ADAM-17 is a poor prognostic indicator for patients with hilar cholangiocarcinoma and is regulated by FoxM1.

BACKGROUND: A-disintegrin and metalloproteinases (ADAMs) are members of a family of multidomain transmembrane and secreted proteins. Specific ADAMs are upregulated in human cancers and correlated with tumor progression and poor outcome, but rarely studied in human hilar cholangiocarcinoma (HC). This study aimed to explore the expression profiles of ADAMs and their potential underlying mechanisms promoting cancer progression. METHODS: mRNA expression of ADAM-9, - 10, - 11, - 12, - 15, - 17, - 28, and - 33 was analyzed in human hilar cholangiocarcinoma (HC) samples. Immunohistochemical (IHC) analysis was used to detect the expression of ADAM-10, - 17, - 28, and FoxM1 in HC. The regulation of ADAM-17 by FoxM1 and their functional study was investigated in vivo and in vitro. RESULTS: ADAM-10, - 17, and - 28 were upregulated in tumors compared with matched non-cancerous tissues. IHC analysis revealed increased expression of ADAM-10, - 17, and - 28 in HC cells, and ADAM17 seems to be an independent prognostic factor. ADAM-17 is regulated by FoxM1. A decrease in the expression of ADAM-17 by silencing FoxM1 led to an inhibition of cell proliferation, tumor growth, and the production of tumor necrosis factor α. IHC analysis showed co-expression of FoxM1 and ADAM-17 in HC specimens. CONCLUSIONS: The findings of the present study show an important role of the cross-talk among FoxM1, ADAM-17, and TNFa in HC development and progression.

ADAM-17 expression is enhanced by FoxM1 and is a poor prognostic sign in gastric carcinoma.

BACKGROUND: The ADAMs proteases are a multifunctional family of proteins, many of which participate in the pathogenesis of cancers. The expression and regulation of ADAMs has not yet been fully examined in gastric cancer. MATERIALS AND METHODS: Using reverse transcription-PCR, messenger RNA expression of ADAM-9, ADAM-10, ADAM-11, ADAM-12, ADAM-15, ADAM-17, ADAM-28, and ADAM-33 was detected in gastric cancer. ADAM-10, ADAM-17, ADAM-28, and FoxM1 expression in gastric cancer was detected by Western blot and immunohistochemistry. The correlation between ADAM-17 and FoxM1 was analyzed in vivo and in vitro. RESULTS: The messenger RNA levels of ADAM-9, ADAM-10, ADAM-15, ADAM-17, ADAM-28, and ADAM-33 were increased in tumor tissues compared with adjacent normal tissue, especially ADAM-10, ADAM-17, and ADAM-28. FoxM1 expression correlated significantly with ADAM-17 expression. FoxM1 regulates ADAM-17 expression in vivo and in vitro, which in turn influences proliferation and tumor growth of gastric cancer cells. Furthermore, Cox regression analysis revealed that FoxM1 and ADAM-17 are independent prognostic factors for patients with gastric cancer. CONCLUSIONS: These results indicate that overexpression of ADAMs may contribute to gastric cancer progression and that ADAM-17 is a downstream target of FoxM1. Overall, the present study highlights the potential for FoxM1 and ADAMs as potential therapeutic targets for patients with gastric carcinoma.

Reciprocal expression of p-AMPKa and p-S6 is strongly associated with the prognosis of gastric cancer.

Activation of AMP-activated protein kinase (AMPK) suppressed mammalian target of rapamycin (mTOR) pathway, resulting in impaired cancer cell proliferation. Two cohorts (50 and 1072 cases) of patients with resected gastric adenocarcinoma were enrolled in the study. Immunohistochemical staining for p-AMPKa, p-ACC, p-mTOR, p-S6, and p-4EBP1 was performed on the 50-patient cohort. Tissue microarray blocks containing samples from 1072 patients of Chinese ethnicity were used for the immunohistochemical detection of p-AMPKa and p-S6 levels. p-AMPK and p-ACC were frequently inactivated in both cohorts of gastric cancer samples, while p-mTOR, p-S6, and p-4EBP1 were frequently activated in the small cohort of gastric cancer. However, only levels of p-AMPKa and p-S6 were associated with the overall survival of gastric cancer patients. In the larger 1072-patient cohort, downregulation of p-AMPKa and upregulation of p-S6 were associated with tumor progression and were independent predictors of survival after resection of primary gastric cancer. Therefore, reciprocal expression of p-AMPKa and p-S6 may be promising prognostic biomarkers in patients with gastric cancer.

PKM2 regulates neural invasion of and predicts poor prognosis for human hilar cholangiocarcinoma.

BACKGROUND: The therapeutic and prognostic value of the glycolytic enzymes hexokinase, phosphofructokinase, and pyruvate kinase (PK) has been implicated in a variety of cancers, while their roles in treatment of and prognosis for hilar cholangiocarcinoma (HC) remain unclear. In this study, we determined the expression of PKM2 in and its impact on biology and clinical outcome of human HC. METHODS: The regulation and function of PKM2 in HC pathogenesis was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival. RESULTS: We found that expression of hexokinase 1 and the M2 splice isoform of PK (PKM2) was upregulated in HC tissues and that this expression correlated with tumor recurrence and outcome. PKM2 expression was increased in HC cases with chronic cholangitis as demonstrated by isobaric tags for relative and absolute quantification. High PKM2 expression was highly correlated with high syndecan 2 (SDC2) expression and neural invasion. PKM2 downregulation led to a decrease in SDC2 expression. Treatment with metformin markedly suppressed PKM2 and SDC2 expression at both the transcriptional and posttranscriptional levels and inhibited HC cell proliferation and tumor growth. CONCLUSIONS: PKM2 regulates neural invasion of HC cells at least in part via regulation of SDC2. Inhibition of PKM2 and SDC2 expression contributes to the therapeutic effect of metformin on HC. Therefore, PKM2 is an independent prognostic factor and potential therapeutic target for human HC.

Development and validation of serological dynamic risk score to predict outcome in gastric cancer with adjuvant chemotherapy: a multicentre, longitudinal, cohort study.

Background: Baseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests. Materials and methods: This was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters. Results: The Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy (P for interaction <0.0001). Compared with the low-low-low risk group, the low-low-high risk group of the long-term state chain (risk state at baseline, 6 months, 1 year) had the worse OS (HR, 6.91; 95%CI: 4.27, 11.19) and DFS (HR, 7.27; 95%CI: 4.55, 11.63). Conclusion: The dynamic risk score is an accurate and user-friendly serological risk assessment tool for predicting outcomes and assisting clinical decisions after gastrectomy.

Activation of SNAT1/SLC38A1 in human breast cancer: correlation with p-Akt overexpression.

BACKGROUND: SNAT1 is a subtype of the amino acid transport system A that has been implicated to play a potential role in cancer development and progression, yet its role in breast cancer remains unclear. In present study, we detected SNAT1 expression in breast cancers and explored its underlying mechanism in promoting breast carcinogenesis. METHODS: RT-PCR and Western blotting were performed to analyze the transcription and protein levels of SNAT1 in breast cancer cell lines and fresh tissues. Tissue microarray blocks containing breast cancer specimens obtained from 210 patients were constructed. Expression of SNAT1 in these specimens was analyzed using immunohistochemical studies. SNAT1 was down-regulated by SNAT1-shRNA in breast cancer cells and the functional significance was measured. RESULTS: SNAT1 was up-regulated in breast cancer cell lines and breast cancer tissues. Overexpression of SNAT1 was observed in 127 cases (60.5%). Expression of SNAT1 was significantly associated with tumor size, nodal metastasis, advanced disease stage, Ki-67, and ER status. Suppression of endogenous SNAT1 leads to cell growth inhibition, cell cycle arrest, and apoptosis of 4T1 cells and lowered the phosphorylation level of Akt. SNAT1 expression correlated significantly with p-Akt expression in human breast cancer samples. CONCLUSIONS: The cross-talk between Akt signaling and SNAT1 might play a critical role in the development and progression of breast cancer, providing an important molecular basis for novel diagnostic markers and new attractive targets in the treatment of breast cancer patients.

Toripalimab in combination with Anlotinib for unresectable hepatocellular carcinoma after SBRT: A prospective, single-arm, single-center clinical study.

Objective: Exposing tumor antigens to the immune system is the key to ensuring the efficacy of immunotherapy. SBRT is the main way to reveal the specifical antigens of tumors which can enhance the immune response. We aimed to explore the clinical efficacy and safety of Toripalimab combined with Anlotinib for uHCC after SBRT. Methods: This is a prospective, single-arm, explorative clinical study. uHCC patients with an ECOG PS score of 0-1, Child-Pugh class A or B, and BCLC stage B or C were included and treated with SBRT(8Gy*3) followed by 6-cycle combinational therapy with Toripalimab and Anlotinib. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of treatment-related adverse events (TRAEs). Continuous variables were presented as medians and ranges. Survivals were studied with the Kaplan-Meier method. Categorical data were expressed as n (percentage). Results: Between June 2020 and October 2022, a total of 20 patients with intermediate-advanced uHCC were enrolled. All cases had multiple intrahepatic metastases, or macrovascular invasion, or both, among whom 5 cases with lymph node or distant metastases. Until September 2022, the median follow-up time was 7.2 months (range, 1.1-27.7 months). Median survival time could not be assessed at the moment, based on iRecist, median PFS was 7.4 months (range, 1.1-27.7 months), ORR 15.0%, and DCR 50.0%. 14 patients experienced treatment-related adverse events with an incidence of 70%. The overall survival rates at 18 months and 24 months were 61.1% and 50.9%, respectively. And the progression-free survival rates were 39.3% and 19.7%. Conclusion: Exposure of specific antigens of HCC via SBRT may improve the efficacy of combinational therapy with Toripalimab and Anlotinib for uHCC with manageable adverse effects, which deserves further exploration. Clinical trial registration: www.clinicaltrials.gov, identifier ChiCTR2000032533.

Measurements of secondary organic aerosol formed from OH-initiated photo-oxidation of isoprene using online photoionization aerosol mass spectrometry.

Isoprene is a significant source of atmospheric organic aerosol; however, the secondary organic aerosol (SOA) formation and involved chemical reaction pathways have remained to be elucidated. Recent works have shown that the photo-oxidation of isoprene leads to form SOA. In this study, the chemical composition of SOA from the OH-initiated photo-oxidation of isoprene, in the absence of seed aerosols, was investigated through the controlled laboratory chamber experiments. Thermal desorption/tunable vacuum-ultraviolet photoionization time-of-flight aerosol mass spectrometry (TD-VUV-TOF-PIAMS) was used in conjunction with the environmental chamber to study SOA formation. The mass spectra obtained at different photon energies and the photoionization efficiency (PIE) spectra of the SOA products can be obtained in real time. Aided by the ionization energies (IE) either from the ab initio calculations or the literatures, a number of SOA products were proposed. In addition to methacrolein, methyl vinyl ketone, and 3-methyl-furan, carbonyls, hydroxycarbonyls, nitrates, hydroxynitrates, and other oxygenated compounds in SOA formed in laboratory photo-oxiadation experiments were identified, some of them were investigated for the first time. Detailed chemical identification of SOA is crucial for understanding the photo-oxidation mechanisms of VOCs and the eventual formation of SOA. Possible reaction mechanisms will be discussed.

Arterial chemoembolization for patients with hepatocellular carcinoma and elevated lactate dehydrogenase is associated with low survival: a cohort study.

PURPOSE: Serum lactate dehydrogenase (LDH) concentration has been used for the evaluation and prediction of prognosis of several tumors, including hepatocellular carcinoma (HCC). However, the relationship between changes in LDH after treatment (ΔLDH) and prognosis is still unclear. Herein, we aimed to determine this association in patients with HCC. METHODS: Multivariate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for HCC were obtained by Cox proportional hazard regression models. As for ΔLDH and overall survival (OS), the nonlinear relationship was evaluated through a restricted cubic spline regression analysis, and threshold effects were further calculated using a two-piece-wise Cox proportional hazard model. RESULTS: The study finally selected 749 patients with HCC treated by transarterial chemoembolization (TACE) for the secondary analysis. Considering the ΔLDH within ± 80 U/L group as the baseline, the risk of death in the ΔLDH ≥ 80 U/L group was significantly increased by 131% (95% CI: 1.74-3.06), and the risk of death in the ΔLDH ≤- 80 U/L group was increased by 24% (HR: 1.23, 95% CI: 0.99-1.55). However, this difference was not statistically significant. Furthermore, with ΔLDH = 0 (100 U/L) as the turning point, an upward U-shaped curve could be formed between ΔLDH and OS. After adjusting for confounders, ΔLDH still had a significant effect on the threshold of OS (P = 0.021). CONCLUSION: After TACE, with the increase of LDH index, HCC patients will be closely related to worse OS.

Phase 2 randomized controlled trial of intravenous or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 as first-line treatment of advanced gastric cancer.

Objective: We conducted a phase 2 trial to compare the safety and efficacy of intravenous paclitaxel or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 in untreated advanced gastric cancer. Methods: Participants with untreated advanced gastric cancer were randomly assigned (1:1:1) to: intravenous paclitaxel 135 mg/m2 or intraperitoneal paclitaxel 80 mg/m2 plus mFOLFOX6 omitting bolus fluorouracil; or mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil 400 mg/m2 bolus, fluorouracil 2,400 mg/m2 46-h continuous infusion). Treatment was every 14 days for up to 9 cycles followed by S-1 maintenance. The primary outcome was progression-free survival. Results: Of 90 enrolled participants, 30 in the intravenous paclitaxel group, 29 in the intraperitoneal paclitaxel group, and 30 in the mFOLFOX6 group were included in the analyses. The median progression-free survival was 6.52, 5.83, and 4.55 months, respectively, for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group. The hazard ratios were 0.56 (95% CI: 0.33-0.94; p = 0.026) and 0.56 (95% CI: 0.33-0.96; p = 0.037), respectively, for the intravenous paclitaxel group and the intraperitoneal paclitaxel group vs. the mFOLFOX6 group. The most common grade 3/4 adverse events for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group, respectively, were neutropenia (30.0%, 34.5%, 33.3%), diarrhea (13.3%, 20.7%, 13.3%), and leukopenia (10.0%, 13.8%, 10.0%). No treatment-related death occurred. Conclusion: The findings of this phase 2 trial suggest that adding intravenous paclitaxel or intraperitoneal paclitaxel to mFOLFOX6 for untreated advanced gastric cancer improved progression-free survival with manageable adverse events.

The effectiveness and safety of the rapid titration strategy of background controlled-release oxycodone hydrochloride for patients with moderate-to-severe cancer pain: A retrospective cohort study.

Background: Oxycodone hydrochloride is a semisynthetic narcotic analgesic agent. This study aimed to explore optimal titration strategy of controlled-release (CR) oxycodone hydrochloride in patients with cancer pain. Methods: 258 patients, who used regular strong opioids (morphine and CR oxycodone hydrochloride) for cancer pain across 25 three grade class hospitals in China during January 15th 2017 to April 30th 2017, were retrospectively studied. The patients were divided into 4 groups according to treatment regimens titrated. The pain remission rate and numeric rating scale (NRS) of cancer pain was recorded at 0, 12, 24, 36, 48, 60, 72 h after opioid titration. The incidence of adverse events (AEs) with therapy were also observed. Results: 12 h after treatment, pain remission rate of Group B, C and D was significantly higher (P < 0.001) than Group A. For the complete remission rate, there were also significant differences among the four groups (P < 0.001). No significant difference was found among four groups for pain remission rate at 24, 72 h after treatment. Multiple comparison of NRS scores showed that the both Group B and C varied significantly with Group D (P = 0.028, P = 0.05, respectively), showing superior analgesic effect over Group D. AEs were significantly different among groups (P < 0.01), with the most frequent AEs in Group A, lowest in Group B. Conclusion: The rapid titration strategy of background CR oxycodone hydrochloride was effectiveness and safety in patients with moderate-to-severe cancer pain.

Thermal desorption/tunable vacuum-ultraviolet time-of-flight photoionization aerosol mass spectrometry for investigating secondary organic aerosols in chamber experiments.

This paper describes thermal desorption/tunable vacuum-ultraviolet photoionization time-of-flight aerosol mass spectrometry (TD-VUV-TOF-PIAMS) for the real-time analysis of secondary organic aerosols (SOAs) in smog chamber experiments. SOAs are sampled directly from atmospheric pressure and are focused through an aerodynamic lens assembly into the mass spectrometer. Once the particles have entered the source region, they impact on a heater and are vaporized. The nascent vapor is then softly ionized by tunable VUV synchrotron radiation. TD-VUV-TOF-PIAMS was used in conjunction with the smog chamber to study SOA formation from the photooxidation of toluene with hydroxyl radicals. The ionization energies (IEs) of these SOA products are sometimes very different with each other. As the ideal photon source is tunable, its energy can be adjusted for each molecular to be ionized. The mass spectra obtained at different photon energies are then to be useful for molecular identification. Real-time analysis of the mass spectra of SOAs is compared with previous off-line measurements. These results illustrate the potential of TD-VUV-TOF-PIAMS for direct molecular characterization of SOAs in smog chamber experiments.

Dissociative photoionization of 1,3-butadiene: experimental and theoretical insights.

The vacuum-ultraviolet photoionization and dissociative photoionization of 1,3-butadiene in a region ∼8.5-17 eV have been investigated with time-of-flight photoionization mass spectrometry using tunable synchrotron radiation. The adiabatic ionization energy of 1,3-butadiene and appearance energies for its fragment ions, C(4)H(5)(+), C(4)H(4)(+), C(4)H(3)(+), C(3)H(3)(+), C(2)H(4)(+), C(2)H(3)(+), and C(2)H(2)(+), are determined to be 9.09, 11.72, 13.11, 15.20, 11.50, 12.44, 15.15, and 15.14 eV, respectively, by measurements of photoionization efficiency spectra. Ab initio molecular orbital calculations have been performed to investigate the reaction mechanism of dissociative photoionization of 1,3-butadiene. On the basis of experimental and theoretical results, seven dissociative photoionization channels are proposed: C(4)H(5)(+) + H, C(4)H(4)(+) + H(2), C(4)H(3)(+) + H(2) + H, C(3)H(3)(+) + CH(3), C(2)H(4)(+) + C(2)H(2), C(2)H(3)(+) + C(2)H(2) + H, and C(2)H(2)(+) + C(2)H(2) + H(2). Channel C(3)H(3)(+) + CH(3) is found to be the dominant one, followed by C(4)H(5)(+) + H and C(2)H(4)(+) + C(2)H(2). The majority of these channels occur via isomerization prior to dissociation. Transition structures and intermediates for those isomerization processes were also determined.

Metformin suppresses breast cancer growth via inhibition of cyclooxygenase-2.

Pre-clinical and on-going trials have indicated the advantage of using metformin as an anticancer drug alone or in combination with other chemotherapeutics for the treatment of patients with breast cancer. However, the mechanisms by which metformin attenuates tumorigenesis remain to be further elucidated. The present study investigated the anticancer effects of metformin in breast cancer and identified potential molecular targets of metformin using western blotting and immunohistochemical analysis. Metformin significantly decreased tumor cell proliferation in vitro and suppressed tumor growth in vivo. Moreover, it induced the activation of AMP-induced protein kinase and suppression of phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1 (p-4E-BP1), a downstream effector of the mTOR signaling pathway, and decreased cyclin D1 levels in in vitro and in vivo experimental models. Additionally, metformin inhibited cyclooxygenase (COX)-2 expression. Clinically, high expression levels of COX-2 and p-4E-BP1 in tissues of patients with breast cancer were significantly associated with enhanced lymphatic metastasis and distant metastasis. Thus, the current data suggested that metformin may have potential value as a synergistic therapy targeting both the COX-2 and mTOR signaling pathways.

A Five-gene Signature for Predicting the Prognosis of Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is a kind of tumor with high incidence and its treatment situation is still very difficult despite the constant renewal and development of treatment methods. OBJECTIVE: To assist the prognosis, monitoring and survival of CRC patients with a model. METHODS: In this study, we established a new prognostic model for CRC. Four groups of CRC data were accessed from the GEO database, and then differential analysis (logFoldChange>1, adjust- P<0.05) was carried out by using the limma package along with the RobustRankAggreg package used to identify the overlapping differentially expressed genes (DEGs). Univariate and multivariate Cox regression analyses were performed on the DEGs to screen the genes related to the patient's prognosis, and a five-gene prognostic prediction model (including RPX, CXCL13, MMP10, FABP4 and CLDN23) was constructed. Then, we further plotted ROC curves to evaluate the predictive performance of the five-gene prognostic signature in the TCGA data sets (the AUC values of 1, 3, 5-year survival were 0.68, 0.632, 0.675, respectively) and an external independent data set GSE2962 (the AUC values of 1, 3, 5-year survival were 0.689, 0.702, 0.631, respectively). RESULTS: The results showed that the model could effectively predict the prognosis of CRC patients, which provides a robust predictive model for the prognosis of CRC patients. CONCLUSION: The model could effectively predict the prognosis of CRC patients, which provides a robust predictive model for the prognosis of CRC patients.

S100 Calcium Binding Protein A10, A Novel Oncogene, Promotes the Proliferation, Invasion, and Migration of Hepatocellular Carcinoma.

Hepatocarcinogenesis is a highly complicated process that is promoted by a series of oncogenes. Our study aims to identify novel oncogenes promoting hepatocellular carcinoma (HCC) by bioinformatic analysis and experimental validation. Here, we reported that S100 calcium binding protein A10 (S100A10) was screened out as a potential novel oncogene in HCC by integrated analysis of OEP000321 dataset and the Cancer Genome Atlas (TCGA)-Liver-Cancer data. Furthermore, S100A10 was highly expressed in HCC samples and observably associated with patients' overall survival (OS). Overexpression of S100A10 in Hep3B and Huh-7 increased the cell proliferation, whereas downregulation of S100A10 in SK-Hep-1 and HepG2 cells reduced the cell viability to almost stop growing. In vivo tumor growth assays showed that S100A10-overexpressing Hep3B cells had a larger tumor size than control. Moreover, S100A10 overexpression promoted Hep3B cells migration and invasion, and S100A10 knockdown inhibited SK-Hep-1 cells migration and invasion, in vitro. In conclusion, it is demonstrated that S100A10 is a novel oncogene in HCC, indicating a possible novel therapeutic strategy of HCC.

Increased SNAT1 is a marker of human osteosarcoma and potential therapeutic target.

BACKGROUND: SLC38A1/SNAT1 has been found to play an essential role in human development, but its role in osteosarcoma (OS) has yet to be evaluated. The purpose of this study was to assess the expression of SLC38A1/SNAT1 in patients with OS, and further investigate the mechanisms by which it affects tumor growth and metastasis. METHODS: Tissue microarray blocks and immunohistochemical studies were carried out to assess the expression of SNAT1 in 165 OS specimens. Its correlation with clinicopathological characteristics was then analyzed. The function of SNAT1 in OS cells was investigated by silencing SNAT1 using SNAT1-shRNA in vitro and in vivo. RESULTS: SNAT1 was highly expressed in 85% OS and significantly closely associated with pulmonary metastasis. Patients with high SNAT1 expression survived for shorter periods than those with low SNAT1 expression. Suppression of endogenous SNAT1 led to inhibition of cell proliferation, cell colony formation, and cell migration in vitro, and retarded tumor growth in xenograft models. Silencing SNAT1 reduced expression of MMP9, vimentin, fibronectin, p-Akt, p-mTOR, and VEGF. CONCLUSIONS: Our results indicated that increased expression of SNAT1 is a common event in OS. SNAT1 played an essential role in the development and progression of osteosarcoma, which may serve as a prognostic and therapeutic marker of OS.

Divergent Evolution of Carbonaceous Aerosols during Dispersal of East Asian Haze.

Wintertime East Asia is plagued by severe haze episodes, characterized by large contributions of carbonaceous aerosols. However, the sources and atmospheric transformations of these major components are poorly constrained, hindering development of efficient mitigation strategies and detailed modelling of effects. Here we present dual carbon isotope (δ13C and Δ14C) signatures for black carbon (BC), organic carbon (OC) and water-soluble organic carbon (WSOC) aerosols collected in urban (Beijing and BC for Shanghai) and regional receptors (e.g., Korea Climate Observatory at Gosan) during January 2014. Fossil sources (>50%) dominate BC at all sites with most stemming from coal combustion, except for Shanghai, where liquid fossil source is largest. During source-to-receptor transport, the δ13C fingerprint becomes enriched for WSOC but depleted for water-insoluble OC (WIOC). This reveals that the atmospheric processing of these two major pools are fundamentally different. The photochemical aging (e.g., photodissociation, photooxidation) during formation and transport can release CO2/CO or short-chain VOCs with lighter carbon, whereas the remaining WSOC becomes increasingly enriched in δ13C. On the other hand, several processes, e.g., secondary formation, rearrangement reaction in the particle phase, and photooxidation can influence WIOC. Taken together, this study highlights high fossil contributions for all carbonaceous aerosol sub-compartments in East Asia, and suggests different transformation pathways for different classes of carbonaceous aerosols.

The prognostic potential and oncogenic effects of PRR11 expression in hilar cholangiocarcinoma.

PRR11 is a newly identified oncogene in lung cancer, yet its role in others tumors remains unclear. Gastrointestinal tissue microarrays were used to evaluate PRR11 expression and its association with clinical outcome was analyzed in patients with hilar cholangiocarcinoma. Overexpression of PRR11 was observed in esophageal, gastric, pancreatic, colorectal, and hilar cholangiocarcinoma. Expression of PRR11 correlated with lymph node metastasis and CA199 level in two HC patient cohorts. After an R0 resection, a high level of PRR11 expression was found to be an independent indicator of recurrence (P = 0.001). In cell culture, PRR11 silencing resulted in decreased cellular proliferation, cell migration, tumor growth of QBC939 cells. Microarray analysis revealed that several genes involved in cell proliferation, cell adhesion, and cell migration were altered in PRR11-knockout cells, including: vimentin (VIM), Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1), early growth response protein (EGR1), and System A amino acid transporter1 (SNAT1). Silencing PRR11 inhibited the expression of UCHL1, EGR1, and SNAT1 proteins, with immunoassays revealing a significant correlation among the levels of these four proteins. These results indicate that PRR11 is an independent prognostic indicator for patients with HC.