Summary Background Proliferation markers and profiles have been recommended for guiding the choice of systemic treatments for breast cancer. However, the best molecular marker or test to use has not ...yet been identified. We did this study to identify factors that drive proliferation and its associated features in breast cancer and assess their association with clinical outcomes and response to chemotherapy. Methods We applied an artificial neural network-based integrative data mining approach to data from three cohorts of patients with breast cancer (the Nottingham discovery cohort (n=171), Uppsala cohort (n=249), and Molecular Taxonomy of Breast Cancer International Consortium METABRIC cohort; n=1980). We then identified the genes with the most effect on other genes in the resulting interactome map. Sperm-associated antigen 5 ( SPAG5 ) featured prominently in our interactome map of proliferation and we chose to take it forward in our analysis on the basis of its fundamental role in the function and dynamic regulation of mitotic spindles, mitotic progression, and chromosome segregation fidelity. We investigated the clinicopathological relevance of SPAG5 gene copy number aberrations, mRNA transcript expression, and protein expression and analysed the associations of SPAG5 copy number aberrations, transcript expression, and protein expression with breast cancer-specific survival, disease-free survival, distant relapse-free survival, pathological complete response, and residual cancer burden in the Nottingham discovery cohort, Uppsala cohort, METABRIC cohort, a pooled untreated lymph node-negative cohort (n=684), a multicentre combined cohort (n=5439), the Nottingham historical early stage breast cancer cohort (Nottingham-HES; n=1650), Nottingham early stage oestrogen receptor-negative breast cancer adjuvant chemotherapy cohort (Nottingham-oestrogen receptor-negative-ACT; n=697), the Nottingham anthracycline neoadjuvant chemotherapy cohort (Nottingham-NeoACT; n=200), the MD Anderson taxane plus anthracycline-based neoadjuvant chemotherapy cohort (MD Anderson-NeoACT; n=508), and the multicentre phase 2 neoadjuvant clinical trial cohort (phase 2 NeoACT; NCT00455533 ; n=253). Findings In the METABRIC cohort, we detected SPAG5 gene gain or amplification at the Ch17q11.2 locus in 206 (10%) of 1980 patients overall, 46 (19%) of 237 patients with a PAM50-HER2 phenotype, and 87 (18%) of 488 patients with PAM50-LumB phenotype. Copy number aberration leading to SPAG5 gain or amplification and high SPAG5 transcript and SPAG5 protein concentrations were associated with shorter overall breast cancer-specific survival (METABRIC cohort copy number aberration: hazard ratio HR 1·50, 95% CI 1·18–1·92, p=0·00010; METABRIC cohort transcript: 1·68, 1·40–2·01, p<0·0001; and Nottingham-HES-breast cancer cohort protein: 1·68, 1·32–2·12, p<0·0001). In multivariable analysis, high SPAG5 transcript and SPAG5 protein expression were associated with reduced breast cancer-specific survival at 10 years compared with lower concentrations (Uppsala: HR 1·62, 95% CI 1·03–2·53, p=0·036; METABRIC: 1·27, 1·02–1·58, p=0·034; untreated lymph node-negative cohort: 2·34, 1·24–4·42, p=0·0090; and Nottingham-HES: 1·73, 1·23–2·46, p=0·0020). In patients with oestrogen receptor-negative breast cancer with high SPAG5 protein expression, anthracycline-based adjuvant chemotherapy increased breast cancer-specific survival overall compared with that for patients who did not receive chemotherapy (Nottingham-oestrogen receptor-negative-ACT cohort: HR 0·37, 95% CI 0·20–0·60, p=0·0010). Multivariable analysis showed high SPAG5 transcript concentrations to be independently associated with longer distant relapse-free survival after receiving taxane plus anthracycline neoadjuvant chemotherapy (MD Anderson-NeoACT: HR 0·68, 95% CI 0·48–0·97, p=0·031). In multivariable analysis, both high SPAG5 transcript and high SPAG5 protein concentrations were independent predictors for a higher proportion of patients achieving a pathological complete response after combination cytotoxic chemotherapy (MD Anderson-NeoACT: OR 1·71, 95% CI, 1·07–2·74, p=0·024; Nottingham-ACT: 8·75, 2·42–31·62, p=0·0010). Interpretation SPAG5 is a novel amplified gene on Ch17q11.2 in breast cancer. The transcript and protein products of SPAG5 are independent prognostic and predictive biomarkers that might have clinical utility as biomarkers for combination cytotoxic chemotherapy sensitivity, especially in oestrogen receptor-negative breast cancer. Funding Nottingham Hospitals Charity and the John and Lucille van Geest Foundation.
This study aimed to investigate the effect of specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1)-mediated deSUMOylation on the malignant behavior of glioma stem cells (GSCs) under ...hypoxia conditions and evaluate the clinical value of prevention in glioma patients.
Under hypoxic conditions, upregulated hypoxia-inducible factor 1α (HIF1α) expression in GSCs activates Wnt/β-catenin signaling pathways, which provide rich nutritional support for glioblastoma (GBM). SENP1-mediated deSUMOylation stabilizes the expression of HIF1α and β-catenin, leading to the occurrence of GSCs-initiated tumorigenesis. Targeting SENP1-mediated deSUMOylation may suppress the malignancy of GSCs and disrupt GBM progression.
The expression of SENP1 in different World Health Organization grades was observed by immunohistochemistry and western blot. Lentivirus-packaged
shRNA downregulated the expression of SENP1 in GSCs, and the downregulated results were verified by western blotting and polymerase chain reaction. The effects of LV-SENP1shRNA on the migration and proliferation of GSCs were detected by scratch and cloning experiments. The effect of LV-
shRNA on the tumor formation ability of GSCs was observed in nude mice. Immunoprecipitation clarified the mechanism of SENP1 regulating the malignant behavior of GSCs under hypoxia. The correlation between the expression level of SENP1 and the survival of glioma patients was determined by statistical analysis.
SENP1 expression in GSCs derived from clinical samples was upregulated in GBM. SUMOylation was observed in GSCs
, and deSUMOylation, accompanied by an increase in SENP1 expression, was induced by hypoxia. SENP1 expression was downregulated in GSCs with lentivirus-mediated stable transfection, which attenuated the proliferation and differentiation of GSCs, thus diminishing tumorigenesis. Mechanistically, HIF1α induced activation of Wnt/β-catenin, which depended on SENP1-mediated deSUMOylation, promoting GSC-driven GBM growth under the hypoxia microenvironment.
Our findings indicate that SENP1-mediated deSUMOylation as a feature of GSCs is essential for GBM maintenance, suggesting that targeting SENP1 against GSCs may effectively improve GBM therapeutic efficacy.
Objectives: Regional bladder wall thickening on noninvasive magnetic resonance (MR) images is an important sign of developing urinary bladder cancer (BCa), and precise segmentation of the tumor mass ...is an essential step toward noninvasive identification of the pathological stage and grade, which is of critical importance for the clinical management of patients with BCa. Methods: In this paper, we proposed a new method based on the high-throughput pixel-level features and a random forest (RF) classifier for the BCa segmentation. First, regions of interest (ROIs) including tumor and wall ROIs were used in the training set for feature extraction and segmentation model development. Then, candidate regions containing both bladder tumor and its neighboring wall tissue in the testing set were segmented. Results: Experimental results were evaluated on a retrospective database containing 56 patients postoperatively confirmed with BCa from the affiliated hospital. The Dice similarity coefficient (DSC) and average symmetric surface distance (ASSD) of the tumor regions were adopted to quantitatively assess the overall performance of this approach. The results showed that the mean DSC was 0.906 (95% confidential interval CI: 0.852-0.959), and the mean ASSD was 1.190 mm (95% CI: 1.727-2.449), which were higher than those of the state-of-the-art methods for tumor region separation. Conclusion: The proposed Pixel-level BCa segmentation method can achieve good performance for the accurate segmentation of BCa lesion on MR images.
Landscape fire smoke, including smoke from all vegetation burning in natural and cultural landscapes, remains a threat to the health of the population. However, the future health impacts of landscape ...fire smoke in China have not been sufficiently investigated. We aimed to estimate the mortality risk attributable to landscape fire-related PM
under different scenarios.
In this health impact assessment study, we used the projected population and landscape fire-related PM
concentration to calculate deaths attributable to short-term exposure to landscape fire smoke PM
during 2021-2100. We did the analysis in three defined future periods: 2021-40 (near term), 2051-70 (medium term), and 2081-2100 (long term), with 1986-2005 as the historical period. We used fire-specific short-term epidemiological functions with the regional parameters specific to China. We assessed the mortality risks of landscape fire-related smoke and further identified their spatiotemporal distribution under two shared socioeconomic pathway (SSP) scenarios: SSP1-2·6, an optimistic scenario with strict control of carbon emissions, and SSP2-4·5, an intermediate scenario with weaker control of carbon emissions.
The national mortality rate attributable to short-term exposure (ie, a few days) to landscape fire-related PM
is projected to increase compared with historical values. The national deaths attributable to landscape fire smoke PM
could peak in 2021-40, with increases of 28·10% (95% CI 14·08-53·11) under the SSP1-2·6 scenario and 37·38% (14·08-53·11) under the SSP2-4·5 scenario. Deaths would then decrease slightly during 2051-70 and 2081-2100. The provinces with the highest projected number of deaths attributable to landscape fire-related PM
are located in east and south-central China, and those with the largest percentage increase in projected deaths are located in northwest and southwest China.
Our results suggest that global warming could increase the contribution of landscape fire smoke to the total PM
concentration, leading to an increase in the mortality rate in China. Our findings could help policy makers implement effective interventions in hotspot areas during different periods to reduce the impact of landscape fire smoke on human health.
The National Natural Science Foundation of China, National Key Research and Development Program of China, and the Wellcome Trust.
Objective This study aims to investigate the predictive factors for the spontaneous recanalization of occluded arteries in patients with acute ischemic stroke. Methods A total of 139 patients with ...consecutive acute ischemic stroke were enrolled from June 2010 to June 2013. The clinical and biochemical parameters were measured in each participant. Occlusion and recanalization of the carotid artery, the middle cerebral artery, and the vertebral and basilar arteries were identified by using computed tomographic angiography or digital subtraction angiography. Results Among the 139 patients, 23 showed spontaneous recanalization, whereas 116 did not. In the patients with spontaneous recanalization, the proportion of atrial fibrillation was significantly lower (0% versus 29.31%, P = .01), whereas the proportion of stage 3 hypertension was significantly higher (60.87% versus 32.76%, P = .01) than that of those without recanalization. Logistic regression analysis showed that the proportion of atrial fibrillation was negatively (odds ratio OR: .117, 95% confidence interval CI: .015-.918, P = .04) associated with spontaneous recanalization, whereas the proportion of stage 3 hypertension was positively (OR: 4.316, 95% CI: 1.533-12.154, P = .01) associated with it. Conclusions Atrial fibrillation is associated with reduced spontaneous recanalization of the large and middle cerebral arteries in patients after acute ischemic stroke-induced occlusion, whereas stage 3 hypertension may contribute to the promotion of the recanalization.
The modulations of lymphocyte subsets and cytokine production due to subcutaneous allergen immunotherapy (SCIT) are not fully clarified.
We investigated the changes in T-lymphocyte subsets and serum ...Dermatophagoides pteronyssinus-specific immunoglobulin G4 (Der-p sIgG4), as well as cytokine production during Der-p SCIT, in patients with allergic asthma.
This study involved 20 patients with allergic asthma who were receiving 156-week Der-p SCIT and 20 patients without SCIT (non-SCIT). We measured symptom and medication scores (SMS), serum Der-p sIgG4 levels, CD4+CD25+Foxp3+ T regulatory (Treg), CD4+IL-4−IFN-γ+ T-helper (Th) 1, and CD4+IL-4+IFN-γ− Th2 lymphocyte percentages in peripheral blood mononuclear cells (PBMCs) with/without Der-p extract stimulation at weeks 0, 4, 12, 16, 52, 104, and 156. Cytokine release inhibition assays were performed by incubation with serum from SCIT and non-SCIT patients, Der-p allergen, and PBMCs. Levels of interleukin (IL)-4, IL-5, IL-10, IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were evaluated in supernatant.
We found that SCIT patients had significantly lower SMS after week 52. Der-p sIgG4 levels in SCIT patients significantly increased at week 16 compared with non-SCIT subjects. CD4+IL-4+IFN-γ− Th2% in SCIT patients showed a significant decrease from weeks 104–156 compared with week 0, while no change was observed in CD4+CD25+Foxp3+ Treg and CD4+IL-4−IFN-γ+ Th1 percentages. IL-5, IL-13, IL-4, IL-17, and TNF-α levels in supernatant of PBMCs cultured with serum of SCIT patients after 16 weeks showed significant lower levels compared with non-SCIT patients, and showed significant reverse associations with Der-p sIgG4 levels.
SCIT induced Dep-p sIgG4 may be involved in downregulating Th2 cytokine production in Der-p allergic asthma patients.
Abstract Background Surgical repair is an effective method to treat ventricular septal defect (VSD) complicating acute myocardial infarction (AMI). However, the mortality rate remains high. This ...study was designed to assess the immediate and mid-term results of transcatheter closure of postinfarct muscular VSDs. Methods Data were retrospectively collected from 42 AMI patients who underwent attempted transcatheter VSD closure between 2008 and 2012 in seven heart centers of China. Results Nine patients underwent emergent VSD closure in the acute phase (within two weeks from VSD) while the others underwent elective closure. The time between VSD occurrence and closure in emergency group and elective group was 7.7 ± 2.3 days and 35 ± 14.5 days, respectively ( p < 0.01). The percentage of procedure success in the emergency group and elective group was 77.8% (7/9) and 97% (32/33), respectively ( p = 0.048). The hospital mortality was higher for emergent closure in comparison to elective closure (66.7% vs. 6.1%, p < 0.01). During a median follow-up of 25 months (0–58 months), two patients died at 8 and 29 months, respectively, and no serious complications occurred in other patients. Conclusion Interventional postinfarct VSD closure is a safe and effective approach that can be performed with a high procedural success rate, with favorable outcomes if it can be undertaken >14 days postinfarct.
Abstract Background Severe burns initiate an inflammatory response characterized by the upregulation of proinflammatory cytokine, which contributes to multiple organ injury. Na+ /H+ exchanger 1 ...(NHE1) plays a significant role in several inflammatory processes. This study was designed to investigate the role of NHE1 in burn-induced inflammation and multiple organ injury. Materials and methods Rats were subjected to a 30% total body surface area full-thickness burn. Cariporide was used to assess the function of NHE1 in burn-induced multiple organ injury by biochemical parameters, histologic changes, and inflammatory cytokine production. Results We found that NHE1 expression was significantly increased after burn injury. Inhibition of NHE1 by cariporide attenuated burn-induced edema and tissue injury in heart, lung, kidney, and small intestine. Cariporide also inhibited plasma levels of tumor necrosis factor α, interleukin 6, and myeloperoxidase activity. Conclusions These results indicate that NHE1 inhibition prevents burn-induced multiple organ injury. The salutary effects afforded by NHE1 inhibition, at least in part, are mediated by attenuating systemic inflammatory response.
Background Familial hypercholesterolemia (FH) is marked by an elevated plasma cholesterol and risk of premature cardiovascular disease. An increased burden of FH is being realized. Objective To ...provide data on FH in Chinese patients with myocardial infarction (MI) and its potential contribution to early MI. Methods A total of 1843 consecutive patients undergoing coronary angiography with their first MI were recruited. The clinical FH was diagnosed using the Dutch Lipid Clinic Network criteria. The prevalence and clinical features of FH and the relationship of FH to risk of early MI were investigated. Results Of the 1843 patients, 48.2% were detected as premature MI (pMI, the onset age ≤55 years for men, ≤60 years for women). The prevalence of definite/probable FH reached 3.9% (7.1% in pMI and 0.9% in non-pMI). Furthermore, we found that the risk of pMI was significantly elevated in both definite/probable FH (vs. unlikely FH, odds ratio, 5.05 1.10–23.23) and possible FH (vs unlikely FH, odds ratio, 2.65 1.22–5.77), independently from classical risk factors and medications. Additionally, patients with definite/probable FH occurred 10 years younger than those with unlikely FH in the onset age of MI (48.63 ± 1.20 vs 58.35 ± 0.30 years, P < .001). When considered in subgroup of pMI or non-pMI, an early onset of MI was also observed in definite/probable FH (pMI, 45.83 ± 0.89 vs 47.87 ± 0.34 years; non-pMI, 60.75 ± 1.96 vs 65.07 ± 0.22 years; both P < .05). Conclusion The prevalence of FH among Chinese patients with MI appeared common, particularly among those with pMI. The phenotypic FH might significantly promote the early onset of MI.
Abstract Background The feasibility and efficacy of simultaneous percutaneous treatment of secundum type atrial septal defect (ASD) combined with pulmonary valve stenosis (PS) have not been proved. ...Objective To evaluate the safety and efficacy on the clinical benefit of simultaneous percutaneous correction of these two pathologies under local anesthesia and without transesophageal echocardiography guidance. Methods Transpulmonary gradient, functional status, pulmonary regurgitation (PR), and tricuspid regurgitation (TR) were studied in 35 patients undergoing percutaneous balloon pulmonary valvuloplasty and ASD closure from March 2004 to July 2012. All patients were followed up until January 2013, an average of 39 months. Results According to color Doppler transthoracic echocardiography (TTE) before the intervention, the ASD defect size and transpulmonary gradient were 17 ± 8.4 mm and 88 ± 37.8 mmHg, respectively. Post-interventionally, the peak-to-peak transpulmonary gradient decreased from 77 ± 37.6 mmHg to 20 ± 16.2 mmHg ( p < 0.001) and the ASD occluder size was 23 ± 10.5 mm. In all those patients, there was no residual shunt detected, and moderate and severe TR decreased from 45.7% (16/35) and 20% (7/35) to 8.6% (3/35) and 5.7% (2/35) before and after intervention detected by TTE, respectively. Eight patients had mild PR after procedure and two of them recovered at 6 months and no patient encountered severe adverse events at the latest follow-up. Conclusion Simultaneous percutaneous corrections of ASD combined with PS are feasible, safe, and effective with satisfactory results.
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