Manganese and IL-12 treatment alters the ovarian tumor microenvironment.

Metal immunotherapy is a novel adjuvant immunotherapy. Mn2+ can activate STING-a type I IFN response protein-that promotes innate immunity and increases anti-tumor activity by promoting macrophage phagocytosis. IL-12, a cytokine that increases the antigen-presenting ability to promote effector T-cell activation, has potent antitumor activity, albeit with severe adverse effects. In this study, we observed that the combination of Mn2+ and IL-12 has a better antitumor effect and possibly reflects a better safety profile, providing a novel approach and theoretical basis for safe and rapid cancer treatment.

UV-light-assisted gas sensor based on PdSe2/InSe heterojunction for ppb-level NO2 sensing at room temperature.

The fabrication of van der Waals (vdWs) heterostructures mainly extends to two-dimensional (2D) materials. Nevertheless, the current processes for obtaining high-quality 2D films are mainly exfoliated from their bulk counterparts or by high-temperature chemical vapor deposition (CVD), which limits industrial production and is often accompanied by defects. Herein, we first fabricated the type-II p-PdSe2/n-InSe vdWs heterostructure using the ultra-high vacuum laser molecular beam epitaxy (LMBE) technique combined with the vertical 2D stacking strategy, which is reproducible and suitable for high-volume manufacturing. This work found that the introduction of 365 nm UV light illumination can significantly improve the electrical transport properties and NO2 sensing performance of the PdSe2/InSe heterojunction-based device at room temperature (RT). The detailed studies confirm that the sensor based on the PdSe2/InSe heterojunction delivers the comparable sensitivity (Ra/Rg = ∼2.6 at 10 ppm), a low limit of detection of 52 ppb, and excellent selectivity for NO2 gas under UV light illumination, indicating great potential for NO2 detection. Notably, the sensor possesses fast response and full recovery properties (275/1078 s) compared to the results in the dark. Furthermore, the mechanism of enhanced gas sensitivity was proposed based on the energy band alignment of the PdSe2/InSe heterojunction with the assistance of investigating the surface potential variations. This work may pave the way for the development of high-performance, room-temperature gas sensors based on 2D vdWs heterostructures through the LMBE technique.

Functional Connectivity of Nucleus Accumbens and Medial Prefrontal Cortex With Other Brain Regions During Early-Abstinence Is Associated With Alcohol Dependence and Relapse: A Resting-Functional Magnetic Resonance Imaging Study.

Background: Alcohol dependence (AD) is a chronic recurrent brain disease that causes a heavy disease burden worldwide, partly due to high relapse rates after detoxification. Verified biomarkers are not available for AD and its relapse, although the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) may play important roles in the mechanism of addiction. This study investigated AD- and relapse-associated functional connectivity (FC) of the NAc and mPFC with other brain regions during early abstinence. Methods: Sixty-eight hospitalized early-abstinence AD male patients and 68 age- and education-matched healthy controls (HCs) underwent resting-functional magnetic resonance imaging (r-fMRI). Using the NAc and mPFC as seeds, we calculated changes in FC between the seeds and other brain regions. Over a follow-up period of 6 months, patients were measured with the Alcohol Use Disorder Identification Test (AUDIT) scale to identify relapse outcomes (AUDIT ≥ 8). Results: Thirty-five (52.24%) of the AD patients relapsed during the follow-up period. AD displayed lower FC of the left fusiform, bilateral temporal superior and right postcentral regions with the NAc and lower FC of the right temporal inferior, bilateral temporal superior, and left cingulate anterior regions with the mPFC compared to controls. Among these FC changes, lower FC between the NAc and left fusiform, lower FC between the mPFC and left cingulate anterior cortex, and smoking status were independently associated with AD. Subjects in relapse exhibited lower FC of the right cingulate anterior cortex with NAc and of the left calcarine sulcus with mPFC compared to non-relapsed subjects; both of these reductions in FC independently predicted relapse. Additionally, FC between the mPFC and right frontal superior gyrus, as well as years of education, independently predicted relapse severity. Conclusion: This study found that values of FC between selected seeds (i.e., the NAc and the mPFC) and some other reward- and/or impulse-control-related brain regions were associated with AD and relapse; these FC values could be potential biomarkers of AD or for prediction of relapse. These findings may help to guide further research on the neurobiology of AD and other addictive disorders.

Uncoupling Protein 2 Drives Myocardial Dysfunction in Murine Models of Septic Shock.

Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Uncoupling protein 2 (UCP2) involves immune response, regulation of oxidative stress, and maintenance of mitochondrial membrane potential as well as energy production. However, whether and how UCP2 plays roles in the development of septic cardiac dysfunction are largely unknown. Here, intraperitoneal injection of LPS significantly activated UCP2 expression accompanied by a significant decrease of cardiac function and caused a significantly lower survival rate in mice. Of note, knockdown of UCP2 through a cardiotropic adenoassociated viral vector carrying a short hairpin RNA (shRNA) specifically targeting the UCP2 evoked resistance to LPS-triggered septic cardiac dysfunction and lethality in vivo. Moreover, UCP2 deficiency ameliorated the reduced levels of intracellular ATP in the LPS-challenged heart tissues and preserved mitochondrial membrane potential loss in primary adult mouse cardiomyocytes in LPS-challenged animals. Mechanistically, we confirmed that the inhibition of UCP2 promoted autophagy in response to LPS, as shown by an increase in LC3II and a decrease in p62. At last, the autophagy inhibitor 3-MA abolished UCP2 knockdown-afforded cardioprotective effects. Those results indicate that UCP2 drives septic cardiac dysfunction and that the targeted induction of UCP2-mediated autophagy may have important therapeutic potential.

Lower mean platelet volume predicts poor prognosis in renal cell carcinoma.

Altered mean platelet volume (MPV) is found in several malignancies. Remarkably, there is little consensus on using the value of MPV in the prognostic evaluations of renal cell carcinoma (RCC). The aim of this study is to examine the feasibility of MPV value as a prognostic indicator of RCC. The retrospective study recruited 306 consecutive RCC patients between January 2009 and December 2009. The relationships between MPV and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of MPV. Of the 306 RCC patients, low MPV levels were detected in 61 (19.9%) patients. Reduced MPV was associated with histology types, T classification, UCLA Integrated Scoring System (UISS) category, and Mayo clinic stage, size, grade, and necrosis score (SSIGN) category (P < 0.05). Patients with decreased MPV had significantly shorter survival time than patients with normal MPV (P < 0.001). Cox regression analysis revealed that reduced MPV was an independent prognostic factor for overall survival (hazard ratio, 1.758; 95% confidence interval [CI], 1.083-2.855, P = 0.023). Moreover, the prognostic accuracy of TNM stage, UISS, and SSIGN prognostic models were improved when MPV was added. In conclusion, reduced MPV is identified as an independent predictor of adverse clinical outcome in RCC.

Higher platelet distribution width predicts poor prognosis in laryngeal cancer.

BACKGROUND: Activated platelets promote cancer progression and metastasis. However, the prognostic value of platelet indices in laryngeal cancer remains poorly understood. The purpose of this study was to investigate the predictive significance of platelet indices in laryngeal cancer. RESULTS: Of the 241 patients, high platelet distribution width (PDW) levels were observed in 116 (48.1 %) patients. In the Kaplan-Meier analysis, increased PDW was significantly associated with a poorer overall survival (p < 0.001). In the multivariate Cox model, PDW was an independent prognostic index for overall survival (HR=4.381, 95% CI=2.313-8.298, P < 0.001). METHOD: The retrospective study included 241 consecutive patients with laryngeal cancer between January 2009 and December 2009. The relationships between PDW and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of PDW. CONCLUSIONS: Elevated PDW might be a novel prognostic marker in laryngeal cancer.

Platelet distribution width correlates with prognosis of gastric cancer.

BACKGROUND: Activated platelets promote tumor cell growth, aberrant angiogenesis, and invasion. However, the value of platelet indices for predicting survival in gastric cancer remains unknown. The goal of this study was to investigate the predictive significance of platelet indices in gastric cancer. RESULT: Reduced platelet distribution width (PDW) was significantly correlated with age, carcinoembryonic antigen, tumor stage, nodule stage, and tumor-nodule-metastases stage. Moreover, decreased PDW correlated with a shorter overall survival in gastric cancer. Multivariate analysis identified PDW as an independent prognostic factor for overall survival (hazard ratio: 0.493, 95% confidence interval: 0.319-0.761, p = 0.001). METHOD: A total of 294 patients with gastric cancer were retrospectively analyzed between January 2009 and December 2009. The association between platelet indices and overall survival were evaluated. The prognostic analysis was carried out with Cox regression model. CONCLUSION: PDW is easily available with routine blood counts. Our data revealed that reduced PDW is unfavorable prognostic factor in gastric cancer. Further studies are warranted.

miR-375 inhibits cancer stem cell phenotype and tamoxifen resistance by degrading HOXB3 in human ER-positive breast cancer.

Cancer stem cell (CSC) formation and epithelial-mesenchymal transition (EMT) are pivotal events in tumor cell invasion and metastasis. They have been shown to occur in resistance to tamoxifen. Moreover, microRNAs (miRNAs) have been associated with CSCs, EMT as well as tamoxifen resistance. Studying molecular mechanism of CSCs, EMT as well as tamoxifen resistance will help us to further understand the pathogenesis and progression of the disease and offer new targets for effective therapies. In the present study, we showed that miR-375 inhibits CSC traits in breast cancer MCF-7 cells. Bioinformatics analysis and experimental validation identified HOXB3 as a direct target of miR-375. Overexpressing miR-375 degraded HOXB3 mRNA in MCF-7 cells. Moreover, overexpression of HOXB3 induced formation of CSC phenotypes, EMT and tamoxifen-resistance as well as enhanced ability of migration and invasion in MCF-7 cells. Most ER-positive breast cancer-related deaths occur, because of resistance to standard therapies and metastasis, restoring miR-375 or targeting HOXB3 might serve as potential therapeutic approaches for the treatment of tamoxifen-resistant breast cancer.

Prospective study found that peripheral lymph node sampling reduced the false-negative rate of sentinel lymph node biopsy for breast cancer.

BACKGROUND: Although sentinel lymph node biopsy (SLNB) can accurately predict the status of axillary lymph node (ALN) metastasis, the high false-negative rate (FNR) of SLNB is still the main obstacle for the treatment of patients who receive SLNB instead of ALN dissection (ALND). The purpose of this study was to evaluate the clinical significance of SLNB combined with peripheral lymph node (PLN) sampling for reducing the FNR for breast cancer and to discuss the effect of "skip metastasis" on the FNR of SLNB. METHODS: At Shandong Cancer Hospital Affiliated to Shandong University between March 1, 2012 and June 30, 2015, the sentinel lymph nodes (SLNs) of 596 patients with breast cancer were examined using radiocolloids with blue dye tracer. First, the SLNs were removed; then, the area surrounding the original SLNs was selected, and the visible lymph nodes in a field of 3-5 cm in diameter around the center (i.e., PLNs) were removed, avoiding damage to the structure of the breast. Finally, ALND was performed. The SLNs, PLNs, and remaining ALNs underwent pathologic examination, and the relationship between them was analyzed. RESULTS: The identification rate of SLNs in the 596 patients was 95.1% (567/596); the metastasis rate of ALNs was 33.7% (191/567); the FNR of pure SLNB was 9.9% (19/191); and after the SLNs and PLNs were eliminated, the FNR was 4.2% (8/191), which was significantly decreased compared with the FNR before removal of PLNs (P = 0.028). According to the detected number (N) of SLNs, the patients were divided into four groups of N = 1, 2, 3, and ≥4; the FNR in these groups was 19.6, 9.8, 7.3, and 2.3%, respectively. For the patients with ≤2 or ≤3 detected SLNs, the FNR after removal of PLNs was significantly decreased compared with that before removal of PLNs (N ≤ 2: 14.0% vs. 4.7%, P = 0.019; N ≤ 3: 12.2% vs. 4.7%, P = 0.021), whereas for patients with ≥4 detected SLNs, the decrease in FNR was not statistically significant (P = 1.000). In the entire cohorts, the "skip metastasis" rate was 2.5% (15/596); the FNR caused by "skip metastasis" was 2.1% (4/191). CONCLUSIONS: The FNR of SLNB was associated with the number of SLNs. For patients with ≤3 detected SLNs, PLN sampling can reduce the FNR of SLNB to an acceptable level of less than 5%. Because of the existence of the "skip metastasis" and distinct metastasis patterns, the FNR of SLNB cannot be completely eliminated.

Estrogen receptor α mediates the effects of notoginsenoside R1 on endotoxin-induced inflammatory and apoptotic responses in H9c2 cardiomyocytes.

Estrogen receptors (ERs) are important for preventing endotoxin-induced myocardial dysfunction. Therefore, plant-derived phytoestrogens, which target ERs may also affect endotoxin-induced toxicity in cardiomyocytes. Our previous study revealed that notoginsenoside-R1 (NG-R1), a predominant phytoestrogen from Panax notoginseng, protects against cardiac dysfunction. However, the effects of NG-R1 on cardiomyocytes and the precise cellular/molecular mechanisms underlying its action remain to be elucidated. In the present study, pretreatment with NG-R1 suppressed the lipopolysaccharide (LPS)-induced degradation of inhibitor of nuclear factor-κB (NF-κB) α, the activation of NF-κB and caspase-3, and the subsequent myocardial inflammatory and apoptotic responses in H9c2 cardiomyocytes. An increase in the mRNA and protein expression of ERα was also observed in the NG-R1-treated cardiomyocytes. However, the expression pattern of ERß remained unaltered. Furthermore, the cardioprotective properties of NG-R1 against LPS-induced apoptosis and the inflammatory response in cardiomyocytes were attenuated by ICI 182780, a non-selective ERα antagonist, and methyl-piperidino-pyrazole, a selective ERα antagonist. These findings suggested that NG-R1 reduced endotoxin-induced cardiomyocyte apoptosis and the inflammatory response via the activation of ERα. Therefore, NG-R1 exerted direct anti-inflammatory and anti-apoptotic effects on the cardiomyocytes, representing a potent agent for the treatment of myocardial inflammation during septic shock.

Maternal and fetal metabonomic alterations in prenatal nicotine exposure-induced rat intrauterine growth retardation.

Prenatal nicotine exposure causes adverse birth outcome. However, the corresponding metabonomic alterations and underlying mechanisms of nicotine-induced developmental toxicity remain unclear. The aims of this study were to characterize the metabolic alterations in biofluids in nicotine-induced intrauterine growth retardation (IUGR) rat model. In the present study, pregnant Wistar rats were intragastrically administered with different doses of nicotine (0.5, 1.0 and 2.0 mg/kg d) from gestational day (GD) 11-20. The metabolic profiles of the biofluids, including maternal plasma, fetal plasma and amniotic fluid, were analyzed using (1)H nuclear magnetic resonance (NMR)-based metabonomic techniques. Prenatal nicotine exposure caused noticeably lower body weights, higher IUGR rates of fetal rats, and elevated maternal and fetal corticosterone (CORT) levels compared to the controls. The correlation analysis among maternal, fetal serum CORT levels and fetal bodyweight suggested that the levels of maternal and fetal serum CORT presented a positive correlation (r=0.356, n=32, P<0.05), while there was a negative correlation between fetal (r=-0.639, n=32, P<0.01) and maternal (r=-0.530, n=32, P<0.01) serum CORT level and fetal bodyweight. The fetal metabonome alterations included the stimulation of lipogenesis and the decreased levels of glucose and amino acids. The maternal metabonome alterations involved the enhanced blood glucose levels, fatty acid oxygenolysis, proteolysis and amino acid accumulation. These results suggested that prenatal nicotine exposure is associated with an altered maternal and fetal metabonome, which may be related to maternal increased glucocorticoid level induced by nicotine.

[Analysis of clinicopathological factors associated with false-negative rate of sentinel lymph node biopsy in breast cancer patients: experience of a single center].

OBJECTIVE: The purpose of this study was to investigate the clinicopathologic factors associated with false-negative rate of sentinel lymph node biopsy (SLNB) in breast cancer, and to explore how to reduce the false-negative rate of SLNB. METHODS: The clinicopathological data of 2265 patients with invasive breast carcinoma who underwent sentinel lymph nodes biopsy (SLNB) in Shandong Cancer Hospital between November 1999 and December 2011 were retrospectively analyzed. We screened 1228 patients who received axillary lymph node dissection after SLNB, and studied the clinicopathological factors that could be associated with false-negative rate of SLNB. RESULTS: The false negative rate of this group was 10.7% (73/683), accuracy rate was 94.1% (1155/1228), and negative predictive value was 88.2% (545/618). Clinical tumor size (all P < 0.05), calendar year of surgery (all P < 0.05) and numbers of detected SLNs (all P < 0.05) were significantly related with false negative rate and accuracy rate of SLNB, determined by single factor analysis. Logistic regression model analysis showed that calendar year of surgery (P = 0.034) and numbers of detected SLNs (P = 0.012) were independent predictive factors for the false negative rate of SLNB. CONCLUSIONS: False negative rate and accuracy rate of SLNB are significantly related to the calendar year of surgery and number of detected SLNs. Strict case selection, standard operation procedure, increaseing numbers of detected SLNs, and improvement of the skill of operators are effective measures to reduce the false negative rate of SLNB.

[Systematic review of validation phase of breast cancer sentinel lymph node biopsy results in China].

OBJECTIVE: To explore the studies and application status of sentinel lymph node biopsy (SLNB) in breast cancer in China by statistically analyzing the relevant domestic literature. METHODS: The literatures published from January 1999 to December 2005 were searched in the databases of China, Info, CBM and CNKI retrieval system with "breast tumor, SLN and SLNB" as the key words. A total of 88 manuscripts were selected with 2 new reports of SLNB. The successful rate, accuracy, false-negative rate and sensitivity of SLNB were analyzed by SPSS 10.0 statistical analysis software. RESULTS: Among a total of 6282 patients, the detection rate of SLNB was 90.82% (5705/6282) and the overall false-negative rate 9.69% (259/2671). The prediction sensitivity, specificity, false positive rate, accuracy, negative and positive predictive value of SLN for axillary lymph nodes status were 90.30%, 99.64%, 0.41%, 86.52%, 92.11% and 99.55% respectively. CONCLUSION: SLNB can accurately predict the axillary lymph node metastasis. And its detection rate is correlated with patient age and tumor location. The detection rate and false-negative rate has nothing to do with the tracer injection site. A combined regimen has a higher detection rate and a low false negative rate. Affecting the whole breast, SLN is not correlated with a particular area of breast. The validation phase of SLNB in breast cancer is currently feasible in China.

Preoperative lymphoscintigraphy predicts the successful identification but is not necessary in sentinel lymph nodes biopsy in breast cancer.

BACKGROUND: Although preoperative lymphoscintigraphy in sentinel lymph node biopsy (SLNB) for breast cancer patients is undergone commonly, its clinical significance remains controversial. METHODS: We retrospectively analyzed our database that contained 636 consecutive breast cancer patients who received preoperative lymphoscintigraphy before SLNB. RESULTS: The sentinel lymph nodes (SLNs) of 86.5% of patients were well imaged by lymphoscintigraphy, and SLN were located extra-axilla in 5.3% patients. The visualization of SLN in lymphoscintigraphy was not associated with histopathologic type, location, and stage of primary tumor, as well as the time interval from injection of radiocolloid to surgery. The negative lymphoscintigraphy results were associated with excision ;biopsy before injection of radiocolloid and positive axillary node statues. The SLN was successfully detected in 625 (98.3%) enrolled patients. Failure of surgical identification of axillary SLN was associated with whether hot spot was imaged by lymphoscintigraphy. However, we identified axillary SLN in 90 (90.9%) out of 99 patients with negative axillary findings in lymphoscintigram. The false negative rate of SLNB in our study was 16.0% (15 of 94) among patients of training group, and there was no significant difference in the false negative rate between patients who had axillary hot spot in lymphoscintigram and those who had not (P = .273). CONCLUSIONS: Visualization of SLN in preoperative lymphoscintigraphy predicted the successful SLN identification. However, it was less informative for the location of SLN during operation. Considering the complexity, time consumed, and cost, lymphoscintigraphy should at present be undergone for investigation purposes only.

[Flow cytometric quantitative analysis of multiple tumor suppressor gene 1 (MTS1) and cyclooxygenase-2 (COX-2) gene expressions in invasive breast cancers and their clinical significance].

OBJECTIVE: The purpose of the present study was to explore the expression and clinical significance of multiple tumor suppressor gene 1 (MTS1) and cyclooxygenase-2 (COX-2) gene in invasive breast cancers. METHODS: Flow cytometry was used to analyze the expression level of MTS1 and COX-2 in cancer tissues and corresponding para-cancer tissues from 66 cases of primary invasive breast cancers. RESULTS: In breast cancer tissues, the expression of MTS1 and COX-2 assessed by relative fluorescence intensity were 0.84 and 10.54, respectively, and were 1.61 and 4.00 in corresponding para-cancer tissues, respectively. There was a significant difference between MTS1 and COX-2 expressions in cancer and corresponding para-cancer tissues (P <0.05). The differences of MTS1 and COX-2 expression of different ages, pathological types, tumor sizes or clinical stages of the breast cancer patients were not significant (P > 0.05). The MTS1 and COX-2 expressions were 1.12 and 5.94, respectively, in lymph node metastasis positive patients, and 0.79 and 13.05, respectively, in lymph node metastasis negative patients. The differences were significant (P <0.05). CONCLUSION: The preliminary research results suggest that MTS1 and COX-2 gene expressions play fairly important role in tumorigenesis and progression of breast cancers. MTS1 and COX-2 protein expressions have correlation with lymph node metastasis. This study provides theoretical basis for use of COX-2 selective inhibitors in prevention and treatment for breast cancer patients.

[Inhibitory and apoptosis regulating effects of adriamycin on different human breast cancer cell lines].

OBJECTIVE: To investigate the inhibitory and apoptosis regulating effects of adriamycin (ADM) on different human breast cancer cell lines and to evaluate the value of apoptosis in breast cancer treatment. METHODS: Human breast cancer cells of the lines Bcap37 and MDA-MB-231 were cultured. ADM of different concentrations was added into the culture fluid. MTT method was used to detect the inhibition rate. Flow cytometry was used to detect the proliferation and apoptosis of the cells. To examine the expression of apoptosis-related molecules: Fas, mutant p53, and Bcl-2 proteins. RESULTS: ADM inhibited the proliferation of Bcap37 cells and MDA-MB-231 cells dose and time-dependently, however, the inhibitory effect of ADM was stronger on the Bcap37 cells than on the MDA-MB-231 cells. After being treated by ADM the expression of Fas was increased and the expression of Bcl-2 was decreased in the Bcap37 cells. However, after being treated by ADM the expressions of Fas, Bcl-2, and mutant p53 in the MDA-MB-231 cells remained almost unchanged. Treated by ADM for 24 hours the apoptotic rate of the Bcap37 cells was increased from 0% to 5.8% (P < 0.05), however, no apoptosis was detected in the MDA-MB-231 cells after treatment of ADM at any time pint. CONCLUSION: With different molecular and biological characteristics, different breast cancer lines are different in chemosensitivity and drug-resistance, which are related to their apoptotic abilities induced by chemotherapeutic drugs.