Mitochondria-targeted polyprodrug nanoparticles induce mitochondrial stress for immunogenic chemo-photodynamic therapy of ovarian cancer.

Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death (ICD) introduces a theoretical principle for antitumor immunity by increasing antigen exposure and presentation. Despite recent research progress, the currently available ICD inducers are still very limited, and many of them can hardly induce sufficient ICD based on traditional endoplasmic reticulum (ER) stress. Accumulating evidence indicates that inducing mitochondrial stress usually shows a higher efficiency in evoking large-scale ICD than that via ER stress. Inspired by this, herein, a mitochondria-targeted polyprodrug nanoparticle (named Mito-CMPN) serves as a much superior ICD inducer, effectively inducing chemo-photodynamic therapy-caused mitochondrial stress in tumor cells. The rationally designed stimuli-responsive polyprodrugs, which can self-assemble into nanoparticles, were functionalized with rhodamine B for mitochondrial targeting, cisplatin and mitoxantrone (MTO) for synergistic chemo-immunotherapy, and MTO also serves as a photosensitizer for photodynamic immunotherapy. The effectiveness and robustness of Mito-CMPNs in reversing the immunosuppressive microenvironment is verified in both an ovarian cancer subcutaneous model and a high-grade serous ovarian cancer model. Our results support that the induction of abundant ICD by focused mitochondrial stress is a highly effective strategy to improve the therapeutic efficacy of immunosuppressive ovarian cancer.

Research trends and prospects on brain metastasis from breast cancer: A bibliometric analysis.

Introduction: Brain metastasis is the terminal event of breast cancer with poor prognoses. Therefore, this article aimed to provide an updated summary on the development, hotspots, and research trends of brain metastasis from breast cancer based on bibliometric analysis. Method: Publications on breast cancer with brain metastasis retrieved from the Web of Science Core Collection. CiteSpace, VOSviewer, and other online bibliometric analysis platforms were used to analyze and visualize the result. Result: In totality, 693 researchers from 3,623 institutions across 74 counties and regions published a total of 2,790 papers in 607 journals. There was a noticeable increase in publications in 2006. The United States was the dominant country with the most publications followed by China. University Texas MD Anderson Cancer Center was the most productive institution, while Dana Farber Cancer Institution was the most cited. Journal of Neuro-Oncology published the most papers, while Journal of Clinical Oncology ranked first based on cocited analysis. Nancy U. Lin was the most productive and cited author with high influence. There was a focus on basic research, clinical trials, local therapy, treatment optimization, and epidemiological studies regarding brain metastases from breast cancer. References focused on pathogenesis, prevention, treatment, and prognosis were cited most frequently, among which the clinical trial of novel treatment attracted most attention from researchers. Reference citation burst detection suggested that new therapies such as the novel tyrosine kinase inhibitor and antibody-drug conjugate may lead the research trends in the future. Conclusion: High-income countries contributed more to the field of breast cancer with brain metastasis, while developing countries like China developed quickly. Furthermore, the success of novel therapies in recent years may lead to the new era of treatment of breast cancer with brain metastasis in the future.

Simultaneous real-time analysis of tear film optical quality dynamics and functional visual acuity in dry eye disease.

BACKGROUND: To assess the effect of tear film instability in dry eye disease (DED) by measuring visual performance and tear film optical quality in a simultaneous real-time analysis system. METHODS: Thirty-seven DED participants and 20 normal controls were recruited. A simultaneous real-time analysis system was developed by adding a functional visual acuity (FVA) channel to a double-pass system. Repeated measurements of FVA and objective scatter index (OSI) were performed simultaneously with this system under blink suppression condition for 20 s. Patient-reported symptoms was evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. Mean FVA, mean OSI, and visual acuity break-up time were defined. The OSI maintenance ratio was calculated as an evaluation index to assess the difference between dynamic OSI changes and baseline OSI. The visual maintenance ratio was also calculated in the same way. RESULTS: Moderate correlations were noted between mean OSI and FVA-related parameters (mean FVA, visual maintenance ratio, visual acuity break-up time: 0.53, - 0.56, - 0.53, respectively, P < 0.01 for all). Moderate to high correlations were noted between OSI maintenance ratio and FVA-related parameters (mean FVA, visual maintenance ratio, visual acuity break-up time: - 0.62, 0.71, 0.64, respectively, all P < 0.01). The metrics derived from the simultaneous real-time analysis system were moderately correlated with the patient-reported symptoms and the visual acuity break-up time possessed the highest correlation coefficients with OSDI total, ocular symptoms, and vision-related function (- 0.64, - 0.63, - 0.62, respectively, P < 0.01). The OSI-maintenance ratio alone appeared to exhibit the best performance of the metrics for the detection of DED with sensitivity of 95.0% and specificity of 83.8% and the combinations of FVA parameters and OSI parameters were valid and can further improve the discriminating abilities. CONCLUSIONS: OSI-related metrics were found to be potential indicators for assessing and diagnosing DED which correlated with both subjective visual performance and patient-reported symptoms; the FVA-related metrics were quantifiable indicators for evaluating visual acuity decline in DED. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR2100051650. Registered 29 September 2021, https://www.chictr.org.cn/showproj.aspx?proj=134612.

Jiawei Yanghe Decoction suppresses breast cancer by regulating immune responses via JAK2/STAT3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei Yanghe Decoction (JWYHD) is a widely used traditional Chinese medicine prescription in the clinical setting for the treatment of autoimmune diseases. Many studies showed that JWYHD has anti-tumor activities in cell and animal models. However, the anti-breast cancer effects of JWYHD and the underlying mechanisms of action remain unknown. AIM OF STUDY: This study aimed to determine the anti-breast cancer effect and reveal the underlying mechanisms of action in vivo, in vitro and in silico. MATERIALS AND METHODS: Orthotopic xenograft breast cancer mouse model and inflammatory zebrafish model were used to observe the anti-tumor effect and immune cell regulation of JWYHD. Moreover, the anti-inflammatory effect of JWYHD were evaluated by the expression of RAW 264.7 cells. JWYHD active ingredients were obtained by UPLC-MS/MS and potential targets were screened by network pharmacology. The therapeutic targets and signaling pathways predicted by computer were assessed by Western blot, real-time PCR (RT-PCR), immunohistochemistry (IHC) staining, and Enzyme-linked immunosorbent assays (ELISA) to explore the therapeutic mechanism of JWYHD against breast cancer. At last, Colivelin and Stattic were used to explore the effect of JWYHD on JAK2/STAT3 pathway. RESULTS: JWYHD significantly decreased the tumor growth in a dose-dependent manner in the orthotopic xenograft breast cancer mouse model. Flow cytometry and IHC results indicated that JWYHD decreased the expressions of M2 macrophages and Treg while increasing M1 macrophages. Meanwhile, ELISA and Western blot results showed a decrease in IL-1ß, IL-6, TNFα, PTGS2 and VEGFα in tumor tissue of JWYHD groups. The results were also verified in LPS-induced RAW264.7 cells and zebrafish inflammatory models. TUNEL assay and IHC results showed that JWYHD significantly induced apoptosis. Seventy-two major compounds in JWYHD were identified by UPLC-MS/MS and Network pharmacology. It was found that the significant binding affinity of JWYHD to TNFα, PTGS2, EGFR, STAT3, VEGFα and their expressions were inhibited by JWYHD. IHC and Western blot analysis showed that JWYHD could decrease the expression of JAK2/STAT3 pathway. Furthermore, Colivelin could reverse the decrease effect of JWYHD in vitro. CONCLUSION: JWYHD exerts a significant anti-tumor effect mainly by inhibiting inflammation, activating immune responses and inducing apoptosis via the JAK2/STAT3 signaling pathway. Our findings provide strong pharmacological evidence for the clinical application of JWYHD in the management of breast cancer.

Baseline serum uric acid level is associated with progression-free survival, disease control rate, and safety in postoperative patients with colorectal cancer treated by FOLFOX, FOLFIRI, or XELOX.

Background: High serum uric acid (SUA) levels increase the risk of overall cancer morbidity and mortality, particularly for digestive malignancies. Nevertheless, the correlation between SUA level and clinical outcomes of the postoperative patients with colorectal cancer (CRC) treated by chemotherapy is unclear. This study aimed at exploring the relationship between baseline SUA level and progression-free survival (PFS), disease control rate (DCR), and safety in postoperative CRC patients receiving chemotherapy. Patients and Methods: We conducted a retrospective study to evaluate the relationship between baseline SUA level and PFS, DCR, and incidence of serious adverse events of 736 postoperative CRC patients treated with FOLFOX, FOLFIRI or XELOX at our center. Results: Data from our center suggested that high baseline SUA level is linked to poor PFS in non-metastatic CRC patients using FOLFOX (HR=2.59, 95%CI: 1.29-11.31, p=0.018) and in male patients using FOLFIRI (HR=3.77, 95%CI: 1.57-39.49, p=0.012). In patients treated by FOLFIRI, a high SUA is also linked to a low DCR (p=0.035). In patients using FOLFOX, high baseline SUA level is also linked to a high incidence of neutropenia (p=0.0037). For patients using XELOX, there is no significant correlation between SUA level and PFS, effectiveness, or safety. Conclusions: These findings imply that a high SUA level is a promising biomarker associated with poor PFS, DCR and safety of postoperative CRC patients when treated with FOLFOX or FOLFIRI.

Overexpression of miR-328-5p influences cell growth and migration to promote NSCLC progression by targeting LOXL4.

Background: Lung cancer is the leading cause of cancer-associated mortality worldwide, and most lung cancers are classified as non-small cell lung cancer (NSCLC). MiR-328 influence the progression of multiple tumors, but the role of miR-328-5p in NSCLC has not been elucidated. The aim of this study was to illuminate the oncogenic role and potential molecular mechanisms of the miR-328-5p and lysyl oxidase like 4 (LOXL4) in NSCLC. Methods: Expression of miR-328-5p was detected by real-time quantitative polymerase chain reaction (qRT-PCR) in tumor and non-tumor adjacent tissues. After Lentivirus-miR-328-5p was employed to intervene this miRNA in NSCLC cell lines, RT-qPCR was used to detect the expression levels of miR-328-5p. Cell Counting Kit-8 (CCK-8), cell colony formation, flow cytometry, wound healing, Transwell assays were used to determine the malignant phenotypes of NSCLC cells. Nude mice models of subcutaneous tumors were established to observe the effect of miR-328-5p on tumorigenesis. Targeting the 3'UTR of LOXL4 by miR-328-5p was verified by integrated analysis including transcriptome sequencing, dual-luciferase and western-blot assays. Results: High miR-328-5p level was observed in NSCLC cells from The Cancer Genome Atlas (TCGA) database and tumor tissues collected from NSCLC patients. Overexpressed miR-328-5p promoted NSCLC cell proliferation, survival, and migration, and promoted tumor growth in vivo. Knockdown of miR-328-5p suppressed tumorigenic activities. Transcriptome sequencing analysis revealed that LOXL4 was downregulated by miR-328-5p, which was confirmed by dual-luciferase reporter and western-blot assays. Conclusions: miR-328-5p showed targeted regulation of LOXL4 to promote cell proliferation and migration in NSCLC.

HOTTIP is upregulated in esophageal cancer and triggers the drug resistance.

PURPOSE: To explore the role of HOTTIP in the development of esophageal cancer and the drug resistance. METHODS: Serum level of HOTTIP in esophageal cancer patients was detected by RT-PCR. After treatment with different concentrations of Adriamycin (ADM) in Eca109 cells for 24 h, IC50 was measured by MTT assay. Subsequently, Eca109 cells were treated with 0, 0.2, 0.4 or 0.8 µg/ml ADM, respectively, followed by extraction of extracellular vesicles (EVs). HOTTIP level in EVs was detected. In addition, Eca109 cells were pre-treated with EVs for 48 h, and different concentrations of ADM for another 24 h. IC50, cell cycle determination and relative levels of HOTTIP and ABCG2 were examined. Pearson correlation test was conducted to assess the correlation between levels of HOTTIP and ABCG2. RESULTS: Serum level of HOTTIP was higher in esophageal cancer patients. IC50 in ADM-treated Eca109 cells for 24 h was 0.43±0.02 µg/ml. EVs1-4 were respectively isolated from Eca109 cells treated with 0, 0.2, 0.4 or 0.8 µg/ml ADM for 24 h, respectively. HOTTIP remained the highest level in EVs4 than the other three groups. Notably, IC50 was much higher in Eca109 cells incubated with EVs4 than those treated with EVs1-3. EVs4 intervention in Eca109 cells for 48 h markedly increased the proliferation index (PI), and relative levels of HOTTIP and ABCG2 than the other three groups. HOTTIP displayed a positive correlation with ABCG2 in Eca109 cells. CONCLUSIONS: HOTTIP is highly expressed in serum of esophageal cancer patients. EVs-containing HOTTIP regulates drug resistance in esophageal cancer by positively activating ABCG2.

Expressions of m6A RNA methylation regulators and their clinical predictive value in cervical squamous cell carcinoma and endometrial adenocarcinoma.

The mortality caused by cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) ranks second among female malignant tumour deaths, but their diagnostic and therapeutic targets are still limited. N6-methyladenosine (m6A) is the most common and extensive modification in mRNA molecules, and its methylation regulators participate in regulating the occurrence and development of many tumours. However, whether m6A RNA methylation regulators can be used as independent prognostic indicators of CESC remains unknown. This study unveiled differential expression of 20 m6A RNA methylation regulators between normal and CESC tumour samples, which RNA sequence data and clinical information were obtained from TCGA database. As a result, five m6A RNA methylation regulators (FTO, HNRNPA2B1, RBM15, IGF2BP1, IGF2BP3) were identified to be significantly linked to CESC tumour status. After Lasso cox regression analysis, six m6A RNA methylation regulators (YTHDC2, YTHDC1, ALKBH5, ZC3H13, RBMX, YTHDF1) were chosen to construct a risk signature. CESC patients were then classified as high-risk and low-risk group based on the median risk score. The overall survival (OS) of the CESC patients in high-risk group was significantly lower than that in low-risk group, and the area under curve (AUC) is 0.718. Moreover, the risk model can be an independent prognosis factors for CESC patients and can predict OS of CESC patients with different clinical factors. In conclusion, m6A RNA methylation regulators are closely correlated with CESC clinical characteristics and the selected six m6A RNA methylation regulators may be useful for CESC patients personalized treatment.

Silibinin Promotes Cell Proliferation Through Facilitating G1/S Transitions by Activating Drp1-Mediated Mitochondrial Fission in Cells.

Heart, liver, and kidney, which are known as the essential organs for metabolism, possess the unique ability to regulate the proliferation function of the body against injury. Silibinin (SB), a natural polyphenolic flavonoid extracted from traditional herb Silybum marianum L., has been used to protect hepatocytes. Whether SB can regulate mitochondrial fission in normal cells and the underlying mechanisms remain unclear. Here, we showed that SB markedly promoted cell proliferation by facilitating G1/S transition via activating dynamin-related protein 1 (Drp1), which in turn mediated mitochondrial fission in these normal cells. SB dose-dependently increased the mitochondrial mass, mtDNA copy number, cellular adenosine triphosphate production, mitochondrial membrane potential, and reactive oxygen species in normal cells. Furthermore, SB dose-dependently increased the expression of Drp1. Blocking Drp1 abolished SB-induced mitochondrial fission. In conclusion, we demonstrate that SB promotes cell proliferation through facilitating G1/S transition by activating Drp1-mediated mitochondrial fission. This study suggests that SB is a potentially useful herbal derivative for the daily prevention of various diseases caused by impaired mitochondrial fission.

[10-gingerol inhibits proliferation of hepatocellular carcinoma HepG2 cells via Src/STAT3 signaling pathway].

OBJECTIVE: To study the inhibitory effect of 10-gingerol on the proliferation of hepatocellular carcinoma HepG2 cells and the role of Src/STAT3 signaling pathway in mediating the effect. METHODS: SYBYL-X2.1 software was used to simulate the interaction between 10-gingerol and Src. HepG2 cells treated with 10-gingerol at 1, 3, 10 or µol/L for 24 h were assessed for cell viability using MTT assay, and EdU staining was used to detect the cell proliferation and calculate the number of positive cells. The expressions of p-Src and p-STAT3 were detected using Western blotting, and the mRNA expressions of the target genes of STAT3 (cyclin D1 and CMCC) were detected using qPCR. RESULTS: 10-gingerol was capable of forming hydrogen bond with such Src residues as TRY-340, MET-341, MET-314, ASP-404, and ILE-336. MTT assay showed that 10-gingerol at 3 and 10 µmol/L significantly lowered the viability of HepG2 cells (P < 0.001). Treatment with 1, 3, and 10 µmol/L 10-gingerol significantly reduces the number of EdU-positive HepG 2 cells (P < 0.001). Western blotting showed that 10-gingerol at 3 and 10 µmol/L significantly decreased the phosphorylation levels of Src and STAT3 in HepG2 cells (P < 0.01). 10-gingerol at 1, 3, and 10 µmol/L significantly decreased the mRNA expressions of cyclin D1 and CMCC as shown by qPCR (P < 0.01). CONCLUSIONS: 10-gingerol can dose-dependently inhibit the proliferation of HepG2 cells and suppress the activation of Src and STAT3.

Alda­1, an aldehyde dehydrogenase­2 agonist, improves long­term survival in rats with chronic heart failure following myocardial infarction.

Alda­1, an aldehyde dehydrogenase 2 (ALDH2) agonist, has been demonstrated to reduce injury caused by acute myocardial infarction (MI) and ischemia/reperfusion. The present study aimed to investigate whether oral administration of Alda­1 improved long­term survival of rats with chronic heart failure (CHF) post­MI. MI model rats treated daily with Alda­1 exhibited an increase in 20­week survival rate compared with untreated MI rats. Alda­1 treatment decreased the heart weight/body weight ratio, collagen volume, left ventricular (LV) internal diameter at the end of diastole and LV internal diameter at the end of systole, while increasing LV ejection fraction with evident LV fractional shortening. Myocardial cell apoptosis index, the activity of caspase­3 and the expression of cleaved­caspase­3 were also reduced by Alda­1 treatment. The protective effects of Alda­1 were associated with reduced 4­hydroxynonenal accumulation. The results of the present study revealed that the long­term treatment with Alda­1 prevented the progression of ventricular remodeling and improved the long­term survival of rats with CHF post­MI.

Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway.

Myocardial cell apoptosis mediated by oxidative stress has previously been identified as a key process in ischemic heart disease. Secoisolariciresinol diglucoside (SDG), a polyphenolic plant lignan primarily found in flaxseed, has been demonstrated to effectively protect myocardial cells from apoptosis. In the present study, the role of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) was investigated in mediating the protective effect of SDG. Findings of the present study revealed that treatment with H2O2 reduced cell viability and induced apoptosis in H9C2 rat cardiomyocytes. However, SDG was able to reduce the effect of H2O2 in a dose­dependent manner. H2O2 reduced the expression level of phosphorylated STAT3 and inhibited the levels of B­cell lymphoma­extra­large and induced myeloid leukemia cell differentiation protein, which are the STAT3 target genes. Conversely, SDG rescued phosphorylation of STAT3 and increased the levels of STAT3 target genes. Treatment with SDG alone led to a dose­dependent increased phosphorylation of JAK2 and STAT3, without activating Src. Furthermore, the anti­apoptotic effects of SDG were partially abolished by a JAK2/STAT3 inhibitor. In addition, molecular docking revealed that SDG may bind to the protein kinase domain of JAK2, at a binding energy of ­8.258 kcal/mol. Molecular dynamics simulations revealed that JAK2­SDG binding was stable. In conclusion, activation of the JAK2/STAT3 signaling pathway contributed to the anti­apoptotic activity of SDG, which may be a potential JAK2 activator.

Effect of pulse high-volume hemofiltration on Toll-like receptor in patients with severe sepsis.

The expression level and prognosis of Toll-like receptor 2 (TLR2) mRNA in peripheral blood mononuclear cells of patients with severe sepsis after applying pulse high-volume hemofiltration (PHVHF) were investigated. Sustained PHVHF treatment was carried out on 40 patients on the basis of conventional treatment for up to 72 h. Acute physiology and chronic health evaluation (APACHE) II scores of patients were compared before and after the treatment. CD4+, CD8+ lymphocyte counts and ratios in the peripheral blood were detected using FASort before and 24 and 48 h of PHVHF treatment. Enzyme-linked immunosorbent assay was adopted to detect tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) concentrations in plasma at different time points before and after 24, 48 and 72 h of treatment, while semi-quantitative reverse transcription-polymerase chain reaction technology was used to test TLR2 mRNA expression. After PHVHF treatment, APACHE II, Sequential Organ Failure Assessment scores were decreased (P<0.05). After 72 h of PHVHF treat-ment, TNF-α, IL-10, TLR2 mRNA expression levels in the plasma of patients were significantly decreased compared to before treatment (P<0.05), and the IL-10 / TNF-α ratio was much higher than before treatment (p<0.05). In conclusion, PHVHF can restore the pro-inflammatory/anti-inflammatory balance of the body, thereby improving the overall condition of the patients by removing inflammatory mediators and lowering TLR2 expression of mononuclear cell surface in peripheral blood.

Effects of dopamine, norepinephrine and dobutamine on gastric mucosal pH of septic shock patients.

The effect of different vasoactive drugs on the pH [intracellular pH (pHi)] of gastric mucosa in patients with septic shock was evaluated in the present study. According to the vasoactive drugs applied, 48 patients with septic shock were divided into 3 groups: A, B and C, with 16 cases each. Cases of group A were treated with dopamine, those of group B with norepinephrine while those of group C were treated with norepinephrine plus dobutamine. The changes of pH of gastric mucosa were observed before treatment (baseline) and 6, 12, 24 and 48 h after treatment, and the hemodynamic indicators were observed before treatment (baseline) and 6 h after administration. The gastric mucosal pH was not significantly different between two of the three groups before treatment (each at P>0.05). The gastric mucosal pH of group A did not change 6, 12, 24 and 48 h after treatment with drugs compared with the baseline (all at P>0.05), while the gastric mucosal pH in groups B and C were each statistically higher at the time points of 6, 12, 24 and 48 h after treatment with drugs compared with the respective baselines (all at P<0.05). Following treatment with drugs, the gastric mucosal pH of group C at all the time points of 6, 12, 24 and 48 h after treatment were significantly higher than those of groups A and B at the same time points after treatment, while there were some statistical differences between groups A and B at these time points (6, 12, 24 and 48 h after treatment; P<0.05). The hemodynamic indicators of the patients before treatment were not significantly different between two of the three groups (all at P>0.05). Compared with the baseline values, the mean arterial pressure and the cardiac index of each group after treatment were significantly increased, the pulmonary capillary wedge pressure and the central venous pressure of groups B and C significantly increased (all at P<0.05) and the heart rate of group A was significantly increased (P<0.05). In conclusion, the gastric mucosal pH of the septic shock patients was increased when treated with norepinephrine or with dobutamine. Additionally, the gastric mucosal pH was significantly higher when the patients were treated with dobutamine and norepinephrine in combination than with norepinephrine or dopamine alone. Dopamine, norepinephrine and dobutamine can improve the systemic hemodynamic conditions in patients with septic shock.

Effect of heart rate on the diagnostic accuracy of 256-slice computed tomography angiography in the detection of coronary artery stenosis: ROC curve analysis.

The aim of the present study was to investigate the effect of heart rate (HR) on the diagnostic accuracy of 256-slice computed tomography angiography (CTA) in the detection of coronary artery stenosis. Coronary imaging was performed using a Philips 256-slice spiral CT, and receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic value of 256-slice CTA in coronary artery stenosis. The HR of the research subjects in the study was within a certain range (39-107 bpm). One hundred patients suspected of coronary heart disease underwent 256-slice CTA examination. The cases were divided into three groups: Low HR (HR <75 bpm), moderate HR (75≤ HR <90 bpm) and high HR (HR ≥90 bpm). For the three groups, two observers independently assessed the image quality for all coronary segments on a four-point ordinal scale. An image quality of grades 1-3 was considered diagnostic, while grade 4 was non-diagnostic. A total of 97.76% of the images were diagnostic in the low-HR group, 96.86% in the moderate-HR group and 95.80% in the high-HR group. According to the ROC curve analysis, the specificity of CTA in diagnosing coronary artery stenosis was 98.40, 96.00 and 97.60% in the low-, moderate- and high-HR groups, respectively. In conclusion, 256-slice coronary CTA can be used to clearly show the main segments of the coronary artery and to effectively diagnose coronary artery stenosis. Within the range of HRs investigated, HR was found to have no significant effect on the diagnostic accuracy of 256-slice coronary CTA for coronary artery stenosis.

Protein tyrosine phosphatase SHP-1 sensitizes EGFR/HER-2 positive breast cancer cells to trastuzumab through modulating phosphorylation of EGFR and HER-2.

BACKGROUND: Trastuzumab resistance in HER-2 positive breast cancer cells is closely related to overexpression of both epidermal growth factor receptor (EGFR) and human epidermal receptor (HER-2). SHP-1 has been demonstrated to downregulate tyrosine kinase activity including EGFR via its phosphatase function, but its effect on HER-2 activity is still unknown. Here, we examined the hypothesis that SHP-1 enhances the anticancer efficacy of trastuzumab in EGFR/HER-2 positive breast cancer cells through combining dual inhibition of EGFR and HER-2. METHODS: Trastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3cells in the presence of trastuzumab. The SHP-1 was ectopically expressed by stable transfection. The activity and expression of EGFR, HER-2, and downstream signaling pathways were tested by Western blot. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was examined by flow cytometry. The binding between SHP-1 and EGFR/HER-2 was evaluated by immunoprecipitation assay and bimolecular fluorescence complementation. The effects of SHP-1 on tumorigenicity and trastuzumab sensitivity were confirmed via in vivo xenograft model. RESULTS: Trastuzumab-resistant SKBr-3 cells showed aberrant co-expression of EGFR and HER-2. Introduction of wild-type SHP-1 inhibited cell proliferation, clone formation, and promoted the apoptosis induced by trastuzumab. Meanwhile, SHP-1 overexpression reduced phosphorylation levels of EGFR and HER-2 both in parental and trastuzumab-resistant SKBr-3 cells. In vivo study showed an increased antitumor effect of trastuzumab in SHP-1 overexpressed xenografts. At last, we discovered that SHP-1 can make complexes with both EGFR and HER-2, and both phospho-EGFR and phosphor-HER-2 levels in wild-type SHP-1 immunoprecipitates were less than those in phosphatase-inactive SHP-1 (C453S) immunoprecipitates, indicating that EGFR and HER-2 are potential substrates of SHP-1. CONCLUSION: Taken together, we have demonstrated that the SHP-1 is a negative regulatory factor of the tyrosine kinase activity of HER-2 and EGFR through inhibiting phosphorylation. Dual targeting of EGFR and HER-2, by combining trastuzumab with SHP-1 overexpression, may improve response in HER-2 overexpressing breast cancer cells that also express high levels of EGFR.

Staging of untreated squamous cell carcinoma of buccal mucosa with 18F-FDG PET: comparison with head and neck CT/MRI and histopathology.

UNLABELLED: This prospective, nonrandomized, case-control study evaluated the impact of (18)F-FDG PET in staging untreated squamous cell carcinoma of the buccal mucosa (BSCC) and compared the results with CT/MRI and histopathology. METHODS: Between January 2002 and April 2004, 102 untreated BSCC patients with cM0 (no evidence of distant metastatic focus on chest radiograph, liver ultrasonograph, and bone scan) were enrolled with either conventional work-up (CWU, n = 51) or PET (CWU+PET, n = 51). All were monitored for at least 6 mo. The comparative diagnostic efficacies of PET and CT/MRI were evaluated using the area under the receiver-operating-characteristic curve (AUC). The primary endpoint was the percentage reduction in futile surgery (preoperative detection of distant metastatic lesions). The secondary endpoint was the 2-y cumulative recurrence rate among study participants (with PET) compared with that of comparable control subjects (without PET). RESULTS: Significant benefits of PET compared with those of CT/MRI for BSCC patients were in the detection of locoregional (AUC, 0.973 vs. 0.928; P = 0.026), regional (AUC, 0.939 vs. 0.837; P = 0.026), and level II (AUC, 0.974 vs. 0.717; P = 0.02) lymph nodes. Two percent (1/51) of the patients experienced a reduction in futile surgery in the CWU+PET group compared with 0% (0/51) in the CWU group. However, no statistical difference was found in the 2-y locoregional control rate between the CWU and the CWU+PET groups. CONCLUSION: The role of (18)F-FDG PET for BSCC with cM0 is limited. Although PET is superior to CT/MRI in identifying cervical nodal metastases, it does not improve locoregional recurrence.