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Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance in vivo. Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.

Background Adriamycin (ADM) is currently one of the most effective chemotherapeutic agents in breast cancer treatment. However, growing resistance to ADM can lead to treatment failure and poor outcome. The underlying molecular mechanisms in ADM resistance in breast cancer remains unclear. PLAC8 is reported as a novel highly-conserved protein and functions as an oncogene or tumor suppressor in various tumors. Methods Here, we analyzed the expression profile of PLAC8 in breast cancer tissues and breast cancer cell lines, and explored the correlation of PLAC8 expression levels with patients’ outcomes and ADM response. One ADM resistant MCF-7 breast cancer cell (MCF-7/ADM) and its parental cell was used as in vitro models to identify the underlying mechanism of PLAC8 and ADM resistance. Breast cancer cells were transfected with PLAC8 knockdown and overexpression vectors, and MTT and colony formation assays were performed to test the cell response to ADM. Then, we tested the effect of PLAC8 on autophagy pathway by flow cytometry and immunofluorescence analysis, and the change of main autophagy-correlated factors expressions: LC3 and p62. Next, combining treatment of autophagy inhibitor/inducer and PLAC8 downregulation/upregulation revealed the participation of PLAC8 in autophagy pathway to synergistically regulate ADM resistance in breast cancer. Results Here, higher PLAC8 expression was correlated with poorer outcome and aggressive phenotype in breast cancer, and breast cancer patients with higher PLAC8 expression showed potential ADM resistance. PLAC8 expression level was also significantly elevated in ADM resistant MCF-7 breast cancer cells (MCF-7/ADM), compared to parental MCF-7 cells. In vitro experiments further confirmed that PLAC8 inhibition by siRNA or enforced overexpression by infecting pcDNA3.1(C)-PLAC8 plasmid correspondingly decreased or increased the ADM resistance. Subsequently, we demonstrated that ectopic PLAC8 expression in MCF-7/ADM cell blocked the accumulation of the autophagy-associated protein LC3II, and resulted in cellular accumulation of p62. Rapamycin-triggered autophagy significantly increased cell response to ADM, while the autophagy inhibitor 3-MA enhanced ADM resistance. Actually, 3-MA and PLAC8 could synergistically enhance ADM resistance via blocking the autophagy process. Additionally, the downregulation of p62 by siRNA attenuated the activation of autophagy and PLAC8 expression in breast cancer cells. Conclusion Our findings suggest that PLAC8, through participation of p62, inhibits autophagy and consequently results in ADM resistance in breast cancer. PLAC8/p62/autophagy pathway may act as novel therapeutic targets in breast cancer treatment and has potential clinical application in overcoming ADM resistance.

Long non‑coding RNA (lncRNA) H19 and Lin28 protein have been shown to participate in various pathophysiological processes, including cellular proliferation, autophagy and epithelial‑mesenchymal transition (EMT). A number of studies have investigated lncRNAs, microRNAs and mRNAs, and their roles in the initiation and progression of cancer, in doing so identifying competitive endogenous RNA (ceRNA) networks, including the H19/let‑7/Lin28 network. However, whether the H19/let‑7/Lin28 ceRNA network is involved in autophagy and EMT in breast cancer (BC) remains unclear. The present study demonstrated that the H19/let‑7/Lin28 loop was required for the downregulation of autophagy in BC cells via western blot analysis, reverse transcription‑quantitative PCR and autophagy flux monitoring. Using wound healing, migration and invasion assays, and morphological assays, the H19/let‑7/Lin28 loop was revealed to promote EMT in BC cells. Moreover, the H19/let‑7/Lin28 network was found to contribute to autophagy by inhibiting EMT in BC cells. To the best of our knowledge, the present study is the first to suggest the important roles of the H19/let‑7/Lin28 ceRNA network in BC autophagy and EMT, thus providing insight for the use of these molecules as prognostic biomarkers and therapeutic targets in BC metastasis.

The APOE ε4 allele is associated with impaired intrinsic functional connectivity in neural networks, especially in the default mode network (DMN). However, effective connectivity (EC) reflects the direct causal effects of one brain region to another, which has rarely been investigated. Recently, Granger causality analysis (GCA) proved suitable for the study of directionality in neuronal interactions. Using GCA, we examined the differences in the EC between the anterior medial prefrontal cortex/posterior cingulate cortex (aMPFC/PCC) and the whole brain in 17 ε4 carrying and 32 non-carrying cognitively intact elderly individuals. Furthermore, correlation analyses were performed between the abnormal EC and cognition/neuropathological indices. Compared with the non-carriers, the results showed that the ε4 carriers exhibited decreased EC from the PCC to the whole brain in the middle temporal gyrus (MTG), the anterior cingulate cortex (ACC), and the precuneus (PCu). Meanwhile, the ε4 carriers demonstrated increased EC from the whole brain to the aMPFC in the inferior parietal lobe (IPL) and the postcentral gyrus (PCG). The correlation analyses suggested that the EC from the IPL/PCG to the aMPFC was related to episodic memory in non-carriers, while the decreased EC from the PCC to the ACC was associated with increased levels of t-tau in the ε4 carriers. In ε4 carriers, a negative influence can be traced from the PCC to both the anterior and posterior DMN subsystems; meanwhile, the anterior DMN subsystem receives compensatory effects from the parietal cortex. Early increases in AD-related pathologies in the PCC may act as first factors during this pathological process.

Tamoxifen resistance represents a daunting challenge to the successful treatment for breast cancer. Krüppel-like factor 4 has critical roles in the development and progression of breast cancer, but its expression, function and regulation in the efficacy of TAM therapy in breast cancer have yet to be investigated. Here, we examined the clinical significance and biologic effects of KLF4 in breast cancer. Firstly, higher expression of KLF4 correlated with increased TAM sensitivity in breast cancer cells, and analysis of GEO datasets indicated that KLF4 expression was positively correlated with ERα and enhanced expression of KLF4 sensitized breast cancer patients to endocrine therapy. Knockdown of KLF4 in MCF-7 and BCAP37 cells led to increased TAM resistance, while ectopic KLF4 expression promoted the responsiveness to TAM in T47D and TAM-resistant MCF-7/TAM cells. Secondly, ectopic KLF4 overexpression suppressed MCF-7/TAM cell growth, invasion and migration. Moreover, KLF4 expression was down-regulated in breast cancer tumor tissues and high expression of KLF4 was associated with favorable outcomes. Mechanistically, KLF4 may enhance the responsiveness of breast cancer cells to TAM through suppressing mitogen-activated protein kinase (MAPK) signaling pathway. We found that ERK and p38 were more activated in MCF-7/TAM compared with MCF-7, and treatment with MAPK-specific inhibitors significantly suppressed cell viability. Knockdown of KLF4 activated ERK and p38 and drove MCF-7 cells to become resistant to TAM. Conversely, overexpression of KLF4 in MCF-7/TAM cells suppressed ERK and p38 signaling and resulted in increased sensitivity to TAM. Therefore, our findings suggested that KLF4 contributed to TAM sensitivity in breast cancer via phosphorylation modification of ERK and p38 signaling. Collectively, this study highlighted the significance of KLF4/MAPK signal interaction in regulating TAM resistance of breast cancer, and suggested that targeting KLF4/MAPK signaling may be a potential therapeutic strategy for breast cancer treatment, especially for the TAM-resistant patients.

Matrix metalloproteinase-1 (MMP1) is a member of the matrix metalloproteinases family, and its aberrant expression is implicated in tumor invasion and metastasis. However, the relationship between MMP1 abnormal expression and clinical outcome in breast cancer patients remains to be elucidated. To address this issue, we conducted immunohistochemistry in breast cancer and adjacent normal tissues, and mined the transcriptional and survival data of MMP1 in breast cancer patients through Oncomine, Kaplan-Meier Plotter, bc-GenExMiner, COSMIC and cBioPortal databases. First, we found that both protein and mRNA levels of MMP1 expression were significantly higher in breast cancer tissues. Second, high MMP1 mRNA expression correlated with worse overall survival among grade II (HR = 1.75; p = 0.011), nodal-negative (HR = 2.00; p = 0.00028), ER-positive (HR = 1.61; p = 0.00027) and HER2-negative (HR = 3.17; p = 0.029) patients with breast cancer by using Kaplan-Meier plotter database. Third, the overexpression of MMP1 was associated with unfavorable survival results including overall survival (HR = 1.6; p = 1.6e-05), relapse free survival (HR = 1.78; p < 1e-16) and distant metastasis free survival (HR = 1.65; p = 5.3e-05) in patients with breast cancer. Taken together, the expression status of MMP1 is a significant prognostic indicator and a potential drug target for breast cancer.

// Xiao Luo 1, * , Yerfan Jiaerken 1, * , Xinfeng Yu 1 , Peiyu Huang 1 , Tiantian Qiu 1 , Yunlu Jia 3 , Kaicheng Li 1 , Xiaojun Xu 1 , Zhujing Shen 1 , Xiaojun Guan 1 , Jiong Zhou 2 and Minming Zhang 1 , for The Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 Department of Radiology, The Second Affiliated Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 2 Department of Neurology, The Second Affiliated Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 3 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Minming Zhang, email: zhangminming@zju.edu.cn Keywords: apolipoprotein E (APOE), cerebral small-vascular disease (CSVD), white matter hyperintensities (WMH), dilated perivascular space (dPVS), cognition Abbreviations: APOE: apolipoprotein E; CSVD: cerebral small-vascular disease; WMH: white matter hyperintensities; dPVS: dilated perivascular space; MBs: microbleeds Received: December 29, 2016 Accepted: April 07, 2017 Published: May 09, 2017 ABSTRACT Objective: It remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data. Method: There were 135 healthy elderly (including e2, e4 allele carriers and e3 homozygotes) who had completed two years’ follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimer’s disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD. Results: We found that APOE e4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE e4 carriers had significantly decreased Aβ 1-42 level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and e4 allele was related with declining trend of cognition. Conclusion: Our findings suggested APOE e4 allele was associated with increased Aβ deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and e4 allele can exert long-term detrimental effects on individual’s trajectory of cognition.

// Hanchu Xiong 1,2,* , Wenhe Zhao 1,2,* , Ji Wang 1,2,* , Benjamin J. Seifer 3 , Chenyang Ye 4 , Yongxia Chen 1,2 , Yunlu Jia 1,2 , Cong Chen 1,2 , Jianguo Shen 1,2 , Linbo Wang 1,2 , Xinbing Sui 2,5 and Jichun Zhou 1,2 1 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China 2 Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China 3 USF Health Morsani College of Medicine, Tampa, FL, USA 4 Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education), Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China 5 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China * These authors have contributed equally to this work Correspondence to: Linbo Wang, email: // Xinbing Sui, email: // Jichun Zhou, email: // Keywords : Lin28; Let-7; breast cancer; metastasis; drug resistance Received : November 09, 2016 Accepted : January 11, 2017 Published : January 29, 2017 Abstract The RNA binding protein Lin28 is best known for the critical role in cell development, recent researches also have implied its oncogenic function in various human cancers, including breast cancer. Specifically, aberrant Lin28 participates in multiple pathological processes, such as proliferation, metastasis, radiotherapy and chemotherapy resistance, metabolism, immunity and inflammation as well as stemness. In this review, we summarize the let-7-dependent and let-7-independent mechanism regulated by Lin28, focusing on its relation with tumor hallmarks in breast cancer, and subsequently discuss our present knowledge of Lin28 to develop a molecular-based therapeutic strategy against breast cancer.

Background Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Recently, dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. Although the long noncoding RNA H19 is involved in various stages of tumorigenesis, its role in tamoxifen resistance remains unknown. Here, we assessed the role of H19 in the development of tamoxifen-resistant breast cancer. Methods Quantitative real-time PCR analyzed expression of H19 in tamoxifen-resistant breast cancer tissues. Knockdown of H19 was used to assess the sensitivity to tamoxifen in vitro and in vivo. Both knockdown and overexpression of H19 were used to analyze the status of autophagy. Real-time quantitative methylation-specific polymerase chain reaction, chromatin immunoprecipitation, immunofluorescence, and Western blot were used to explore the tamoxifen resistance mechanism of H19. Results In this study, we observed that the expression of H19 was substantially upregulated in tamoxifen-resistant breast cancer cell line and tumor tissues, and knockdown of H19 enhanced the sensitivity to tamoxifen both in vitro and in vivo. Furthermore, knockdown of H19 significantly inhibited autophagy in MCF7 tamoxifen-resistant (MCF7/TAMR) cells. Conversely, overexpression of H19 promoted autophagy. Interestingly, overexpression of H19 in MCF7 tamoxifen-sensitive cells could recapitulate tamoxifen resistance. Moreover, an increase in methylation in the promoter region of Beclin1 was observed in MCF7/TAMR-shH19 cells. In the double knockdown groups, both shH19+shSAHH and shH19+shDNMT3B rescued the Beclin1 promoter region methylation levels and reactivated autophagy functions. A chromatin immunoprecipitation assay further validated that DNMT3B binds to the Beclin1 promoter region and the knockdown of H19 increases this binding. Conclusions Our findings demonstrate that H19 induces autophagy activation via the H19/SAHH/DNMT3B axis, which could contribute to tamoxifen resistance in breast cancer. Electronic supplementary material The online version of this article (10.1186/s13045-019-0747-0) contains supplementary material, which is available to authorized users.

The cysteine‐rich lysosomal protein placenta‐specific 8 (PLAC8), also called onzin, has been shown to be involved in many types of cancers, and its role is highly dependent on cellular and physiological contexts. However, the precise function of PLAC8 in breast cancer (BC) progression remains unclear. In this study, we investigated both the clinical significance and biological functions of PLAC8 in BC progression. First, high PLAC8 expression was observed in primary BC tissues compared with adjacent normal tissues through immunohistochemistry analysis. The results of in vitro and in vivo assays further confirmed that PLAC8 overexpression promotes cell proliferation and suppress BC cell apoptosis, whereas PLAC8 silencing has the opposite effect. In addition, the forced expression of PLAC8 greatly induces cell migration, partially by affecting the EMT‐related genes, including down‐regulating E‐cadherin expression and facilitating vimentin expression. Further mechanistic analysis confirmed that PLAC8 contributes to cell proliferation and suppresses cell apoptosis in BC by activating the PI3K/AKT/NF‐κB pathway. The results of our study provide new insights into an oncogenic role of PLAC8 and reveal a novel PLAC8/ PI3K/AKT/NF‐κB pathway as a potential therapeutic target for BC.

The apolipoprotein E (APOE) ɛ4 allele is the best-known genetic risk factor for developing sporadic Alzheimer's disease (AD). According to neuroimaging studies, the APOE ɛ4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ4 carriers (with at least one copy of APOE ɛ4 allele) and 22 well-matched ɛ3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ3 homozygotes, APOE ɛ4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r = 0.64, p < 0.05; r = 0.65, p < 0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r = 0.71, p < 0.05). In our study, the presence of the APOE ɛ4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers.

Cong Chen,1,2 Shumin Huang,3 Aihua Huang,2,4 Yunlu Jia,1,2 Ji Wang,1,2 Zeqin Zhang,1,2 Misha Mao,1,2 Linbo Wang,1,2 Jichun Zhou1,2 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China; 3The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China; 4Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China Background: Ductal carcinoma in situ with microinvasion (DCISM) represents ~1% of all breast cancer cases. Risk factors for lymph node (LN) metastasis and appropriate adjuvant therapy for DCISM are still widely debated. Methods: We retrieved DCISM data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results registry database (1998–2013). Chi-squared tests and logistic regression models were applied to investigate the potential risks of LN metastasis. Univariate and multivariate Cox proportional hazards regressions were performed to estimate the prognostic factors of DCISM. Survival outcomes were estimated using the Kaplan–Meier method. A 1:1 propensity score matching was used to minimize potential bias. Results: Overall, 6,219 patients with DCISM met our inclusion criteria. Younger age and higher grade disease were identified as risk factors for LN metastasis. In the multivariable analysis, LN metastasis and chemotherapy were prognostic factors for worse overall survival and breast cancer-specific survival. Furthermore, propensity score matching and subgroup analysis showed that chemotherapy may not be effective for DCISM patients. Conclusion: Younger patients with high-grade disease tend to have LN involved in DCISM. Adjuvant chemotherapy might not be necessary for patients with DCISM. Keywords: SEER database, breast cancer, ductal carcinoma in situ with microinvasion, adjuvant chemotherapy, lymphatic metastasis

Cong Chen,1,2 Shumin Huang,3 Aihua Huang,1,2 Yunlu Jia,1,2 Ji Wang,1,2 Misha Mao,1,2 Jichun Zhou,1,2 Linbo Wang1,2 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China; 3Department of Pediatric Health Care, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China Background: Despite the considerable experience gained thus far using endoscopic technologies, the role of total endoscopic thyroidectomy (ET) for papillary thyroid cancer (PTC) remains controversial. We conducted a systematic review and meta-analysis to investigate the safety and effectiveness of total ET compared with conventional open thyroidectomy (OT) in PTC. Methods: A systematic search was conducted using the PubMed, Embase and Cochrane Library electronic databases up to March 2018. The quality of included studies was evaluated using the Newcastle–Ottawa Scale. Review Manager software version 5.3 was used for the meta-analysis. Results: Twelve studies including 2,672 patients were ultimately included in the systematic review and meta-analysis. ET was associated with longer operative time (P

Accumulating evidence suggests that placenta-specific 8 (PLAC8) plays an important role in normal cellular process and human diseases, including multiple types of human tumors, and its role is highly relied upon in cellular and physiologic contexts. However, there are no reports on its expression profile and biological roles during lung cancer development. In the current study, both the clinical implications and biological effects of PLAC8 in lung cancer (LC) progression were investigated, and we identified and described the novel Krüppel-like factor 4 (KLF4)/PLAC8 regulatory pathway in cancer progression. Elevated PLAC8 levels were positively correlated with tumor size, histological grade, and tumor node metasis (TNM) stage, and LC patients with high PLAC8 expression suffered poor outcomes. In vitro and in vivo assays further revealed that endogenous PLAC8 promoted cell proliferation and tumor formation. We also found downregulated PLAC8 protein in several LC cell lines following the induction of KLF4, and immunohistochemistry analysis of LC tissues by microarray indicated a potential inverse correlation between PLAC8 and KLF4 expression. Luciferase reporter analysis and chromatin immunoprecipitation assays determined that KLF4 negatively regulated PLAC8 promoter activity via directly binding to the promoter region. Furthermore, the growth inhibition resulting from KLF4 overexpression was partially rescued by ectopic PLAC8 expression. Together, our data uncovered a previously unidentified role of PLAC8 as a central mediator in LC progression. PLAC8 was transcriptionally repressed by KLF4, and the novel KLF4/PLAC8 axis may act as a promising candidate target for LC diagnosis and therapy.

Summary Background There is a growing literature documenting a variety of brain abnormalities associated with obesity. However, little is known about the effects of obesity on inter-hemispheric connectivity in aging people. Methods Participants included 61 cognitively intact elderly (including people with obesity, overweight, and lean controls) who underwent structural MRI, resting-state functional magnetic resonance imaging (rsfMRI) and standard neuropsychological batteries. Techniques including FreeSurfer and Voxel-mirrored Homotopic Connectivity (VMHC) were employed to evaluate inter-hemispheric structural and functional connectivity respectively. Results There were no differences of cognitive abilities and vascular risks among groups. When compared to lean controls, obese group had greater VMHC in fusiform gyrus (FG); while overweight group had greater VMHC in FG, calcarine gyrus, inferior temporal gyrus (ITG), and postcentral gyrus (PCG). Moreover, the obesity group had lower VMHC in calcarine gyrus and PCG than overweight group (p Conclusions The present study suggested, increased inter-hemispheric information transmission in networks supporting visual and sensorimotor function may lead to gain in weight, by possibly mediating diet behaviours of individuals.

Amnestic mild cognitive impairment can be further classified as single-domain aMCI (SD-aMCI) with isolated memory deficit, or multi-domain aMCI (MD-aMCI) if memory deficit is combined with impairment in other cognitive domains. Prior studies reported these clinical subtypes presumably differ in etiology. Thus, we aimed to explore the possible mechanisms between different aMCI subtypes by assessing alteration in brain activity and brain vasculature, and their relations with CSF AD biomarkers. 49 healthy controls, 32 SD-aMCI, and 32 MD-aMCI, who had undergone structural scans, resting-state functional MRI (rsfMRI) scans and neuropsychological evaluations, were identified. Regional homogeneity (ReHo) was employed to analyze regional synchronization. Periventricular white matter hyperintensities (PWMH) and deep WMH (DWMH) volume of each participant was quantitatively assessed. AD biomarkers from CSF were also measured. SD-aMCI showed decreased ReHo in medial temporal gyrus (MTG), and increased ReHo in lingual gyrus (LG) and superior temporal gyrus (STG) relative to controls. MD-aMCI showed decreased ReHo, mostly located in precuneus (PCu), LG and postcentral gyrus (PCG), relative to SD-aMCI and controls. As for microvascular disease, MD-aMCI patients had more PWMH burden than SD-aMCI and controls. Correlation analyses indicated mean ReHo in differenced regions were related with memory, language, and executive function in aMCI patients. However, no significant associations between PWMH and behavioral data were found. The Aβ level was related with the ReHo value of STG in SD-aMCI. MD-aMCI displayed different patterns of abnormal regional synchronization and more severe PWMH burden compared with SD-aMCI. Therefore aMCI is not a uniform disease entity, and MD-aMCI group may show more complicated pathologies than SD-aMCI group.

The contemporary surgery has reported the safety of laparoscopic surgery (LAP) for patients with gastrointestinal stromal tumors (GISTs). However, its use is still debated due to suspicion of the oncologic equivalence to open surgery (OPEN). We conducted a systematic review and meta-analysis of updated original articles to investigate the short- and long-term clinical outcomes of LAP compared with OPEN for GISTs.A systematic search was performed in PubMed, Embase, Web of Science, Cochrane Library and CNKI. Comparative studies of laparoscopic and open surgery for GISTs were published before November 2016. The Newcastle-Ottawa scale was utilized to conduct quality assessment. The Review Manager (RevMan) software version 5.0 was used for meta-analysis.Twenty-four studies involving 2140 patients were included for the meta-analysis. The meta-analysis results showed that, compared with OPEN, LAP indicated potentially favorable outcomes in terms of operative time (WMD, -30.71; 95% CI, -58.48 to -2.95; P = 0.03); intraoperative blood loss (WMD, -60.90; 95% CI, -91.53 to -30.28; P 0.0001); time to flatus (WMD, -1.10; 95% CI, -1.41 to -0.79; P 0.00001); time to oral intake (WMD, -1.25; 95% CI, -1.64 to -0.86; P 0.00001); length of hospital stay (WMD, -3.42; 95% CI, -4.37 to -2.46; P 0.00001); overall complications (OR, 0.38; 95% CI, 0.27 to 0.54; P 0.00001); and recurrence (OR, 0.45; 95% CI, 0.30 to 0.66; P 0.0001).Laparoscopic surgery is safe and feasible for the treatment of GISTs including less operative time and intraoperative blood loss, earlier postoperative recovery, shorter hospital stay, and lower rate of overall complications and recurrence.

Apolipoprotein E (APOE) e4 allele is the best established genetic risk factor for sporadic Alzheimer’s disease (AD). However, there is a need to understand the effects of this genotype on the brain by simultaneously assessing intrinsic brain network and cerebral spinal fluid (CSF) biomarkers changes in healthy older e4 carriers. Thirteen cognitively intact, elderly APOE e4 carriers and 22 e3 homozygotes were included in the present study. Eigenvector centrality mapping (ECM) was used to identify brain network hub organization based on resting-state functional MRI (rsfMRI). We evaluated comprehensive cognitive ability and tested levels of Aβ1–42, total-tau (t-tau) and phosphorylated-tau (p-tau181) in CSF. Comparisons of ECM between two groups were conducted, followed by correlations analyses between EC values with significant group differences and cognitive ability/CSF biomarkers. APOE e4 carriers showed significantly decreased EC values in left medial temporal lobe (MTL), left lingual gyrus (LG) and increased EC values in left middle frontal gyrus (MFG) as compared to non-carriers. Correlation analysis demonstrated that left LG EC value correlated with Rey Auditory Verbal Learning Test total learning (RAVLT, r = 0.57, p

APOE is one of the strongest genetic factors associated with information processing speed (IPS). Herein, we explored the neural substrates underlying APOE-related IPS alteration by measuring lobar distribution of white matter hyperintensities (WMH), cortical grey matter volume (GMV) and thickness. Using the ADNI database, we evaluated 178 cognitively normal elderly individuals including 34 APOE e2 carriers, 54 APOE e4 carriers and 90 e3 homozygotes. IPS was determined using Trail Making Tests (TMT). We quantified lobar distribution of WMH, cortical GM lobar volume, cortical thickness among three groups. Finally, we used Pearson's correlation and general linear models to examine structural MRI markers in relation to IPS. There were significant differences of IPS among groups, with e4 carriers displaying the worst performance. Across groups, significant differences in frontal and parietal WMH load were observed (the highest in e4 carriers); however, no significant differences in cortical GMV and thickness were found. Pearson's correlation analysis showed parietal WMH volume was significantly related with IPS, especially in e4 carriers. Subsequently a general linear model demonstrated that parietal WMH volume, age and the interaction between parietal WMH volume and age, was significantly associated with IPS, even after adjusting total intracranial volume (TIV), gender and vascular risk factors. Disruption of WM structure, rather than atrophy of GM, plays a more critical role in APOE e4 allele-specific IPS. Moreover, specific WMH loci are closely associated with IPS; increased parietal WMH volume, especially in e4 carriers, was independently contributed to slower IPS.

// Wenxian Hu 1, * , Yunlu Jia 1, * , Xiangsheng Xiao 2 , Kezhen Lv 3 , Yongxia Chen 1 , Linbo Wang 1 , Xiao Luo 1 , Tianze Liu 2 , Wenbin Li 2 , Yixin Li 2 , Changlin Zhang 2 , Zhenglong Yu 4 , Wenlin Huang 2, 5 , Bing Sun 4 , Wu-guo Deng 2, 5 1 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China 2 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China 3 Department of Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China 4 Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China 5 State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China * These authors contributed equally to this work Correspondence to: Wenxian Hu, email: 13967169904@163.com Bing Sun, email: dysunbing@163.com Wu-guo Deng, email: dengwg@sysucc.org.cn Keywords: KLF4, hTERT, MAPK, lung cancer, cancer prognosis Received: January 07, 2016 Accepted: April 16, 2016 Published: May 02, 2016 ABSTRACT Kruppel-like factor 4 (KLF4) is a transcription factor that contributes to diverse cellular processes and serves as a tumor suppressor or oncogene in various cancers. Previously, we have reported on the tumor suppressive function of KLF4 in lung cancer; however, its precise regulatory mechanism remains elusive. In this study, we found that KLF4 negatively regulated hTERT expression and telomerase activity in lung cancer cell lines and a mouse model. In addition, the KLF4 and hTERT expression levels were significantly related to the clinicopathological features of lung cancer patients. Promoter reporter analyses revealed the decreased hTERT promoter activity in cells infected with Ad-KLF4, and chromatin immunoprecipitation analysis demonstrated that endogenous KLF4 directly bound to the promoter region of hTERT. Furthermore, the MAPK signaling pathway was revealed to be involved in the KLF4/hTERT modulation pathway. Forced expression of KLF4 profoundly attenuated lung cell proliferation and cancer formation in a murine model. Moreover, hTERT overexpression can partially rescue the KLF4-mediated suppressive effect in lung cancer cells. Taken together, these results demonstrate that KLF4 suppresses lung cancer growth by inhibiting hTERT and MAPK signaling. Additionally, the KLF4/hTERT/MAPK pathway is a potential new therapeutic target for human lung cancer.