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s Atherosclerosis is a chronic multifactorial cardiovascular disease. A Western diet has been reported to affect atherosclerosis through regulation of adipose function. In high cholesterol diet-fed ApoE–/– mice, adipocyte HIF-1α deficiency or direct HIF-1α inhibition by the selective pharmacological HIF-1α inhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation, which lowers cholesterol levels and reduces inflammatory responses, resulting in improved dyslipidemia and atherogenesis. Smpd3, the gene encoding neutral sphingomyelinase, is identified as a new target gene directly regulated by HIF-1α that is involved in ceramide generation. Epididymal adipose tissue injected with lentivirus-SMPD3 reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1α-deficient mice. Therefore, inhibitors of HIF-1α may constitute a novel approach to slow atherosclerotic progression.

Severe ice conditions in the Bohai Sea could cause serious harm to maritime traffic, offshore oil exploitation, aquaculture, and other economic activities in the surrounding regions. In addition to providing sea ice forecasts for disaster prevention and risk mitigation, sea ice numerical models could help explain the sea ice variability within the context of climate change in marine ecosystems, such as spotted seals, which are the only ice-dependent animal that breeds in Chinese waters. Here, we developed NEMO-Bohai, an ocean–ice coupled model based on the Nucleus for European Modelling of the Ocean (NEMO) model version 4.0 and Sea Ice Modelling Integrated Initiative (SI3) (NEMO4.0-SI3) for the Bohai Sea. This study will present the scientific design and technical choices of the parameterizations for the NEMO-Bohai model. The model was calibrated and evaluated with in situ and satellite observations of the ocean and sea ice. The model simulations agree with the observations with respect to sea surface height (SSH), temperature (SST), salinity (SSS), currents, and temperature and salinity stratification. The seasonal variation of the sea ice area is well simulated by the model compared to the satellite remote sensing data for the period of 1996–2017. Overall agreement is found for the occurrence dates of the annual maximum sea ice area. The simulated sea ice thickness and volume are in general agreement with the observations with slight overestimations. NEMO-Bohai can simulate seasonal sea ice evolution and long-term interannual variations. Hence, NEMO-Bohai is a valuable tool for long-term ocean and ice simulations and climate change studies.

Background: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed “surgicogenomics”. Objective: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson’s disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome. Methods: Retrospective clinical data was extracted from 150 patient’s charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score. Results: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2. Conclusion: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.

Graft-versus-host disease (GVHD) is an important complication after allogeneic haematopoietic stem cell transplantation (HSCT). Corticosteroids are the standard first-line treatment. Steroid-resistant/-dependent (SR/D) acute and chronic GVHD (aGVHD, cGVHD) lead to significant morbidity/mortality. The JAK2 inhibitor ruxolitinib has recently been shown in clinical trials to be effective in SR/D aGVHD and cGVHD. We retrospectively analysed the efficacy and safety of ruxolitinib in a cohort of SR/D aGVHD and cGVHD patients treated in a non-trial setting. In the aGVHD cohort, there were 14 men and 12 women, median age at 38 (19–63) years. At day 28 post-ruxolitinib, the overall response rate (ORR) was 86% (complete response, CR, 36%; partial response, PR, 50%). Continued ruxolitinib beyond day 28 resulted in a final CR of 68%. However, 3/15 (20%) of CR patients developed cGVHD. In the cGVHD cohort, there were 16 men and 15 women, median age at 33 (21–64) years. The ORR, CR and PR rates changed with continued ruxolitinib treatment, being 86%, 17% and 69% at 1 month; 79%, 38% and 41% at 3 months; and 83%, 52% and 31% at 6 months. Five patients had overlap GVHD, four of whom achieved CR. Multivariate analysis showed that superior overall survival and failure-free survival were associated with CR at day 28 for aGVHD, and CR at 1 year for cGVHD. Ruxolitinib treatment was efficacious for SR/D aGVHD and cGVHD, and continued treatment for at least 6 months was needed to maximize benefit.

Since a portion of patients with nasopharyngeal carcinoma (NPC) do not benefit much from current standard treatments, it is still needed to discover new therapeutic drugs to improve the prognosis of the patients. Considering that Chinese traditional medicine plays a role in inhibiting tumor progression, in this study, we aimed to investigate whether a Chinese herbal formula, Qing Yan Li Ge Tang (QYLGT), has the anticancer activity in NPC cells and explore the underlying mechanism as well. MTT assay, colony formation assay, immunoblotting assay, and DNA laddering assay were performed to assess cell viability, cell colony formation, protein expression, and DNA fragmentation, respectively. Results show that QYLGT was able to inhibit the cell viability and decrease colony formation ability in NPC cells. QYLGT could also increase the formation of intracellular vacuoles and induce the autophagy-related protein expressions, including Atg3, Atg6, and Atg12-Atg5 conjugate in NPC cells. Treatment with an autophagy inhibitor, 3-methyladenine, could significantly recover QYLGT-inhibited cell viability of NPC cells. In addition, QYLGT did not significantly induce apoptosis in NPC cells. We also found that QYLGT had the ability to activate phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) pathway. Treatment with PI3K inhibitors, LY294002 and wortmannin, or mTOR inhibitors, rapamycin and Torin 1, could not only recover QYLGT-inhibited cell viability of NPC cells but also inhibit Atg3 expression. Taken together, our results demonstrated that QYLGT could induce autophagic cell death in NPC cells through the PI3K/Akt/mTOR pathway.

Background Sex determining region Y-box 2 (SOX2) has been reported as a potential therapeutic target for cancer. However, the role of SOX2 in cervical cancer remains largely undetermined. This study was performed to evaluate the correlation of SOX2 with clinical characteristics and prognosis in cervical cancer. Methods Multiple databases were systematically searched for eligible publications. The combined odds ratios (ORs) or hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were used to assess the effect sizes. Results A total of 17 studies with 1906 participants were identified. SOX2 expression was higher in cervical cancer than in the normal control group (OR = 10.83, 95% CI = 6.64–17.67, P < 0.001), while no significant difference was observed between cervical cancer and cervical intraepithelial neoplasia. SOX2 expression was not associated with age, tumor stage, and lymph node metastasis, but was correlated with tumor grade (grade 2–3 vs. grade 1: OR = 4.59, 95% CI = 2.76–7.62, P < 0.001) and tumor size (≥4 cm vs. ≤4 cm: OR = 1.66, 95% CI = 1.05–2.60, P = 0.028). Based on multivariate Cox analysis, SOX2 expression was not correlated with overall survival, but was closely associated with poor recurrence-free survival (HR = 5.83, 95% CI = 1.35–25.16, P = 0.018) and progress-free survival HR = 2.29, 95% CI = 1.01–5.19, P = 0.046). Conclusion SOX2 may serve as a novel prognostic factor and a promising molecular target for cervical cancer.

Despite several recent advances, current therapy and prevention strategies for myocardial infarction are far from satisfactory, owing to limitations in their applicability and treatment effects. Nanoparticles (NPs) enable the targeted and stable delivery of therapeutic compounds, enhance tissue engineering processes, and regulate the behaviour of transplants such as stem cells. Thus, NPs may be more effective than other mechanisms, and may minimize potential adverse effects. This review provides evidence for the view that function-oriented systems are more practical than traditional material-based systems; it also summarizes the latest advances in NP-based strategies for the treatment and prevention of myocardial infarction.

Upregulated expression of immune checkpoint molecules correlates with exhausted phenotype and impaired function of cytotoxic T cells to evade host immunity. By disrupting the interaction of PD-L1 and PD1, immune checkpoint inhibitors can restore immune system function against cancer cells. Growing evidence have demonstrated apigenin and luteolin, which are flavonoids abundant in common fruits and vegetables, can suppress growth and induce apoptosis of multiple types of cancer cells with their potent anti-inflammatory, antioxidant and anticancer properties. In this study, the effects and underlying mechanisms of luteolin, apigenin, and anti-PD-1 antibody combined with luteolin or apigenin on the PD-L1 expression and anti-tumorigenesis in KRAS-mutant lung cancer were investigated. Luteolin and apigenin significantly inhibited lung cancer cell growth, induced cell apoptosis, and down-regulated the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3. Both luteolin and apigenin showed potent anti-cancer activities in the H358 xenograft and Lewis lung carcinoma model in vivo, and the treatment with monoclonal PD1 antibody enhanced the infiltration of T cells into tumor tissues. Apigenin exhibited anti-tumor activity in Genetically engineered KRASLA2 mice. In conclusion, both apigenin and luteolin significantly suppressed lung cancer with KRAS mutant proliferation, and down-regulated the IFN-γ induced PD-L1 expression. Treatment with the combination of PD-1 blockade and apigenin/luteolin has a synergistic effect and might be a prospective therapeutic strategy for NSCLC with KRAS-mutant.

The pulsatile stress in the microcirculation may contribute to development or progression of chronic kidney disease. However, there is no prospective data confirming whether pulsatile stress in early life affect renal function in middle age. The authors performed a longitudinal analysis of 1738 participants aged 6–15 years at baseline, an ongoing Adolescent Prospective Cohort with a follow‐up of 30 years. The authors evaluated the association between pulsatile stress in childhood and adult subclinical renal damage (SRD), adjusting for related covariates. Pulsatile stress was calculated as resting heart rate × pulse pressure. Renal function was assessed with estimated glomerular filtration rate (eGFR) and urine albumin‐to‐creatinine ratio (uACR). The results showed that pulsatile stress in childhood was associated with adult SRD (Relative Risk, 1.43; p = .032), and the predictive value of combined pulse pressure and heart rate for SRD was higher than either of them alone. The high pulsatile stress in childhood increased the risk of adult SRD in males (RR, 1.92; p = .003), but this association was not found in females (RR, 0.91; p = .729). Further, the participants were categorized into four groups on the basis of pulsatile stress status in childhood and adulthood. Male patients with high pulsatile stress during childhood but normal pulsatile stress as adults still had an increased risk of SRD (RR, 2.04; 95% CI, 1.18–3.54), while female patients did not (RR, 0.96; 95% CI, 0.46–1.99). The study demonstrated that high pulsatile stress in childhood significantly increased the risk of adult SRD, especially in males. Adequate control of pulse pressure and heart rate from childhood, in the long‐term, is very important for preventing kidney damage.

Expression of β-crystallin B2 (CRYβB2) is elevated in African American (AA) breast tumors. The underlying mechanisms of CRYβB2-induced malignancy and the association of CRYβB2 protein expression with survival have not yet been described. Here, we report that the expression of CRYβB2 in breast cancer cells increases stemness, growth, and metastasis. Transcriptomics data revealed that CRYβB2 upregulates genes that are functionally associated with unfolded protein response, oxidative phosphorylation, and DNA repair, while down-regulating genes related to apoptosis. CRYβB2 in tumors promotes de-differentiation, an increase in mesenchymal markers and cancer-associated fibroblasts, and enlargement of nucleoli. Proteome microarrays identified a direct interaction between CRYβB2 and the nucleolar protein, nucleolin. CRYβB2 induces nucleolin, leading to the activation of AKT and EGFR signaling. CRISPR studies revealed a dependency on nucleolin for the pro-tumorigenic effects of CRYβB2. Triple-negative breast cancer (TNBC) xenografts with upregulated CRYβB2 are distinctively sensitive to the nucleolin aptamer, AS-1411. Lastly, in AA patients, higher levels of nucleolar CRYβB2 in primary TNBC correlates with decreased survival. In summary, CRYβB2 is upregulated in breast tumors of AA patients and induces oncogenic alterations consistent with an aggressive cancer phenotype. CRYβB2 increases sensitivity to nucleolin inhibitors and may promote breast cancer disparity.

Aims Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms. Method and results MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and type 2 innate lymphoid cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation. Conclusion IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis. Translational perspective Accumulating evidence suggests that modulation of innate and adaptive immune responses is a promising therapeutic strategy for myocardial infarction. In this study, we demonstrate that IL-5 exerts cardioprotective effects on infarcted myocardium by promoting eosinophil accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis. Hence, regulation of cardiac IL-5 level or eosinophil count may become a therapeutic approach for post-myocardial infarction cardiac repair in humans.

Freezing of gait (FOG) is considered one of the most disturbing and least understood symptoms in Parkinson’s disease (PD). The reported prevalence rates of FOG in PD vary widely, ranging from 5 to 85.9%. We conducted a systematic review and meta-analysis to provide a reliable estimate of the average point prevalence of FOG in PD, and we further investigated the study characteristics that might have influenced the estimate. We searched different databases to identify studies that report the prevalence of FOG in PD or include relevant raw data for further calculation. The last inclusion date was February 20, 2020. The modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used for the quality assessment, and articles that met the predefined criteria were included in the quantitative analysis. Sixty-six studies were selected from 3392 references. A weighted prevalence of 50.6% in 9072 PD patients experienced FOG based on the special questionnaires (the FOG-Q and NFOG-Q), which was about twice as high as that assessed by the specific items of the clinical rating scales (UPDRS item2.14 and MDS-UPDRS item3.11) (23.2%) or simple clinical questions (25.4%). The weighted prevalence was 37.9% for early stage (≤ 5 years) and 64.6% for advanced stage (≥ 9 years). Moreover, a higher prevalence was calculated from the population-based studies than that in multicenter and single-center studies (47.3% vs. 33.5% and 37.1%, respectively). The result from this systematic review confirms that FOG is very common in PD and its prevalence is usually underestimated in hospital settings. Importantly, a more accurate assessment of FOG in future clinical researches would involve the use of special FOG scale rather than a single item on a scale or a general clinical inquiry.

Kai Yuan,1,2 Jin Long Zhang,2 Jie Yu Yan,2 Bing Yuan,1 Jin Xin Fu,2 Yan Wang,2 Xue Dong Sun,3 Yang Guan,2 Feng Duan,2 Mao Qiang Wang1,2 1Medical School of Chinese PLA, Beijing, 100853, People’s Republic of China; 2Department of Interventional Radiology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 3School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of ChinaCorrespondence: Mao Qiang WangDepartment of Interventional Radiology, The Fifth Medical Center, Chinese PLA General Hospital, 28 Fu-Xing Road, Beijing, 100853, People’s Republic of ChinaTel +86 10-66937190Email wangmq@vip.sina.comPurpose: To assess the long-term outcome of performing uterine artery embolization (UAE) using small particles in women with symptomatic adenomyosis (AD).Methods: Twenty-seven consecutive women (median age 42 years, range 29– 53 years) with AD, in eight cases AD combined with fibroids, who underwent UAE between February 2015 and January 2019, were retrospectively analyzed. The embolization was performed using small-sized polyvinyl alcohol particles (100 μm and 300 μm). The patients completed the Uterine Fibroid Symptom and Quality of Life questionnaire at baseline and at a 42-month follow-up (range 24– 71). The junction zone (JZ) thickness and uterine volume were also calculated at baseline and at a three-month follow-up.Results: The total symptom severity score (SSS) decreased from a median of 59 (range 34– 78) at baseline to a median of 9 (range 3– 47) at the end of this study; the health-related quality of life score (HRQOL) increased from a median of 38 (range 23– 49) at baseline to a median of 84 (range 46– 97) at 42 months. Twenty of the 27 patients were asymptomatic. The clinical response of the remaining seven women was little improvement in their symptoms, and one of the seven women underwent a hysterectomy at 35 months. Twenty-six of the 27 (96%) patients had a preserved uterus at the 42-month follow-up. There was no difference after UAE in SSS, HRQOL, junction zone (JZ) thickness, and uterus volume between patients with pure AD and those with AD combined with fibroids (p = 0.729, 0.710, 0.973, and > 0.99). There was no difference in the JZ thickness and uterus volume at baseline between the asymptomatic women and the women with an insufficient response (p = 0.854 and 0.253), and there were no major complications afterwards.Conclusion: From the long-term follow-ups, it could be seen that UAE using small particles is safe and effective in treating AD, especially in preserving the uterus. There is no relationship between the clinical outcomes and the initial presence of AD, with or without fibroids, and the JZ thickness at baseline does not seem to be a predictor for the long-term outcome of UAE.Keywords: adenomyosis, uterine artery embolization, UFS–QoL, interventional radiology

Acute myocardial infarction (AMI) is an event of ischemic myocardial necrosis caused by acute coronary artery occlusion, which ultimately leads to a large loss of cardiomyocytes. The prerequisite of salvaging ischemic myocardium and improving cardiac function of patients is to provide adequate blood perfusion in the infarcted area. Apart from reperfusion therapy, it is also urgent and imperative to promote angiogenesis. Recently, growing evidence based on promising preclinical data indicates that mesenchymal stem cells (MSCs) can provide therapeutic effects on AMI by promoting angiogenesis. Extracellular vesicles (EVs), membrane-encapsulated vesicles with complex cargoes, including proteins, nucleic acids, and lipids, can be derived from MSCs and represent part of their functions, so EVs also possess the ability to promote angiogenesis. However, poor control of the survival and localization of MSCs hindered clinical transformation and made scientists start looking for new approaches based on MSCs. Identifying the role of MSCs and their derived EVs in promoting angiogenesis can provide a theoretical basis for improved MSC-based methods, and ultimately promote the clinical treatment of AMI. This review highlights potential proangiogenic mechanisms of transplanted MSCs and the derived EVs after AMI and summarizes the latest literature concerning the novel methods based on MSCs to maximize the angiogenesis capability.

Background and purpose. A single nucleotide polymorphism at nucleotide 196 (G/A) in the human brain-derived neurotrophic factor ( BDNF) gene produces an amino acid substitution (valine to methionine) at codon 66(Val66Met). It is unclear whether carriers of this substitution may have worse functional outcomes after stroke. We aimed to explore the distribution of Val66Met polymorphism and evaluate the effect of different genotypes on stroke functional recovery. Methods. Several databases were searched using the keywords BDNF or brain-derived neurotrophic factor, codon66, G196A, rs6265, or Val66Met, and stroke. Results. A total of 25 articles were relevant to estimate the distribution of alleles; 5 reports were applied in the meta-analysis to assess genetic differences on recovery outcomes. The genetic model analysis showed that the recessive model should be used; we combined data for AA versus GA+GG (GG—Val/Val, GA—Val/Met, AA—Met/Met). The results showed that stroke patients with AA might have worse recovery outcomes than those with GA+GG (odds ratio = 1.90; 95% CI: 1.17-3.10; P = .010; I2 = 69.2%). Overall, the A allele may be more common in Asian patients (48.6%; 95% CI: 45.8%-51.4%, I2 = 54.2%) than Caucasian patients (29.8%; 95% CI: 7.5%-52.1%; I2 = 99.1%). However, in Caucasian patients, the frequency of the A allele in Iranians (87.9%; 95% CI: 83.4%-92.3%) was quite higher than that in other Caucasians (18.7%; 95% CI: 16.6%-20.9%; I2 = 0.00%). Conclusion. Val66Met AA carriers may have worse rehabilitation outcomes than GA+GG carriers. Further studies are needed to determine the effect of Val66Met polymorphism on stroke recovery and to evaluate this relationship with ethnicity, sex, age, stroke type, observe duration, stroke severity, injury location, and therapies.

Placentation and tumorigenesis have many common features. Human placentation builds a maternal–fetal connection, circumvents maternal immune rejection of the fetus, and utilizes mechanisms that support tumorigenesis, such as proliferation, invasion, angiogenesis, and immune tolerance. Trophoblasts of the human placenta mimic the behavior of malignant cells, proliferating and invading the uterine decidua until reaching the myometrium and remodeling the spiral arteries that establish a new vascular system and escape the maternal immune response. These processes are under precise temporal and spatial regulation, and their dysregulation is associated with different pregnancy syndromes, including preeclampsia (PE), a pregnancy syndrome that is the leading cause of maternal and perinatal mortality and morbidity. At present, the precise mechanisms underlying the development of PE remain unclear. Here, we summarize and dissect the features between physiological placentation and pathological tumorigenesis to explore the pathogenesis of PE – which we believe to be the result of insufficient placentation, compared to the overaggression of tumorigenesis – to provide novel strategies to prevent and treat PE.

Purpose - The present study aimed to identify differently expressed peptides involved in BC as potential biomarkers. Experimental Design - The serum proteomic profiling of 128 serum samples from 64 BC patients and 64 healthy controls (HC), using magnetic beads based immobilized metal ion affinity chromatography (MB-IMAC-Cu) separation followed by MALDI-TOF MS. ClinProTools software identified a number of distinct markers. Then, we performed liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) to identify the candidate serum biomarker based on serum proteomics analysis. Finally, enzyme-linked immunosorbent assays (ELISAs) were used to verify the expression of the candidate serum biomarker in BC patients. Results - BC patients could be identified with sensitivity of 87.32% and specificity of 89.46%. Of 41 m/z peaks that differed between BC and HC, six peaks were significantly different between BC and HC (P0.01, fold change1.5), with peak 1 upregulated and peaks 2-6 downregulated in the BC group. The upregulated peak 1 (m/z: 6638.63) is identified as a region of apolipoprotein C1 (APOC1), and validation showed that APOC1 expression increased from healthy controls to those with FA as well as mastopathy, and finally BC patients. Conclusions and Clinical Relevance - The present study indicates that APOC1 could serve as a candidate serum diagnostic biomarker for BC.

Stage 1 hypertension, newly defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guideline, has been the subject of significant interest globally. This study aims to assess the impact of the new blood pressure (BP) stratum on subsequent subclinical cardiovascular outcomes in low‐risk young adults. This longitudinal study consisted of 1020 young adults (47.7% female; ages 18–23 years) free of cardiovascular disease from the Hanzhong Adolescent Hypertension Cohort with up to 25‐year follow‐up since 1992–1995. Outcomes were available through June 2017. Young adults with stage 1 hypertension accounted for 23.7% of the cohort. When it comes to middle adulthood, subjects with early life stage 1 hypertension were more likely to experience BP progression, and they had a 1.61‐fold increased risk of high‐risk brachial‐ankle pulse wave velocity (baPWV) and a 2.92‐fold risk of left ventricular hypertrophy (LVH) comparing with their normotensive counterparts. Among participants without any active treatment in midlife, the risk associated with stage 1 hypertension for BP progression was 2.25 (95% confidence interval [CI] = 1.41–3.59), high‐risk baPWV was 1.58 (95% CI = 1.09–2.79), LVH was 2.75 (95% CI = 1.16–6.48), and subclinical renal damage (SRD) was 1.69 (95% CI = 1.02–2.82) compared with the normal BP group. Overall, young adults with stage 1 hypertension had significantly higher risks for midlife subclinical cardiovascular outcomes than normotensive subjects. BP management targeting low‐risk young adults is of importance from both clinical and public health perspectives.

Rectal cancer is a life‑threatening disease worldwide. Chemotherapy resistance is common in rectal adenocarcinoma patients and has unfavorable survival outcomes; however, its related molecular mechanisms remain unknown. To identify genes related to the initiation and progression of rectal adenocarcinoma, three datasets were obtained from the Gene Expression Omnibus database. In total, differentially expressed genes were analyzed from 294 tumor and 277 para-carcinoma samples from patients with rectal cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functions were investigated. Cytoscape software and MicroRNA Enrichment Turned Network were applied to construct a protein-protein interaction network of the dependent hub genes and related microRNAs. The Oncomine database was used to identify hub genes. Additionally, Gene Expression Profiling Interactive Analysis was applied to determine the RNA expression level. Tumor immune infiltration was assessed using the Tumor Immune Estimation Resource database. The expression profiles of hub genes between stages, and their prognostic value, were also evaluated. During this study, data from The Cancer Genome Atlas were utilized. In rectal adenocarcinoma, four hub genes including CXCL1, CXCL2, CXCL3, and GNG4 were highly expressed at the gene and RNA levels. The expression of CXCL1, CXCL2, and CXCL3 was regulated by has-miR-1-3p and had a strong positive correlation with macrophage and neutrophil. CXCL2 and CXCL3 were differentially expressed at different tumor stages. High expression levels of CXCL1 and CXCL3 predicted poor survival. In conclusion, the CXCL1 and CXCL3 genes may have potential for prognosis and molecular targeted therapy of rectal adenocarcinoma., Graphical abstract

Introduction: Programming directional leads poses new challenges as the optimal strategy is yet to be established. We designed a randomized control study to establish an evidence-based programming algorithm for patients with Parkinson’s disease undergoing subthalamic nucleus deep brain stimulation with directional leads. Methods: Fourteen consecutive patients were randomized to programming with either early or delayed (i.e., starting with a “ring mode”) steered stimulation. Motor scores, number of programming visits, calls to the clinic, battery consumption, and stimulation adjustments required were recorded and compared between groups, using the Wilcoxon signed-ranks test, after 3 months of open-label programming. Results: Thirteen patients (25 electrodes) were included, of which 23 were steerable. Nine out of 14 electrodes allocated to delayed steered stimulation were changed to steered mode due to side effects during the course of the study. No patients (11 electrodes) initially allocated to early steered stimulation were converted to ring mode. The 2 study arms did not differ in any of the considered measures at 3 months. Conclusion: Programming with early or delayed steered stimulation is equally effective in the short term. However, delayed steering is less time consuming and is not always needed.

A combination of chemotherapy and targeted magnetic hyperthermia (TMH) via a designed magnetic nanocrystal (MNC) drug delivery system was considered as an effective tumor synergistic therapy strategy. In this paper, we successfully synthesized tumor neovascular-targeted Mn-Zn ferrite MNCs, which encapsulated paclitaxel (PTX) in a biocompatible PEG-phospholipid (DSPE-PEG2000) layer and surface, simultaneously coupled with a tripeptide of arginine-glycine-aspartic acid (RGD). The high-performance RGD-modified MNC loaded with PTX (MNCs-PTX@RGD) embodied excellent magnetic properties, including high-contrast magnetic resonance imaging (MRI) and remarkable magnetically induced heat generation ability. We established the mouse model bearing subcutaneous 4T1 breast tumor, and demonstrated that MNCs-PTX@RGD could be effectively located in the tumor neovascular epithelial cells under the guidance of in vivo MRI. Notably, MNCs-PTX@RGD could easily penetrate into the tumor tissue from the tumor-fenestrated vascular networks for capturing a sufficient temperature (around 43 °C) exposed to an alternative current magnetic field (ACMF, 2.58 kA m-1, 390 kHz), leading to an effective TMH effect. Subsequently, the TMH-mediated temperature elevation accelerated the PTX release from the inner lipid layer, promoting the synergetic thermo-chemotherapy in vivo. The amplifying synergistic treatment strategy obviously improved the anti-tumor efficacy of MNCs-PTX@RGD, and simultaneously increased the survival time of the mice to more than 46 days, which provided a broad development prospect in clinical applications.

Background No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD). Objective Study's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD. Methods Thirty-five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single-blind study. All patients were reevaluated in short- (3 months), mid- (6 months), and long-term (2.5 years) follow-up after surgery. The primary outcome measure was the change in the Non-Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non-motor symptoms (NMS). Analysis was performed primarily in the intention-to-treat population. Results Randomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: -11.78-21.53, P = 0.566]). In short- and mid-term follow-up, monotherapy was safe and feasible in more than half of patients (60% in short- and 51.5% in mid-term follow-up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders. Conclusions This trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background:Posaconazole is superior to fluconazole/itraconazole in preventing invasive fungal diseases (IFDs) in neutropenic patients. Whether the higher cost of posaconazole is offset by decreases in IFDs in a given institute requires cost-effective analysis encompassing the spectrum of IFDs and socioeconomic factors specific to that geographic area.Methods:This study performed a cost-effective analysis of posaconazole prophylaxis for IFDs in an Asian teaching hospital, employing decision modeling and data of IFDs and medication costs specific to the institute, in neutropenic patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).Results:In the cost-effectiveness analysis, the higher cost of posaconazole was partially offset by a reduction in the cost of treating IFDs that were prevented, resulting in an incremental cost of 125,954 Hong Kong dollars/16,148 USD per IFD avoided. Over a lifetime horizon, assuming same case fatality rate of IFDs in both groups, use of posaconazole results in 0.07 discounted life years saved. This corresponds to an incremental cost of 116,023 HKD/14,875 USD per life year saved. This incremental cost per life year saved in posaconazole prophylaxis fulfilled the World Health Organization defined threshold for cost-effectiveness.Conclusion:Posaconazole prophylaxis was cost-effective in Hong Kong.

Background/objectives Chronic kidney disease (CKD) is a global public health problem, including in China. The aim of this study was to identify the risk factors for the development and progression of subclinical renal disease (SRD) in a Chinese population. We also examined whether the impact of the risk factors on SRD changed over time. Subjects/methods To identify the predictors of SRD, we performed a cross-sectional study of the 2432 subjects in our Hanzhong Adolescent Hypertension Cohort. A subgroup of 202 subjects was further analyzed over a 12-year period from 2005 to 2017 to determine the risk factors for the development and progression of SRD. Results In cross-sectional analysis, elevated blood pressure, male gender, diabetes, body mass index, and triglyceride were independently associated with a higher risk of SRD. In longitudinal analysis, an increase in total cholesterol over a 4-year period and an increase in serum triglyceride over a 12-year period were independently associated with progression of albuminuria. Finally, increases in both total cholesterol and serum uric acid over a 4-year follow-up showed an independent association with a modest reduction in estimated glomerular filtration rate (eGFR). Conclusions In this study of a Chinese cohort, we show several metabolic abnormalities as independent risk factors for subclinical renal disease in a Chinese cohort. In addition, we demonstrate that the effects of total cholesterol, triglycerides and uric acid on the development and progression of albuminuria or the decline in eGFR vary at different points of follow-up. These findings highlight the importance of early detection of metabolic abnormalities to prevent SRD.

Transforming growth factor β (TGF-β)/Smad3 signaling plays a central role in chronic heart disease. Here, we report that targeting Smad3 with a Smad3 inhibitor SIS3 in an established mouse model of hypertension significantly improved cardiac dysfunctions by preserving the left ventricle (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS), while reducing the LV mass. In addition, SIS3 treatment also halted the progression of myocardial fibrosis by blocking α-smooth muscle actin-positive (α-SMA+) myofibroblasts and collagen matrix accumulation, and inhibited cardiac inflammation by suppressing interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP1), intercellular cell adhesion molecule-1 (ICAM1) expression, and infiltration of CD3+ T cells and F4/80+ macrophages. Interestingly, treatment with SIS3 did not alter levels of high blood pressure, revealing a blood pressure-independent cardioprotective effect of SIS3. Mechanistically, treatment with SIS3 not only directly inactivated TGF-β/Smad3 signaling but also protected cardiac Smad7 from Smurf2-mediated proteasomal ubiquitin degradation. Because Smad7 functions as an inhibitor for both TGF-β/Smad and nuclear factor κB (NF-κB) signaling, increased cardiac Smad7 could be another mechanism through which SIS3 treatment blocked Smad3-mediated myocardial fibrosis and NF-κB-driven cardiac inflammation. In conclusion, SIS3 is a therapeutic agent for hypertensive heart disease. Results from this study demonstrate that targeting Smad3 signaling with SIS3 may be a novel and effective therapy for chronic heart disease., Graphical Abstract, Meng and colleagues developed a novel and effective therapy for hypertensive heart disease by specifically targeting Smad3, a key mediator of downstream TGF-β signaling, with a Smad3 inhibitor SIS3. They found that SIS3 treatment significantly improved cardiac dysfunctions and suppressed myocardial fibrosis and inflammation in an established mouse model of hypertension.

Background Dyslipidemia is a disorder of lipid metabolism and associated with insulin resistance. The relationship between longitudinal body mass index (BMI) changes from childhood to adulthood and long-term dyslipidemia was explored in this study. Methods We assessed the longitudinal relationship between BMI changes since childhood and dyslipidemia among 1738 participants in rural areas of Hanzhong City, Shaanxi. All participants were initially examined between the ages of 6 and 15 years in 1987 and were reexamined in 1995, 2013 and 2017; the total follow-up duration was 30 years. Anthropometric measurements and blood biochemistry indexes were measured. Results We found that gradual progression of normal weight to overweight (OR = 1.65; 95% CI = 1.27, 2.15) or persistent overweight (OR = 2.45; 95% CI = 1.52, 3.96) from childhood to adulthood was associated with an increased risk of dyslipidemia in adulthood. And these risks were largely disappeared if the overweight or obesity during childhood was resolved by adulthood. The higher the BMI in adulthood and the younger the age at which overweight begins, the higher the risk of dyslipidemia. Conclusions Early weight loss and any degree of weight loss from childhood to adulthood can help improve dyslipidemia in adulthood. We further emphasize the importance of weight management and control in public health primary prevention.

Thyroid cancer (TC) is a frequently occurring malignant tumor with a rising steadily incidence. microRNA (miRNA/miR)-193a-3p is an miRNA that is associated with tumors, playing a crucial role in the genesis and progression of various cancers. However, the expression levels of miR-193a-3p and its molecular mechanisms in TC remain to be elucidated. The present study aimed to probe the expression of miR-193a-3p and its clinical significance in TC, including its underlying molecular mechanisms. Microarray and RNA sequencing data gathered from three major databases, specifically Gene Expression Omnibus (GEO), ArrayExpress and The Cancer Genome Atlas (TCGA) databases, and the relevant data from the literature were used to examine miR-193a-3p expression. Meta-analysis was also conducted to evaluate the association between clinicopathological parameters and miR-193a-3p in 510 TC and 59 normal samples from the TCGA database. miRWalk 3.0, and the TCGA and GEO databases were used to predict the candidate target genes of miR-193a-3p. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction network enrichment analyses were conducted by using the predicted candidate target genes to investigate the underlying carcinogenic mechanisms. A dual luciferase assay was performed to validate the targeting regulatory association between the most important hub gene cyclin D1 (CCND1) and miR-193a-3p. miR-193a-3p expression was considerably downregulated in TC compared with in the non-cancer controls (P

Breast cancer is one of the most common cancers in women worldwide. In the past decades, many advances have been made in understanding and treating breast cancer. However, due to the highly heterogeneous nature of this disease, a precise characterization of breast cancer on the molecular level is of great importance but not yet readily available. In the present study, we systematically profiled proteomes and N-glycoproteomes of cancerous, paracancerous, and distal noncancerous tissues from patients with breast cancer. The data revealed distinct proteomic and N-glycoproteomic landscapes between different tissues, showing biological insights obtained from the two data sets were complementary. Specifically, the complement and angiogenesis pathways in the paracancerous tissues were activated. Taken together, the changes that occurred in paracancer tissue and N-glycoproteomics are important complements to the conventional proteomic analysis of cancer tissue. Their combination provides more precise and sensitive molecular correlates of breast cancer. Our data and strategy shed light on precisely defining breast cancer, providing valuable information for individual patient diagnosis and treatment. The MS data of this study have been deposited under the accession number IPX0001924000 at iProX.

Dyspnea can be present as non-motor symptom in patients with Parkinson’s disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor and non-motor symptoms in PD. However, new-onset dyspnea has been reported after DBS surgery. We have studied respiratory characteristics of PD patients with bilateral STN-DBS to assess the impact of DBS on pulmonary function. STN-DBS PD patients with dyspnea after surgery (cases) were matched with STN-DBS PD patients without dyspnea (controls). Motor and pulmonary function were assessed with stimulation and without medication (on stim/off med), and without stimulation and medication (off stim/off med). Pulmonary function was investigated with spirometry and dyspnea with the Medical Research Council Dyspnea Scale (MRCDS) and the Borg Scale (BS). Seven cases (five men, 58.30 ± 6.70 years of age) and seven controls (six men, 61.10 ± 6.30 years of age) were enrolled. MRCDS and BS revealed the presence of dyspnea in both groups. No significant changes in pulmonary function were found in both cases and controls in on stim/off med vs. off stim/off med condition (p

Background/aim Rta, a transactivator of Epstein-Barr virus, is associated with progression of nasopharyngel carcinoma (NPC); however, its mechanism of contribution to the pathogenesis of NPC remains unclear. Interleukin-6 (IL-6), a tumor promoter, is detected in NPC. This in vitro study examined whether and how Rta promotes NPC progression by up-regulating IL-6. Materials and methods Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, ELISA, immunoblotting assays, reporter gene assays, and transwell migration assays were performed. Results In NPC cells, Rta up-regulated IL-6 expression at the mRNA and protein levels, and the Rta's C-terminus was essential for promoter activation and expression of IL-6. The induction of IL-6 by Rta also required activation of extracellular signal-regulated kinase 1/2 and activator protein-1. Furthermore, IL-6 secreted from Rta-expressing NPC cells promoted migration of Rta-negative NPC cells by activating IL-6 receptor/Janus kinase/signal transducer and activator of transcription 3 pathway. Conclusion Rta contributes to progression of NPC cells through induction of IL-6 in vitro.

The mechanism by which miR‐605‐3p regulates hepatocellular carcinoma (HCC) metastasis has not been clarified. In this study, we found that miR‐605‐3p was down‐regulated in HCC and that low miR‐605‐3p expression was associated with tumour thrombus and tumour satellites. HCC patients with low miR‐605‐3p expression showed shorter overall survival and disease‐free survival after surgery. Overexpression of miR‐605‐3p inhibited epithelial‐mesenchymal transition and metastasis of HCC through NF‐κB signalling by directly inhibiting expression of TRAF6, while silencing of miR‐605‐3p had the opposite effect. We also found that SNHG16 directly bound to miR‐605‐3p as a competing endogenous RNA. Mechanistically, high expression of SNHG16 promoted binding to miR‐605‐3p and inhibited its activity, which led to up‐regulation of TRAF6 and sustained activation of the NF‐κB pathway, which in turn promoted epithelial‐mesenchymal transition and metastasis of HCC. TRAF6 increased SNHG16 promoter activity by activating NF‐κB, thereby promoting the transcriptional expression of SNHG16 and forming a positive feedback loop that aggravated HCC malignancy. Our findings reveal a mechanism for the sustained activation of the SNHG16/miR‐605‐3p/TRAF6/NF‐κB feedback loop in HCC and provide a potential target for a new HCC treatment strategy.

Purpose To prospectively assess safety and efficacy of prostatic artery embolization (PAE) with bleomycin-eluting microspheres for benign prostatic hyperplasia (BPH) in a canine model. Materials and Methods Twelve adult male beagles (mean age, 1.6 y ± 0.2; range, 1.2–2.0 y) were randomly assigned to group A (n = 6; PAE with bleomycin-eluting 30–60-μm HepaSphere microspheres) and group B (n = 6; PAE with bland 30–60-μm HepaSphere microspheres) between April 2017 and November 2018. Plasma bleomycin concentration in group A was measured within 7 days. Prostate volume (PV) and ischemic volume after PAE were measured by magnetic resonance imaging. Prostates and adjacent organs were harvested after the last magnetic resonance study and histopathologically examined. Results Plasma bleomycin concentration peaked at 10 minutes at 2,055.0 ng/mL ± 606.1 and lasted for 1,440 min at low levels after PAE. PV reduction percentage was greater in group A than in group B at 1 month (74.1% ± 4.3 vs 63.7% ± 3.5; P = .006) and 3 months (61.5% ± 6.7 vs 46.1% ± 3.8; P = .001) after PAE. Proportion of prostate ischemic volume was greater in group A than in group B (75.3% ± 3.0 vs 62.0% ± 7.1; P = .006) at 1 month after PAE. Proportion of prostate ischemic volume at 1 month positively correlated with PV percentage reduction at 3 months in group A (r = 0.840, P = .036) and group B (r = 0.844, P = .035). There were no complications or nontarget embolization to surrounding organs after the procedures. Conclusions In a canine model, PAE with bleomycin-eluting microspheres was feasible and well tolerated and caused ischemic necrosis and reduction in PV.

Introduction: Venous thromboembolism (VTE) is a frequent and serious complication in cancer patients. Nonetheless, patients with hematological cancers receive less attention as compared with their solid tumor counterparts regarding this potentially fatal complication.Areas covered: Risk factors that are associated with the development of VTE in hematological cancers are discussed, based on a PubMed literature search. Since different hematological malignancies carry different risks of VTE, risk assessment in individual types of hematological cancers, including acute leukemias, lymphomas, myeloma, and myeloproliferative neoplasms are examined separately. Clinical relevance of VTE assessment and current guidelines on thromboprophylaxis in patients with hematological malignancies are also briefly reviewed.Expert opinion: When assessing VTE risk in patients with hematological cancers, in addition to the non-cancer specific risk factors, individual cancer-type-specific and the therapy-related factors must be taken into consideration. Primary thromboprophylaxis should be considered in high-risk patients.

Cisplatin is a platinum-based first-line drug for treating ovarian cancer. However, chemotherapy tolerance has limited the efficacy of cisplatin for ovarian cancer patients. Research has demonstrated that cisplatin causes changes in cell survival and death signaling pathways through its interaction with macromolecules and organelles, which indicates that investigation into the DNA off-target effects of cisplatin may provide critical insights into the mechanisms underlying drug resistance. The multifunctional protein p62 works as a signaling hub in the regulation of pro-survival transcriptional factors NF-κB and Nrf2 and connects autophagy and apoptotic signals, which play important roles in maintaining cell homeostasis. In this review, we discuss the role of p62 in cisplatin resistance by exploring p62-associated signaling pathways based on current studies and our work. Insights into these resistance mechanisms may lead to more effective therapeutic strategies for ovarian cancer by targeting p62.

Background Freezing of gait (FOG) is a common, disabling symptom of Parkinson’s disease (PD), but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers. The main focus of this review is to summarize the possible mechanisms underlying FOG, the risk factors for screening and predicting the onset of FOG, and the clinical trials involving various therapeutic strategies. In addition, the limitations and recommendations for future research design are also discussed. Main body In the mechanism section, we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG. In the risk factor section, gait disorders, PIGD phenotype, lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence. In the treatment section, we summarized the clinical trials of pharmacological and non-pharmacological treatments. Despite the limited effectiveness of current medications for FOG, especially levodopa resistant FOG, there were some drugs that showed promise such as istradefylline and rasagiline. Non-pharmacological treatments encompass invasive brain and spinal cord stimulation, noninvasive repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) and vagus nerve stimulation (VNS), and physiotherapeutic approaches including cues and other training strategies. Several novel therapeutic strategies seem to be effective, such as rTMS over supplementary motor area (SMA), dual-site DBS, spinal cord stimulation (SCS) and VNS. Of physiotherapy, wearable cueing devices seem to be generally effective and promising. Conclusion FOG model hypotheses are helpful for better understanding and characterizing FOG and they provide clues for further research exploration. Several risk factors of FOG have been identified, but need combinatorial optimization for predicting FOG more precisely. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggested that some therapeutic strategies showed promise.

Objective This study aims to investigate the relationship between serum uric acid and arterial stiffness in a healthy population. Methods Among the 979 participants, baPWV was non-invasively measured, the circulating levels of uric acid were tested, and the uric acid polymorphisms (rs2231142 and rs11722228) were genotyped. Then, the Mendelian randomization method was employed to test the relationship between serum uric acid and arterial stiffness in a healthy population. Results After adjusting for age, gender, antihypertensive medication, body mass index, waist-to-hip ratio, urea nitrogen, creatinine and diabetic mellitus, there was a significant allelic difference in uric acid levels for each genotype ( P < 0.0001 for rs2231142; P = 0.007 for rs11722228). However, there were no differences on the potential confounders between the genotypes of rs2231142 and rs11722228 ( P > 0.05). The baPWV was significantly associated with circulating levels of uric acid after adjusting for cardiovascular risk factors and other potential confounders ( P = 0.002). However, neither the single polymorphism, nor the accumulation of culprit alleles was associated with baPWV ( P = 0.92 for rs2231142; P = 0.60 for rs11722228; P for trend = 0.77 for the combined analysis of culprit alleles). Conclusion These results do not support the causal role of circulating levels of uric acid in the development of arterial stiffness.

Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18‐ to 65‐year‐old AML patients refractory to first‐line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high‐dose cytarabine consolidation, with clofarabine (30 mg/m2/d, Days 1‐5), cytarabine (750 mg/m2/d, Days 1‐5), and mitoxantrone (12 mg/m2/d, Days 3‐5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo‐HSCT). The mutational profile of a 69‐gene panel was evaluated. Twenty‐six men and 26 women at a median age of 46 (22‐65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty‐two CR/CRi patients underwent allo‐HSCT. The 2‐year overall survival (OS), relapse‐free survival (RFS), and event‐free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo‐HSCT (P = .005), and superior RFS and EFS were associated with allo‐HSCT (P, Fifty‐two patients with relapsed/refractory acute myeloid leukemia (AML) were treated with clofarabine, cytarabine, and mitoxantrone. The overall response rate (ORR) was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematological recovery, CRi: 21.2%), with 22 CR/CRi patients undergoing allogeneic hematopoietic stem cell transplantation (allo‐HSCT), while in CR; resulting in a 2‐year OS of 84.3% in CR patients and 90% in patients receiving allo‐HSCT. Clofarabine, cytarabine, and mitoxantrone resulted in high ORR and was safe in refractory/relapsed AML.

In order to study the therapeutic effect and possible mechanism of Precise Hyperthermic Intraperitoneal Chemotherapy (HIPEC) on gastric cancer, the expression of RP11-356I2.2 in gastric cancer cell lines and tissues was detected by real-time fluorescence quantitative PCR (RT-PCR). Chi-square test was used to analyze the correlation between the expression and clinic pathological parameters. Western blotting was used to detect the expression of RP11-356I2.2 and tumor suppressor geneKLF17 after precise HIPEC. The effect of RP11-356I2.2 on KLF17 protein was observed and expressed by Western blotting and immunofluorescence. COX regression model was used to analyze the relationship between the expression of RP11-356I2.2 and KLF17 and the prognosis of patients with gastric cancer. The results of RT-PCR showed that RP11-356I2.2 was lower in BGC-823, MKN-28, MGC-803, SGC-7901 and MKN-45 than normal stomach cells GES-1 (P

Rationale: The crosstalk between cardiac microvascular endothelial cells (CMECs) and cardiomyocytes (CMs) has emerged as a key component in the development of, and protection against, cardiac diseases. For example, activation of endothelial nitric oxide synthase (eNOS) in CMECs, by therapeutic strategies such as ischemic preconditioning, plays a critical role in the protection against myocardial ischemia/reperfusion (I/R) injury. However, much less is known about the signals produced by CMs that are able to regulate CMEC biology. Here we uncovered one such mechanism using Tongxinluo (TXL), a traditional Chinese medicine, that alleviates myocardial ischemia/reperfusion (I/R) injury by activating CMEC eNOS. The aim of our study is to identify the signals produced by CMs that can regulate CMEC biology during I/R. Methods: Ex vivo, in vivo, and in vitro settings of ischemia-reperfusion were used in our study, with the protective signaling pathways activated in CMECs identified using genetic inhibition (p70s6k1 siRNA, miR-145-5p mimics, etc.), chemical inhibitors (the eNOS inhibitor, L-NNA, and the small extracellular vesicles (sEVs) inhibitor, GW4869) and Western blot analyses. TritonX-100 at a dose of 0.125% was utilized to inactivate the eNOS activity in endothelium to investigate the role of CMEC-derived eNOS in TXL-induced cardioprotection. Results: We found that while CMEC-derived eNOS activity was required for the cardioprotection of TXL, activation of eNOS in CMECs by TXL did not occur directly. Instead, eNOS activation in CMECs required a crosstalk between CMs and CMECs through the uptake of CM-derived sEVs. We further demonstrate that TXL induced CM-sEVs contain increased levels of Long Intergenic Non-Protein Coding RNA, Regulator Of Reprogramming (Linc-ROR). Upon uptake into CMECs, linc-ROR downregulates its target miR-145-5p leading to activation of the eNOS pathway by facilitating the expression of p70s6k1 in these cells. The activation of CMEC-derived eNOS works to increase survival in both the CMECs and the CMs themselves. Conclusions: These data uncover a mechanism by which the crosstalk between CMs and CMECs leads to the increased survival of the heart after I/R injury and point to a new therapeutic target for the blunting of myocardial I/R injury.

Imbalance of redox homeostasis may be responsible for the resistance of cancer to chemotherapy. Currently, increasing studies demonstrated that vitamin K3 (VK3), which promoted the production of ROS, had potential to be developed as an anti-tumor agent. We found SKOV3/DDP cells with high levels of p62 were insensitive to VK3 compared with SKOV3 cells. Furthermore, Nrf2 downstream antioxidant genes such as HO-1(heme oxygenase 1) and NQO1 (NAD (P) H: quinone oxidoreductase 1) were upregulated in SKOV3/DDP cells with VK3 treatment, which indicated VK3 activated Nrf2 signaling in SKOV3/DDP cells. Moreover, co-localization of p62 and Keap1 was also observed. Suppression of p62 expression increased the apoptosis induced by VK3, and the expression of Nrf2, HO-1 and NQO1 were all downregulated in SKOV3/DDP cells. Our results suggested that overexpressed p62 may protect cells from oxidative damage caused by VK3 through activating Keap1/Nrf2 signaling in ovarian cancer.

Background Levodopa-carbidopa intestinal infusion is an effective treatment for motor fluctuations in Parkinson's disease. However, it has been recently associated with emergent complex/atypical dyskinesias. We sought to characterize patients who developed these dyskinesias after levodopa infusion initiation, and to compare these patients to a control population with conventional motor fluctuations. Methods 208 Parkinson's disease patients, treated with levodopa intestinal infusion due to motor fluctuations, were screened for onset and/or worsening of dyskinesias after initiation of levodopa infusion, resistant to the routine titration, and presenting with atypical or unexpected patterns. Patients with extensive follow-up data were enrolled for a longitudinal analysis. Cases were compared to a control sample with conventional motor fluctuations in order to investigate predisposing factors, difference in dyskinesia phenotype, management strategies and dropouts. Results Thirty patients out of 208 (14.4%) reported atypical (i.e. long-lasting) biphasic, biphasic-like (i.e. continuous) or mixed (peak-dose and continuous biphasic) dyskinesias after levodopa infusion. They were compared at baseline and follow-up to a sample of 49 patients with conventional motor fluctuations on levodopa infusion. Both groups had similar demographic and clinical features, except the former having higher prevalence of biphasic dyskinesias while on oral therapy. Biphasic-like dyskinesias in nearly half the number of cases improved with increasing the dopaminergic load, while mixed dyskinesias had the worst outcome and highest dropout rate (58%). Conclusions Atypical biphasic, biphasic-like and complex dyskinesias could hinder the course of patients treated with levodopa infusion. This study further informs the selection process of advanced therapies, particularly in dyskinetic patients.

Neuroendocrine tumors (NETs) are an extremely heterogenous group of malignancies with variable clinical behavior. Molecular imaging of patients with NETs allows for effective patient stratification and treatment guidance and is crucial in selection of targeted therapies. Positron emission tomography (PET) with the radiotracer L-[18F]FDOPA is progressively being utilized for non-invasive in vivo visualization of NETs and pancreatic β-cell hyperplasia. While L-[18F]FDOPA-PET is a valuable tool for disease detection and management, it also exhibits significant diagnostic limitations owing to its inherent physiological uptake in off-target tissues. We hypothesized that the D-amino acid structural isomer of that clinical tracer, D-[18F]FDOPA, may exhibit superior clearance capabilities owing to a reduced in vivo enzymatic recognition and enzyme-mediated metabolism. Here, we report a side-by-side evaluation of D-[18F]FDOPA with its counterpart clinical tracer, L-[18F]FDOPA, for the non-invasive in vivo detection of NETs. In vitro evaluation in five NET cell lines, including invasive small intestinal neuroendocrine carcinomas (STC-1), insulinomas (TGP52 and TGP61), colorectal adenocarcinomas (COLO-320) and pheochromocytomas (PC12), generally indicated higher overall uptake levels of L-[18F]FDOPA, compared to D-[18F]FDOPA. While in vivo PET imaging and ex vivo biodistribution studies in PC12, STC-1 and COLO-320 mouse xenografts further supported our in vitro data, they also illustrated lower off-target retention and enhanced clearance of D-[18F]FDOPA from healthy tissues. Cumulatively our results indicate the potential diagnostic applications of D-[18F]FDOPA for malignancies where the utility of L-[18F]FDOPA-PET is limited by the physiological uptake of L-[18F]FDOPA, and suggest D-[18F]FDOPA as a viable PET imaging tracer for NETs.

BackgroundNon-muscle-invasive bladder cancer (NMIBC) still poses a heavy load for resulting in many new cases which contribute significantly to medical costs. Although many NMIBC guidelines have been developed, their implementation remains deficient.ObjectiveThis study was conducted in order to analyze the knowledge of and compliance with the guidelines for NMIBC of Chinese urologists and to identify associated factors.MethodsWe conducted an online survey between August 2019 and January 2021. Respondents who were more than 65 years old or did not give informed consent were excluded. Linear/logistic regressions were performed to identify factors associated with the knowledge of and compliance with the guidelines of urologists, respectively. McNemar’s tests were used to explore the divergence between knowledge and compliance.ResultsA total of 814 responses were received, and 98.77% of urologists acknowledged the positive effects of high-quality guidelines. The average knowledge score was 6.10 ± 1.28 (out of a full score of 9), and it was positively associated with educational level and the number of guidelines consulted. Only 1.61% and 39.36% of the respondents realized that the guidelines did not recommend further chemotherapy or BCG infusion for low-risk patients. There were 38.87% and 51.84% respondents “often” or more frequently utilizing BCG therapy for intermediate- and high-risk NMIBC patients, respectively. Divergence between knowledge and compliance in performing a second TURBT after incomplete initial resection reached statistical significance (p < 0.001).ConclusionsAlthough the vast majority of urologists acknowledged the positive effects of guidelines, knowledge of and compliance with some recommendations of NMIBC guidelines are still inadequate. Factors associated with guidelines, individual professionals, patients, organizations, and the environment jointly contributed to the non-compliance.

Background Colorectal cancer is one of the most high-risk human malignant tumors. Tumor-associated macrophages (TAMs) represent a substantial proportion of all tumor-infiltrating immune cells in the tumor microenvironment (TME), as it generally displays M1 or M2 phenotype with tumor-inhibiting or tumor-promoting activity. Cucurbitacin B has been reported to produce varieties of pharmacological effects for the treatment of cancer. Methods Cell viability and proliferation were measured by CCK8 as well as colony formation assays, and cell apoptosis were analyzed by flow cytometry. The underlying mechanism was determined using western blot, microscale thermophores and immunofluorescence assays. In addition, the supernatant of cucurbitacin B-induced M2-like macrophages and colon cells were co-cultured in vitro, transwell and wound healing assay were employed to the related phenotypes. Two mouse model were established to investigate the anti-apoptosis and anti-metastasis of cucurbitacin B. Results Herein, our study was performed to evaluate the anti-tumor and anti-metastasis effect of cucurbitacin B. It was observed that cucurbitacin B inhibited the phosphorylation of JAK2 and STAT3, and translocation from the cytosol to the nucleus. Meanwhile, we observed that cucurbitacin B bound to STAT3. Further experimentation demonstrated that cucurbitacin B reduced the polarization of M2 macrophage by down-regulating JAK2/STAT3 signaling pathway. Cucurbitacin B-induced M2-like macrophages was found to diminish the migration of CRC cells. In vitro study suggested that cucurbitacin inhibited the CRC cells proliferation via JAK2/STAT3 and suppressed the cell migration by suppressing M2-like macrophages polarization. Consistent with in vitro results, the cucurbitacin B therapy significantly inhibited tumor growth and metastasis in mice. Moreover, in vivo the treatment with cucurbitacin B enhanced anti-tumor immunity by regulating M2-like macrophages and promoted the expression of CD4 and CD8 in tumor microenvironment. Conclusion Collectively, our results provided that cucurbitacin B might be a potential candidate agent for adjuvant therapy in the process of CRC growth and metastasis.

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder and characterized by early childhood-onset impairments in social interaction and communication, restricted and repetitive patterns of behavior or interests. So far there is no effective treatment for ASD, and the pathogenesis of ASD remains unclear. Genetic and epigenetic factors have been considered to be the main cause of ASD. It is known that endocannabinoid and its receptors are widely distributed in the central nervous system, and provide a positive and irreversible change toward a more physiological neurodevelopment. Recently, the endocannabinoid system (ECS) has been found to participate in the regulation of social reward behavior, which has attracted considerable attention from neuroscientists and neurologists. Both animal models and clinical studies have shown that the ECS is a potential target for the treatment of autism, but the mechanism is still unknown. In the brain, microglia express a complete ECS signaling system. Studies also have shown that modulating ECS signaling can regulate the functions of microglia. By comprehensively reviewing previous studies and combining with our recent work, this review addresses the effects of targeting ECS on microglia, and how this can contribute to maintain the positivity of the central nervous system, and thus improve the symptoms of autism. This will provide insights for revealing the mechanism and developing new treatment strategies for autism.

Background: To date, the clinical management of advanced hepatocellular carcinoma (HCC) patients remains tough and the mechanisms of E2F transcription factor 1 (E2F1) underlying HCC are obscure. Materials and Methods: Our study integrated datasets mined from several public databases to comprehensively understand the deregulated expression status of E2F1. Tissue microarrays and immunohistochemistry staining was used to validate E2F1 expression level. The prognostic value of E2F1 was assessed. In-depth subgroup analyses were implemented to compare the differentially expressed levels of E2F1 in HCC patients with various tumor stages. Functional enrichments were used to address the predominant targets of E2F1 and shedding light on their potential roles in HCC. Results: We confirmed the elevated expression of E2F1 in HCC. Subgroup analyses indicated that elevated E2F1 level was independent of various stages in HCC. E2F1 possessed moderate discriminatory capability in differentiating HCC patients from non-HCC controls. Elevated E2F1 correlated with Asian race, tumor classification, neoplasm histologic grade, eastern cancer oncology group, and plasma AFP levels. Furthermore, high E2F1 correlated with poor survival condition and pooled HR signified E2F1 as a risk factor for HCC. Enrichment analysis of differentially expressed genes, coexpressed genes, and putative targets of E2F1 emphasized the importance of cell cycle pathway, where CCNE1 and CCNA2 served as hub genes. Conclusions: We confirmed the upregulation of E2F1 and explored the prognostic value of E2F1 in HCC patients. Two putative targeted genes (CCNE1 and CCNA2) of E2F1 were identified for their potential roles in regulating cell cycle and promote antiapoptotic activity in HCC patients.

Tuberculosis (TB), a contagious disease mainly caused by Mycobacterium tuberculosis (M. tb), Mycobacterium bovis (M. bovis), and Mycobacterium caprae (M. caprae), poses a major global threat to the health of humans and many species of animals. Developing an ante-mortem detection technique for different species would be of significance in improving the surveillance employing a One Health strategy. To achieve this goal, a universal indirect ELISA was established for serologically detecting Mycobacterium tuberculosis complex infection for multiple live hosts by using a fusion protein of MPB70, MPB83, ESAT6, and CFP10 common in M. tb, M. bovis, and M. caprae as the coating antigen (MMEC) and HRP-labeled fusion protein A and G as a secondary antibody. After testing the known positive and negative sera, the receiver operating characteristic curves were constructed to decide the cut-off values. Then, the diagnostic sensitivity and specificity of MMEC/AG-iELISA were determined as 100.00% (95% CI: 96.90%, 100.00%) and 100.00% (95% CI: 98.44%, 100.00%) for M. bovis infection of cattle, 100.00% (95% CI: 95.00%, 100.00%) and 100.0% (95% CI: 96.80%, 100.00%) for M. bovis infection of sheep, 90.74% (95% CI: 80.09%, 95.98%) and 98.63% (95% CI: 95.14%, 99.76%) for M. bovis infection of cervids, 100.00% (95% CI: 15.81%, 100.00%) and 98.81% (95% CI: 93.54%, 99.97%) for M. bovis infection of monkeys, 100.00% (95% CI: 86.82%, 100.00%) and 94.85% (95% CI: 91.22%, 97.03%) for M. tb infection of humans. Furthermore, this MMEC/AG-iELISA likely detects M. caprae infection in roe deer. Thus this method has a promising application in serological TB surveillance for multiple animal species thereby providing evidence for taking further action in TB control.

Background Radiotherapy after breast-conserving surgery (BCS) is not always necessary in older women staged T1N0M0 with low-risk invasive breast cancer, but few studies have concluded the detailed tumor size as a reference for avoiding radiotherapy. The study was conducted to explore and identify the optimal cutoff tumor size. Methods The study population was from the Surveillance, Epidemiology, and End Results (SEER) database in 2010–2016. Propensity score matching was used to balance the confounders between groups. Predictors associated with survival were analyzed by Kaplan–Meier, X-tile, Cox proportional hazards model and competing risk model. Results A total of 52049 women and 3846 deaths were included in the cohort with a median follow-up of 34 months. Based on the cutoff value determined by X-tile analysis, the study population were divided into small tumor group (≤14 mm in diameter) and large tumor group (>14 mm in diameter). Small tumors and radiotherapy were correlated with better breast cancer-specific survival (BCSS). In subgroup analysis, the absolute benefit of BCSS in 6 years attributed to radiotherapy was only 0.90% (RT vs. non- RT:98.77% vs. 97.87%) for patients with small tumors but up to 3.33% (RT vs. non- RT:97.10% vs. 93.77%) for those with large tumors. Conclusion Small tumors and adjuvant radiotherapy were associated with improved long-term prognosis, and 14 mm in diameter was the cutoff tumor size of omitting radiotherapy for patients aged 65 or older with T1N0M0 stage, ER+ and HER2-breast carcinoma after BCS., Graphical abstract Image 1, Highlights • Breast tumor size of 14 mm was the optimal cutoff predicting OS and BCSS. • Small tumors (≤14 mm) and radiotherapy were associated with improved OS and BCSS. • The benefit of radiotherapy was significant in patients with large tumors (>14 mm). • Radiotherapy could be omitted in elders with small low-risk breast tumor after BCS.