Effects of extreme meteorological factors and high air pollutant concentrations on the incidence of hand, foot and mouth disease in Jining, China.

Background: The evidence on the effects of extreme meteorological conditions and high air pollution levels on incidence of hand, foot and mouth disease (HFMD) is limited. Moreover, results of the available studies are inconsistent. Further investigations are imperative to elucidate the specific issue. Methods: Data on the daily cases of HFMD, meteorological factors and air pollution were obtained from 2017 to 2022 in Jining City. We employed distributed lag nonlinear model (DLNM) incorporated with Poisson regression to explore the impacts of extreme meteorological conditions and air pollution on HFMD incidence. Results: We found that there were nonlinear relationships between temperature, wind speed, PM2.5, SO2, O3 and HFMD. The cumulative risk of extreme high temperature was higher at the 95th percentile (P95th) than at the 90th percentile(P90th), and the RR values for both reached their maximum at 10-day lag (P95th RR = 1.880 (1.261-2.804), P90th RR = 1.787 (1.244-2.569)), the hazardous effect of extreme low temperatures on HFMD is faster than that of extreme high temperatures. The cumulative effect of extreme low wind speeds reached its maximum at 14-day lag (P95th RR = 1.702 (1.389-2.085), P90th RR = 1.498(1.283-1.750)). The cumulative effect of PM2.5 concentration at the P90th was largest at 14-day lag (RR = 1.637 (1.069-2.506)), and the cumulative effect at the P95th was largest at 10-day lag (RR = 1.569 (1.021-2.411)). High SO2 concentration at the P95th at 14-day lag was associated with higher risk for HFMD (RR: 1.425 (1.001-2.030)). Conclusion: Our findings suggest that high temperature, low wind speed, and high concentrations of PM2.5 and SO2 are associated with an increased risk of HFMD. This study not only adds insights to the understanding of the impact of extreme meteorological conditions and high levels of air pollutants on HFMD incidence but also holds practical significance for the development and enhancement of an early warning system for HFMD.

Epidemiological characteristics and antibody kinetics of elderly population with booster vaccination following both Omicron BA.5 and XBB waves in China.

After the termination of zero-COVID-19 policy, the populace in China has experienced both Omicron BA.5 and XBB waves. Considering the poor antibody responses and severe outcomes observed among the elderly following infection, we conducted a longitudinal investigation to examine the epidemiological characteristics and antibody kinetics among 107 boosted elderly participants following the Omicron BA.5 and XBB waves. We observed that 96 participants (89.7%) were infected with Omicron BA.5, while 59 (55.1%) participants were infected with Omicron XBB. Notably, 52 participants (48.6%) experienced dual infections of both Omicron BA.5 and XBB. The proportion of symptomatic cases appeared to decrease following the XBB wave (18.6%) compared to that after the BA.5 wave (59.3%). Omicron BA.5 breakthrough infection induced lower neutralizing antibody titers against XBB.1.5, BA.2.86, and JN.1, while reinfection with Omicron XBB broadened the antibody responses against all measured Omicron subvariants and may alleviate the wild type-vaccination induced immune imprinting. Boosted vaccination type and comorbidities were the significant factors associated with antibody responses. Updated vaccines based on emerging severe acute respiratory syndrome coronavirus 2 variants are needed to control the Coronavirus Disease 2019 pandemic in the elderly.

Association of FTH1-Expressing Circulating Tumor Cells With Efficacy of Neoadjuvant Chemotherapy for Patients With Breast Cancer: A Prospective Cohort Study.

BACKGROUND: The association between different phenotypes and genotypes of circulating tumor cells (CTCs) and efficacy of neoadjuvant chemotherapy (NAC) remains uncertain. This study was conducted to evaluate the relationship of FTH1 gene-associated CTCs (F-CTC) with/without epithelial-mesenchymal transition (EMT) markers, or their dynamic changes with the efficacy of NAC in patients with non-metastatic breast cancer. PATIENTS AND METHODS: This study enrolled 120 patients with non-metastatic breast cancer who planned to undergo NAC. The FTH1 gene and EMT markers in CTCs were detected before NAC (T0), after 2 cycles of chemotherapy (T1), and before surgery (T2). The associations of these different types of CTCs with rates of pathological complete response (pCR) and breast-conserving surgery (BCS) were evaluated using the binary logistic regression analysis. RESULTS: F-CTC in peripheral blood ≥1 at T0 was an independent factor for pCR rate in patients with HER2-positive (odds ratio [OR]=0.08, 95% confidence interval [CI], 0.01-0.98, P = .048). The reduction in the number of F-CTC at T2 was an independent factor for BCS rate (OR = 4.54, 95% CI, 1.14-18.08, P = .03). CONCLUSIONS: The number of F-CTC prior to NAC was related to poor response to NAC. Monitoring of F-CTC may help clinicians formulate personalized NAC regimens and implement BCS for patients with non-metastatic breast cancer.

Glucagon Enhances Chemotherapy Efficacy By Inhibition of Tumor Vessels in Colorectal Cancer.

Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti-cancer therapy. In a series of in vitro experiments, glucagon inhibited cell migration and tube formation in both endothelial and tumor cells. In vivo studies demonstrated decreased tumor blood vessels and fewer pseudo-vessels in mice treated with glucagon. The combination of glucagon and chemotherapy exhibited enhanced tumor inhibition. Mechanistic studies demonstrated that glucagon increased the permeability of blood vessels, leading to a pronounced disruption of vessel morphology. Signaling pathway analysis identified a VEGF/VEGFR-dependent mechanism whereby glucagon attenuated angiogenesis through its receptor. Clinical data analysis revealed a positive correlation between elevated glucagon expression and chemotherapy response. This is the first study to reveal a role for glucagon in inhibiting angiogenesis and vascular mimicry. Additionally, the delivery of glucagon-encapsulated PEGylated liposomes to tumor-bearing mice amplified the inhibition of angiogenesis and vascular mimicry, consequently reinforcing chemotherapy efficacy. Collectively, the findings demonstrate the role of glucagon in inhibiting tumor vessel network and suggest the potential utility of glucagon as a promising predictive marker for patients with CRC receiving chemotherapy.

Vascular endothelial growth factor B regulates insulin secretion in ß cells of type 2 diabetes mellitus mice via PLCγ and the IP3R­evoked Ca2+/CaMK2 signaling pathway.

Vascular endothelial growth factor B (VEGFB) plays a crucial role in glucolipid metabolism and is highly associated with type 2 diabetes mellitus (T2DM). The role of VEGFB in the insulin secretion of ß cells remains unverified. Thus, the present study aimed to discuss the effect of VEGFB on regulating insulin secretion in T2DM development, and its underlying mechanism. A high­fat diet and streptozocin (STZ) were used for inducing T2DM in mice model, and VEGFB gene in islet cells of T2DM mice was knocked out by CRISPR Cas9 and overexpressed by adeno­Associated Virus (AAV) injection. The effect of VEGFB and its underlying mechanism was assessed by light microscopy, electron microscopy and fluorescence confocal microscopy, enzyme­linked immunosorbent assay, mass spectrometer and western blot analysis. The decrement of insulin secretion in islet ß cell of T2DM mice were aggravated and blood glucose remained at a high level after VEGFB knockout (KO). However, glucose tolerance and insulin sensitivity of T2DM mice were improved after the AAV­VEGFB186 injection. VEGFB KO or overexpression can inhibit or activate PLCγ/IP3R in a VEGFR1­dependent manner. Then, the change of PLCγ/IP3R caused by VEGFB/VEGFR1 will alter the expression of key factors on the Ca2+/CaMK2 signaling pathway such as PPP3CA. Moreover, VEGFB can cause altered insulin secretion by changing the calcium concentration in ß cells of T2DM mice. These findings indicated that VEGFB activated the Ca2+/CaMK2 pathway via VEGFR1­PLCγ and IP3R pathway to regulate insulin secretion, which provides new insight into the regulatory mechanism of abnormal insulin secretion in T2DM.

Neutralizing immunity against SARS-CoV-2 Omicron BA.1 by infection and vaccination.

The emergence of the SARS-CoV-2 Omicron BA.1 (B.1.1.529) variant has raised questions regarding resistance to neutralizing antibodies elicited by natural infection or immunization. We examined the neutralization activity of sera collected from previously SARS-CoV-2-infected individuals and SARS-CoV-2 naive individuals who received BBIBP-CorV or CoronaVac to BA.1 and the earlier variants Alpha, Beta, and Delta. Both sera from convalescent patients over three months after infection and two-dose BBIBP-CorV or CoronaVac vaccine recipients barely inhibited BA.1, less effectively neutralized Beta and Delta, and moderately neutralized Alpha. However, administering a single dose of BBIBP-CorV or CoronaVac in previously infected individuals or a third dose booster vaccination of BBIBP-CorV or CoronaVac in previously vaccinated individuals enhances neutralizing activity against BA.1 and other variants, albeit with a lower antibody titer for BA.1. Our data suggest that a booster vaccination is important to broaden neutralizing antibody responses against the variants.

GAD1 alleviates injury-induced optic neurodegeneration by inhibiting retinal ganglion cell apoptosis.

The degeneration of the optic nerve narrows the visual field, eventually causing overall vision loss. This study aimed to identify global protein changes in the retina of optic nerve crushing (ONC) mice and to identify key regulators and pathways involved in injury-induced cell death during the progression of optic neurodegeneration. Label-free quantitative proteomics combined with bioinformatic analysis was performed on retinal protein extracts from ONC and sham-operated mice. Among the 1433 proteins detected, 121 proteins were differentially expressed in the retina of ONC mice. Further bioinformatic analysis showed that various metabolic pathways, including glutamate metabolism and γ-aminobutyric acid (GABA) synthesis, were significantly dysregulated in the injured mouse retinas. Glutamate decarboxylase 1 (GAD1) is the enzyme that converts glutamate into GABA, which was significantly up-regulated during ONC injury. Exogenous GAD1 treatment increased retinal ganglion cell (RGC) survival in the ONC-injured retina. In addition, changes in GAD1 expression were also observed in several other ophthalmic diseases. Vascular endothelial growth factor B (VEGF-B) has previously been reported to protect RGCs from apoptosis and positively regulated the expression of GAD1 in the retina. Notably, combination treatment with GAD1 and VEGF-B also provided strong protection against injury-induced RGC apoptosis. These results suggest that GAD1 expression may serve as an intrinsic protective mechanism that is commonly activated during retinal injury. Targeting GAD1 may serve as a potential strategy to treat optic neurodegenerative diseases.

Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1.

In recent years, studies have demonstrated that vascular endothelial growth factor B (VEGFB) can affect the metabolism of fatty acids and glucose, and it is expected to become a target for the diagnosis and treatment of metabolic diseases such as obesity and diabetes. At present, the specific mechanism that VEGFB regulates lipid and glucose metabolism balance is not completely understood. The present study used systemic VEGFB gene­knockout mice to investigate the effects of downregulation of the VEGFB gene on lipid metabolism and insulin secretion, and to explore the mechanism of the VEGFB pathway involved in the regulation of glucose and lipid metabolism. The morphological changes in the liver and pancreas of mice after VEGFB gene deletion were observed under a light microscope and a scanning electron microscope, and the effects of VEGFB gene deletion on lipid metabolism and blood glucose balance were detected by a serological technique. The detection indexes included total cholesterol (TC), triglyceride (TG), low­density lipoprotein cholesterol (LDL­C) and high­density lipoprotein cholesterol. Simultaneously, fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), fasting insulin and glucagon were measured. Insulin sensitivity was assessed by using the insulin tolerance tests and glucose tolerance tests, and function of ß­cell islets was evaluated by using the insulin resistance index (HOMA­IR) and pancreatic ß­cell secretion index (HOMA­ß). Τhe protein expression changes of vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) in mouse islets were detected by western blotting and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) after the VEGFB gene was knocked down to analyze the mechanism of VEGFB that may be involved in glucose and lipid metabolism. It was observed that after VEGFB was knocked down, mouse hepatocytes exhibited steatosis and increased secretory vesicles in islet cells. The lipid metabolism indexes such as TG, TC and LDL increased significantly; however, the levels of FBS, postprandial blood glucose and HbA1c decreased, whereas the glucose tolerance increased. Serum insulin secretion increased and HOMA­IR decreased since VEGFB was knocked down. Western blotting and RT­qPCR results revealed that the expression levels of VEGFR1 and neuropilin­1 decreased after the VEGFB gene was knocked down, while the expression levels of VEGFA and VEGFR2 increased. The absence of VEGFB may be involved in the regulation of glucose and lipid metabolism in mice by activating the VEGFA/VEGFR2 signaling pathway. VEGFB is expected to become a new target for the treatment of metabolic diseases such as obesity and diabetes. At present, the mechanism of VEGFB involved in regulating lipid metabolism and glucose metabolism is not completely clear. It was identified that downregulating VEGFB improved lipid metabolism and insulin resistance. The role of VEGFB/VEGFR1 pathway and other family members in regulating glucose and lipid metabolism was detected, which provided a theoretical and experimental basis for VEGFB to affect the regulation of glucose and lipid metabolism balance.

A Biodegradable High-Efficiency Magnetic Nanoliposome Promotes Tumor Microenvironment-Responsive Multimodal Tumor Therapy Along with Switchable T2 Magnetic Resonance Imaging.

We explored the catalytic activity and magnetic resonance imaging (MRI) capacity of Cu-doped ultrasmall iron oxides with different doping ratios. Then, we screened a highly efficient ultrasmall active catalyst (UAC). Subsequently, a biodegradable magnetic nanoliposome was developed for multimodal cancer theranostics through pH-sensitive liposome coating of these UACs. Upon entering the body, the magnetic nanoliposomes significantly prolonged the metabolic time of UACs and promoted their accumulation in tumors. Then, the strong photothermal (PT) effect of the magnetic nanoliposome quickly ablated the tumor, showing promising PT therapy. Upon entering tumor cells, the magnetic nanoliposome rapidly degraded into many UACs and released chemotherapeutic drugs, contributing to chemotherapy. In addition, UACs not only catalyzed Fenton-type reaction to produce excessive reactive oxygen species (ROS) but also inhibited the synthesis of endogenous GSH by inactivating glutamyl cysteine ligase, contributing to cancer ferroptosis. Furthermore, the assembly-dissociation process of UACs showed the function of magnetic relaxation switches, significantly enhancing tumor MRI signal change, achieving a more accurate diagnosis of the tumor. Therefore, this magnetic nanoliposome splits into many UACs upon drug release and regulates the tumor microenvironment to overproduce ROS for enhanced synergistic tumor theranostics, which provides a strategy for developing next-generation magnetic catalysts with biodegradability and multimodal antitumor theranostics.

Targeting Hyaluronic Acid and Peritoneal Dissemination in Colorectal Cancer.

Peritoneal metastasis (PM) from colorectal cancer (CRC) carries a significant mortality rate for patients and treatment is challenging. The development of PM is a multistep process involving detachment, adhesion, invasion and colonization of the peritoneal cavity. Cytoreductive surgery and HIPEC (hyperthermic intraperitoneal chemotherapy) for PM from CRC has some benefit but overall survival is poor and recurrence rates are high. Treatments to prevent the development of peritoneal metastasis could have the potential to improve CRC survival and disease-free outcomes. The ability of cancer cells to invade the peritoneum and become established as metastatic tumors is influenced by a multifactorial process. Hyaluronic acid (HA) has been shown to coat the mesothelial cells of the peritoneum and has been demonstrated to be utilized in various malignancies as part of the metastatic process in peritoneal dissemination. CD44, RHAMM (CD168) and ICAM-1 have all been shown to be binding partners for HA. Targeting HA-mediated binding may prevent adhesion to distant sites within the peritoneum through suppression of interaction of these molecules. Here we review the current literature and discuss key molecules involved with PM dissemination, with the potential to target these mechanisms in the delivery of future treatments.

Persistence of the SARS-CoV-2 Antibody Response in Asymptomatic Patients in Correctional Facilities.

SARS-CoV-2 has caused a global health disaster with millions of death worldwide, and the substantial proportion of asymptomatic carriers poses a huge threat to public health. The long-term antibody responses and neutralization activity during natural asymptomatic SARS-CoV-2 infection are unknown. In this study, we used enzyme-linked immunosorbent assays (ELISA) and neutralization assay with purified SARS-CoV-2S and N proteins to study the antibody responses of 156 individuals with natural asymptomatic infection. We found robust antibody responses to SARS-CoV-2 in 156 patients from 6 to 12 months. Although the antibody responses gradually decreased, S-IgG was more stable than N-IgG. S-IgG was still detected in 79% of naturally infected individuals after 12 months of infection. Moderate to potent neutralization activities were also observed in 98.74% of patients 6 months after infection. However, this proportion decreased at 8-month (46.15%) and 10-month (39.11%) after infection, respectively. Only 23.72% of patients displayed potent neutralization activity at 12 months. This study strongly supports the long-term presence of antibodies against SARS-CoV-2 in individuals with natural asymptomatic infection, although the magnitude of the antibody responses started to cripple 6 months after infection.

Silencing CTNND1 Mediates Triple-Negative Breast Cancer Bone Metastasis via Upregulating CXCR4/CXCL12 Axis and Neutrophils Infiltration in Bone.

Bone metastasis from triple-negative breast cancer (TNBC) frequently results in poorer prognosis than other types of breast cancer due to the delay in diagnosis and intervention, lack of effective treatments and more skeletal-related complications. In the present study, we identified CTNND1 as a most reduced molecule in metastatic bone lesion from TNBC by way of high throughput sequencing of TNBC samples. In vivo experiments revealed that knockdown of CTNND1 enhanced tumor cells metastasis to bones and also increased neutrophils infiltration in bones. In vitro, we demonstrated that knockdown of CTNND1 accelerated epithelial-mesenchymal transformation (EMT) of tumor cells and their recruitment to bones. The involvement by CTNND1 in EMT and bone homing was achieved by upregulating CXCR4 via activating the PI3K/AKT/HIF-1αpathway. Moreover, TNBC cells with reduced expression of CTNND1 elicited cytotoxic T-cells responses through accelerating neutrophils infiltration by secreting more GM-CSF and IL-8. Clinically, patients with triple-negative breast cancer and lower level of CTNND1 had shorter overall survival (OS) and distant metastasis-free survival (DMFS). It was concluded that downregulation of CTNND1 played a critical role in facilitating bone metastasis of TNBC and that CTNND1 might be a potential biomarker for predicting the risk of bone metastases in TNBC.

Evaluating active versus passive sources of human brucellosis in Jining City, China.

Human brucellosis (HB) remains a serious public health concern owing to its resurgence across the globe and specifically in China. The timely detection of this disease is the key to its prevention and control. We sought to describe the differences in the demographics of high-risk populations with detected cases of HB contracted from active versus passive sources. We collected data from a large sample population from January to December 2018, in Jining City, China. We recruited patients that were at high-risk for brucellosis from three hospitals and Centers of Disease Control and Prevention (CDCs). These patients were classified into two groups: the active detection group was composed of individuals receiving brucellosis counseling at the CDCs; the passive detection group came from hospitals and high-risk HB groups. We tested a total of 2,247 subjects and 13.3% (299) presented as positive for HB. The positive rates for active and passive detection groups were 20.5% (256/1,249) and 4.3% (43/998), respectively (p < 0.001). The detection rate of confirmed HB cases varied among all groups but was higher in the active detection group than in the passive detection group when controlled for age, sex, ethnicity, education, career, and contact history with sheep or cattle (p < 0.05). Males, farmers, those with four types of contact history with sheep or cattle, and those presenting fever, hyperhidrosis and muscle pain were independent factors associated with confirmed HB cases in multivariate analysis of the active detection group. Active detection is the most common method used to detect brucellosis cases and should be applied to detect HB cases early and avoid misdiagnosis. We need to improve our understanding of brucellosis for high-risk populations. Passive HB detection can be supplemented with active detection when the cognitive changes resulting from brucellosis are low. It is important that healthcare providers understand and emphasis the timely diagnosis of HB.

Potent and Persistent Antibody Response in COVID-19 Recovered Patients.

SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Virus-specific antibodies can be detected in infected patients approximately two weeks after symptom onset. In this study, we set up ELISA technology coating with purified SARS-CoV-2 S and N proteins to study the antibody response of 484 serum samples. We established a surrogate viral inhibition assay using SARS-CoV-2 S protein pseudovirus system to determine the neutralization potency of collected serum samples. Here, we report robust antibody responses to SARS-CoV-2 in 484 recovered patients varying from 154 to 193 days, with 92% of recovered patients displaying a positive virus-specific spike glycoprotein IgG (s-IgG) response, while the ratio of positive spike glycoprotein IgM (s-IgM) reached 63%. Furthermore, moderate to potent neutralization activities were also observed in 62% of patients, correlating significantly with s-IgG response. This study strongly supports the long-term presence of antibodies in recovered patients against SARS-CoV-2, although all serum samples were collected from individuals with mild or moderate symptoms.

Vascular endothelial growth factor B inhibits insulin secretion in MIN6 cells and reduces Ca2+ and cyclic adenosine monophosphate levels through PI3K/AKT pathway.

BACKGROUND: Type 2 diabetes (T2D) is characterized by insufficient insulin secretion caused by defective pancreatic ß-cell function or insulin resistance, resulting in an increase in blood glucose. However, the mechanism involved in this lack of insulin secretion is unclear. The level of vascular endothelial growth factor B (VEGF-B) is significantly increased in T2D patients. The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation. It is speculated that VEGF-B is related to pancreatic ß-cell dysfunction and is an important factor affecting ß-cell secretion of insulin. As an in vitro model of normal pancreatic ß-cells, the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects. AIM: To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation. METHODS: The MIN6 mouse pancreatic islet ß-cell line was used as the model system. By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells, we examined the effects of VEGF-B on insulin secretion, Ca2+ and cyclic adenosine monophosphate (cAMP) levels, and the insulin secretion signaling pathway. RESULTS: Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca2+ and cAMP in MIN6 cells. Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1 (PLCγ1), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), and other proteins in the insulin secretion pathway. Upon knockdown of VEGF-B, MIN6 cells exhibited increased insulin secretion and Ca2+ and cAMP levels and upregulated expression of PLCγ1, PI3K, AKT, and other proteins. CONCLUSION: VEGF-B can regulate insulin secretion by modulating the levels of Ca2+ and cAMP. VEGF-B involvement in insulin secretion is related to the expression of PLCγ1, PI3K, AKT, and other signaling proteins. These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2D.

SIPA1 Is a Modulator of HGF/MET Induced Tumour Metastasis via the Regulation of Tight Junction-Based Cell to Cell Barrier Function.

BACKGROUND: Lung cancer is the leading cause of cancer death. SIPA1 is a mitogen induced GTPase activating protein (GAP) and may hamper cell cycle progression. SIPA1 has been shown to be involved in MET signaling and may contribute to tight junction (TJ) function and cancer metastasis. METHODS: Human lung tumour cohorts were analyzed. In vitro cell function assays were performed after knock down of SIPA1 in lung cancer cells with/without treatment. Quantitative polymerase chain reaction (qPCR) and western blotting were performed to analyze expression of HGF (hepatocyte growth factor), MET, and their downstream markers. Immunohistochemistry (IHC) and immunofluorescence (IFC) staining were performed. RESULTS: Higher expression of SIPA1 in lung tumours was associated with a poorer prognosis. Knockdown of SIPA1 decreased invasiveness and proliferation of in vitro cell lines, and the SIPA1 knockdown cells demonstrated leaky barriers. Knockdown of SIPA1 decreased tight junction-based barrier function by downregulating MET at the protein but not the transcript level, through silencing of Grb2, SOCS, and PKCµ (Protein kinase Cµ), reducing the internalization and recycling of MET. Elevated levels of SIPA1 protein are correlated with receptor tyrosine kinases (RTKs), especially HGF/MET and TJs. The regulation of HGF on barrier function and invasion required the presence of SIPA1. CONCLUSIONS: SIPA1 plays an essential role in lung tumourigenesis and metastasis. SIPA1 may be a diagnostic and prognostic predictive biomarker. SIPA1 may also be a potential therapeutic target for non-small cell lung cancer (NSCLC) patients with aberrant MET expression and drug resistance.

Tim-3 promotes cell aggressiveness and paclitaxel resistance through NF-κB/STAT3 signalling pathway in breast cancer cells.

OBJECTIVE: Although T-cell immunoglobulin and mucin-domain containing molecule-3 (Tim-3) has been recognized as a promising target for cancer immunotherapy, its exact role in breast cancer has not been fully elucidated. METHODS: Tim-3 gene expression in breast cancer and its prognostic significance were analyzed. Associated mechanisms were then explored in vitro by establishing Tim-3-overexpressing breast cancer cells. RESULTS: In a pooled analysis of The Cancer Genome Atlas (TCGA) database, Tim-3 gene expression levels were significantly higher (P<0.001) in breast cancer tissue, compared with normal tissues. Tim-3 was a prognosis indicator in breast cancer patients [relapse-free survival (RFS), P=0.004; overall survival (OS), P=0.099]. Tim-3 overexpression in Tim-3low breast cancer cells promoted aggressiveness of breast cancer cells, as evidenced by enhanced proliferation, migration, invasion, tight junction deterioration and tumor-associated tubal formation. Tim-3 also enhanced cellular resistance to paclitaxel. Furthermore, Tim-3 exerted its function by activating the NF-κB/STAT3 signalling pathway and by regulating gene expression [cyclin D1 (CCND1), C-Myc, matrix metalloproteinase-1(MMP1), TWIST, vascular endothelial growth factor (VEGF) upregulation, concomitant with E-cadherin downregulation). Lastly, Tim-3 downregulated tight junction-associated molecules zona occludens (ZO)-2, ZO-1 and occludin, which may further facilitate tumor progression. CONCLUSIONS: Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.