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Leftover food consumption is very prevalent among the Chinese older adults, however, the potential effects of leftover eating consumption on depression have not yet been investigated.The study aims to determine the association between leftover consumption on depression among older adults.Data of leftover consumption frequency was collected in a cross-sectional study with a provincial representative sample of 5992 older adults (aged 60 or older) in 2019. Depression symptoms were assessed by the 9-item screener Patient Health Questionnaire (PHQ-9). Multiple logistic regression models were applied to analyze the association of the frequency of leftover eating consumption and the presence and the severity of depression.After controlling for all the covariates, the participants who consume leftover food everyday had higher risk of having depression symptom comparing to those who had the lowest frequency of leftover eating (OR: 1.675, 95% CI: 1.435-1.956, p 0.001). The participants who consume leftover food every day was also associated with more severe depression symptoms (OR: 1.621, 95% CI: 1.397-1.881, p 0.001), when comparing to the reference group. The associations seemed stronger in men than women.The causal relationship between leftover consumption behavior and depression could not be determined due to the cross-sectional design. Moreover, the variety or handling method of the leftover food was not specified.Leftovers eating frequency was associated with the presence and severity of depression symptoms among older adults.

PIGK gene, encoding a key component of glycosylphosphatidylinositol (GPI) transamidase, was recently reported to be associated with inherited GPI deficiency disorders (IGDs). However, little is known about the specific downstream effects of PIGK on neurodevelopment due to the rarity of the disease and the lack of in vivo study. Here, we described 2 patients in a Chinese family presented with profound global developmental delay, severe hypotonia, seizures, and postnatal progressive global brain atrophy including hemisphere, cerebellar and corpus callosum atrophy. Two novel compound heterozygous variants in PIGK were identified via genetic analysis, which was proved to cause significant decrease of PIGK protein and reduced cell surface presence of GPI-APs in the patients. To explore the role of Pigk on embryonic and neuronal development, we constructed Pigk knock-down zebrafish and knock-in mouse models. Zebrafish injected with a small dose of morpholino oligonucleotides displayed severe developmental defects including small eyes, deformed head, curly spinal cord, and unconsumed yolk sac. Primary motor neuronal dysplasia and extensive neural cell apoptosis were further observed. Meanwhile, the mouse models, carrying the two variants respectively homologous with the patients, both resulted in complete embryonic lethality of the homozygotes, which suggested the intolerable effect caused by amino acid substitution of Asp204 as well as the truncated mutation. Our findings provide the in vivo evidence for the essential role of PIGK during the embryonic and neuronal development. Based on these data, we propose a basis for further study of pathological and molecular mechanisms of PIGK-related neurodevelopmental defects.

Background Long noncoding RNAs (lncRNAs) are important regulators in tumor progression. However, their biological functions and underlying mechanisms in hypoxia adaptation remain largely unclear. Results Here, we established a correlation between a Chr3q29-derived lncRNA gene and tongue squamous carcinoma (TSCC) by genome-wide analyses. Using RACE, we determined that two novel variants of this lncRNA gene are generated in TSCC, namely LINC00887_TSCC_short (887S) and LINC00887_TSCC_long (887L). RNA-sequencing in 887S or 887L loss-of-function cells identified their common downstream target as Carbonic Anhydrase IX (CA9), a gene known to be upregulated by hypoxia during tumor progression. Mechanistically, our results showed that the hypoxia-augmented 887S and constitutively expressed 887L functioned in opposite directions on tumor progression through the common target CA9. Upon normoxia, 887S and 887L interacted. Upon hypoxia, the two variants were separated. Each RNA recognized and bound to their responsive DNA cis-acting elements on CA9 promoter: 887L activated CA9’s transcription through recruiting HIF1α, while 887S suppressed CA9 through DNMT1-mediated DNA methylation. Conclusions We provided hypoxia-permitted functions of two antagonistic lncRNA variants to fine control the hypoxia adaptation through CA9.

Background Paclitaxel (PTX) has been suggested to be a promising front-line drug for gastric cancer (GC), while P-glycoprotein (P-gp) could lead to drug resistance by pumping PTX out of GC cells. Consequently, it might be a hopeful way to combat drug resistance by inhibiting the out-pumping function of P-gp. Results In this study, we developed a drug delivery system incorporating PTX onto polyethylene glycol (PEG)-modified and oxidized sodium alginate (OSA)-functionalized graphene oxide (GO) nanosheets (NSs), called PTX@GO-PEG-OSA. Owing to pH/thermal-sensitive drug release properties, PTX@GO-PEG-OSA could induced more obvious antitumor effects on GC, compared to free PTX. With near infrared (NIR)-irradiation, PTX@GO-PEG-OSA could generate excessive reactive oxygen species (ROS), attack mitochondrial respiratory chain complex enzyme, reduce adenosine-triphosphate (ATP) supplement for P-gp, and effectively inhibit P-gp’s efflux pump function. Since that, PTX@GO-PEG-OSA achieved better therapeutic effect on PTX-resistant GC without evident toxicity. Conclusions In conclusion, PTX@GO-PEG-OSA could serve as a desirable strategy to reverse PTX’s resistance, combined with chemo/photothermal/photodynamic therapy. Graphic Abstract

In this study, we explored the cross-sectional associations between living and built environments and depression among older Chinese adults. Data from 5822 participants were obtained. Depression symptoms were evaluated through the use of the Patient Health Questionnaire (PHQ-9), with a score higher than 4 categorized as having depression symptoms. The living environment was assessed by asking about dust in the environment and barrier-free facilities. We considered the presence of amenities within a 10 min walking distance and the proportion of green space within an 800 m distance from participants’ dwellings to reflect the built environment. Data were analyzed by multilevel logistic regression. Participants living in a non-dusty environment with proximity to green space had a lower risk of depression (non-dusty environment: OR = 0.784, 95% CI = 0.642, 0.956; green space: OR = 0.834, 95% CI = 0.697, 0.998). However, having no access to barrier-free facilities and hospital proximity increased the depression risk (barrier-free facilities: OR = 1.253, 95% CI = 1.078, 1.457; hospital: OR = 1.318, 95% CI = 1.104, 1.574). Dusty environments, access to barrier-free facilities and proximity to hospitals and green spaces were associated with depression symptoms among older Chinese adults.

Online takeaway food has become very popular in China. However, the potential effects of online takeaway food consumption on eating behaviours among individuals during the transition stage from adolescence to young adulthood have not yet been assessed. This study aimed to examine the effects of takeaway food consumption on emotional overeating behaviour among college students. Data were collected from 1450 college students from six universities in Anhui, China. The frequency of emotional overeating during the past 4 weeks was assessed by the emotional overeating questionnaire (EOQ). Data on the frequency of online takeaway food consumption and other potential risk factors at the individual, interpersonal, physical environment, and macro-system levels were assessed by questionnaire. Multilevel linear regression analyses were employed to explore the association between takeaway food consumption and emotional overeating behaviour. Compared to those who consumed online takeaway food less than 1 day per week, participants who consumed this food 4–5 days per week and participants who consumed this food 6–7 days per week had significantly higher EOQ scores (β = 0.14, p

Background: CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells’ apoptosis. However, the certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells’ mitochondrial damage, remained unclear. Moreover, theranostic efficiency of HMON@CuS might be well improved by applying multi-modal imaging, which could offer an optimal therapeutic region and time window. Herein, new nanotheranostics agents were reported by Gd doped HMON decorated by CuS nanocrystals (called HMON@CuS/Gd).Results: HMON@CuS/Gd exhibited appropriate size distribution, good biocompatibility, L-Glutathione (GSH) responsive degradable properties, high photo-thermal conversion efficiency (82.4%) and a simultaneous reactive oxygen species (ROS) generation effect. Meanwhile, HMON@CuS/Gd could efficiently enter GC cells, induce combined mild PTT (43-45 °C) and PDT under mild NIR power density (0.8W/cm2). Surprisingly, it was found that PTT might not be the only factor of cell apoptosis, as ROS induced by PDT also seemed playing an essential role. The NIR-induced ROS could attack mitochondrial transmembrane potentials (MTPs), then promote mitochondrial reactive oxygen species (mitoROS) production. Meanwhile, mitochondrial damage dramatically changed the expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by inducing more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-9/caspase-3-depended cell apoptosis pathway. Our in vivo data also showed that HMON@CuS/Gd exhibited good fluorescence (FL) imaging (wrapping fluorescent agent), enhanced T1 imaging under magnetic resonance imaging (MRI) and infrared thermal (IRT) imaging capacities. Guided by FL/MRI/ IRT trimodal imaging, HMON@CuS/Gd could selectively cause mild photo-therapy at cancer region, efficiently inhibit the growth of GC cells without evident systemic toxicity in vivo. Conclusion: HMON@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on GC.

Epithelial ovarian cancer (EOC) is one of the most common and lethal gynecological cancers. Novel therapeutic agents have been developed for EOC, but patient survival remains poor. Trastuzumab has been approved for breast and gastric cancers with high expression of human epidermal growth factor receptor 2 (HER2), but it has not achieved any clinical success in EOC. Dysregulated Wnt/β-catenin signaling is involved in cancer development, but whether it plays a role in EOC resistance to trastuzumab remains largely unknown. Here, we observed that high expression of Wnt3a, β-catenin and TCF7L2, which can form a signaling axis in the Wnt/β-catenin pathway, commonly existed in HER2-positive EOC tissue samples and was correlated with a poor patient prognosis. Cell proliferation and migration assays and nude mouse xenograft model experiments demonstrated that the Wnt3a/β-catenin/TCF7L2 signaling axis promoted tumor cell growth and metastasis and reduced tumor sensitivity to trastuzumab. Analysis of downstream Akt signaling suggested that the function of the Wnt3a/β-catenin/TCF7L2 signaling axis was mediated, at least in part, through increasing Akt phosphorylation. Overall, this study reveals a crucial role for the Wnt3a/β-catenin/TCF7L2 signaling axis in EOC resistance to trastuzumab and the potential application of HER2-targeted drugs combined with inhibitors of this signaling axis for EOC treatment.

This study strategically fabricates a nucleic acid functionalized gold nanoparticle and graphene oxide composite probe (AuNP/GO probe) to achieve both the recognition and in situ monitoring of cytoplasmic target precursor microRNAs (pre-miRNAs) and mature microRNAs (miRNAs) in living cells. The pre-miRNA-21 detection with AuNP probes has a good linear range of 0–300 nM and a limit of detection (LOD) of 4.5 nM, whereas the GO probe has a linear relationship with mature miRNA-21 from 0.1 to 10 nM with a LOD of 1.74 nM. This assay was utilized to directly visualize the relative expression levels of pre- and mature forms of miRNA-21 and let-7a. The results suggested that the expression levels of precursor miRNAs remain constant in cancer cells and normal cells. However, the expression levels of mature miRNAs vary widely, demonstrating the “up-regulation” of miRNA-21 and “down-regulation” of let-7a in cancer cells in contrast to that in normal cells. The practicality of this strategy was verified by in situ monitoring changes in cytoplasmic pre-miRNA-21 and mature miRNA-21 in response to small-molecule inhibitors of miRNA-21.

Histone lysine specific demethylase 1 (LSD1 or KDM1A) is a potential therapeutic target in oncology due to its overexpression in various human tumors. We report herein a new class of benzofuran acylhydrazones as potent LSD1 inhibitors. Among the 31 compounds prepared, 14 compounds exhibited excellent LSD1 inhibitory activity with IC50 values ranging from 7.2 to 68.8 nM. In cellular assays, several compounds inhibited the proliferations of various cancer cell lines, including PC-3, MCG-803, U87 MG, PANC-1, HT-29 and MCF-7. This opens up the opportunity for further optimization and investigation of this class compounds for potential cancer treatment.

Cancer is an age‐associated disease, potentially related to the altered immune system of elderly individuals. However, cancer has gradually decreased incidence in the eldest globally such as the most common lung cancer, the mechanisms of which remain to be elucidated. In this study, it was found that the number of lung‐resident γδT cells was significantly increased with altered gene expression in aged mice (20–24 months) versus young mice (10–16 weeks). Aged lung Vγ4+ and Vγ6+ γδT cells predominantly produced interleukin‐17A (IL‐17A), resulting in increased levels in the serum and lungs. Moreover, the aged mice exhibited smaller tumors and reduced numbers of tumor foci in the lungs after challenge with intravenous injection of B16/F10 melanoma cells compared with the young mice. Aged lung Vγ4+ and Vγ6+ γδT cells were highly cytotoxic to B16/F10 melanoma cells with higher expression levels of CD103. The markedly longer survival of the challenged aged mice was dependent on γδT17 cells, since neutralization of IL‐17A or depletion of indicated γδT cells significantly shortened the survival time. Consistently, supplementation of IL‐17A significantly enhanced the survival time of young mice with lung melanoma. Furthermore, the anti‐tumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota, as demonstrated through co‐housing of the aged and young mice. Intrinsically altered lung γδT17 cells underlying age‐dependent changes control lung melanoma, which will help to better understand the lung cancer progression in the elderly and the potential use of γδT17 cells in anti‐tumor immunotherapy., In the aged mice (20–24 months), the number of lung‐resident γδT cells was significantly increased with altered gene expression compared with the young mice (10–16 weeks). Aged lung γδT cells predominantly produced interleukin‐17A (IL‐17A), which played a critical role in resistance to the development of lung melanoma in the aged. Furthermore, the anti‐tumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota.

Supplemental Digital Content is available in the text, Background: Many observational studies have reported an association between weight fluctuation and all-cause mortality. However, the conclusions obtained from these studies have been unclear. Objective: The current meta-analysis aimed to clarify the association between weight fluctuation and all-cause mortality. Data source: We electronically searched PubMed, Embase, and Web of Science for articles reporting an association between weight fluctuation and all-cause mortality that were published before April 30, 2018. Study appraisal and synthesis methods: The methodological quality of each study was appraised using the modified Newcastle Ottawa Quality Assessment Scale. The hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were extracted from the included studies and pooled using random-effect models. Meta-regression approaches were also performed to explore sources of between-study heterogeneity. Results: A total of 15 studies were eligible for the current meta-analysis. The pooled overall HR for all-cause mortality in the group with the greatest weight fluctuations compared with the most stable weight category was 1.45 (95% CI: 1.29–1.63). Considerable between-study heterogeneity was observed, some of which was partially explained by the different follow-up durations used by the included studies. Moreover, publication bias that inflated the risk of all-cause mortality was detected using Egger's test (P = .001). Conclusion: Weight fluctuation might be associated with an increased risk of all-cause mortality.

Among various methods, the use of targeting nucleic acid therapy is a promising method for inhibiting gastric cancer (GC) cells' rapid growth and metastasis abilities. In this study, vitamin B12-labeled poly (d,l-lactide-co-glycolide) and polyethylene glycol nanoparticles (PLGA-PEG-VB12 NPs) were developed for microRNAs-532-3p mimics incorporating as targeting gene delivery systems (miR-532-3p@PLGA-PEG-VB12 NPs) to fight against transcobalamin II (CD320)-overexpressed GC cells' progression. The PLGA-PEG-VB12 NPs with appropriate particle sizes and good bio-compatibility could be selectively delivered into CD320-overexpressed GC cells, and significantly decrease the expression of apoptosis repressor with caspase recruitment domain (ARC). Following that, more pro-apoptotic protein (Bax) flowed from cytoplasm into mitochondria to form Bax oligomerization, thus induced mitochondrial damage, including mitochondrial membrane potentials (MMPs) loss and excessive production of mitochondrial reactive oxygen species (mitoROS). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by induced more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-depended cell apoptosis pathway. Therefore, our designed miR-532-3p@PLGA-PEG-VB12 NPs showed enhanced GC targeting ability, and could induce apoptosis through activating ARC/Bax/mitochondria-mediated apoptosis signaling pathway, finally remarkably suppressed proliferation of GC cells both in vitro and in vivo, which presented a promising treatment for GC.

Background β-Arrestins have been found to regulate cell proliferation, invasion and migration; transmit anti-apoptotic survival signals; and affect other characteristics of tumours. However, their role in gastric cancer (GC) is not clear. We investigated the role and mechanism of β-arrestins in the regulation of GC. Methods We first examined β-arrestins mRNA levels in 17 pairs of GC tissues by qRT-PCR. We also used immunohistochemistry to further examine the expression of β-arrestins in 60 paraffin-embedded primary GC tissues and 20 normal gastric tissues. Then, the function of β-arrestin1 was investigated in vitro and in vivo. Results β-Arrestin1 was upregulated in GC tissue and was associated with tumour stage, lymph node metastasis, invasion depth and patient sex. High expression of β-arrestin1 expression predicted poor prognosis in GC. β-Arrestin1 promoted GC cell proliferation, migration and invasion, and it suppressed E-cadherin expression and upregulated Vimentin expression via AKT/ERK signalling pathway. The in vivo metastasis assays showed that knockdown of β-arrestin1 reduced lung metastasis and inhibited EMT. Conclusion The upregulation of β-arrestin1 predicts poor prognosis and promotes metastasis and epithelial-mesenchymal transition in GC through AKT/ERK signalling pathway. This study may provide therapeutic advances for the treatment and early diagnosis of patients with metastatic GC.

To explore the application value of intraoperative ultrasound (IU) in laparoscopic lymphadenectomy of gastric cancer.Patients with gastric cancer undergoing laparoscopic radical D2 gastrectomy at General Surgery of the Second Affiliated Hospital of Anhui Medical University between August 2016 and May 2018 were prospectively enrolled and were randomly divided into IU group (n=78) and conventional group (n=91). The conventional group underwent laparoscopy only. In IU group, the laparoscopy examination was followed with intraoperative ultrasound by ultrasound specialist. The lesser curvature, peripheral gastric organs and gastric lymph nodes were scanned. Lymph nodes were considered positive if maximum diameter was greater than 10 mm or internal hyperechoic features and normal oval shape were lost. The postoperative pathological results were used as the gold standard to analyze the sensitivity of positive lymph nodes by IU detection [true positive lymph nodes/(true positive lymph node+false negative lymph nodes)×100%], specificity [true negative lymph nodes/(true negative lymph nodes+false positive lymph nodes)×100%] and the accuracy rate[(true positive lymph nodes+ true negative lymph nodes/total lymph nodes)×100%]. A consistency check between N staging diagnosed by IU and by postoperative pathology was performed with Kappa test(Kappa0.75 indicating good consistency). Number of dissected lymph node, number of positive lymph node detected by pathology and the operation time were compared between the IU group and the conventional group.Among 169 gastric cancer patients, 95 were males and 74 were females with age of (63±8) years. Among 1 794 lymph nodes detected by IU from 78 patients in IU group, predicted positive lymph nodes were 832 and 740 positive nodes were confirmed by postoperative pathology. True positive lymph nodes were 679 and true negative lymph nodes were 901 by IU, and a total of 1 580 lymph nodes were accurately diagnosed by IU. The sensitivity and specificity of IU for N staging of gastric cancer were 91.8%(679/740) and 85.5%(901/1 054), respectively. Overall accuracy was 88.1%(1 580/1 794), which was in good accordance with postoperative N staging(Kappa=0.758). There was no significant difference in number of lymph node detected between the IU group and conventional group during laparoscopic gastric cancer surgery(23.0±6.9 vs. 22.0±7.7, t=0.880, P=0.380). However, the numbers of lymph nodes in the third station (No.10, No.11, No.12) in the IU group were significantly higher than those in the conventional group [No.10: median 1 (0-1) vs. 0 (0-1), Z=-6.307, P0.001; No.11: median 1(0-2) vs. 0(0-1), Z=-5.895, P0.001; No.12: median 1 (0-1) vs. 0 (0-1), Z=-6.693, P0.001]. There was no significant difference in the number of positive lymph node between IU group and the conventional group(P0.05), but the number of positive lymph nodes dissected in stage III patients of IU group was significantly higher than that in stage III patients of conventional group (14.6±4.8 vs. 14.0±3.6, t=2.531, P=0.011). The operative time of IU group was(272.0±12.0) minutes, which was significantly longer than (249.0±7.0) minutes of conventional group (t=14.638, P0.001). However, with the increase of patients undergoing IU, the operation time of IU showed a downward trend. The average operation time of the last 20 patients was 264 minutes, and the average IU time was 15 minutes.Intraoperative ultrasound is more accurate N-staging of gastric cancer. Although increasing operation time, it is helpful for lymph node dissection in laparoscopic gastric cancer surgery, especially by providing good support for laparoscopic No.10, No.11 and No.12 lymph nodes dissection.

The aim of this study was to evaluate tumor markers of molecular abnormalities that display tissue specificity, as to detect circulating tumor cells (CTCs) in breast cancer patients. Quantitative real-time RT-PCR was used to determine h-MAM, BCSG1, CK19, and c-erbB2 mRNA levels in peripheral blood (PB) of breast cancer patients. Results were compared with other epithelial cancers (lung or esophagus cancer), benign breast disease, and healthy individuals. We found that h-MAM mRNA was only detectable in the PB of patients with breast cancer (49 of 65, 75.4%), but not in patients with other epithelial cancers, benign breast disease, or healthy individuals. No significant differences in the expression level and positive detection rate of BCSG1, CK19, and c-erbB2 mRNA were observed between breast cancer and other epithelial cancers. Furthermore, the expression level and positive detection rate of h-MAM mRNA in PB were significantly correlated to the breast cancer pathologic stage (p=0.012 and p=0.015, respectively). Chemotherapy, radiotherapy, or total tumor resection (after 7 days of treatment) resulted in a significant decrease in the expression level of h-MAM mRNA in PB compared to the levels prior to the treatment (p

Background: CD4+CD25+ regulatory T (Treg) cells and T-helper 17 (Th17) cells play important roles in acute cerebral infarction (ACI). Our previous findings have suggested that oxidized low-density lipoprotein (Ox-LDL) could influence Treg/Th17 ratio in ACI patients. However, the mechanisms are still not clear. Methods and Results: We evaluated the effects of ox-LDL on Th17/Treg cell apoptosis and proliferation in vitro. Our results demonstrated that with increased ox-LDL concentrations, the frequency and suppressive function of Treg cells was decreased while the frequency of Th17 cells was elevated in control subjects. In addition, AnnexinV+ apoptotic rate, Fas/Fas ligand (FasL) expression, and Caspase-3 activity were escalated in Treg cells while were no significant changes in Th17 cells. Simultaneously, 5-Bromo-29-Deoxyuridine (BrdU) and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl Tetrazolium Bromide (MTT) incorporation of Th17 cells was elevated accompanied by upregulated nuclear factor-κB (NF-κB) activity. However, Th17 proliferation was decreased when pre-incubated with Pyrrolidine dithiocarbamate (PDTC, inhibitor of NF-κB activation). Furthermore, there were significant changes induced by ox-LDL in Treg apoptosis, Fas/FasL/Caspase-3 expression of Treg cells, and Th17 proliferation, NF-κB activation of Th17 in ACI patients than in patients with transient ischemic attack (TIA) and control subjects (PPConclusion: These data support that ox-LDL may influence the Th17/Treg balance by modulating Fasmediated Treg apoptosis and NF-κB-associated Th17 proliferation. Ox-LDL also induced a more significant alteration of Treg and Th17 in ACI patients than in TIA and control groups, suggesting a novel role in the pathogenesis of ACI.

Objectives The epithelial cell adhesion molecule (EpCAM) is one of the most commonly used markers of cancer stem cells (CSCs), but the clinical and prognostic significance of EpCAM in gastric cancer (GC) remains disputable. Motivated by heterogeneous and inconclusive results, we conducted a systematic review and meta-analysis to systematically summarize and elucidate the association between EpCAM overexpression and GC patients. Methods The PubMed, Cochrane Library, Medline, Web of Knowledge and the China National Knowledge Infrastructure (CNKI) databases were searched to identify relevant studies. The RevMan 5.3 software was used for the meta-analysis. Fixed-effects or random-effects models were applied depending on the presence of heterogeneity. The pooled odds ratio (ORs) and 95% confidence intervals (CIs) were applied to estimate the associations between EpCAM and gastric cancer. For the significant heterogeneity studies, sensitivity analyses were applied based on the population to test the robustness of the pooled results and identify possible sources of heterogeneity. Results A total of 11 studies including 1960 GC patients met our inclusion criteria. The results of the meta-analyses revealed that there were significant differences in EpCAM overexpression and tumour size (OR = 2.97, 95% CI: 2.13~4.13, P < 0.00001), the nature of the tissue (OR = 80.30, 95% CI: 29.21~220.81, P < 0.00001), lymph node metastasis (OR = 2.78, 95% CI: 1.23~6.27, P = 0.01), and the cumulative 5-year overall survival rate (OR = 0.54, 95% CI:0.29~0.99, P = 0.05). No significant associations were identified between EpCAM overexpression and gender (OR = 0.89, 95% CI: 0.66~1.19, P = 0.43), age (OR = 1.13, 95% CI: 0.58~2.20, P = 0.73), tumour stage (OR = 2.26, 95% CI: 0.79~6.45, P = 0.13), distant metastasis (OR = 2.15, 95% CI: 0.20~22.69, P = 0.52), TNM stage (OR = 5.14, 95% CI: 0.77~34.37, P = 0.09), Lauren type (OR = 1.18, 95% CI: 0.08~16.45, P = 0.9), differentiation (OR = 1.88, 95% CI: 0.65~5.41, P = 0.24). However, due to significant heterogeneity in tumor stage, lymph node metastasis, TNM stage, differentiation and Lauren type, these results should be taken carefully. Conclusions The meta-analysis demonstrated that the expression of EpCAM in the gastric cancer group was greater than that in the control group. Moreover, EpCAM overexpression was associated with larger tumour size, lymphnode metastasis and worse prognosis in gastric cancer. Due to significant heterogeneity, the sensitivity analysis suggests that population factor may be an important source of heterogeneity, and these results should be treated with caution. EpCAM may be useful as a novel prognostic factor, and large-scale and well-designed studies are needed to validate our results in the future.

Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor activity of the novel engineered monoclonal antibody humanized chA21 (HuA21) that targets HER2 on the basis of chA21, and we describe the underlying mechanisms. Our results reveal that HuA21 markedly inhibits the proliferation and migration of HER2-overexpressing breast cancer cells and causes enhanced antibody-dependent cell-mediated cytotoxicity potency against HER2-overexpressing tumor cells. In particular, HuA21, but not trastuzumab (Tra), markedly suppresses growth and enhances the internalization of the antibody in Tra-resistant BT-474 breast cancer cells. These characteristics are highly associated with the intrinsic ability of HuA21 to down-regulate HER2 activation and inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways. Furthermore, the combination of HuA21 with Tra synergistically enhances the anti-tumor effects in vitro and in vivo and inhibits HER2 activation and the ERK1/2 and Akt signaling pathways. Altogether, our results suggest that HuA21 may represent a unique anti-HER2 antibody with potential as a therapeutic candidate alone or in combination with other anti-HER2 reagents in cancer therapy.

It was well studied that ErbB2 (HER2/p185 her2/neu ) overexpression in human malignant cancers correlates with poor prognosis and chemo-resistance. Although Trastuzumab (Herceptin) has been widely used in patients with ErbB2-overexpressing metastatic breast cancer, many patients either do not respond to Trastuzumab therapy or progress within 1 year of initiating Trastuzumab treatment. Previously, we reported a novel tumor-inhibitory antibody chA21, which recognized ErbB2 extracellular domain with an epitope distinct from other tumor-inhibitory anti-ErbB2 antibodies. Here, we report that chA21 combined with Paclitaxel or Trastuzumab significantly enhances the tumor-inhibition effects on ErbB2-overexpressing breast and ovarian cancer in xenograft mice. Moreover, the study reveals that the effects by chA21 to cause an enhanced inhibition on cancer cell proliferation and angiogenesis was highly associated with the intrinsic ability of chA21 to down-regulate ErbB2 receptor, inhibit downstream MAPK and PI3K-AKT signal transduction and activate natural killer cells. Our findings show that chA21 may represent a unique anti-ErbB2 antibody with potentials as therapeutic candidate alone or combination with other anti-ErbB2 reagents in cancer therapy.

Paired box protein 5 (PAX5) plays a lineage determination role in B-cell development. However, high expression of PAX5 has been also found in various malignant diseases, including B-lymphoproliferative disorders (B-LPDs), but its functions and mechanisms in these diseases are still unclear. Here, we show that PAX5 induces drug resistance through association and activation of receptor-interacting serine/threonine-protein kinase 2 (RIP2; also known as RIPK2), and subsequent activation of NF-κB signaling and anti-apoptosis gene expression in B-lymphoproliferative cells. Furthermore, PAX5 is able to interact with RIP1 and RIP3, modulating both RIP1-mediated TNFR and RIP2-mediated NOD1 and NOD2 pathways. Our findings describe a new function of PAX5 in regulating RIP1 and RIP2 activation, which is at least involved in chemotherapeutic drug resistance in B-LPDs.

p185(her2/neu) belongs to the ErbB receptor tyrosine kinase family, which has been associated with human breast, ovarian, and lung cancers. Targeted therapies employing ectodomain-specific p185(her2/neu) monoclonal antibodies (mAbs) have demonstrated clinical efficacy for breast cancer. Our previous studies have shown that p185(her2/neu) mAbs are able to disable the kinase activity of homomeric and heteromeric kinase complexes and induce the conversion of the malignant to normal phenotype. We previously developed a chimeric antibody chA21 that specifically inhibits the growth of p185(her2/neu)-overexpressing cancer cells in vitro and in vivo. Herein, we report the crystal structure of the single-chain Fv of chA21 in complex with an N-terminal fragment of p185(her2/neu), which reveals that chA21 binds a region opposite to the dimerization interface, indicating that chA21 does not directly disrupt the dimerization. In contrast, the bivalent chA21 leads to internalization and down-regulation of p185(her2/neu). We propose a structure-based model in which chA21 cross-links two p185(her2/neu) molecules on separate homo- or heterodimers to form a large oligomer in the cell membrane. This model reveals a mechanism for mAbs to drive the receptors into the internalization/degradation path from the inactive hypophosphorylated tetramers formed dynamically by active dimers during a "physiologic process."

Embryonic development associated gene (EDAG), which is overexpressed in hematopoietic neoplasms and leukemia cell lines, has been reported to participate in the leukemia cell differentiation and proliferation. This study investigated whether retrovirus-mediated transfer of a siRNA against EDAG can reduce the growth of leukemia cells which highly express EDAG in vitro and in vivo. The stable transfected cells were identified with RT-PCR, the effect of EDAG/siRNA on the growth of the human erythroleukemia cell line HEL was analyzed by MTT assay, and angiogenic factor IL-8 release was evaluated by ELISA and RT-PCR. The results showed that EDAG/siRNA can silence the expression of EDAG in HEL cells. Down-regulation of EDAG expression by retrovirus-mediated siRNA inhibited the cell proliferation and tumor growth. Knockdown of EDAG expression by siRNA is also associated with decreased expression of the anti-angiogenic factor IL-8, suggesting that EDAG stimulates tumor growth at least in part by regulating angiogenesis. This study suggests that siRNA-mediated gene silencing of EDAG could potentially be a therapeutic strategy for EDAG over-expressing leukemia cells.

Decidual lymphocytes may mediate fetal trophoblast recognition and regulate maternal immune reaction and play an essential role in the maintenance of normal pregnancy. The aim of this study was to compare the percentage of T cells, natural killer (NK) cells and natural killer T (NKT) cells within decidual parietalis of normal pregnant controls (NP) and patients with intraheptic cholestasis of pregnancy (ICP), and to investigate the production of interleukin-4 (IL-4), interferon-gamma (IFN-gamma) in the culture supernatant of decidual parietalis mononuclear cells (DPMCs). Compared with controls, the decidua parietalis from ICP were characterized with significant increased percentages of CD3-CD56+ cells, CD3+CD56+ cells, CD56+CD16+ cells, CD56+CD16- cells, CD56+NKG2D+ cells, and the significant decreased percentages of CD3+ cells, CD3+CD4+ cells. There were no differences found for the percentage of CD3+CD8+ cells, CD56+NKG2A+ cells between control and study group. In addition, the enhanced concentration of IFN-gamma was presented in culture supernatant of DPMCs from ICP. It was suggested that the increased NK cells, NKT cells and the decreased T cells in the decidual parietalis and over-secretion of IFN-gamma could be correlated with the pathophysiology of ICP patients.