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Background: Alzheimer's disease (AD) was driven by the interplay between modifiable environmental factors and β-amyloid (Aβ) pathology. We aimed to investigate the interaction effects of mild depressive symptoms (MDS) with Aβ on AD development., Methods: Longitudinal data of 1746 non-demented adults (mean age = 73 years, female = 53 %, maximum = 10 years) were derived from the Alzheimer's Disease Neuroimaging Initiative cohort. MDS was separately defined by the baseline status, longitudinal latent class, and average intensity during follow-up. Amyloid-positive (A+) status was determined based on cerebrospinal fluid levels of β-amyloid. Regression models were employed to analyze the interactive effects of MDS with A+ on cognitive decline, neurodegeneration, and AD incidence., Results: Individuals with both A+ status and MDS at baseline experienced the fastest neurodegeneration (p < 0.01), cognitive decline (p < 0.05), and a higher risk of developing AD (HR = 5.23, p < 0.001). Furthermore, A+ participants with the trajectory of increasing depressive symptoms demonstrated more pronounced neurodegeneration (p < 0.001), cognitive decline (p < 0.01), and elevated risk of AD (HR = 10.45, p < 0.001). Finally, A+ status in combination with a higher average intensity of depressive symptoms was associated with faster brain atrophy (p < 0.01) and brain metabolism decline (p < 0.05), cognitive decline (p < 0.05), and higher AD risk (HR = 13.99, p < 0.001)., Conclusion: These findings emphasized that the MDS-Aβ interaction relationship should be considered in risk stratification, prediction, and early management of neurodegeneration and cognitive decline in the pre-dementia stage., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Dysfunction of the glymphatic system in the brain in different stages of altered glucose metabolism and its influencing factors are not well characterized., Aim: To investigate the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states, the present study employed diffusion tensor imaging along the perivascular space (DTI-ALPS) index., Methods: Sample size was calculated using the pwr package in R software. This cross-sectional study enrolled 22 patients with normal glucose metabolism (NGM), 20 patients with prediabetes, and 22 patients with type 2 diabetes mellitus (T2DM). A 3.0T magnetic resonance imaging was used to evaluate the function of the glymphatic system. The mini-mental state examination (MMSE ) was used to assess general cognitive function. The DTI-ALPS index of bilateral basal ganglia and the mean DTI-ALPS index was calculated. Further, the correlation between DTI-ALPS and clinical features was assessed., Results: The left-side, right-side, and mean DTI-ALPS index in the T2DM group were significantly lower than that in the NGM group. The right-side DTI-ALPS and mean DTI-ALPS index in the T2DM group were significantly lower than those in the prediabetes group. DTI-ALPS index lateralization was not observed. The MMSE score in the T2DM group was significantly lower than that in the NGM and prediabetes group. After controlling for sex, the left-side DTI-ALPS and mean DTI-ALPS index in the prediabetes group were positively correlated with 2-hour postprandial blood glucose level; the left-side DTI-ALPS index was negatively correlated with total cholesterol and low-density lipoprotein level. The right-side DTI-ALPS and mean DTI-ALPS index were negatively correlated with the glycosylated hemoglobin level and waist-to-hip ratio in the prediabetes group. The left-side, right-side, and mean DTI-ALPS index in the T2DM group were positively correlated with height. The left-side and mean DTI-ALPS index in the T2DM group were negatively correlated with high-density lipoprotein levels., Conclusion: Cerebral glymphatic system dysfunction may mainly occur in the T2DM stage. Various clinical variables were found to affect the DTI-ALPS index in different glucose metabolism states. This study enhances our understanding of the pathophysiology of diabetic brain damage and provides some potential biological evidence for its early diagnosis., Competing Interests: Conflict-of-interest statement: The authors declare that this study was conducted without any business or financial relationship that could be interpreted as a potential conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: BCL-2 family proteins are important for tumour cell survival and drug resistance in multiple myeloma (MM). Although proteasome inhibitors are effective anti-myeloma drugs, some patients are resistant and almost all eventually relapse. We examined the function of BCL-2 family proteins in stromal-mediated resistance to carfilzomib-induced cytotoxicity in MM cells., Methods: Co-cultures employing HS5 stromal cells were used to model the interaction with stroma. MM cells were exposed to CFZ in a 1-hour pulse method. The expression of BCL-2 family proteins was assessed by flow cytometry and WB. Pro-survival proteins: MCL-1, BCL-2 and BCL-X L were inhibited using S63845, ABT-199 and A-1331852 respectively. Changes in BIM binding partners were examined by immunoprecipitation and WB., Results: CFZ induced dose-dependent cell death of MM cells, primarily mediated by apoptosis. Culture of MM cells on HS-5 stromal cells resulted in reduced cytotoxicity to CFZ in a cell contact-dependent manner, upregulated expression of MCL-1 and increased dependency on BCL-X L . Inhibiting BCL-X L or MCL-1 with BH-3 mimetics abrogated stromal-mediated protection only at high doses, which may not be achievable in vivo . However, combining BH-3 mimetics at sub-therapeutic doses, which alone were without effect, significantly enhanced CFZ-mediated cytotoxicity even in the presence of stroma. Furthermore, MCL-1 inhibition led to enhanced binding between BCL-X L and BIM, while blocking BCL-X L increased MCL-1/BIM complex formation, indicating the cooperative role of these proteins., Conclusion: Stromal interactions alter the dependence on BCL-2 family members, providing a rationale for dual inhibition to abrogate the protective effect of stroma and restore sensitivity to CFZ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Galas-Filipowicz, Chavda, Gong, Huang, Khwaja and Yong.)

Although the implantation of intact tumor fragments is a common practice to generate orthotopic xenografts to study tumor invasion and metastasis, the direct implantation of tumor cell suspensions is necessary when prior manipulations of tumor cells are required. However, the establishment of orthotopic xenografts using tumor cell suspensions is not mature, and a comparative study directly comparing their engraftment and metastatic capabilities is lacking. It is unclear whether tumor fragments are superior to cell suspensions for successful engraftment and metastasis. In this study, we employed three GC cell lines with varying metastatic capacities to stably express firefly luciferase for monitoring tumor progression in real time. We successfully minimized the risk of cell leakage during the orthotopic injection of tumor cell suspensions without Corning Matrigel by systematically optimizing the surgical procedure, injection volume, and needle size options. Comparable high engraftment and metastatic rates between these two methods were demonstrated using MKN-45 cells with a strong metastatic ability. Importantly, our approach can adjust the rate of tumor progression flexibly and cuts the experimental timeline from 10-12 weeks (for tumor fragments) to 4-5 weeks. Collectively, we provided a highly reproducible procedure with a shortened experimental timeline and low cost for establishing orthotopic GC xenografts via the direct implantation of tumor cell suspensions.

Objective: To monitor hemodynamic changes during serial balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). Methods: General clinical data of CTEPH patients diagnosed from October 2017 to January 2022 in Beijing Chaoyang Hospital were collected, and 83 patients who underwent at least 1 BPA treatment were included to analyze their 6 min walking distance, WHO functional class, N-terminal B-type natriuretic peptide precursor (NT-proBNP), troponin I (cTnI) and haemodynamic indices. Baseline and follow-up after the final BPA clinical data and hemodynamics, functional status and serial hemodynamics before each series of BPA were collected to evaluate the efficacy of BPA for CTEPH patients. Complications and managements were documented to confirm the safety of BPA for CTEPH patients. Results: Three hundred and forty BPA procedures were performed in 83 CTEPH patients. The median number of BPA procedures was 4.0 and a total of 2104 vessels were dilated. In general, mPAP [from 50.0(42.0-55.25) mmHg(1 mmHg=0.133 kPa) to 32.0(27.0-42.0) mmHg, P <0.001], PVR[from (806.6±323.2) dyn·s·cm -5 to 420.0(295.0-613.5) dyn·s·cm -5 , P <0.001] were significantly improved compared with baseline, but not CO and CI. Functional parameters including WHO functional class Ⅰ/Ⅱ/Ⅲ/Ⅳ (from 0/35/34/14 to 43/32/7/1, P <0.001), 6MWD [from 364.5(300.0-429.5)m to 461.0(409.0-501.0)m, P <0.001], NT-proBNP [from 1 357.0(232.0-2 715.0) ng/L to 141.0(57.0-627.8) ng/L, P <0.001] were significantly improved compared with baseline. A cumulative (compared to baseline) and serial (compared to preceding BPA session) analysis of the sequential BPA session confirmed that a major hemodynamic improvement in PVR and mPAP occurred in the first 3 serial BPA treatments. There was a dose-response relationship: the more segments that were treated, the greater were the subsequent reduction in PVR and mPAP. There were 32.0 complications (9.4%) associated with BPA procedures, and the most common complication was pulmonary hemorrhage caused by catheter-related vascular injury. Conclusions: BPA is an effective and safe alternative for technically non-operable CTEPH patients. The hemodynamic benefits of BPA in CTEPH patients were cumulative and correlated with the total number of vessels successfully dilated.

Heritable pulmonary arterial hypertension (HPAH) is a rare type of pulmonary arterial hypertension that often presents with progressive exertional dyspnea and for which there is no significant effective drug. A HPAH patient was admitted to our hospital more than three years ago, and the gene mutation was bone morphogenetic protein 2 (BMPR2). For the first 45 months, she was given oral imatinib 100 mg once daily, and her symptoms and hemodynamics improved significantly, with no apparent side effects. It is reported that, in combination with the characteristics of the case and related literatures, it provides clinicians with other feasible treatment options for HPAH.

Background: The aim of this study was to investigate the clinical characteristics of patients between active and inactive Takayasu's arteritis with pulmonary artery involvement (PTA) and to identify better markers of disease activity in these patients., Methods: Sixty-four PTA patients in Beijing Chao-yang hospital (2011 to 2021) were included. According to National Institutes of Health criteria, 29 patients were in active stage and 35 were in inactive stage. Their medical records were collected and analyzed., Results: Compared with inactive group, patients in active group were younger. More patients in active stage presented fever (41.38% vs 5.71%), chest pain (55.17% vs 20%), increased C-reactive protein (2.91 vs 0.46 mg/L), erythrocyte sedimentation rate (35.0 vs 9 mm/h), and platelet count (291 vs 221 × 10 9 /L). Pulmonary artery wall thickening was more common in active group (51.72% vs 11.43%). These parameters were restored after treatment. The incidence of pulmonary hypertension was comparable between groups (34.48% vs 51.43%), but patients in active group had lower pulmonary vascular resistance (PVR) (361.0 vs 891.0 dyn·s·cm -5 ) and higher cardiac index (2.76 ± 0.72 vs 2.01 ± 0.58 L/min/m 2 ). On multivariate logistic regression analysis, chest pain [odds ratio (OR) 9.37, 95%CI (1.98-44.38), P = 0.005], increased platelet count (>242.5 × 10 9 /L) [OR 9.03, 95%CI (2.10-38.87), P = 0.003] and pulmonary artery wall thickening [OR 7.08, 95%CI (1.44-34.89), P = 0.016] were independently associated with disease activity., Conclusion: Chest pain, increased platelet count, and pulmonary artery wall thickening are potential new indicators of disease activity in PTA. Patients in active stage may have lower PVR and better right heart function., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2023. Published by Elsevier B.V.)

Background: New therapeutic targets are needed to improve the outcomes for gastric cancer (GC) patients with advanced disease. Evasion of programmed cell death (apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions., Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR (ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using (CellTiter-Glo) CTG assay in vitro. Western Blot (WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Co-immunoprecipitation (Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR (RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity., Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time- and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression., Conclusion: We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations (CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC., (© 2023 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Background: The feasibility and significance of imaging pulmonary artery (PA) remodeling with 68  Ga-fibroblast activating protein inhibitor (FAPI) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have not yet been addressed., Methods: 68  Ga-FAPI-04 uptake in the PA and ascending artery was evaluated in 13 patients with CTEPH and 13 matched non-CTEPH controls. The correlations of PA 68  Ga-FAPI-04 uptake and remodeling parameters derived from right heart catheterization (RHC) were analyzed., Results: Of the 13 patients with CTEPH, nine (69%) showed visually enhanced 68  Ga-FAPI-04 uptake, whereas none of the control subjects had increased 68  Ga-FAPI-04 uptake in the PA. The prevalence of enhanced uptake in the main, lobar, and segmental PAs was 45% (17/38), 33% (16/48), and 28% (44/159), respectively. 68  Ga-FAPI-04 activity in the PA was positively correlated with pulmonary arterial diastolic pressure (r = 0.571, P = 0.041)., Conclusion: 68  Ga-FAPI-04 has the potential for imaging fibroblast activation in the PA wall, and 68  Ga-FAPI-04 activity in PA is positively correlated with pulmonary arterial diastolic pressure., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an activated conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins and influence on pro-survival proteins. This study identifies a new mechanism by which MARCHF5 regulates apoptotic cell death by restraining BAK activating conformation change and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Purpose: The aim of this study was to explore the association of cardiac fibroblast activation with clinical parameters and cardiovascular magnetic resonance (CMR) imaging parameters in patients with chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: Thirteen CTEPH patients were prospectively enrolled. All of the patients underwent cardiac 68 Gallium-labelled fibroblast activation protein inhibitor ( 68  Ga-FAPI-04)-positron emission tomography/computed tomography (PET/CT), right heart catheterisation, and echocardiography, and 11 of them additionally underwent CMR. Thirteen control subjects were selected to establish the normal range of cardiac 68  Ga-FAPI-04 uptake. Cardiac 68  Ga-FAPI-04 uptake higher than that in the blood pool was defined as abnormal. The global and segmental maximum standardised uptake values (SUV max ) of the right ventricle (RV) were measured and further expressed as target-to-background ratio (TBR RV ) with left ventricular lateral wall activity as background. Late gadolinium enhancement (LGE) was visually evaluated, and native-T1 times, enhanced-T1 times, and extracellular volume (ECV) were quantitatively measured., Results: Ten CTEPH patients (77%) had abnormal 68  Ga-FAPI-04 uptake in RV, mainly located in the free wall, which was significantly higher than that in controls (TBR RV : 2.4 ± 0.9 vs 1.0 ± 0.1, P < 0.001). The TBR RV correlated positively with the thickness of RV wall (r = 0.815, P = 0.001) and inversely with RV fraction area change (RVFAC) (r =  - 0.804, P = 0.001) and tricuspid annular plane systolic excursion (TAPSE) (r =  - 0.678, P = 0.011). No correlation was found between 68  Ga-FAPI-04 activity and CMR imaging parameters., Conclusion: Fibroblast activation in CTEPH, measured by 68  Ga-FAPI-04 imaging, is mainly localised in the RV free wall. Enhanced fibroblast activation reflects the thickening of the RV wall and decreased RV contractile function., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients which can significantly improve symptoms and pulmonary hemodynamics. Therefore, this retrospective study evaluated the long-term outcomes after pulmonary endarterectomy (PEA) and analyze the predictors of long-term outcomes for chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: From 2002-2020, 76 CTEPH patients successfully discharged after PEA in Beijing Chaoyang Hospital were followed-up by scheduled clinical visits or telephone interviews. The follow-up time lasted for 18 years and median time was 7.29 years., Results: The survival rate at 1,3,5,10,15 years postoperatively was 100.00%, 97.10%, 95.40%, 89.80% and 82.90%, respectively. Multivariate logistics regression analysis showed that postoperative mPAP (hazard ratio: 1.144; 95%confidence interval: 1.018-1.285; P  = 0.023) was associated with a higher risk of late death, right atrium right and left diameters (hazard ratio: 1.113; 95%confidence interval, 1.006-1.231; P  = 0.038) were associated with a higher risk of major adverse events., Conclusion: Pulmonary endarterectomy is an effective way to treat CTEPH. Long-term outcome is excellent for patients who undergoing pulmonary endarterectomy who survived from peri-operation time. Postoperative mPAP is a significant prognostic factor for long-term death and right atrium right and left diameters is a significant prognostic factor for major adverse events. That shows patients with high postoperative mPAP and right atrium right and left diameter should be followed up closely.

Dipeptidyl peptidase-4 (DPP4) is highly participated in regulating diabetes mellitus (DM), and inhibitors of DPP4 may act as potential DM drugs. Therefore, we performed a novel artificial intelligence (AI) protocol to screen and validate the potential inhibitors from Traditional Chinese Medicine Database. The potent top 10 compounds were selected as candidates by Dock Score. In order to further screen the candidates, we used numbers of machine learning regression models containing support vector machines, bagging, random forest and other regression algorithms, as well as deep neural network models to predict the activity of the candidates. In addition, as a traditional method, 2D QSAR (multiple linear regression) and 3D QSAR methods are also applied. The AI methods got a better performance than the traditional 2D QSAR method. Moreover, we also built a framework composed of deep neural networks and transformer to predict the binding affinity of candidates and DPP4. Artificial intelligence methods and QSAR models illustrated the compound, 2007&#95;4105, was a potent inhibitor. The 2007&#95;4105 compound was finally validated by molecular dynamics simulations. Combining all the models and algorithms constructed and the results, Hypecoum leptocarpum might be a potential and effective medicine herb for the treatment of DM., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: To explore the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the detection of active pulmonary artery (PA) lesions in patients with Takayasu's arteritis (TA)., Methods and Results: Consecutive TA patients with PA involvement were prospectively recruited. Clinical activity was assessed according to the National Institutes of Health (NIH) criteria. CT pulmonary angiography (CTPA) or magnetic resonance pulmonary angiography was performed for evaluation of vascular structural characteristics, and mural thickening was considered as radiologically active. A vascular segment with 18F-FDG uptake ≥ liver was considered as PET-active. A total of 38 18F-FDG PET/CT scans were performed in 29 patients. In terms of disease activity, the sensitivity of 18F-FDG PET/CT did not significantly differ from radiological imaging (71.4% vs. 92.9%, P = 0.250), but 18F-FDG PET/CT had higher specificity (91.7% vs. 37.5%, P = 0.001) and accuracy (84.2% vs. 57.9%, P = 0.022). Although the majority of PET-active PA segments (54.9%) showed mural thickening, 14 PA segments with normal structure were also PET-active. 18F-FDG activity did not significantly differ between the PA and aorta in clinically active patients. In addition, 18F-FDG activity of the PA was positively correlated with inflammatory markers. Changes in 18F-FDG activity in PA during follow-up reflected therapeutic effects., Conclusion: 18F-FDG PET/CT can effectively evaluate PA activity in TA patients, and its diagnostic performance is superior to radiological imaging. The 18F-FDG activity of PA shows a good correlation with clinical disease status and inflammatory markers and can be used to monitor therapeutic effects., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

A definitive diagnosis of heparin-induced thrombocytopenia (HIT) is difficult to make, especially in patients undergoing cardiac surgery. In this retrospective cohort study, we assessed the platelet count trends and the response to fondaparinux in a population of patients of suspected HIT after pulmonary endarterectomy (PEA). Patients enrolled in this study were over the age of 18 years, and survived longer than 7 days after PEA between January 1, 2011 and December 31, 2015. HIT likelihood was assessed by the 4 T's score and interpreted by our institutional algorithm. 54 patients were operated, and 49 patients met the inclusion criteria. Six patients met the criteria for suspected HIT and were treated with fondaparinux until the platelet recovered. No significant difference was observed of clinical characteristics between intermediate to high HIT likelihood patients (HIT SUSPECTED) and low HIT likelihood patients (NO HIT SUSPECTED). HIT SUSPECTED patients reached platelet count lowest later (about 5.5 days after PEA), while NO HIT SUSPECTED patients is about 4.0 days after PEA. Percentage of platelet counts decrease (> 50%) was larger than NO HIT SUSPECTED patients (< 50%). There was no difference in mortality or residual pulmonary hypertension between HIT SUSPECTED and NO HIT SUSPECTED patients. Two HIT SUSPECTED patients who used heparin after PEA died, the other four survived by replacing heparin or low molecular weight heparin with fondaparinux. Suspected HIT patients should be surveilled carefully. Platelet counts trends may have some hints in the prevention of HIT. Fondaparinux may be effective for patients with suspected HIT.

Objective: To analyze the efficacy and safety of Balloon Pulmonary Angioplasty (BPA) in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Methods: A total of 38 CTEPH patients received at least one BPA treatment between February 2017 and April 2019 were enrolled. World Health Organization functional class(WHO-FC), 6-minute walking distance(6WMD), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance(PVR), N-terminal pro brain natriuretic peptide(NT-proBNP) and echocardiographic indicators were collected at baseline and before each BPA procedure. Results: 38 patients received 95 times of BPA [ 2 (1, 4) times per person] totally. MPAP was 50 (43, 56) mmHg(1 mmHg=0.133 kPa) before BPA and 41(32, 50) mmHg after at least one BPA procedure, P <0.001. MPAP decreased from 50(42, 55) to 34(28, 49) mmHg ( P =0.003) in 17 cases after 3-5 BPA procedures. In 15 cases, PVR decreased from 852(583, 1 140)dyn·s·cm -5 to 496(406, 802)dyn·s·cm -5 , P =0.009. Besides, there were 13 patients with WHO Function Class Ⅰ/Ⅱ before BPA, 25 patients with Ⅲ/Ⅳ class before BPA, 29 patients with Ⅰ/Ⅱ class after BPA treatment, and 9 patients with Ⅲ/Ⅳ after BPA treatment, P <0.001. 6 WMD before and after BPA increased from 360(290, 442)m to 449(376, 505)m, P =0.015. The Meyer score of lung perfusion scanning got improved, from 0.54(0.53, 0.58) to 0.50(0.44, 0.58), P <0.001. Among all registered patients, 21 of whom NT-proBNP decreased from 1 285(606, 2 794) to 472(148, 745), P =0.014. The inner diameter of the right ventricular decreased from 54(41, 54)mm before surgery to 42(34, 49)mm after surgery, P <0.001. 6(6.3%, 6/95) complications occurred in 95 times of BPA. Conclusion: For inoperable patients with CTEPH, BPA can significantly improve disease severity, 6 MWD, heart function, decrease mPAP, PVR and improve lung perfusion, which is a safe and effective therapy.

Novel targets are required to improve the outcomes for patients with colorectal cancers. In this regard, the selective inhibitor of the pro-survival protein BCL2, venetoclax, has proven highly effective in several hematological malignancies. In addition to BCL2, potent and highly selective small molecule inhibitors of its relatives, BCLxL and MCL1, are now available, prompting us to investigate the susceptibility of colorectal cancers to the inhibition of one or more of these pro-survival proteins. While targeting BCLxL, but not BCL2 or MCL1, on its own had some impact, most (15/17) of the immortalized colorectal cancer cell lines studied were efficiently killed by the combined targeting of BCLxL and MCL1. Importantly, these in vitro findings were confirmed in a xenograft model and, interestingly, in all (5/5) patient derived tumor organoids evaluated. Our results lend strong support to the notion that BCLxL and MCL1 are highly promising targets for further evaluation in efforts to improve the treatment of colorectal cancers.

MCL1, a BCL2 relative, is critical for the survival of many cells. Its turnover is often tightly controlled through both ubiquitin-dependent and -independent mechanisms of proteasomal degradation. Several cell stress signals, including DNA damage and cell cycle arrest, are known to elicit distinct E3 ligases to ubiquitinate and degrade MCL1. Another trigger that drives MCL1 degradation is engagement by NOXA, one of its BH3-only protein ligands, but the mechanism responsible has remained unclear. From an unbiased genome-wide CRISPR-Cas9 screen, we discovered that the ubiquitin E3 ligase MARCH5, the ubiquitin E2 conjugating enzyme UBE2K, and the mitochondrial outer membrane protein MTCH2 co-operate to mark MCL1 for degradation by the proteasome-specifically when MCL1 is engaged by NOXA. This mechanism of degradation also required the MCL1 transmembrane domain and distinct MCL1 lysine residues to proceed, suggesting that the components likely act on the MCL1:NOXA complex by associating with it in a specific orientation within the mitochondrial outer membrane. MTCH2 has not previously been reported to regulate protein stability, but is known to influence the mitochondrial localization of certain key apoptosis regulators and to impact metabolism. We have now pinpointed an essential but previously unappreciated role for MTCH2 in turnover of the MCL1:NOXA complex by MARCH5, further strengthening its links to BCL2-regulated apoptosis.

Multiple myeloma is an incurable and fatal cancer of immunoglobulin-secreting plasma cells. Most conventional therapies aim to induce apoptosis in myeloma cells but resistance to these drugs often arises and drives relapse. In this study, we sought to identify the best adjunct targets to kill myeloma cells resistant to conventional therapies using deep profiling by mass cytometry (CyTOF). We validated probes to simultaneously detect 26 regulators of cell death, mitosis, cell signaling, and cancer-related pathways at the single-cell level following treatment of myeloma cells with dexamethasone or bortezomib. Time-resolved visualization algorithms and machine learning random forest models (RFMs) delineated putative cell death trajectories and a hierarchy of parameters that specified myeloma cell survival versus apoptosis following treatment. Among these parameters, increased amounts of phosphorylated cAMP response element-binding protein (CREB) and the pro-survival protein, MCL-1, were defining features of cells surviving drug treatment. Importantly, the RFM prediction that the combination of an MCL-1 inhibitor with dexamethasone would elicit potent, synergistic killing of myeloma cells was validated in other cell lines, in vivo preclinical models and primary myeloma samples from patients. Furthermore, CyTOF analysis of patient bone marrow cells clearly identified myeloma cells and their key cell survival features. This study demonstrates the utility of CyTOF profiling at the single-cell level to identify clinically relevant drug combinations and tracking of patient responses for future clinical trials.

Previous studies have shown that small molecule inhibitors of NLRP3 may be a potential treatment for Parkinson's disease (PD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3), heat shock protein HSP 90-beta (HSP90AB1), caspase-1 (CASP1) and cellular tumor antigen p53 (TP53) have significant involvement in the pathogenesis pathway of PD. Molecular docking was used to screen the traditional Chinese medicine database TCM Database@Taiwan. Top traditional Chinese medicine (TCM) compounds with high affinities based on Dock Score were selected to form the drug-target interaction network to investigate potential candidates targeting NLRP3, HSP90AB1, CASP1, and TP53 proteins. Artificial intelligence model, 3D-Quantitative Structure-Activity Relationship (3D-QSAR) were constructed respectively utilizing training sets of inhibitors against the four proteins with known inhibitory activities (pIC 50 ). The results showed that 2007&#95;22057 (an indole derivative), 2007&#95;22325 (a valine anhydride) and 2007&#95;15317 (an indole derivative) might be a potential medicine formula for the treatment of PD. Then there are three candidate compounds identified by the result of molecular dynamics., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

There is currently no effective treatment for acute myeloid leukemia, and surgery is also ineffective as an important treatment for most tumors. Rapidly developing artificial intelligence technology can be applied to different aspects of drug development, and it plays a key role in drug discovery. Based on network pharmacology and virtual screening, candidates were selected from the molecular database. Nine artificial intelligence algorithm models were used to further verify the candidates' potential. The 350 training results of the deep learning model showed higher credibility, and the R-square of the training set and test set of the optimal model reached 0.89 and 0.84, respectively. The random forest model has an R-square of 0.91 and a mean square error of only 0.003. The R-square of the Adaptive Boosting model and the Bagging model reached 0.92 and 0.88, respectively. Molecular dynamics simulation evaluated the stability of the ligand-protein complex and achieved good results. Artificial intelligence models had unearthed the promising candidates for STAT3 inhibitors, and the good performance of most models showed that they still had practical value on small data sets.

Although observational studies have reported a positive association between obstructive sleep apnea syndrome (OSAS) and breast cancer (BC) risk, causality remains inconclusive. We aim to explore whether OSAS is associated with etiology of BC by conducting a two-sample Mendelian randomization (MR) study in a Chinese population and Asian population from the Breast Cancer Association Consortium (BCAC). We found a detrimental causal effect of OSAS on BC risk in the primary analysis of our samples (IVW OR, 2.47 for BC risk per log-odds increment in OSAS risk, 95% CI = 1.86-3.27; P = 3.6×10 -10 ). This was very similar to results of the direct observational case-control study between OSAS and BC risk (OR = 2.80; 95% CI = 2.24-3.50; P =1.4×10 -19 ). Replication in the Asian population of the BCAC study also supported our results (IVW OR, 1.33 for BC risk per log-odds increment in OSAS risk, 95% CI = 1.13-1.56; P = 0.0006). Sensitivity analyses confirmed the robustness of our findings. We provide novel evidence that genetically determined higher risk of OSAS has a causal effect on higher risk of BC. Further studies focused on the mechanisms of the relationship between OSAS and breast carcinogenesis are needed.

Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select BCL-2 prosurvival proteins to induce apoptosis have been developed for cancer therapy. Venetoclax, which targets BCL-2, has been effective as therapy for patients with chronic lymphocytic leukemia, and MCL-1-targeting BH3-mimetic drugs have been extensively evaluated in preclinical studies for a range of blood cancers. Recently, BCL-W, a relatively understudied prosurvival member of the BCL-2 protein family, has been reported to be abnormally upregulated in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma patient samples. Therefore, to determine if BCL-W would be a promising therapeutic target for B-cell lymphomas, we have examined the role of BCL-W in the sustained growth of human BL- and DLBCL-derived cell lines. We found that CRISPR/CAS9-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL cell lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a range of BH3-mimetic drugs targeting other BCL-2 prosurvival proteins. Our results suggest that BCL-W is not universally required for the sustained growth and survival of human BL and DLBCL cell lines. Thus, targeting BCL-W in this subset of B-cell lymphomas may not be of broad therapeutic benefit., (© 2020 by The American Society of Hematology.)

Prosurvival BCL-2 family proteins are potent inhibitors of apoptosis and often overexpressed in lymphoid malignancies. In multiple myeloma (MM), MCL-1 expression contributes to survival of malignant plasma cells, and overexpression correlates with poor prognosis. In this study, we investigated whether sensitivity to the novel MCL-1 inhibitor S63845 could be predicted using cytogenetics, focusing on amplification of 1q21, the chromosomal region that contains the MCL1 locus. In addition, we studied the relation of MCL-1 inhibitor sensitivity with other diagnostic characteristics and BCL-2 family protein expression. In 31 human myeloma cell lines and in bone marrow aspirates from 47 newly diagnosed MM patients, we measured the effect of S63845 alone, or combined with BCL-2 inhibitor ABT-199 (venetoclax), and BCL-XL inhibitor A-1155463 or A-1331852 on cell viability. We demonstrated for the first time that MM cells from patients with 1q21 amplification are significantly more sensitive to inhibition of MCL-1. We suggest that this increased sensitivity results from high relative MCL1 expression resulting from amplification of 1q21. Additionally, and partially independent from 1q21 status, high serum β2 microglobulin level and presence of renal insufficiency correlated with increased sensitivity to MCL-1 inhibitor treatment. Combining S63845 with other BH3 mimetics synergistically enhanced apoptosis compared with single inhibitors, and sensitivity to inhibitor combinations was found in a large proportion of MM insensitive to MCL-1 inhibition alone. Collectively, our data indicate that amplification of 1q21 identifies an MM subset highly sensitive to MCL-1 inhibitor treatment and can be used as a predictive marker to guide selection of therapy., (© 2019 by The American Society of Hematology.)

A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a diacylhydrazine moiety were designed and synthesized. Their structures were confirmed by melting points, 1 H NMR, 13 C NMR, and elemental analysis (EA). Their antifungal and insecticidal activities were evaluated. The antifungal activity result indicated that most title compounds against Cercospora arachidicola , Alternaria solani , Phytophthora capsici , and Physalospora piricola exhibited apparent antifungal activities at 50 mg/L, and better than chlorothalonil or carbendazim. The EC 50 values of (R)-N'-benzoyl-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide ( I- 5) against six tested phytopathogenic fungi were comparable to those of chlorothalonil. The CoMSIA model showed that a proper hydrophilic group in the R 1 position, as well as a proper hydrophilic and electron-donating group in the R 2 position, could improve the antifungal activity against Physalospora piricola , which contributed to the further optimization of the structures. Meanwhile, most title compounds displayed good insecticidal activities, especially compound (R)-N'-(4-nitrobenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-3). The insecticidal mechanism results indicated that compound III-3 can serve as effective insect Ca 2+ level modulators by disrupting the cellular calcium homeostasis in Mythimna separata., Competing Interests: The authors declare no conflicts of interest.

Objective: To analyze the clinical characteristics and the effect of targeted drug therapy of portopulmonary hypertension (PoPH). Methods: A total of 5 patients with PoPH who were admitted to the Department of Pulmonary and Critical Care Medicine of Beijing Chao-Yang Hospital from January 1, 2017 to December 31, 2018 were included. The clinical information and follow-up data were collected. The patient's medical history, clinical manifestations, right cardiac catheterization (RHC), classification of cardiac and hepatic function, treatment and prognosis were analyzed. Results: Among the 5 patients with PoPH, 3 were male and 2 were female. The median age was 56 years. The underlying diseases of portal hypertension were all cirrhosis, and 1 patient combined with hepatopulmonary syndrome (HPS). Dyspnea was the main respiratory symptom in all the 5 patients, and the median time from symptom onset to diagnosis was 1 year (5 months to 8 years). RHC was used as the diagnostic criteria for pulmonary hypertension in all patients, with a median mean pulmonary arterial pressure of 42 mmHg (1 mmHg=0.133 kPa) and a median pulmonary vascular resistance of 538 dyn·s·cm(-5). 3 cases were in Child-Pugh liver function grade B, and 2 were in grade A. The hepatic reserve function was not matched with the severity of cardiac insufficiency. Liver transplantation was performed in 1 patient, whose right ventricular dysfunction can be alleviated by targeted drug therapy after operation. All the 5 patients received targeted drug therapy of pulmonary hypertension. In the 3 patients who were regularly treated with targeted drugs and followed up on time, the cardiac function was improved during the follow-up period. There was no improvement or even deterioration of cardiac function in 2 patients who were not regularly treated or followed up. One patient died after liver transplantation. The cause of death was severe pneumonia and right ventricular dysfunction. The survival time after transplantation was 1 year. Conclusions: In PoPH patients, the hepatic reserve function is not matched with the heart function classification. PoPH can coexist with HPS. Regular application of pulmonary hypertension targeting drugs may benefit patients with PoPH.

To determine the value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in differentiating malignancy of pulmonary artery (PA) from pulmonary thromboembolism (PTE) based on a larger number of cases by pooling our cases and those from the literature. Consecutive patients with a PA lesion who had undergone 18 F-FDG PET/CT in our hospital were retrospectively reviewed. Moreover, PubMed, Embase, and Medline were searched for literature reporting individual maximum standardised uptake value (SUV max ) of the malignant PA lesion and/or PTE. 18 F-FDG activity was compared between PA malignancy and PTE by pooling the data from literature and our patients. Receiver operating characteristic curve analysis was performed to determine the ability of SUV max to differentiate PA malignancy from PTE. From our database, we identified 11 patients with pulmonary artery sarcoma (PAS), and nine cases of PTE. Fifty patients with a malignant PA lesion (40 cases of PAS and 10 cases of tumor embolism) and 22 subjects with PTE were extracted from the literature. In our cases, the SUV max of PAS (11.1 ± 4.9, range: 5.5-19.9) was significantly higher than that of PTE (1.9 ± 0.6, range: 1.1-3.2; P < 0.001). There was no significant difference in the SUV max between the literature data and our cases in malignant lesions or in PTE. Based on the pooled analysis of the literature data and our cases (61 cases of malignant lesions and 31 cases of PTE), the area under the curve for SUV max to differentiate PA malignancy from PTE was 0.996 (95% CI: 0.989-1.000). At a cutoff value of 3.3, the sensitivity, specificity, and accuracy were 98.4%, 96.8%, and 97.8%, respectively. The 18 F-FDG uptake value is an accurate index for determining PA malignancy.

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.

The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. SIGNIFICANCE: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance. See related commentary by Thangavadivel and Byrd, p. 320 . This article is highlighted in the In This Issue feature, p. 305 ., (©2018 American Association for Cancer Research.)

Objective: To compare the value of cardiac MRI (CMRI), ultrasonic cardiogram (UCG), multidetector CT (MDCT) in assessing right ventricular function (RV) in patients with PAH. Methods: A total of 31 consecutive patients with PAH (17 males and 14 females, 55±12 years) in Beijing Chao-Yang Hospital from August 2012 to February 2014 were prospectively enrolled. All patients underwent CMRI to get parameters including right ventricular end-systolic volume (ESV), end-diastolic dimension (EDV), stroke volume (SV), ejection fraction (EF), ventricular mass index (VMI). UCG parameters included Tei index, RV fractional area change (FAC), ESV, EDV. MDCT parameters included right /left ventricular internal diameter (RVd/LVd), right /left ventricular diastole maximum area (RVa/LVa), Cobb angle.These parameters obtained by MRI, UCG and MDCT were correlated with those of RHC respectively by Spearman or Pearson correlation analysis. Results: Six minutes walk distance had moderate negative correlation with CMRI-EF (40±9), VMI 44-115(71±20) g/m(2,) Cobb angle(67°±12°); RHC-SV had moderate negative correlation with CMRI-SV(57±21) ml, EF, VMI, UCG-EF(41±14), Tei(0.82±0.29), FAC(30±9), RVd(45±7) mm, RVa(2 484±596) mm(2), Cobb angle ; Right cardiac work index had moderate negative correlation with CMRI-EF, RVd and Cobb angle. Conclusions: MRI-EF is the best parameter to reflect RV function. CMRI is the optimal method to assess RV function, and then is the MDCT and the last is UCG.

Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1 /Ikaros and IKZF3 /Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC "axis," as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38 , and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies., (© 2018 by The American Society of Hematology.)

Objective: To investigate the diagnostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin Ⅰ (TnI) for detecting right ventricular dysfunction (RVD) in patients with non-high-risk acute pulmonary thromboembolism (APE). Methods: A retrospective analysis was performed in 96 adult patients [44 males, 52 females, aged (61±14) years] with non-high-risk APE from January 2015 to June 2016. All patients were divided into RVD group and non-RVD group according to whether there was right ventricular enlargement on echocardiography. The baseline data, serumTnI and NT-proBNP levels were compared between the 2 groups and the diagnostic value of the 2 cardiac markers for RVD was analyzed. Results: There were no significant differences in age, gender, body mass index between the 2 groups ( P> 0.05). The creatinine clearance rate of the RVD group was lower than that of the non-RVD group [96.4 (77.5,99.6) vs 101.7 (95.1,106.5), P= 0.021]. NT-proBNP [2 300 (1 056,3 396) vs 188 (61,535), P< 0.01] and TnI [0.13 (0.09,0.25) vs 0.00 (0.00,0.02), P< 0.01] were significant higher in the RVD group than in the non-RVD group. The univariate logistic regression analyses showed that NT-proBNP (per 100 ng/L, OR 1.199, 95% CI 1.117-1.287), TnI (per 0.01 μg/L, OR 1.164, 95% CI 1.079-1.256) and creatinine clearance rate ( OR 0.968, 95% CI 0.938-0.998) were significantly associated with RVD. Multivariate regression analysis showed that NT-proBNP (per 100 ng/L, OR 1.155, 95% CI 1.074-1.241) and TnI (per 0.01 μg/L, OR 1.079, 95% CI 1.011-1.151) were independently associated with RVD. The areas under the ROC curve (AUC) of NT-proBNP, TnI, and the combination of them were 0.908 (95% CI 0.841-0.976), 0.896 (95% CI 0.826-0.966) and 0.925 (95% CI 0.862-0.988), respectively. The cut-off value of NT-proBNP was 503.5 ng/L, with a sensitivity of 85.7%, specificity of 75.4%, positive predictive value (PPV) of 66.7% and negative predictive value (NPV) of 90.2%.The cut-off value of TnI was 0.05 μg/L, and the sensitivity, specificity, PPV and NPV was 80.0%, 86.9%, 77.8% and 88.3%, respectively. The optimal probability derived from the logistic regression model in which the 2 biomarkers were the independent variables was 0.779, with a sensitivity, specificity, PPV and NPV of 65.7%, 96.7%, 92.0%, 83.1%, respectively. Conclusion: Both NT-proBNP and TnI had preferably good diagnostic value for RVD in patients with non-high-risk APE, but their clinical application needed comprehensive evaluation combined with the overall manifestations of the patients and experimental methods. The diagnostic value was higher when the 2 biomarkers were evaluated together.

Objective: To analyze the clinical features of 3 cases of Takayasu arteritis(TA) with pulmonary cavities on chest computed tomography(CT). Methods: The clinical data of 3 TA patients with cavities on the chest CT who were admitted into Beijing Chaoyang Hospital were retrospectively analyzed. A literature search was performed with "Takayasu arteritis" and "pulmonary" as the key words in China Knowledge Resource Intergrated Database (CNKI) and Pubmed Database for publications from Jan 1, 2000 to Dec. 31,2017. The relevant literatures were reviewed. Results: Among the 3 patients, 2 were males and 1 was female, aging 49, 28 and 28 years, respectively. They presented with cough, fever and chest pain, and chest CT showed cavities, single or multiple, either with thick or thin wall, or wedge-shaped consolidation, residual stripes after being absorbed, and one case had pulmonary biopsy results which showed hemorrhagic infarction. They were all misdiagnosed before as pneumonia, pulmonary tuberculosis, pulmonary thromboembolism. After being treated by combination therapy of glucocorticoids and immunosuppressive agents, the disease improved significantly. A total of 777 cases with TA involving pulmonary arteries were reported, from which 13 cases with involvement of pulmonary parenchyma were described. Therefore total 16 cases including the 3 cases in this article were included for analysis. Twelve cases showed patchy or wedge-shaped ground-glass opacity and consolidation, and peripheral lung stripes remained after being absorbed. Two cases showed pleural effusion, and 4 cases showed cavities, 3 cases were misdiagnosed as pulmonary tuberculosis, 7 as pulmonary infection, and 5 as pulmonary thromboembolism. Conclusions: TA with pulmonary arteries involved is susceptible to be misdiagnosed and missed, and therefore, in patients with cough, hemoptysis, chest pain and cavities in pulmonary parenchyma, TA should be suspected. Early diagnosis and appropriate treatment can lead to a better prognosis.

BACKGROUND Studies have shown that intermittent hypoxia mimics obstructive sleep apnea in causing pulmonary inflammation, but the mechanism is not yet clear.TLR-4 is a recognized proinflammatory factor, so the purpose of this study was to assess the function of TLR-4 in pulmonary inflammation induced by chronic intermittent hypoxia simulating obstructive sleep apnea. MATERIAL AND METHODS Healthy male Wistar rats were divided into 3 groups (8 in each group): the normoxia control group (CG), the intermittent hypoxia group (IH), and the TLR4 antagonist TAK242 treatment group (3 mg/kg, daily), with exposure durations of 12 weeks and 16 weeks (HI). The morphological changes of lung tissue were determined with hematoxylin-eosin (HE) staining. The expressions of the TLR-4 pathway in lung tissue were tested by Western blotting and RT-PCR. The levels of IL-6 and TNF-a in serum and lung tissue were detected by enzyme-linked immunosorbent assay (ELISA). The levels of SOD and MDA in lung tissue were detected by use of SOD and MDA kits, respectively. RESULTS After TAK242 treatment, damage to lung tissue was increased, and the expressions of TLR-4, MYD88, P65, IL-6, TNF-α, MDA, and SOD were decreased. Intermittent hypoxic exposure caused alveolar expansion, thickening of alveolar septum, and fusion of adjacent alveoli into larger cysts under intermittent hypoxia in a time-dependent manner. Compared with the CG and HI groups, the mean lining interval (MLI) become more thickened and the alveolar destruction index (DI) increased significantly in the IH group. CONCLUSIONS Chronic intermittent hypoxia causes pulmonary inflammatory response and the inflammatory pathway involved in TLR4 receptor may be one of the mechanisms that trigger lung inflammation.

Sepsis, as a systemic inflammatory response syndrome (SIRS) subtype, is generally characterized by infection. Emerging evidence has highlighted dysregulated microRNAs (miRNAs) are involved in the progression of sepsis. The aim of the study was to investigate the effects of miR-335-5p on inflammatory responses in a septic mouse model. The hypothesis was subsequently asserted that the FASN gene and AMPK/ULK1 signaling pathway may participate in the regulation of miR-335-5p. A septic mouse model was established in order to validate the effect of miR-335-5p on the inflammatory response by means of suppressing the endogenous expression of FASN by siRNA against FASN in endothelial cells. A target prediction program and luciferase activity was employed to ascertain as to whether miR--335-5p targets FASN. The levels of inflammatory factors including IL-6 and IL-1β were determined by means of ELISA assay. RT-qPCR and western blot analysis were used to determine the AMPK/ULK1 signaling pathway-, apoptosis- and autophagy-related genes. Flow cytometry was employed in order to evaluate sepsis-induced cell apoptosis in response to miR-335-5p and FASN alternations. FASN was identified as a target gene of miR--335-5p. Gain- and loss-of-function studies revealed that miR-335-5p acted to enhance autophagy, reduce cell apoptosis, promote cell cycle entry in endothelial cells, and reduce inflammatory response through the modulation of pro- and anti-apoptotic factors in endothelial cells. The effect of miR-335-5p on endothelial cells was increased when FASN was suppressed by siRNA as well as when the AMPK/ULK1 signaling pathway was activated, suggesting that miR-335-5p influences sepsis by targeting and inhibiting FASN, and activating the AMPK/ULK1 signaling pathway. Our study provides evidence indicating that overexpressed miR-335-5p enhances autophagy by targeting FASN through activation of the AMPK/ULK1 signaling pathway working to alleviate the inflammatory response in septic mouse models, emphasizing the value of the functional upregulation of miR-335-5p as therapeutic strategy for sepsis., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: To find key microRNA (miR) associated with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Affymetrix miR microarray data and GSE56914 data downloaded from GEO database (http: //www.ncbi.nlm.nih.gov/geo/) were obtained and integrated. The microarray data were obtained from peripheral blood samples of CTEPH patients and the matched control. Differentially expressed miRs were screened. Target genes of these miRs were searched. Then, functional enrichment analyses for these miRs were performed. After that, disease network including miRs, target genes and pathways was constructed. Results: Five important miRs including hsa-miR-885-5p, hsa-miR-501-5p, hsa-miR-615-3p, hsa-miR-610, and hsa-miR-346 were identified. Furthermore, hsa-miR-885-5p and hsa-miR-501-5p were significantly enriched in cell cycle pathway. Hsa-miR-615-3p was involved in cytokine-cytokine receptor interaction, axon guidance, focal adhesion and cell cycle pathway. Hsa-miR-610 was significantly enriched in focal adhesion pathway, and hsa-miR-346 was involved in cytokine-cytokine receptor interaction, axon guidance, and focal adhesion pathway. Conclusions: Hsa-miR-885-5p, hsa-miR-501-5p, hsa-miR-615-3p, hsa-miR-610 and hsa-miR-346 are important miRs for the development of CTEPH.

Breast cancer is known as the most prevalent cancer in women worldwide, and has an undeniable negative impact on public health, both physically, and mentally. This study aims to investigate the effects of toll-like receptor 4 (TLR4) gene silencing on proliferation and apoptosis of human breast cancer cells to explore for a new theoretical basis for its treatment. TLR4 small interference RNA (siRNA) fragment recombinant plasmids were constructed, including TLR4 siRNA-1, TLR4 siRNA-2, and TLR4 siRNA-3. Human breast cancer MCF-7 and MDA-MB-231 cells were assigned into blank, negative control (NC), TLR4 siRNA-1, TLR4 siRNA-2, and TLR4 siRNA-3 groups. MCF-7 and MDA-MB-231 cell growth was detected by MTT assay. Apoptosis and cell cycle were determined by flow cytometry. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were conducted to determine the expression of TLR4, CDK4, cyclin D1, Livin, Bcl-2, p53, c-FLIP, and caspase-3. In comparison with the NC and blank groups, the TLR4 siRNA-1, TLR4 siRNA-2, and TLR4 siRNA-3 groups showed decreased the expression of TLR4, inhibited proliferation of MCF-7 and MDA-MB-231 cells and promoted MCF-7 and MDA-MB-231 cell apoptosis, and the cells were blocked in G1 phase. In comparison with the NC and blank groups, in the TLR4 siRNA-1, TLR4 siRNA-2, and TLR4 siRNA-3 groups, siRNA-TLR4 significantly increased expression of p53 and caspase-3 in MCF-7 and MDA-MB-231 cells, while it decreased the expressions of CDK4, cyclinD1, Livin, Bal-2, and c-FLIP. The study demonstrates that TLR4 gene silencing inhibits proliferation and induces apoptosis of MCF-7 and MDA-MB-231 cells., (© 2018 Wiley Periodicals, Inc.)

The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer. Using S63845-resistant cells combined with CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) technology, we identified deletion of BAK and up-regulation of prosurvival proteins as potential mechanisms that confer resistance to S63845 in breast cancer. Collectively, our findings provide a strong rationale for the clinical evaluation of MCL-1 inhibitors in breast cancer., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Myelopoiesis is under the control of a complex network containing various regulation factors. Deregulation of any important regulation factors may result in serious consequences including acute myeloid leukemia (AML). In order to find out the genes that may take a part in AML development, we analyzed data from AML cDNA microarray (GSE2191) in the NCBI data pool and noticed that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is abnormally over-expressed in AML patients. Then we investigated the function and mechanisms of hnRNP A1 in myeloid development. A gradually decreased hnRNP A1 expression was detected during granulocytic differentiation in ATRA-induced-NB4 and HL-60 cells and cytokines-induced hematopoietic stem and progenitor cells. By function-loss and winning experiments we demonstrated hnRNP A1's inhibition role via inhibiting expression of C/EBPα, a key regulator of granulocytic differentiation, in the granulocytic differentiation. During granulocytic differentiation the decrease of hnRNP A1 reduces inhibition on C/EBPα expression, and the increased C/EBPα promotes the differentiation. We also demonstrated that miR-451 promotes granulocytic differentiation via targeting to and down-regulating hnRNP A1, and hnRNP A1 positively regulates c-Myc expression. Summarily, our results revealed new function and mechanisms of hnRNP A1 in normal granulocytiesis and the involvement of a feed-back loop comprising c-Myc, miR-451 and hnRNP A1 in AML development., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interests.

Objective: To analyze the differential gene expression of patients with idiopathic pulmonary fibrosis and pulmonary hypertension (IPF-PH). Methods: The expression profile data of GSE15197 was downloaded from the Gene Expression Omnibus (GEO) database. Bonferroni algorithm was used to identify the differentially expressed genes of pulmonary tissues from IPF-PH, idiopathic pulmonary arterial hypertension (IPAH) and Normal groups. Principal component analysis was used to extract the principal components of three types of samples and differentially expressed genes were obtained. Gene annotation and gene association analysis were used to analyze gene function and related signaling pathways. Results: Gene expression profiles of pulmonary tissues from IPF-PH, IPAH and Normal groups were compared and analyzed, and 160 differentially expressed genes were found ( P <0.05). Nine principal component were found with the cumulative contribution rate of >0.85, and there were 44 significant differences genes with the loading coefficient >80% in principal component one, which was mainly related to the expression of cilium, gamma-glutamyltransferase, and phospholipase. The signaling pathway of differential expression genes were mainly involved in the biosynthesis of leukotriene biosynthetic process and gamma-glutamyltransferase activity. Conclusion: The differential gene expression and their functional annotation can provide important clues for the pathogenic genes of IPF-PH, and may provide a theoretical basis for exploring potential biomarkers and drug targets.