviors in response to the CUMS‐induced anhedonia model of depression. This study demonstrated the modulatory effect of TREK‐1 on dendrite morphology, dendrite spine density, glutamatergic synaptic transmission, and synaptogenesis in the hippocampus. TREK‐1 is involved in the pathogenesis of depression by regulating neuronal plasticity.

BACKGROUND Acute vasoreactivity testing (AVT) which reflects the compliance of the pulmonary vascular bed has been proven to be of prognostic value. The purpose of the present study is to explore the sex differences of hemodynamics during the AVT and their impact on event-free survival in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS Eighty-six patients underwent a right heart catheterization and AVT at Shanghai Pulmonary Hospital from February 2009 to February 2018. Univariate and multiple stepwise regression analysis were performed to determine the predictors of independent event-free survival, and receiver operating characteristic curve was plotted to determine the cut-off value of independent parameters in CTEPH. RESULTS There were no significant differences in both demographics and hemodynamics between male and female patients with CTEPH. Except ΔPVR/PVR showed a significantly higher difference in female than male patients (P = 0.034). Male patients had higher mRAP of pre- and post-AVT than female patients in the event-free subgroup, while, female patients showed higher PVR of pre-AVT than male patients in the event subgroup (P

Pulmonary hypertension (PH) refers to a clinical and pathophysiological syndrome in which pulmonary vascular resistance and pulmonary arterial pressure are increased due to structural or functional changes in pulmonary vasculature caused by a variety of etiologies and different pathogenic mechanisms. It is followed by the development of right heart failure and even death. In recent years, most studies have found that PH and cancer shared a complex common pathological metabolic disturbance, such as the shift from oxidative phosphorylation to glycolysis. During the shifting process, there is an upregulation of glutamine decomposition driven by glutaminase. However, the relationship between PH and glutamine hydrolysis, especially by glutaminase is yet unclear. This review aims to explore the special linking among glutamine hydrolysis, glutaminase and PH, so as to provide theoretical basis for clinical precision treatment in PH.

BackgroundPatients with pulmonary arterial hypertension (PAH) have reduced exercise capacity and poor quality of life. Exercise-based rehabilitation in PAH results in clinically relevant improvements in exercise capacity and hemodynamics. To clarify the mechanism, we will evaluate the effect of aerobic exercise training rehabilitation on right ventricular (RV) remodeling and function as determined measured by cardiac magnetic resonance imaging (CMR).MethodsWe will conduct a 26-week multicenter randomized controlled trial. Patients on stable and unchanged PAH-targeted medication are randomly assigned (1:1) to the control and training groups. The primary endpoint is the RV stroke volume (RVSV) change from baseline to Week 26, determined by CMR. Comprehensive RV function is also performed using CMR. Other characteristics of the RV and left ventricle, World Health Organization functional class, 6-min walk distance, and N-terminal pro-B-type natriuretic peptide are included in secondary endpoints. We also investigate the proteomic, metabolomic, and transcriptomic changes after exercise training as exploratory endpoints.Ethics and DisseminationThe study and protocol were approved by the Ethics Committee of Shanghai Pulmonary Hospital (Approved No. of ethics committee: L20-17). The results will be disseminated at medical conferences and in journal publications. All participants will sign written informed consent.Trial Registration NumberChiCTR2000031650.

Cardiopulmonary exercise testing and pulmonary function test are important methods for detecting human cardio-pulmonary function. Whether they could screen vasoresponsiveness in idiopathic pulmonary artery hypertension (IPAH) patients remains undefined. One hundred thirty-two IPAH patients with complete data were retrospectively enrolled. Patients were classified as vasodilator-responsive (VR) group and vasodilator-nonresponsive (VNR) group on the basis of the acute vasodilator test. Pulmonary function test and cardiopulmonary exercise testing were assessed subsequently and all patients were confirmed by right heart catheterization. We analyzed cardiopulmonary exercise testing and pulmonary function test data and derived a prediction rule to screen vasodilator-responsive patients in IPAH. Nineteen of VR-IPAH and 113 of VNR-IPAH patients were retrospectively enrolled. Compared with VNR-IPAH patients, VR-IPAH patients had less severe hemodynamic effects (lower RAP, m PAP, PAWP, and PVR). And VR-IPAH patients had higher anaerobic threshold (AT), peak partial pressure of end-tidal carbon dioxide (PETCO2), oxygen uptake efficiency (OUEP), and FEV1/FVC (P all

Cardiopulmonary exercise testing and pulmonary function test are important methods for detecting human cardio-pulmonary function. Whether they could screen vasoresponsiveness in idiopathic pulmonary artery hypertension (IPAH) patients remains undefined. One hundred thirty-two IPAH patients with complete data were retrospectively enrolled. Patients were classified as vasodilator-responsive (VR) group and vasodilator-nonresponsive (VNR) group on the basis of the acute vasodilator test. Pulmonary function test and cardiopulmonary exercise testing were assessed subsequently and all patients were confirmed by right heart catheterization. We analyzed cardiopulmonary exercise testing and pulmonary function test data and derived a prediction rule to screen vasodilator-responsive patients in IPAH. Nineteen of VR-IPAH and 113 of VNR-IPAH patients were retrospectively enrolled. Compared with VNR-IPAH patients, VR-IPAH patients had less severe hemodynamic effects (lower RAP, m PAP, PAWP, and PVR). And VR-IPAH patients had higher anaerobic threshold (AT), peak partial pressure of end-tidal carbon dioxide (P ET CO 2 ), oxygen uptake efficiency (OUEP), and FEV 1 /FVC (P all

Background: The 2015 European pulmonary hypertension (PH) guidelines recommend a risk stratification strategy for pulmonary arterial hypertension (PAH). We aimed to investigate the validation and potential prognostic information in Chinese patients.Methods: The risk assessment variables proposed by the PH guidelines were performed by using the WHO function class, 6-min walking distance, brain natriuretic peptide or its N-terminal fragment, right arterial pressure, cardiac index, mixed venous saturation, right atrium area, pericardial effusion, peak oxygen consumption, and ventilatory equivalents for carbon dioxide. An abbreviated version also was applied.Results: A total of 392 patients with idiopathic PAH (IPAH) were enrolled between 2009 and 2018. After a median interval of 13 months, re-evaluation assessments were available for 386 subjects. The PAH guidelines risk tool may effectively discriminate three risk groups and mortality (p < 0.001) both at the baseline and re-evaluation. Meanwhile, its simplified risk version was valid for baseline and accurately predicted the risk of death in all the risk groups (p < 0.001). At the time of re-evaluation, the percentage of low-risk group has an increase, but a greater proportion achieved the high-risk group and a lesser proportion maintained in the intermediate-risk group.Conclusion: The 2015 European PH guidelines and its simplified version risk stratification assessment present an effective discrimination of different risk groups and accurate mortality estimates in Chinese patients with IPAH. Changes of risk proportion at re-evaluation implicated that natural treatment decisions may not be consistently with goal-oriented treatment strategy.

Yu-Chan Yang,1 Ke Zeng,2 Wei Wang,2 Zhi-Gang Gong,1 Yi-Lei Chen,1 Jian-Ming Cheng,1 Min Zhang,1 Yan-Wen Huang,1 Xin-Bo Men,2 Jian-Wei Wang,2 Songhua Zhan,1 Wen-Li Tan1 1Department of Radiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Department of Massage, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of ChinaCorrespondence: Songhua Zhan; Wen-Li TanDepartment of Radiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203, People’s Republic of China, Email zhansonghua@sina.com; 13764935974@163.comObjective: To investigate the changes of regional homogeneity (Reho) values before and after spinal manipulative therapy (SMT) in patients with chronic low back pain (CLBP) through rest blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI).Methods: Patients with CLBP (Group 1, n = 20) and healthy control subjects (Group 2, n = 20) were recruited. The fMRI was performed three times in Group 1 before SMT (time point 1, TP1), after the first SMT (time point 2, TP2), after the sixth SMT (time point 3, TP3), and for one time in Group 2, which received no intervention. The clinical scales were finished in Group 1 every time before fMRI was performed. The Reho values were compared among Group 1 at different time points, and between Group 1 and Group 2. The correlation between Reho values with the statistical differences and the clinical scale scores were calculated.Results: The bilateral precuneus and right mid-frontal gyrus in Group 1 had different Reho values compared with Group 2 at TP1. The Reho values were increased in the left precuneus and decreased in the left superior frontal gyrus in Group 1 at TP2 compared with TP1. The Reho values were increased in the left postcentral gyrus and decreased in the left posterior cingulate cortex and the superior frontal gyrus in Group 1 at TP3 compared with TP1. The ReHo values of the left precuneus in Group 1 at TP1 were negatively correlated with the pain degree at TP1 and TP2 (r = − 0.549, − 0.453; p = 0.012, 0.045). The Reho values of the middle temporal gyrus in Group 1 at TP3 were negatively correlated with the changes of clinical scale scores between TP3 and TP1 (r = 0.454, 0.559; p = 0.044, 0.01).Conclusion: Patients with CLBP showed abnormal brain function activity, which was altered after SMT. The Reho values of the left precuneus could predict the immediate analgesic effect of SMT.Keywords: blood-oxygen-level-dependent functional magnetic resonance imaging, spinal manipulation therapy, chronic low back pain, regional homogeneity

Background Pulmonary hypertension in left heart disease (PH-LHD), which includes combined post- and precapillary PH (Cpc-PH) and isolated postcapillary PH (Ipc-PH), differs significantly in prognosis. We aimed to assess whether cardiopulmonary exercise testing (CPET) predicts the long-term survival of patients with PH-LHD. Methods A single-center observational cohort enrolled 89 patients with PH-LHD who had undergone right heart catherization and CPET (mean pulmonary arterial pressure > 20 mm Hg and pulmonary artery wedge pressure ≥ 15 mm Hg) between 2013 and 2021. A receiver operating characteristic curve was plotted to determine the cutoff value of all-cause death. Survival was estimated using the Kaplan–Meier method and analyzed using the log-rank test. The Cox proportional hazards model was performed to determine the association between CPET and all-cause death. Results Seventeen patients died within a mean of 2.2 ± 1.3 years. Compared with survivors, nonsurvivors displayed a significantly worse 6-min walk distance, workload, exercise time and peak oxygen consumption (VO2)/kg with a trend of a lower oxygen uptake efficiency slope (OUES) adjusted by Bonferroni’s correction. Multivariate Cox regression revealed that the peak VO2/kg was significantly associated with all-cause death after adjusting for Cpc-PH/Ipc-PH. Compared with Cpc-PH patients with a peak VO2/kg ≥ 10.7 ml kg−1 min−1, Ipc-PH patients with a peak VO2/kg −1 min−1 had a worse survival (P Conclusions The peak VO2/kg is independently associated with all-cause death in patients with PH-LHD. The peak VO2/kg can also be analyzed together with Cpc-PH/Ipc-PH to better indicate the prognosis of patients with PH-LHD.

ObjectivesThe aim was to elucidate the relationship between liver function and idiopathic pulmonary arterial hypertension (IPAH).Design and settingRetrospective, longitudinal study in urban tertiary care centre in Shanghai, China.Participants407 IPAH consecutive incident patients age 18–65 years were retrospectively enrolled from January 2008 to December 2018.Outcome measurementsThe primary endpoint was all-cause mortality. The cut-off value was determined by receiver operating characteristic curve (ROC), which was validated by Cox proportional hazard model was internally validated by bootstrap analysis and used for survival analysis. The Cox model was (internally) validated and cross-validated areas under the curve (AUC) should be reported.ResultsThe prevalence of abnormal liver function tests (LFTs) at baseline was 77.6%. Hyperbilirubinaemia is the most common abnormal biochemical liver test: abnormal total bilirubin (TBIL in 51.6% patients). During the follow-up, 160 patients died. Patients with mixed liver dysfunction have worse prognosis than those with normal LFTs or isolated abnormal bilirubin metabolism. Comparing with patients with hepatocellular injury, the survival of patients with abnormal bilirubin metabolism is lower. Multivariable Cox models revealed a positive association between TBIL, γ-glutamyltransferase (GGT) and mortality showing that each Ig increment in TBIL and GGT was associated with a higher all-cause mortality (TBIL: HR 4. 29 (95% CI 1. 21 to 15. 27), p=0. 02; GGT: HR 2. 76 (95% CI 1. 18 to 6. 45), p=0. 02). A novel formula named Liver Function Predict Index (LFPI) was constructed (LFPI=−0.002*6MWD+1.014*lg GGT+1.458*lg TBIL) to predict prognosis. ROC curve analysis did further identify 2.729 as the best cut-off value for LFPI (AUC 0.75, pConclusionsLiver dysfunction is frequent in IPAH, and characterised by a predominantly cholestatic enzyme profile. LFTs abnormalities are associated with worse survival and LFPI was a new and simple predictor for prognosis of IPAH.

Systemic sclerosis (SSc) is associated with interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). This study aimed to explore the prevalence, clinical features, hemodynamic characteristics and prognosis of different severity of ILD in a cohort of patients with SSc-associated precapillary pulmonary hypertension (SSc-PH) and investigate the differences between SSc-PAH and idiopathic pulmonary arterial hypertension (IPAH) patients.SSc-PH patients and IPAH patients, admitted to Shanghai Pulmonary Hospital (August 1, 2008-January 31, 2020) and diagnosed by right-sided heart catheterization (RHC) or echocardiography, were retrospectively included. SSc-PH patients had a baseline chest high-resolution computed tomography (HRCT), and PH classification was based on the extent of ILD. Clinical, pulmonary function, hemodynamic characteristics and survival data were extracted.The study included 45 SSc-PH patients (60% had coexisting ILD and 77.8% were SSc-Group 1 PH/SSc-PAH [without ILD or with mild ILD], 22.2% were SSc-Group 3 PH/SSc-PH with severe ILD) and 52 IPAH patients. SSc-PH with ILD had lower arterial oxygen partial pressure (PaOILD was common in SSc-PH patients. Careful phenotyping of PH in SSc-PH patients is very important as it is imperative to recognize its impact on clinical course, treatment and survival.• ILD was common in Chinese SSc-PH patients. • SSc-PH patients with ILD had lower PaO

Background Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China. Methods Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world. Results In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million. Conclusions The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.

OBJECTIVE This study intended to explore the relation between heart rate recovery at 1 minutes (HRR1) during the recovery phase of cardiopulmonary exercise test (CPET) and exercise capacity in female systemic lupus erythematosus associated pulmonary arterial hypertension (SLE-PAH) patients. METHODS Twenty-one female SLE-PAH patients underwent right heart catheterization (RHC), pulmonary function test (PFT) and CPET. Forty-two healthy subjects matched with SLE-PAH patients in age, sex and BMI were recruited as a control group. The correlations between HRR1 with clinical and CPET parameters were performed. RESULTS Peak HR, ΔHR, HRR1, Peak HR-warm HR1min , Peak HR-warm HR2min and CR were significantly lower in SLE-PAH than in controls (P

Background: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) still experience reduced exercise capacity despite pulmonary endarterectomy (PEA). Exercise training improves the exercise capacity and quality of life (QoL) in patients with PH, but data on the effects of exercise training on these patients are scarce. The aim of this meta-analysis and systematic review was to evaluate the effectiveness and safety of exercise training in CTEPH after PEA.Methods: We searched the relevant literature published before January 2020 for the systematic review and meta-analysis using the PubMed, EMBASE, and Cochrane Library databases. The primary outcome was a change in the 6-min walking distance (6 MWD). We also assessed the effect of exercise on the peak oxygen uptake (VO2) or peak VO2/kg, oxygen uptake anaerobic threshold, workload, oxygen pulse, hemodynamics, arterial blood gases, oxygen saturation, N-terminal pro-brain-type natriuretic peptide (NT-proBNP), quality of life (QoL) and pulmonary function tests.Results: We included 4 studies with 208 exercise-training participants. In the pooled analysis, short-term exercise training can improve the 6 MWD of 58.89 m (95% CI: 46.26–71.52 m, P < 0.0001). There was a significant increase in the peak VO2/kg or peak VO2 after exercise training (3.15 ml/min/kg, 95% CI: 0.82–5.48, P = 0.008; 292.69 ml/min, 95% CI: 24.62–560.75, P = 0.032, respectively). After exercise training, the maximal workload and O2 pulse significantly improved. Three months of exercise training increased the right ventricular ejection fraction by 3.53% (95% CI: 6.31–11.94, P < 0.00001, I2 = 0) independently of PEA surgery. In addition, NT-proBNP plasma levels significantly improved with exercise training after PEA [weighted mean difference (WMD): −524.79 ng/L, 95% CI: 705.16 to −344.42, P < 0.0001, I2 = 0]. The partial pressure of oxygen and pH improved progressively over 12 weeks of exercise training (WMD: 4 mmHg, 95% CI: 1.01–8.33, P = 0.01; WMD: 0.03, 95% CI: 0.02–0.04, P < 0.0001, respectively). Subscales of the QoL measured by the SF-36 questionnaire had also improved. In addition, exercise training was well-tolerated with a low dropout rate, and no major adverse events occurred during exercise training.Conclusion: Exercise training may be associated with a significant improvement in the exercise capacity and QoL among CTEPH patients after PEA and was proven to be safe. However, more large-scale multicentre studies are needed to confirm the effectiveness and safety of exercise training in CTEPH patients after PEA.PROSPERO registration number:CRD42021235275.

BACKGROUND: Platelet distribution width (PDW) has been recognized as risk predictors of idiopathic pulmonary arterial hypertension. This study aims to investigate whether in-hospital PDW would be useful to predict all-cause death in patients with severe pulmonary hypertension due to chronic lung diseases (CLD-PH).METHODS: Early in-hospital PDW was measured in 67 severe CLD-PH patients who were confirmed by right heart catheterization and followed up. Event-free survival was estimated using the Kaplan–Meier method and analyzed with the log-rank test. Cox proportional hazards models were performed to determine the association between the PDW level and all-cause death.RESULTS: Pulmonary function test and echocardiography parameters were different among patients divided by 17% (the upper reference range of the PDW). There were no significant differences in both clinical variables and RHC parameters among patients with PDW ≥ or < 17%. During median of 2.4 (2.5, 3.7) years of follow-up, 44 patients died. A significant association was noted between in-hospital PDW level and the adjusted risk of all-cause mortality (hazard ratio [HR], 1.245; 95% confidence interval [CI], 1.099-1.409). Compared with those with PDW < 17%, the HR for all-cause death increased to 5.067 (95% CI: 2.420-10.609, P < 0.001) among patients with PDW ≥ 17 %. Higher levels of PDW were also associated with increased risk of all-cause death.CONCLUSIONS: In-hospital PDW was independently associated with all-cause death in patients with severe CLD-PH. This potentially could be used to estimate the severity of severe CLD-PH.

Background: Right ventricular (RV) function is a great determination of the fate in patients with pulmonary arterial hypertension (PAH). Monitoring RV structure back to normal or improvement should be useful for evaluation of RV function. The aims of this study were to assess the prognostic relevance of changed right heart (RH) dimensions by echocardiography and attenuated RH remodeling (ARHR) in idiopathic PAH (IPAH).Methods: We retrospectively analyzed 232 consecutive adult IPAH patients at baseline assessment and included RH catheterization and echocardiography. ARHR at the mean 20 ± 12 months' follow-up was defined by a decreased right atrium area, RV mid-diameter, and left ventricular end-diastolic eccentricity index. The follow-up end point was all-cause mortality.Results: At mean 20 ± 12 months' follow-up, 33 of 232 patients (14.2%) presented with ARHR. The remaining 199 surviving patients were monitored for another 25 ± 20 months. At the end of follow-up, the survival rates at 1, 3, and 5 years were 89, 89, and 68% in patients with ARHR, respectively, and 84, 65 and 41% in patients without ARHR (log-rank p = 0.01). ARHR was an independent prognostic factor for mortality. Besides, ARHR was available to further stratify patients' risk assessment through the French PAH non-invasive-risk criteria.Conclusions: Echocardiographic ARHR is an independent determinant of prognosis in IPAH at long-term follow-up. ARHR might be a useful tool to indicate the RV morphologic and functional improvement associated with better prognostic likelihood.

BACKGROUND: The aim of the present study was to investigate the role of key cardiopulmonary exercise testing (CPET) parameters in the identification of pre-capillary components in patients with pulmonary hypertension associated with left heart disease (PH-LHD), and to evaluate their correlations with hemodynamic parameters. METHODS: Ninety patients with PH-LHD underwent right-heart catheterization, echocardiography, and CPET. The differences in related indexes between a combined post- and pre-capillary PH (Cpc-PH) group (n=47) and an isolated post-capillary PH (Ipc-PH) group (n=43) were compared. Correlation analysis was performed. Logistic regression and receiver operator characteristic (ROC) analyses were performed to assess the ability of CPET variables to distinguish patients with Cpc-PH from those with Ipc-PH. RESULTS: The hemodynamics, hyperventilation and right ventricular function of Cpc-pH group were worse than those of Ipc-pH group. The parameters related to minute ventilation versus carbon dioxide production (VE/VCO(2)) played a significant role in the differentiation of Cpc-PH and Ipc-PH, and had a moderate positive correlation with pulmonary vascular resistance (PVR). Univariate and multivariate logistic analyses showed that lowest percentage of VE/VCO(2) in predicted value (VE/VCO(2)%pred) was the single best predictor of Cpc-PH, and the area under ROC curve also confirmed that lowest VE/VCO(2)%pred (≥137%) could serve as a novel diagnostic marker for Cpc-PH. On the basis of this lowest VE/VCO(2)%pred threshold, patients were divided into two groups. Most hemodynamic parameters were worse in patients with a lowest VE/VCO(2)%pred ≥137%. CONCLUSIONS: VE/VCO(2)-related parameters are powerful prognosticators for the presence of pre-capillary components in patients with PH-LHD, especially lowest VE/VCO(2)%pred.

BACKGROUND: Acute vasoreactivity testing (AVT) during right heart catheterization (RHC) is performed in certain subsets of patients with pulmonary arterial hypertension (PAH) in order to identify those who benefit from calcium channel blockers. The present study aimed to investigate the prognostic value of pre-AVT, post-AVT, and changes in AVT (ΔAVT) parameters for idiopathic PAH (IPAH) patients with a negative acute response, and to identify sex differences that could be of prognostic value. METHODS: A total of 487 incident IPAH patients (171 males and 316 females) with a negative acute response to AVT were recruited from Shanghai Pulmonary Hospital between 2009 and 2018. Outcomes were predicted using the Kaplan-Meier curve and univariate/multivariate Cox regression analyses. All patients were followed up till January 2020, with outcome specified as all-cause mortality. RESULTS: Inhalation of iloprost aerosol improved the hemodynamic parameters for all patients. Post-PVR was decreased, and post-cardiac output (post-CO) and post-cardiac index (post-CI) were increased compared with pre-AVT parameters among males. Increased post- artery oxygen saturation (post-SaO(2)) and decreased post-mean right atrium pressure (post-mRAP) were also observed in females. For all patients, pre-CO ≥3.25 L/min, post-mPAP

Cervical cancer is a common female malignant tumor that seriously threatens human health. This study explored the anticervical cancer effects and potential mechanisms of Rotundifuran (RTF), a natural product isolated from Vitex trifolia L. In this study, we found that RTF can suppress the proliferation of cervical cancer cell lines, including HeLa and SiHa cells (with the IC50 less than 10 μM), via induction of apoptosis in vitro, and the antitumor effect of RTF is further confirmed on the HeLa cell-inoculated xenograft model. In addition, our results proved that the antitumor effects of RTF might be related with the reactive oxygen species- (ROS-) induced mitochondrial-dependent apoptosis through MAPK and PI3K/Akt signal pathways. Using proteomics analysis and the drug affinity responsive target stability- (DARTS-) combined mass spectrometry (DARTS-MS), Cyr61 was indicated as a potential target for RTF in cervical cancer cells. Our present study would be beneficial for the development of RTF as a candidate for treatment of cervical cancer in the future.

The aim of this article was to conduct a bibliometric analysis of global research trends in the field of exercise and metabolomics between 2005 and 2020. Systematic articles were obtained from the literature in the Web of Science core collection database from 2005 to 2020. The relationship between the number of publications, citations, countries, journals, authors, and the evolution of research hotspots was analyzed. A total of 807 studies were included in the analysis. From 2005 to 2020, the number of citations and the number of published articles showed an upward trend. Keyword co-occurrence indicates that research hotspots are focused on exercise, physical activity, metabolomics, obesity, insulin resistance, inflammation, and cardiovascular disease. Keyword clustering indicates that the research frontier is focused on the field of sports medicine, which includes molecular-level studies of exercise interventions in disease and studies of the physiological mechanisms by which exercise alters the body. Overall, this trinity of models, combining chronic disease with exercise interventions and molecular-level studies of metabolomics, has become the forefront of research in the field. This historical review of the field of exercise and metabolomics will further provide a useful basis for hot issues and future development trends.

To investigate the changes in the functional connectivity (FC) in the right insula between migraine without aura (MWoA) and healthy controls by using resting-state functional magnetic resonance imaging (rs-fMRI), and to observe the instant alteration of FC in MWoA during electroacupuncture (EA) stimulation at Shuaigu (GB8).A total of 30 patients with MWoA (PM group) and 30 healthy controls (HC group) underwent rs-fMRI scans. The PM group underwent a second rs-fMRI scan while receiving EA at GB8. The right insula subregions, including the ventral anterior insula (vAI), dorsal anterior insula (dAI) and posterior insula (PI), were selected as the seed points for FC analysis.Aberrant FC, including dAI with right postcentral gyrus, PI with left precuneus, was found among PM before EA (PMa), PM during EA (PMb) and HC. Meanwhile, decreased FC between dAI and the right postcentral gyrus was found in the PMa compared to the HC and PMb. Increased FC between the PI and left precuneus was found in the PMa compared to the HC and PMb. Correlation analysis showed that the FC value of the right postcentral gyrus in PMa was negatively correlated with the scores of Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety. The FC value of the left precuneus in PMa was positively correlated with the visual analogue scale score.The alteration of FC between the right insula subregions and multiple brain regions may be an important index for MWoA. EA at GB8 was able to adjust the FC between the right insula subregions and parietal lobe, namely, the right dAI and right postcentral gyrus, and the right PI and left precuneus, thereby rendering an instant effect in the management of MWoA.

Background: The 2015 European pulmonary hypertension guidelines recommend a risk stratification strategy for pulmonary arterial hypertension (PAH). We aimed to investigate the validation and potential prognostic information in our patients.Methods: The risk assessment variables proposed by the PH guidelines was performed, using World Health Organization function class, 6-min walking distance, brain natriuretic peptide or its N-terminal fragment, right arterial pressure, cardiac index, mixed venous saturation, right atrium area, pericardial effusion, peak oxygen consumption and ventilatory equivalents for carbon dioxide. An abbreviated version also was applied.Results: The 392 patients were enrolled between 2009 and 2018. After a median interval of 13 months, re-evaluation assessments were available for 386 subjects. The PH guidelines risk tool may effectively discriminate three risk group and mortality (p< 0.001) both at baseline and re-evaluation. Meanwhile, its simplified risk version was valid for baseline and accurately predicted the risk of death in all risk group (p< 0.001). At the time of re-evaluation, the percentage of low risk group has an increase, but a greater proportion achieved high risk group and a lesser proportion maintained in intermediate risk group.Conclusions: The 2015 European PH guidelines and its simplified version risk stratification assessment present effective discrimination of different risk groups and accurate mortality estimates in patients with IPAH. Changes of risk proportion at re-evaluation implicated that natural treatment decisions may not be consistently with goal-oriented treatment strategy.

Background: Superoxide dismutases (SODs) are an important family of antioxidant enzymes that modulate reactive oxygen species levels. It is largely unknown which SOD isoform(s) change in vivo in idiopathic pulmonary arterial hypertension (IPAH) patients. Methods: A total of 133 consecutive adult IPAH patients who underwent bone morphogenetic protein receptor type 2 (BMPR2) genetic counseling were enrolled in this prospective study. The plasma activities of three subtypes of SOD [copper–zinc (Cu/Zn-SOD), manganese (Mn-SOD), and extracellular SOD (Ec-SOD)] were examined. Results: The activities of SODs were significantly lower in IPAH patients than in healthy subjects. However, only Ec-SOD activity in BMPR2 mutation patients was significantly decreased compared to those in patients without a mutation. The reduced Ec-SOD activity was markedly associated with mean pulmonary arterial pressure, pulmonary vascular resistance (PVR), and 6-min walking distance (6MWD). The reduction of Mn-SOD activity was only associated with 6MWD. There was no association between Cu/Zn-SOD and hemodynamics. Patients with a lower Ec-SOD level had a worse survival compared to those with a higher baseline. The reduced Ec-SOD activity and the raised PVR increased the mortality risk. Conclusions: Ec-SOD was correlated with BMPR2 mutation, hemodynamic dysfunction, and poor outcomes. Circulating Ec-SOD could be a potentially vital antioxidant enzyme in the pathogenesis of IPAH.

Background: The elevated gamma-glutamyltransferase (GGT) activity is regarded as an indicator of cardiovascular disease, with males having higher values than females. The greater incidence of idiopathic pulmonary arterial hypertension (IPAH) is observed in women, whereas prognosis is poor in men. The present study aims to investigate the potential association of GGT on male patients.Methods: Serum GGT levels were measured in 338 consecutive adult IPAH patients, who underwent bone morphogenetic protein receptor type 2 (BMPR2) genetic counseling, and matched with healthy subjects by sex and age. The followed interval was 48 ± 34 months.Results: Increased serum GGT levels were more common in patients with IPAH than controls (p < 0.001). GGT values were significantly higher in male patients than those of females (p < 0.001). Compared with female patients with BMPR2 mutation, GGT level in male patients with BMPR2 mutation was further increased (p = 0.002). Higher GGT levels were associated with worse hemodynamics and Nterminal pro B-type natriuretic peptide in all patients. However, males with a GGT concentration ≥ 53 U/L had a worse survival than those of females. Contrarily, if GGT concentration

BACKGROUND: Although soluble suppression of tumorigenicity-2 (sST2) has been identified as a clinical biomarker for pulmonary hypertension (PH) by previous studies, the implication of sST2 combined with hemodynamic parameters in PH has not been well studied. This study aimed to evaluate the relationship between sST2 and hemodynamic parameters and to evaluate the predictive value of sST2 for mortality in patients with PH. METHODS: One hundred eighty-four incident patients with PH and 14 healthy controls were retrospectively enrolled by Shanghai Pulmonary Hospital for this retrospective study. After all patients underwent right heart catheterization, blood samples were collected and serum sST2 concentration was assessed by the Presage™ ST2 assay. Kaplan-Meier curve and Cox regression analyses were used to predict survival and the association between survival and different factors such as sST2, SvO(2). RESULTS: During a follow-up of 44.9 (IQR 28.5–64.4) months, 65 patients died. The median concentration of sST2 in PH patients was 33.1 ng/mL, which is higher than that in control group (23.1 ng/mL, P=0.005). Furthermore, for PH group, the level of sST2 was higher in non-survivors than that in survivors. Cox regression analyses demonstrated that sST2 and SvO(2) were independent risk factors for survival. In Kaplan-Meier curve analyses, elevated sST2 level and reduced SvO(2) predicted a poor outcome for patients with PH. CONCLUSIONS: Higher sST2 was independently associated with increased mortality, as well as lower SvO(2) in patients with PH. Especially, the combination of higher sST2 and lower SvO(2) had the strongest predictive value of mortality in patients with PH.

Background: to evaluate the safety and efficacy of Polymethylmethacrylate-augmented screw fixation (PASF) in the treatment of elderly patients with thoracolumbar spinal tuberculosis accompanied with severe osteoporosis.Methods: 34 elderly patients with thoracolumbar spinal tuberculosis accompanied with severe osteoporosis underwent PASF after anterior or posterior debridement and bone grafting in our hospital from January 2010 to January 2012. The follow-ups were performed at 1, 3, 6, and 12 months postoperatively and then annually thereafter. The segmental cobb angle was measured to evaluate kyphosis improvement. The laboratory examination including ESR and CRP was also monitored. The pre- and postoperative VAS score, ODI score, and neurological function of ASIA scale were also recorded.Results: The included 21 patients completed the operation successfully. In all patients with neurological dysfunction, the ASIA grade improved by at least 1 grade. One month postoperatively, the VAS score, ODI, segmental Cobb angle, ESR, and CRP were significantly improved compared with those preoperatively (PConclusion: For elderly patients with thoracolumbar spinal tuberculosis complicated with severe osteoporosis, after anterior or posterior debridement and bone grafting, together with postoperative systematic anti-tuberculosis and anti-osteoporosis treatments, PASF is safe and effective without catastrophic complications such as intraspinal cement leakage. During the 5-year follow-up, there was no tuberculosis recurrence or implant failure.

Runt-related transcription factor 2 (RUNX2) plays a pivotal role in the pathogenesis of pulmonary arterial hypertension (PAH); yet, whether circulating levels of RUNX2 can predict survival of patients with idiopathic PAH (IPAH) is still unclear. The present study aimed to investigate the correlation between circulating levels of RUNX2 and survival of patients with IPAH. Blood samples were collected from 46 incident patients with IPAH and 30 healthy controls in Shanghai Pulmonary Hospital. Levels of RUNX2 were measured using ELISA. Linear regression and cox proportional hazards analysis were performed to assess the prognostic value of RUNX2 levels in predicting survival using the Kaplan–Meier method. Nonsurvivors had significantly shorter 6MWD, higher levels of NT-proBNP, increased mRAP, mPAP, mPAWP, PVR, and decreased CO as well as CI, compared with survivors ( p < .05). Plasma levels of RUNX2 were significantly higher in nonsurvival and survival patients with IPAH compared with controls ( p ≤ .001), and higher in nonsurvivors than in survivors ( p = .001). RUNX2 levels served as an independent predictor of survival in these patients ( p < .001). RUNX2 levels ≥41.5 ng/ml had a sensitivity of 80.0% and a specificity of 74.2% by ROC analysis. Patients with a RUNX2 level

Background Acute pulmonary embolism (PE) is a critical disease and often leads to a high mortality and morbidity. Several studies have identified predictors of PE recurrence, but whether these predictors have prognostic value and how they vary during varied follow-up periods remain unclear. Methods We retrospectively assessed the occurrence of recurrent PE and the survival time of patients with a diagnosis of acute PE at Shanghai Pulmonary Hospital from May 2007 to May 2018. Potential predictors of recurrent PE were evaluated at different points (1, 3, 6, 12, 24, 60 and 120-month) during a long-term follow-up for each patient. Patients were stratified into two groups by gender to analyze the impact of sex in period-guided prognostic prediction. Receiver operating characteristic curve analysis, survival analysis and multivariate Cox proportional hazards analysis were implemented as statistical analysis methods. Results In total, 597 acute PE patients were included, of whom 62 reported a PE recurrence. Male patients tend to have a lower risk of PE recurrence than female patients during 3- to 60-month follow-up period but have a higher risk of PE recurrence than female patients during 120-month follow-up period. The independent predictors of recurrence-free survival varied among different follow-up periods: In all patients, diabetes was an independent predictor only within 30 days follow-up period and female was considered as an independent predictor during 3- to 120-month follow-up period. Among male patients, hyperlipidemia and Log D-dimer (cut-off value =3.436) was observed as a predictor of recurrent PE within 6-month and over 12-month follow-up respectively. However, there is no unified independent prognostic indicator for female patients identified. Conclusions In the early stage of follow-up, male PE patients have better prognosis, but with the extension of follow-up, female PE patients have better prognosis. The independent predictors of recurrence-free survival vary in different follow-up periods in PE patients when stratified based on gender and associated medical conditions.

Chronic stress, a causal factor for depression, can also cause cognitive impairments and tau pathology. However, whether and how the selective serotonin reuptake inhibitor antidepressant escitalopram ameliorates these effects are still unclear. In the present study, rats were subjected to chronic mild unpredictable stress for 8 weeks. Following the initial 4 weeks, the stressed animals were separated into susceptible (depressive) and unsusceptible (resistant) groups based on behavioral tests. Then, escitalopram (10 mg/kg i.p.) was administered for 28 days. Pathophysiological changes were assessed by performing behavioral and biochemical analyses. The results showed that both depressive and resistant rats displayed spatial memory deficits and an accumulation of tau in the hippocampus. Increased levels of corticosterone and insulin and a decreased level of glucocorticoid receptor were found in both depressive and resistant rats. We also found that activity-dependent phosphorylated insulin receptor substrate and glycogen synthase kinase-3β (Ser9 site) were significantly decreased in both depressive and resistant rats. However, other important kinases, such as cyclin-dependent kinase 5 and mitogen-activated protein kinase kinase-1/2, did not change in our study. Furthermore, we found that the mRNA expression of tau was increased in depressive and resistant rats. No significant change in LC3B expression was found. Interestingly, almost all the pathological changes in depressive and resistant rats previously mentioned could be reversed by escitalopram. Our results suggested that escitalopram ameliorates cognitive impairments and selectively attenuates phosphorylated tau accumulation in stressed rats through the regulation of hypothalamic-pituitary-adrenal axis activity and the insulin receptor substrate/glycogen synthase kinase-3β signaling pathway.

Tian-Xiang Chen,1 Bigyan Pudasaini,1 Jian Guo,2 Su-Gang Gong,1 Rong Jiang,1 Lan Wang,1 Qin-Hua Zhao,1 Wen-Hui Wu,1 Ping Yuan,1 Jin-Ming Liu1 1Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University, Shanghai, People’s Republic of China; 2Department of Pulmonary Function Test, Shanghai Pulmonary Hospital, Tongji University, Shanghai, People’s Republic of China Background: Sex differences in chronic thromboembolic pulmonary hypertension (CTEPH) have been revealed in few studies. Although right heart catheterization (RHC) is the gold standard for clinical diagnosis and assessment of prognosis in pulmonary hypertension (PH), cardiopulmonary exercise testing (CPET) has been a more widely used assessment of functional capacity, disease severity, prognosis, and treatment response in PH. We hypothesized that the “sex-specific” CPET indices could estimate the severity of inoperable CTEPH.Methods: Data were retrieved for 33 male (age, mean ± standard deviation [SD] =62.5±13.4 years) and 40 female (age, mean ± SD =56.3±11.8 years) patients with stable CTEPH who underwent both RHC and CPET at Shanghai Pulmonary Hospital from February 2010 to February 2016. Univariate and forward/backward multiple stepwise regression analysis was performed to assess the predictive value of CPET indices to hemodynamic parameters. Event-free survival was estimated using the Kaplan–Meier method and analyzed with the log-rank test. Cox proportional hazards models were performed to determine the independent event-free survival predictors.Results: Numerous CPET parameters were different between male and female patients with CTEPH and the control group. There were no significant differences in both clinical variables and RHC parameters between male and female patients with CTEPH. O2 pulse, workload, minute ventilation (VE), and end-tidal partial pressure of O2 (PETO2) at anaerobic threshold, as well as peak O2 pulse, workload, VE, and nadir VE/CO2 were significantly higher in male patients than in female patients (P

Lan Wang,1,* Yuan-Zhe Jin,2,* Qin-Hua Zhao,1 Rong Jiang,1 Wen-hui Wu,1 Su-Gang Gong,1 Jing He,1 Jin-Ming Liu,1 Zhi-Cheng Jing1,3 1Department of Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; 2Department of Cardiology, The Fourth Affiliated Hospital of China Medical University, Liaoning, China; 3Thrombosis and Vascular Medicine Center, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China *These authors contributed equally to this work Abstract: Studies have shown that vasodilators such as iloprost can be useful for treating pulmonary hypertension (PH). However, in patients with COPD, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange. The efficacy and safety of iloprost inhalation was assessed in 67 patients with PH associated with COPD (COPD-PH), diagnosed by right heart catheterization. Of these, 37 patients had severe PH (mean pulmonary arterial pressure [mPAP] >35 mmHg or mPAP 25–35 mmHg with low cardiac index [