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Primary central nervous system lymphoma (PCNSL) is an aggressive and rare malignancy with poor prognosis. However, there are no reliable prognostic biomarkers for PCNSL in clinical practice. Here, we aimed to identify a reliable prognostic biomarker for predicting the survival of PCNSL patients. In this study, multiplex immunofluorescence and digital imaging analysis were used to characterize tumor-associated macrophages (TAMs) immunophenotypes and the expression of programmed cell death ligand 1 on TAMs, with regard to prognosis from diagnostic tumor tissue samples of 59 PCNSL patients. We found that the M2-to-M1 ratio was a more reliable prognostic biomarker for PCNSL than M1-like or M2-like macrophage infiltration. In addition, the combination of programmed death-ligand 1 (PD-L1) expression on TAMs and the M2-to-M1 ratio in PCNSL demonstrated improved performance in prognostic discrimination than PD-L1-positive TAMs or M2-to-M1 ratio. To validate the prognostic significance of the combined TAMs associated biomarkers, they were integrated into the International Extranodal Lymphoma Study Group (IELSG) index and termed as IELSG-M index. Kaplan-Meier plots showed that the IELSG-M index could discriminate patients into low-, intermediate- or high-risk subgroups, better than IELSG, in terms of prognosis. The areas under the receiver operating characteristic curves of IELSG-M was 0.844 for overall survival; superior to the IELSG model (0.580). Taken together, this study's findings showed that the combination of PD-L1 on TAMs and the M2-to-M1 ratio could be strong prognostic predictive biomarkers for PCNSL and the IELSG-M index had improved prognostic significance than the IELSG index.

Purpose This retrospective cohort study aimed to evaluate primary treatment and recent survival trends in patients with primary diffuse large B-cell lymphoma of CNS from 1995 to 2016. Methods Using the SEER data, patients diagnosed with non-HIV associated PCNSL-DLBCL aged ⩾18 years between 1995 and 2016 were identified. The year of diagnosis was divided into the time periods-1(1995–2002), the time periods-2(2003–2012) and the time periods-3(2013–2016). We used Chi-square tests, the Kaplan–Meier method, log-rank test and Cox regression model in the analysis. Results Overall, 3760 patients were included. Both the use of radiotherapy alone and the application of combined chemoradiotherapy decreased significantly, following the wider use of chemotherapy alone during 1995–2016. There was a significant improvement in PCNSL cancer-specific survival (period-1: 13 months vs period-2: 19 months vs period-3: 41 months, P P = 0.101). However, there was an increase in CSS from the time period-2 to the time period-3 in the elderly patients (period-2: 5 months vs period-3: 9 months, P

Background Radiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated. Methods In this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients’ samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry. Results ALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-β receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients. Conclusion Our results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.

Purpose: Diffuse large B cell lymphoma (DLBCL) with MYC rearrangement or double expression of MYC and BCL-2 (DE DLBCL) has a relatively poor prognosis and does not respond well to standard R-CHOP. In the current study, we aimed to investigate the efficacy and safety of R-split-EPOCH plus high dose methotrexate (HD-MTX) in the particular patient population. Methods: A total of 28 patients diagnosed with DE DLBCL or DLBCL with MYC rearrangement between January 2015 and December 2018 were included and retrospectively analyzed. All the participants underwent R-split-EPOCH plus HD-MTX as introduction therapy, with split infusion of etoposide, doxorubicin, and vincristine for 48 hours on D1-2 and D10-11, respectively. Results: The overall objective response (ORR) rate was 100%, with 24 (85.7%) complete response (CR) and 4 (14.3%) partial response (PR). The CR rate was 76.9% and 93.3% for DLBCL patients with MYC rearrangement and DE DLBCL patients, respectively. The 1- and 3-year PFS rate was 100% and 74.9%, respectively. The 1- and 3-year OS rate was 100% and 92.9%, respectively. Grade 3/4 non-hematological toxicity and grade 3/4 hematological toxicity occurred in 50% and 85.7% of patients, respectively. No treatment-related death was reported. Conclusions: R-split-EPOCH plus HD-MTX regimen is an effective and feasible treatment option for DE DLBCL and DLBCL with MYC rearrangement.

IQ motif-containing GTPase-activating protein 3 (IQGAP3), the latest found IQGAP family protein, may act as a crucial factor in the process of cancer development and progression; however, its clinical value in breast cancer remains unestablished so far. Our team explored the correlation between the IQGAP3 expression profile and clinicopathological features in breast cancer. IQGAP3 levels in breast cancer cell lines and tumor tissues were detected through real-time PCR and western blotting. We evaluated IQGAP3 expression in archived paraffin-embedded tissue specimens of 257 breast cancer patients, and determined the relationship between IQGAP3 expression and sensitivity to radiation therapy (RT), using subgroup analysis. We also analyzed the association between IQGAP3 expression and the clinical characters and prognosis of breast cancer. There was a significant upregulation of IQGAP3 in breast cancer cell lines and human tumor tissues at both mRNA and protein levels. In addition, 42.8% of the breast cancer specimens had high expression of IQGAP3, which was significantly related to clinical stage (P = 0.001), T category (P = 0.002), N category (P = 0.001), locoregional recurrence (P = 0.002), distant metastasis (P = 0.001), and vital status (P = 0.001). Univariate and multivariate statistical analyses showed that IQGAP3 is an independent prognostic factor for all the breast cancer patients (P = 0.003, P = 0.001). Subgroup analysis revealed that IQGAP3 expression is correlated with radiation therapy resistance and is an independent predictor for radiation therapy outcome. Our findings suggest that IQGAP3 may be a reliable novel biomarker to provide personalized prognosis and identify patients who can profit from a more aggressive RT regimen for improving breast cancer patient survival.

BACKGROUND: Nutritional status is a key factor influencing the prognosis of patients with cancer. The Geriatric Nutritional Risk Index (GNRI) has been used to predict mortality risk and long-term outcomes. In this study, we aimed to evaluate the predictive value of pretreatment GNRI in patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 1,065 patients with biopsy-proven non-disseminated nasopharyngeal carcinoma were included. Based on a cutoff value of pretreatment GNRI, patients were divided into two groups (low ≤107.7 and high >107.7). Combining GNRI and baseline Epstein-Barr virus (EBV) DNA, all patients were further stratified into three risk groups, namely, high-risk (high EBV DNA and low GNRI), low-risk (low EBV DNA and high GNRI), and medium-risk (except the above) groups. Multivariate analyses were performed using the Cox proportional hazards model to assess the predictive value of the GNRI. RESULTS: Among the 1,065 patients, 527 (49.5%) and 538 (50.5%) were divided into low and high GNRI groups, respectively. Within a median follow-up of 83 months, patients with a high GNRI score exhibited significantly higher overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) compared to those with low GNRI scores (P

Recent translational studies highlighted the inhibition of transforming growth factor (TGF)-β signaling as a promising target to treat pulmonary arterial hypertension (PAH). However, it remains unclear whether alterations in TGF-β signaling are consistent between PAH patients and animal models. Therefore, we compared TGF-β signaling in the lungs of PAH patients and rats with experimental PAH induced by monocrotaline (MCT) or SU5416+hypoxia (SuHx). In hereditary PAH (hPAH) patients, there was a moderate increase in both TGFβR2 and pSMAD2/3 protein levels, while these were unaltered in idiopathic PAH (iPAH) patients. Protein levels of TGFβR2 and pSMAD2/3 were locally increased in the pulmonary vasculature of PAH rats under both experimental conditions. Conversely, the protein levels of TGFβR2 and pSMAD2/3 were reduced in SuHx while slightly increased in MCT. mRNA levels of plasminogen activator inhibitor (PAI)-1 were increased only in MCT animals and such an increase was not observed in SuHx rats or in iPAH and hPAH patients. In conclusion, our data demonstrate considerable discrepancies in TGFβ-SMAD signaling between iPAH and hPAH patients, as well as between patients and rats with experimental PAH.

Histone deacetylases (HDACs) are increased in pulmonary arterial hypertension (PAH), and inhibiting HDACs can be a promising treatment for PAH. However, previous studies on experimental PAH revealed controversial results, and adverse effects are common. Quisinostat is a “second generation” HDACs inhibitor, which is highly potent against class I and II HDACs, with prolonged pharmacodynamics response. It has been shown to be well tolerated by phase I trial. Collectively, we hypothesized that quisinostat can be used to treat PAH. Proliferation and inflammation were measured after quisinostat treatment on microvascular endothelial cells (MVECs), which were isolated from lungs of PAH patients. Experimental PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 followed by 4-weeks hypoxia and 2-weeks normoxia. At week 6, rats were randomized to receive either DMSO or quisinostat until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10. In vitro, quisinostat reduced proliferation in PAH MVECs, as well as inflammatory response as shown by decreased TNFα, IL-6, MCP-1 and VCAM-1. In vivo, quisinostat treatment reduced RV systolic pressure, RV afterload and total pulmonary resistance in SuHx rats. Further tissue analysis by histology revealed that quisinostat reduced pulmonary vascular remodeling by reducing intima layer thickness. Meanwhile, quisinostat had no effect on RV function. Quisinostat can partly reverse RV afterload and pulmonary vascular remodeling in established experimental PAH. Therefore, quisinostat may be a promising intervention for PAH.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by obstructed pulmonary vasculatures. Current therapies for PAH are limited and only alleviate symptoms. Reduced levels of BMPR2 are associated with PAH pathophysiology. Moreover, reactive oxygen species, inflammation and autophagy have been shown to be hallmarks in PAH. We previously demonstrated that MnTBAP, a synthetic metalloporphyrin with antioxidant and anti-inflammatory activity, inhibits the turn-over of BMPR2 in human umbilical vein endothelial cells. Therefore, we hypothesized that MnTBAP might be used to treat PAH. Human pulmonary artery endothelial cells (PAECs), as well as pulmonary microvascular endothelial (MVECs) and smooth muscle cells (MVSMCs) from PAH patients, were treated with MnTBAP. In vivo, either saline or MnTBAP was given to PAH rats induced by Sugen 5416 and hypoxia (SuHx). On PAECs, MnTBAP was found to increase BMPR2 protein levels by blocking autophagy. Moreover, MnTBAP increased BMPR2 levels in pulmonary MVECs and MVSMCs isolated from PAH patients. In SuHx rats, MnTBAP reduced right ventricular (RV) afterload by reversing pulmonary vascular remodeling, including both intima and media layers. Furthermore, MnTBAP improved RV function and reversed RV dilation in SuHx rats. Taken together, these data highlight the importance of MnTBAP as a potential therapeutic treatment for PAH.

Background: Mutations in bone morphogenetic protein receptor type II (BMPR2) are leading to the development of hereditary pulmonary arterial hypertension (PAH). In non-hereditary forms of PAH, perturbations in the transforming growth factor-&beta, (TGF-&beta, )/BMP-axis are believed to cause deficient BMPR2 signaling by changes in receptor expression, the activity of the receptor and/or downstream signaling. To date, BMPR2 expression and its activity in the lungs of patients with non-hereditary PAH is poorly characterized. In recent decades, different animal models have been used to understand the role of BMPR2 signaling in PAH pathophysiology. Specifically, the monocrotaline (MCT) and Sugen&ndash, Hypoxia (SuHx) models are extensively used in interventional studies to examine if restoring BMPR2 signaling results in PAH disease reversal. While PAH is assumed to develop in patients over months or years, pulmonary hypertension in experimental animal models develops in days or weeks. It is therefore likely that modifications in BMP and TGF-&beta, signaling in these models do not fully recapitulate those in patients. In order to determine the translational potential of the MCT and SuHx models, we analyzed the BMPR2 expression and activity in the lungs of rats with experimentally induced PAH and compared this to the BMPR2 expression and activity in the lungs of PAH patients. Methods: the BMPR2 expression was analyzed by Western blot analysis and immunofluorescence (IF) microscopy to determine the quantity and localization of the receptor in the lung tissue from normal control subjects and patients with hereditary or idiopathic PAH, as well as in the lungs of control rats and rats with MCT or SuHx-induced PAH. The activation of the BMP pathway was analyzed by determining the level and localization of phosphorylated Smad1/5/8 (pSmad 1/5/8), a downstream mediator of canonical BMPR2 signaling. Results: While BMPR2 and pSmad 1/5/8 expression levels were unaltered in whole lung lysates/homogenates from patients with hereditary and idiopathic PAH, IF analysis showed that BMPR2 and pSmad 1/5/8 levels were markedly decreased in the pulmonary vessels of both PAH patient groups. Whole lung BMPR2 expression was variable in the two PAH rat models, while in both experimental models the expression of BMPR2 in the lung vasculature was increased. However, in the human PAH lungs, the expression of pSmad 1/5/8 was downregulated in the lung vasculature of both experimental models. Conclusion: BMPR2 receptor expression and downstream signaling is reduced in the lung vasculature of patients with idiopathic and hereditary PAH, which cannot be appreciated when using human whole lung lysates. Despite increased BMPR2 expression in the lung vasculature, the MCT and SuHx rat models did develop PAH and impaired downstream BMPR2-Smad signaling similar to our findings in the human lung.

Despite the clinical value of HMGB1 in non-Hodgkin lymphoma (NHL), the impact of HMGB1 protein expression on survival of patients with mature T-cell and NK-cell lymphoma (T/NK-CL) is unknown. Here, we evaluated correlations of HMGB1 expression in tumor tissues with pathophysiological characteristics of disease and determined the prognostic value of HMGB1 expression in relapsed/refractory T/NK-CL. HMGB1 expression was detected by immunohistochemistry (IHC) in 66 cases of relapsed/refractory T/NK-CL, and specimens were classified as high or low HMGB1 expression. Univariate and multivariate Cox regression analyses identified prognostic factors associated with progression-free survival (PFS) and overall survival (OS). High HMGB1 expression was significantly correlated with increased Ki67 levels and progressive lymphoma subtypes. Univariate Cox regression analysis showed that high HMGB1 expression was associated with unfavorable PFS (P = 0.006) and poorer OS (P < 0.001). Prognostic factors identified by univariate analysis were prognostic index for peripheral T-cell lymphoma non-specified (PIT) score ≥ 2, bone marrow involvement, Ki67 ≥ 70%, and high HMGB1 expression. Multivariate Cox regression analysis revealed that high HMGB1 expression was an independent prognostic factor for poorer PFS [hazard ratio (HR) 3.593; 95% confidence interval (CI) 1.171-11.027; P = 0.025] and OS [HR 7.663; 95% CI 2.367-24.803; P = 0.001]. A proposal prognostic model combining HMGB1 and Ki67 expression showed improved prognostic capacity and may help guide treatment planning. High HMGB1 expression may be a promising prognostic predictor and a potential therapeutic target for relapsed/refractory T/NK-CL. Furthermore, to apply HMGB1 as one of the best bio-maker, an external independent control cohort is needed.

To the editor: Kojonazarov et al. recently reported severe emphysema in the SU5416/Hypoxia (SuHx) rat model of pulmonary hypertension (1). The authors found that adult male Wistar Kyoto (WKY) rats had increased air-to-tissue ratio as judged by non-gated in vivo micro-computed tomography (CT), and an increased mean linear intercept (MLI) as surrogate of emphysema (1, 2). Le Cras and Abman now responded to the Kojonazarov report by underlining the “important role of the developmental timing of disrupted VEGF signaling” (3). They cite earlier studies conducted on the ovine fetus showing that VEGF inhibition caused vascular remodeling, reduction in vascular/airway growth, and neonatal pulmonary hypertension at birth (4). Although SU5416 is known to induce emphysema in rats housed in room air at Denver altitude (1609m altitude) (5, 6), we contended in our response letter (11) that, at least in male Sprague Dawley (SD) rats, the combination of VEGFR inhibition and hypoxia does not lead to any biologically relevant emphysema or other significant parenchymal lung disease (7) but to pulmonary arterial hypertension (PAH) due to severe angioproliferative remodeling (7, 8).

Background: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). Methods: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (α-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. Results: Patients with PAH with lower RV ejection fraction ( Conclusions: RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.

Vortex generators (VGs) are commonly adopted to control the flow separation, and many researches have investigated their effects on the aerodynamic performance of wind turbines. However, nearly no attentions are paid to the VGs’ installation angle. Thus, in this paper, to investigate the effects of the VGs’ installation angle on airfoils, numerical simulations are conducted by CFD on the finite wing of NACA0012. According to the finite airfoil with or without VGs, three-dimensional models are established and numerical simulations are carried out in detail. It could be seen clearly that the VGs’ installation angle produces a significant impact on the aerodynamic performances. For some installation angles, special ranging from 45° to 90°, VGs can improve the lift-drag ratio apparently, even by 34.5%. While angle ranges from 15° to 30°, VGs negatively influence the lift-drag ratio. Furthermore, the fluctuation phenomenon is discussed through analysis of the streamlines and vortices. Based on those results, optimal aerodynamic performances could be achieved by the active control of the VGs’ installation angle.

Right ventricular failure (RVF) is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH). Although the exact pathophysiology underlying RVF remains unclear, inflammation may play an important role, as it does in left heart failure. Perivascular pulmonary artery and systemic inflammation is relatively well studied and known to contribute to the initiation and maintenance of the pulmonary vascular insult in PAH. However, less attention has been paid to the role of cardiac inflammation in RVF and PAH. Consistent with many other types of heart failure, cardiac inflammation, triggered by systemic and local stressors, has been shown in RVF patients as well as in RVF animal models. RV inflammation likely contributes to impaired RV contractility, maladaptive remodelling and a vicious circle between RV and pulmonary vascular injury. Although the potential to improve RV function through anti-inflammatory therapy has not been tested, this approach has been applied clinically in left ventricular failure patients, with variable success. Because inflammation plays a dual role in the development of both pulmonary vascular pathology and RVF, anti-inflammatory therapies may have a potential double benefit in patients with PAH and associated RVF.

Translational research is essential to develop strategies for the treatment of pulmonary arterial hypertension (PAH) using animal models which reproduce the severity, the progressive nature and resistance to treatment of human PAH, including severe arterial remodeling and progressive right ventricular (RV) failure. We read with interest the letter by Kojonazariov et al. who propose to have found “severe emphysema in the SU5416/Hypoxia (SuHx) rat model of pulmonary hypertension”. The authors report that Wistar-Kyoto rats exposed to the combination of VEGFR2 inhibition by SU5416 and chronic hypoxia had moderately increased RVSP and RV mass compared to normoxic untreated animals. They applied in vivo micro-computed tomography (CT) to demonstrate an increase in lung volume and decreased lung density, an unaltered amount of lung tissue, but an increased air-to-tissue ratio, and claim these findings were confirmed by histological analysis, including mean linear intercept as surrogate of emphysema. Indeed, SU5416 has been previously shown to induce emphysema in normoxia, but this required repetitive SU5416 dosing (3 times weekly over 3 weeks) and occurred more predominantly in rats younger than 4 weeks of age (Norbert Voelkel, personal communication). In addition, emphysema could be negated, at the cost of the development of severe angioproliferative hypertension, by concomitant exposure to hypoxia.

Rationale: Multiple mechanisms have been discovered underlying the pathogenesis of pulmonary arterial hypertension (PAH), including reactive oxygen species (ROS), inflammation and reduced bone morphogenic protein receptor (BMPR)2. MnTBAP can mimic the effects of manganese-superoxide dismutase to reduce ROS. Moreover, MnTBAP can reduce inflammation in endothelial cells via up-regulation of BMPR2. Collectively, we hypothesized that MnTBAP can be used to treat PAH. Methods: Experimental PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 followed by 4-weeks hypoxia and 2-weeks normoxia. At week 6, animals were randomized to receive either saline or MnTBAP until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10. Heart and lung tissues were collected. Results: MnTBAP reduced RV afterload and total pulmonary resistance in SuHx rats. Moreover, MnTBAP improved RV function by increasing stroke volume and TAPSE, as well as reducing RV end diastolic diameter and stiffness. Further tissue analysis by histology revealed that MnTBAP reduced pulmonary vascular remodeling by reducing both intima and media layer thickness. Conclusion: MnTBAP treatment can partly reverse RV afterload and pulmonary vascular remodeling in established experimental PAH. Together with the improved cardiac function, MnTBAP may be a promising intervention for PAH.

Introduction: Oxidation of catecholamines and serotonin by monoamine oxidase–A (MAO-A) may play a role in pulmonary hypertension (PH). MAO-A inhibition (MAOi) decreased proliferation in pulmonary artery intima, and was beneficial in several models of left heart failure. We hypothesized that MAOi will be beneficial in the setting of PH. Methods: Male Wistar rats underwent surgical banding of the pulmonary trunk (PTB) or sham surgery (sham, n=7). Two weeks later, echocardiography was performed and PTB rats were randomized to MAOi (PTB+MAOi, n=12) and treated with clorgyline (2 mg/kg i.p. 3x/week) or saline (PTB, n=12). Rats were treated for five weeks before evaluation echo and pressure-volume-loops (PV loop) were obtained. During echo and PV loops rats where anesthetized with sevoflurane (mix in 1.5L/min O2, 7% for induction, 3.5% for maintainance). Results: MAO-A activity increased almost 3-fold in PTB compared to sham, whereas MAOi completely reversed this. PTB increased total heart- and RV weight, which was partly reversed by MAOi. The ratio of RV weight to left ventricle + septum weight did not change after MAOi. MAOi did not improve RV function or reduce RV dilatation as analyzed by echocardiography or PV loops (Fig. 1). Conclusion: Despite normalization of MAO-A activity in PTB rats, no functional improvements or changes in cardiac size were observed. Histological analyses will further elucidate these findings.

Background Early diagnosis is critical to reduce the mortality caused by nasopharyngeal carcinoma (NPC). MicroRNAs (miRNAs) are dysregulated and play important roles in carcinogenesis. Therefore, this study aimed to identify diagnostically relevant circulating miRNA signatures in patients with NPC. Methods Total RNA was extracted from whole blood samples obtained from 120 patients with NPC, 30 patients with head-neck tumors (HNT), and 30 healthy subjects (HSs), and examined by using a custom microarray. The expression levels of four miRNAs identified by using the microarray were validated with quantitative real-time reverse transcription polymerase chain reaction. The 120 patients with NPC and 30 HSs were randomly assigned to training group-1 and validation group-1, respectively. By using significance analysis of microarray (SAM), the specific miRNA expression profiles in whole blood from patients with NPC are obtained. By using lasso regression and adaptive boosting, a diagnostic signature was identified in training group-1, and its accuracy was verified in validation group-1. By using the same methods, another signature to distinguish patients with NPC from those with HNT and HSs was identified in training group-2 and confirmed in validation group-2. Results There were 117 differentially expressed miRNAs (upregulated and downregulated fold change ≥ 1.5) between the patients with NPC and HSs, among which an 8-miRNA signature was identified with 96.43% sensitivity and 100% specificity [area under the curve (AUC) = 0.995] to diagnose NPC in training group-1 and 86.11% sensitivity and 88.89% specificity (AUC = 0.941) in validation group-1. Compared with traditional Epstein–Barr virus (EBV) seromarkers, this signature was more specific for NPC. Furthermore, a 16-miRNA signature to differentiate NPC from HNT and HS (HNT-HS) was established from 164 differentially expressed miRNAs, which diagnosed NPC and HNT-HS with 100% accuracy (AUC = 1.000) in training group-2 and 87.04% (AUC = 0.924) in validation group-2. Conclusions The present study identified two miRNA signatures for the highly accurate diagnosis and differential diagnosis of patients with NPC from HSs and patients with HNT. The identified miRNAs might represent novel serological biomarkers and potential therapeutic targets for NPC. Electronic supplementary material The online version of this article (10.1186/s12967-019-1923-2) contains supplementary material, which is available to authorized users.

Patients with Non‐Hodgkin lymphoma (NHL) treated by conventional chemotherapeutic drugs usually require a long recovery period. However, metronomic combination chemotherapy (MCC) enhances therapeutic efficacy and decreases side effects in the treatment of NHL. In this study, we tested and compared the effects of metronomic chemotherapy (MC) using podophyllotoxin derivative etoposide (VP‐16) alone and that of MCC using both VP‐16 and everolimus (RAD001) in the treatment of NHL. Two types of NHL cells, OCI‐LY‐10 and SU‐DHL‐6, were employed for the experiments. Cell proliferation, apoptosis, and cell senescence were measured to test the effects of drugs in each experiment. In addition, the influences of MC and MCC on the cell cycle and autophagy pathway were evaluated to study the functional mechanisms behind their effects. Finally, we conducted analyses of the growth inhibitory effect and synergistic activity for different MCC. The results showed that MC using low‐dose VP‐16 alone demonstrated strong treatment effects in terms of inducing apoptosis, cell senescence, and reducing tumor cell proliferation, and this treatment also led to changes of the cell cycle. Compared with MC, MCC using VP‐16 and RAD001 together demonstrated even stronger treatment effects, with both the cell cycle and autophagy‐related proteins being affected. Considering the synergistic activity, our results showed the MCC of VP‐16 48 hours + RAD001 24 hours is the optimal method for treating NHL.

BACKGROUND: Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB).METHODS: Male Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses.RESULTS: PTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats.CONCLUSION: Treatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle.

Background: Reactive oxygen species (ROS) play a crucial role in the pathogenesis of pulmonary arterial hypertension (PAH). Monoamine oxidases (MAO), a class of enzymes located in the outer mitochondrial membrane, are important ROS sources. Increased MAO-A expression in endothelial cells and cardiomyocytes was found to contribute to vascular dysfunction and left heart failure. MAO-A inhibition can improve vascular dysfunction and heart failure. Collectively, given the effects of MAO-A on both vascular and cardiac function, we hypothesized that inhibition of MAO-A can be used to treat PAH. Methods: PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 (25 mg/kg) followed by 4-weeks exposure to hypoxia and 2-weeks of normoxia. At week 8, animals were randomized to receive either intraperitoneal injection of saline or the MAO-A inhibitor clorgyline 10 mg/kg, followed by 2 mg/kg every 3 days until week 10. Echocardiography and RV catheterization was performed at week 10 and heart and lung tissues were collected for further analysis. Results: Compared to the vehicle group, clorgyline treatment reduced right ventricular (RV) systolic pressure and RV afterload. Moreover, clorgyline improved RV function by reducing RV hypertrophy and stiffness. Further tissue analysis by histology revealed that clorgyline reduced pulmonary vascular remodeling by reducing intima layer thickness. Conclusion: Clorgyline partly reversed RV systolic pressure and RV afterload in established experimental PAH. Together with the observed reduced RV remodeling, MAO-A inhibition may be a promising intervention for PAH.

Background: IQ motif-containing GTPase activating protein 3 (IQGAP3), the latest found protein of IQGAP family, may act as a crucial factor in the process of cancer development and progression; however, its clinical value in breast cancer remains unestablished so far. Our team explored the correlation between IQGAP3 expression profile and the clinicopathological features in breast cancer. Methods: IQGAP3 levels in breast cancer cell lines and tumor tissues were detected by real-time PCR and western blotting and compared to the normal control groups. Protein expression of IQGAP3 was evaluated immunohistochemically in specimens (archived paraffin embedded) of 257 breast cancer patients. We also analyze the association between IQGAP3 expression and the clinical characters and prognosis. The relationship between IQGAP3 expression and sensitivity to radiation therapy was determined by subgroup analysis. Results: There was significant upregulation of IQGAP3 in breast cancer cell lines and human tumor tissues at both the mRNA and protein level compared to the normal ones. In addition, 110/257 (42.8%) of archived paraffin embedded breast cancer specimens had high protein expression of IQGAP3. High expression of IQGAP3 was significantly related to clinical stage (P=0.001), T category (P=0.002), N category (P=0.001), locoregional recurrence(P=0.002), distant metastasis (P=0.001), and vital status (P=0.001). Univariate and multivariate statistical analysis showed that IQGAP3 was an independent prognostic factor of the whole cohort breast cancer patients (P=0.003, P=0.001). Subgroup analysis revealed IQGAP3 expression correlates with radiation therapy resistance and was also an independent predictor for radiation therapy outcome. Conclusions: Our findings suggest that high IQGAP3 expression predicts poor prognosis and radiation therapy resistance in breast cancer. In addition, IQGAP3 may be a reliable novel biomarker to provide personalized prognostication and identify patients who can profit from more aggressive RT regimen for improving the survival of breast cancer patients.

Background: Inflammation plays a crucial role in the pathogenesis of pulmonary arterial hypertension (PAH), partly by stimulating proliferation of pulmonary arterial smooth muscle cells (SMC) and endothelial cells (EC). 6-Mercaptopurine (6-MP) is an immunosuppressive drug used to treat various autoimmune and chronic inflammatory diseases. Recently, we and others have shown that 6-MP not only inhibits macrophage and T cell activation, but also reduces the proliferation of SMC and EC as well as the inflammatory response of EC. Collectively, given the effects of 6-MP on inflammation, SMC and EC, we hypothesized that 6-MP may become a promising treatment of PAH. Methods: PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 (25 mg/kg) followed by 4-week exposure to hypoxia and 2-week normoxia. At week 6, animals were randomized into vehicle or 6-MP treatment group, by receiving vehicle (DMSO) or 6-MP (7.5 mg/kg/day) in water until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10, after which they were exsanguinated. Both heart and lung tissues were collected for further analysis. Results: Compared to the vehicle group, 6-MP reduced RV systolic pressure, RV afterload and total pulmonary resistance. Moreover, 6-MP improved cardiac function by reducing RV stiffness, and increasing stroke volume and cardiac output. In addition, it partly reversed RV remodeling by reducing RV fibrosis. Conclusion: 6-MP partly reversed RV systolic pressure and RV afterload in established PAH. Together with the observed improved RV remodeling and cardiac function, 6-MP may be a promising intervention for PAH.

Background Prostate cancer is known to have ethnic and regional differences. The study aimed to clinically evaluate the detection rate of prostate cancer on transrectal ultrasonography (TRUS)-guided prostate biopsy and analyze its characteristics among the northern Han Chinese population at a single center. Methods Between October 2009 and September 2016, a total of 1027 Chinese men, who had undergone TRUS-guided prostate biopsy at Qingdao Municipal Hospital, were retrospectively analyzed. Prostate biopsies were performed in the case of an abnormally elevated serum PSA level, and/or abnormal digital rectal examination (DRE) findings, and/or suspicious prostatic imaging findings. Results Of the 1022 men enrolled in the analysis, 438 patients (42.8%) were diagnosed with prostate adenocarcinoma histologically. When serum PSA levels were divided into five subgroups (less than 4.0, 4.0 to 10.0, 10.0 to 20.0, 20.0 to 100.0, and ≥ 100.0 ng/ml), the detection rates of prostate cancer were 12.4, 15.9, 34.1, 66.2, and 93.8%, respectively. With serum PSA levels of 4.0 to 10.0 ng/ml, the cancer detection rates for a normal DRE and a suspect DRE finding were 13.5 and 58.2%, respectively. Accordingly, the cancer detection rates for a normal imaging and a suspect imaging finding were 13.5 and 58.2%, respectively. Besides, a large proportion of the patients were in the clinically advanced stage. Conclusions The present study data reported a relatively higher prostate cancer detection rate of 42.8% and that the majority of the patients presented with clinically advanced prostate cancers within a local clinical urologic practice. An early detection and screening program for prostate cancer is of great need to reduce the burden from this disease among the northern Han Chinese population.

Background Numerous studies have shown Kinesin family member 20A (KIF20A) may play a critical role in the development and progression of cancer. However, the clinical value of KIF20A in nasopharyngeal carcinoma (NPC) is unknown. Here, we investigated the expression pattern of KIF20A in NPC and its correlation with clinicopathological features of patients. Methods Real-time PCR and Western blotting were used to quantify KIF20A expression in NPC cell lines and clinical specimens compared with normal controls. KIF20A protein expression was also examined in archived paraffin embedded tumor samples from 105 patients with pathologically confirmed NPC by immunohistochemistry (IHC). Statistical analyses were applied to assess the associations between KIF20A expression and the clinicopathological features and survival outcomes. Effects on migration and invasion were assessed by wound healing and transwell invasion assays after KIF20A silencing. Results KIF20A was significantly overexpressed at both the mRNA and protein levels in NPC cell lines and human tumor tissues. 45/105 (42.9%) of NPC specimens expressed high levels of KIF20A among the KIF20A detectable cases. Statistical analysis revealed that high KIF20A expression was significantly associated with gender (P = 0.046), clinical stage (P

To further investigate the mechanism of the interaction between the response of single pile and pile-soil on the condition of lateral load, on the basis of the normal type of the coefficient of subgrade reaction, this paper reaches the transfer matrix solution of single pile subject to lateral load by combining matrix transfer method with finite element method assuming that the coefficient of subgrade reaction is constant in each finite element. With the matrix solutions obtained, a computer program is developed using MATLAB to compute the pile responses and parametric studies are carried out on the effect of the constraint conditions of pile head and tip, effect of soil properties etc. and the results are discussed in detail.

A combination method of virtual simulation techniques was proposed for fatigue life of vertical shiplifts big modulus gear. A Three-dimensional assembly model of rack and pinion mechanism was established by SolidWorks and its plug GearTrax, then dynamics simulation was conducted based on ADAMS, the relative error between simulation results and static load was 2.2%, indicating the accuracy of the simulation. Bending stress of the big modulus gear was analysed by ANSYS, the error was 1.6% compared with the theoretical value. Using the obtained load history data and bending stress results, the big modulus gears fatigue life was predicted based on nominal stress method, the result showed that the big modulus gear could well meet the design requirements.

Intact nitric oxide (NO) signalling is critical to maintaining appropriate pulmonary vascular tone. NO bioavailability is reduced in patients with pulmonary arterial hypertension. This study aimed to examine the impact of NO plasma metabolites (NOx) relative to haemodynamic dysfunction and mortality in patients with idiopathic pulmonary arterial hypertension (IPAH).A total of 104 consecutive adult IPAH patients who had undergone genetic counselling when first diagnosed were enrolled in this prospective study.The median concentration of NOx (μmol·L−1) was significantly lower in IPAH patients compared with healthy subjects, and was decreased further in 19 carriers of the bone morphogenetic protein-receptor type-2 (BMPR2) mutation compared to non-carriers. Reduced concentrations of NOx were correlated with mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR) and cardiac output. Compared with higher baseline NOx concentrations, patients with a NOx concentration of ≤10 μmol·L−1 had a markedly worse survival. After adjustment for clinical features, a BMPR2 mutation and haemodynamics, a lower NOx level remained an increased risk of mortality.Patients with IPAH had lower levels of plasma NOx, which correlated inversely with mPAP, PVR and survival. Plasma NOx may be an important biomarker and prognostic indicator, suggesting that reduced NO synthesis contributes to the pathogenesis of IPAH.

The FE model of a combined gantry milling machine was constructed. The joint stiffness of bolt fastening, ball screw, and roller guideway were calculated. The static analysis, modal analysis and harmonic analysis of the whole machine were carried out. The results indicated that the static stiffness and minimum dynamic stiffness of the spindle could satisfy the accuracy requirements of milling, but the stiffness of the X-axis feed system was comparatively low, while the stiffness of the rest and the cross-beam could be relatively abundant. The result of “considering joint stiffness” modal analysis was more accurate than “unconsidering joint stiffness”, especially the 5th-order natural frequency had a difference of up to 52.2%. The harmonic analysis result showed that the response amplitude of the spindle center was comparatively large in three directions when the 1st-order and the 17th-order natural frequency were working, so the frequencies should be avoided while working.

Background Pain due to oral mucositis (OM) is a major problem during concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. Methods We enrolled 56 NPC patients receiving CCRT and allocated them into two groups: moderate pain group (n = 27) and a severe pain group (n = 29) according to the degree of pain reported (moderate = numerical rating scale (NRS) score 4–6 or severe = NRS score 7–10) at initiation of controlled-release oxycodone (CRO) treatment. Results Total dose of CRO was significantly higher in severe pain patients than in moderate pain patients (791.60 ± 332.449 mg vs. 587.27 ± 194.940 mg; P = 0.015). Moderate pain patients had significantly better quality of life (P = 0.037), lower weight loss (P = 0.030) and more active CCRT response (90.9% vs. 64.0%; P = 0.041). Although 24-h pain control rate was comparable in the two groups (85.2% vs. 86.2%; P = 0.508), the moderate pain group score eventually stabilized at ~ 2 vs. 3 in the severe pain group (P

This paper analyzes the current situation of the development of the CHINA RAILWAY Express (Xiamen), using the SWOT analysis method to analyze the current situation, the opportunities and the threats of the current RAILWAY Express. In addition, this paper specific recommendations to provide a reference for the future development of RAILWAY Express.

The retroperitoneoscopic renal pedicle lymphatic disconnection has been performed mainly via a renal adipose (RA) capsule approach. In this study, we reported a novel technique via extra-adipose (EA) capsule approach and compared the two approaches for intractable chyluria.From December 2002 to March 2008, retroperitoneoscopic renal pedicle lymphatic disconnection was performed on 41 patients with 23 EA and 18 RA. The stripping of hilar vessels and ureterolympholysis were performed in both approaches, while the mobilization of the kidney was only performed in RA. Comparisons of the two approaches were conducted, including mean operative time, intraoperative blood loss, postoperative bed rest, and hospital stay, as well as operative outcome.Patients were treated successfully without major complications. EA showed the same advantages as RA in terms of intraoperative blood loss (54.9±19.3 mL vs 59.3±26.5 mL, P0.05), postoperative hospital stay (6.6±1.0 d vs 7.2±0.9 d, P0.05). Chyluria disappeared in all patients immediately after the operations. EA was significantly superior to RA in operative time (78.9±18.3 min vs 101.8±20.6 min, P0.05) and the postoperative bed rest time (20.7±1.7 h vs 72.0±0.0 h, P0.05). No recurrence or nephroptosis was diagnosed in any patient within the follow-up of 21 to 84 months.Retroperitoneoscopic renal pedicle lymphatic disconnection for chyluria is safe and efficacious. EA offers significantly shorter operative time and earlier return to postoperative ambulation.

To investigate the in vitro and in vivo activities and related mechanism of apogossypolone (ApoG2) alone or in combination with adriamycin (ADM) against human hepatocellular carcinoma (HCC).The IC50 of ApoG2 in vitro was tested by WST assay, and the synergistic effect was analyzed using the CalcuSyn method. Cell apoptosis was determined using 4',6-diamidino-2- phenylindole staining and flow cytometric analysis. Western blotting was used to determine the expression of apoptosis-related proteins. In vivo activity was evaluated in the xenograft model in nude mice, and apoptosis in tumor tissues was determined by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) assay.The IC50 of ApoG2 in HCC cells was 17.28-30.63 micromol/L. When ApoG2 was combined with ADM, increased cytotoxicity and apoptosis were observed in SMMC-7721 cells compared to treatment with ApoG2 alone. The Western blotting results indicated that the ApoG2 induced apoptosis in SMMC-7721 cells by downregulating anti-apoptotic proteins Bcl-2, Mcl-1, and Bcl-XL, up-regulating pro-apoptotic protein Noxa, and promoting the activities of caspases-9 and -3. The tumor growth of xenograft SMMC-7721 was inhibited in nude mice when ApoG2 was administered orally without causing damage to the normal tissues. The in vivo study also indicated an increasing anti-tumoral effect when ApoG2 at 100 or 200 mg/kg dosages were used together with ADM at 5.5 mg/kg, with relative tumor proliferation rate (T/C) values of 0.456 and 0.323, respectively. Apoptosis induced in vivo by ApoG2 alone or combined with ADM was confirmed by TUNEL assay in tumor tissues.ApoG2 is a potential non-toxic target agent that induces apoptosis by upregulating Noxa, while inhibiting anti-apoptotic proteins and promoting the effect of chemotherapy agent ADM in HCC.