High expression levels of centromere protein A plus upregulation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway affect chemotherapy response and prognosis in patients with breast cancer

Centromere proteins (CENPs) are involved in mitosis, and CENP gene expression levels are associated with chemotherapy responses in patients with breast cancer. The present study aimed to examine the roles and underlying mechanisms of the effects of CENP genes on chemotherapy responses and breast cancer prognosis. Using data obtained from the Gene Expression Omnibus (GEO) database, correlation and Cox multivariate regression analyses were used to determine the CENP genes associated with chemotherapy responses and survival in patients with breast cancer. Weighted gene co-expression network and correlation analyses were used to determine the gene modules co-expressed with the identified genes and the differential expression of gene modules associated with the pathological complete response (PCR) and residual disease (RD) subgroups. CENPA, CENPE, CENPF, CENPI, CENPJ and CENPN were associated with a high nuclear grade and low estrogen and progesterone receptor expression levels. In addition, CENPA, CENPB, CENPC and CENPO were independent factors affecting the distant relapse-free survival (DRFS) rates in patients with breast cancer. Patients with high expression levels of CENPA or CENPO exhibited poor prognoses, whereas those with high expression levels of CENPB or CENPC presented with favorable prognoses. For validation between databases, the Cancer Genome Atlas (TCGA) database analysis also revealed that CENPA, CENPB and CENPO exerted similar effects on overall survival. However, according to the multivariate analyses, only CENPA was an independent risk factor associated with DRFS in GEO database. In addition, in the RD subgroup, patients with higher CENPA expression levels had a worse prognosis compared with those with lower CENPA expression levels. Among patients with high expression levels of CENPA, the PI3K/Akt/mTOR pathway was more likely to be activated in the RD compared with the PCR subgroup. The same trend was observed in TCGA data. These results suggested that high CENPA expression levels plus upregulation of the PI3K/Akt/mTOR signaling pathway may affect DRFS in patients with breast cancer.     

BRCA1-associated protein 1 serves as a tumor suppressor in hepatocellular carcinoma by deubiquitinating and stabilizing PTEN

BRCA1-associated protein 1 (BAP1) or its mutants have been known to play critical regulatory roles in tumor biology, yet their role in hepatocellular carcinoma (HCC) remains largely unclear. In this study, we detected the mutations of all the exons of BAP1 in 105 HCC patients using Sanger sequencing, and found eight somatic mutations in 6 (5.71%) patients. We also found that the mRNA and protein levels of BAP1 were markedly downregulated in HCC versus the adjacent non-tumor tissues. Wild-type BAP1 but not mutant BAP1 significantly inhibited HCC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor progression and metastasis in vivo. Mechanistically, BAP1 complexed with PTEN and stabilized PTEN via deubiquitination and, furthermore, negatively regulated HCC cell EMT by deactivating the AKT/GSK-3β/Snail pathway. However, those tumor-inhibitory effects of BAP1 were abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated to aggressive tumor phenotypes, which also independently associated with poorer recurrence-free survival and overall survival after curative hepatectomy. Conclusively, our results indicate that BAP1, significantly downregulated, somatically mutated and negatively regulating EMT in HCC, serves as a tumor suppressor of HCC by deubiquitinating and stabilizing PTEN.     

Assessment of health-related quality of life in Chinese patients with minimal hepatic encephalopathy

AIM:To evaluate the health-related quality of life (HRQOL) based on the Chinese version of SF-36 and Chronic Liver Disease Questionnaire (CLDQ) in subjects with chronic hepatitis B,liver cirrhosis,including patients with minimal hepatic encephalopathy (MHE). METHODS:The SF-36 and CLDQ were administered to 160 healthy volunteers,20 subjects with chronic hepatitis B and 106 patients with cirrhosis (33 cases exhibited MHE). HRQOL scores were compared among the different study groups. The SF-36 includes eight health concepts:physical functioning,role-physical,body pain,general health,vitality,social functioning,role-emotion,and mental health. Six domains of CLDQ were assessed:abdominal symptoms,fatigue,systemic symptoms,activity,emotional function and worry. RESULTS:Compared with healthy controls (96.9 ± 4.5,86.6 ± 18.4,90.1 ± 12.5,89.0 ± 5.7,87.5 ± 4.3,95.8 ± 7.1,88.5 ± 15.9,88.7 ± 5.2 in SF-36 and 6.7 ± 0.5,6.1 ± 0.6,6.3 ± 0.6,6.5 ± 0.5,6.3 ± 0.5,6.8 ± 0.4 in CLDQ),patients with chronic hepatitis B (86.3 ± 11.0,68.8 ± 21.3,78.9 ± 14.4,60.8 ± 10.5,70.8 ± 8.6,76.1 ± 12.6,50.0 ± 22.9,72.2 ± 10.6 and 5.5 ± 1.0,4.5 ± 1.0,5.2 ± 1.1,5.3 ± 0.9,4.8 ± 0.9,4.9 ± 1.0) and cirrhosis (52.8 ± 17.4,32.8 ± 27.9,61.6 ± 18.9,30.2 ± 18.3,47.9 ± 20.1,54.0 ± 19.2,28.9 ± 26.1,51.1 ± 17.8 and 4.7 ± 1.2,3.9 ± 1.2,4.7 ± 1.2,4.7 ± 1.3,4.7 ± 1.0,4.4 ± 1.1) had lower HRQOL on all scales of the SF-36 and CLDQ (P < 0.01 for all). Increasing severity of liver cirrhosis (based on the Child-Pugh score/presence or absence of MHE) was associated with a decrease in most components of SF-36 and CLDQ,especially SF-36.CONCLUSION:The Chinese version of SF-36 along with CLDQ is a valid and reliable method for testing MHE in patients with liver cirrhosis. Cirrhosis and MHE are associated with decreased HRQOL.     

A multi-group model of Schistosoma japonicum transmission dynamics and control: model calibration and control prediction

Previously we formulated a quantitative model to characterize site-specific schistosomiasis transmission. In this paper, we present a procedure to calibrate the model to data collected in endemic villages of south-western Sichuan, China, with the objective of reducing parametric uncertainty to allow the model to describe local transmission with relative confidence. A Bayesian approach using local epidemiological data and expert opinion is employed to calibrate the model. Results indicate that, after calibration, the output uncertainty is reduced substantially. The calibrated model is then used for prediction of the effects of different intervention options. Simulations reflect a bimodal transmission in both human (early summer and early fall) and snail (late summer and late fall) infections in this area, for which there is some field evidence. Also shown in the simulations are relatively high reinfection rates following chemotherapy in these endemic villages. These results suggest that a sustainable control strategy is essential in reducing transmission, and that transmission can be reduced by chemotherapy, focal snail (e.g. snail clusters) control, and egg control. Our work demonstrates the feasibility of characterizing site-specific schistosomiasis transmission using a mathematical model and a calibration approach that integrates diverse field data, and the use of the calibrated model to design control strategies.     

Imaging characteristics of Rosai-Dorfman disease in the central nervous system

Background and purpose

Rosai-Dorfman disease (RDD) is a rare, lymphoproliferative disorder of uncertain etiology. The Central Nervous System (CNS) is a very rare site for RDD and only a few imaging appearances have been described. The purpose of this study is to present the largest series of cases in the CNS imaging literature to increase familiarity with this entity and further identify features that may distinguish RDD from meningioma.

Materials and methods

Findings from imaging examinations in 10 patients with pathologically confirmed RDD were retrospectively reviewed. Two radiologists evaluated the lesion location, shape, size, number, edge, cerebral edema, homogeneous or heterogeneous appearance, attenuation and signal intensity, degree of enhancement, and the relation between lesions and meninges.

Results

RDD in CNS showed similar features in imaging: an extra-axial, well-circumscribed, dura-based mass, isodense or hyperdense on CT, isointensity on T1-weighted imaging and isointensity with hypointensity on T2-weighted imaging. The mass enhanced markedly and homogeneously after the administration of contrast agent and demonstrated dural tail sign in all cases. Significant perifocal edema was associated with the masses. Remarkably, seven patients (77.8%) showed strong hypointensity within isointensity on T2-weighted or FLAIR images and no calcification was observed in CT images or pathologic specimens.

Conclusions

Although RDD in the CNS is a rare process, it should be considered in the differential diagnoses for meningioma. We believe that a typical representation of hypointensity irrelevant to calcification on T2-weighted or FLAIR images can suggest the diagnosis of RDD.     

Diffusion tensor imaging of normal white matter maturation from late childhood to young adulthood: voxel-wise evaluation of mean diffusivity, fractional anisotropy, radial and axial diffusivities, and correlation with reading development

Using diffusion tensor MR imaging (DTI) and advanced voxel-wise analysis tools, we study diffusivity and anisotropy changes of white matter from late childhood to young adulthood, and correlate quantitative diffusion indices with Chinese and English reading performance scores. Seventy-five normal healthy school going ethnic Chinese students and young adults of three age groups were recruited (group 1, n=24, mean+/-SD=7.4+/-0.3 years; group 2, n=27, mean+/-SD=10.3+/-0.5 years; group 3, n=24, mean+/-SD=22.8+/-2.3 years). DTI was performed with 3 mm isotropic resolution to cover the entire brain. Voxel-wise analysis was performed using Tract-Based Spatial Statistics (TBSS) to localize regions of white matter showing significant changes of fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities between groups. We found increased FA and decreased MD with increasing age in regions of cerebellar white matter, right temporal white matter, and a large portion of the superior frontal and parietal white matter driven by both the reduction of radial diffusivity and axial diffusivity with the former to a greater extent. Changes were continual from late childhood to young adulthood. Findings were confirmed by region-of-interest analysis in specific white matter tracts. After controlling for the effect of age, significant correlation was found between diffusion indices of the anterior limb of the left internal capsule and Chinese reading score (p=0.05), and of the corona radiata and English reading score (p=0.026 and p=0.029 for left and right, respectively).These DTI indices likely reflect the multiple biological processes that occur during brain development which provide the neural substrate for ongoing functional connectivity including for reading development.