Clinical Value of Laboratory Biomarkers for the Diagnosis and Early Identification of Culture-Positive Sepsis in Neonates.

Background: Neonatal sepsis (NS) is an important cause of mortality and morbidity in newborn infants. However, early diagnosis of proven sepsis (culture-positive sepsis) is difficult. We aimed to define the best combination of biomarkers to diagnose the onset of neonatal sepsis, distinguish culture-positive neonatal sepsis and predict the time of confirmation of neonatal sepsis. Methods: This retrospective cohort study was conducted from January 2016 to December 2020. Clinical characteristics and laboratory results were collected from the electronic medical records. Hematology profiles and biochemical indices were obtained upon hospital admission. Multivariate logistic regression analysis was used to evaluate the risk factors and construct a nomogram. The performance of the nomogram was evaluated by receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Multivariable linear regression was used to identify the association between admission-to-diagnosis interval (ADI) and correlated variables. Results: Overall, 148 infants with neonatal sepsis (67 culture positive sepsis and 81 culture negative sepsis) and 150 controls were included. C-reactive protein (CRP) (p<0.001), platelets (PLT) (p=0.011), urea nitrogen (BUN) (p=0.001) and conjugated bilirubin (BC) (p=0.007) were independent risk factors for neonatal sepsis. The diagnostic nomogram based on CRP, PLT, BUN and BC showed excellent diagnostic accuracy for neonatal sepsis (AUC=0.928). The nomogram based on red blood cell distribution width (RDW) and mean platelet volume (MPV) was efficient in distinguishing proven neonatal sepsis from clinical sepsis, with an AUC of 0.700 in the training group and 0.689 in the validation group. Decision curve analysis (DCA) showed that the nomogram had good clinical utility. Multivariable analysis revealed gestational age, CRP, and MPV were significantly associated with admission-to-diagnosis interval in culture-positive sepsis (p < 0.001). Conclusion: Different combinations biomarkers were performant to diagnose the onset of neonatal sepsis, distinguish culture-positive neonatal sepsis, predict the time of confirmation, and aid in individual therapy.

A new 7-gene survival score assay for pancreatic cancer patient prognosis prediction.

Gene expression features that are valuable for pancreatic ductal adenocarcinoma (PDAC) prognosis are still largely unknown. We aimed to explore pivotal molecular signatures for PDAC progression and establish an efficient survival score to predict PDAC prognosis. Overall, 163 overlapping genes were identified from three statistical methods, including differentially expressed genes (DEGs), coexpression network analysis (WGCNA), and target genes for miRNAs that were significantly related to PDAC patients' overall survival (OS). Then, according to the optimal value of the cross-validation curve (lambda = 0.031), 7 non-zero coefficients (ARNTL2, DSG3, PTPRR, ANLN, S100A14, ANKRD22, and TSPAN7) were selected to establish a prognostic prediction model of PDAC patients. We further confirmed the expression level of 7 genes using RT-PCR, western blot, and immunohistochemistry staining in PDAC patients' tissues. Our results showed that the ROC curve of the 7-mRNA model indicated good predictive ability for 1- and 2-year OS in three datasets (TCGA: 0.71, 0.69; ICGC: 0.8, 0.74; GEO batch: 0.61, 0.7, respectively). The hazard ratio (HR) of the low-risk group had a similar significant result (TCGA: HR = 0.3723; ICGC: HR = 0.2813; GEO batch: HR = 0.4999; all P < 0.001). Furthermore, Log-rank test results in three cohorts showed that the 7-mRNA assay excellently predicted the prognosis and metastasis, especially in TNM stage I&II subgroups of PDAC. In conclusion, the strong validation of our 7-mRNA signature indicates the promising effectiveness of its clinical application, especially in patients with TNM stages I&II.

S100A16 induces epithelial-mesenchymal transition in human PDAC cells and is a new therapeutic target for pancreatic cancer treatment that synergizes with gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a poor 5-year survival rate of approximately 6%, mostly due to poor treatment response and early progression. The S100 gene family participates in various pathophysiological processes in various malignancies. S100A16 is a member of the S100 family, which is abnormally expressed in PDAC; however, its biological functions and mechanisms of action remain unclear. We analysed the Gene Expression Omnibus (GEO) public database and the gene ChIP data collected in our previous study of human PDAC cell line PANC-1 cocultured with M2 macrophages to identify differentially expressed genes (DEGs). Twenty-three overexpressed genes were identified by screening. Then, the selected genes were analysed using The Cancer Genome Atlas (TCGA) database to assess whether they have significant impact on the overall survival (OS) of PDAC patients. Of the 14 DEGs identified, S100A16 was associated with poor prognosis and was selected for further investigation; the results indicate that S100A16 is positively correlated with epithelial-mesenchymal transition (EMT)-related genes in the TCGA dataset. Subsequent in vitro and in vivo experiments demonstrated that S100A16 induces the EMT to promote the metastasis of human PDAC cells and that the effect is mediated by the enhanced expression of TWIST1 and activation of the STAT3 signalling pathway. The antitumour effect of gemcitabine (GEM) was enhanced in combination with S100A16 downregulation. In conclusion, our findings suggest that S100A16 is a novel potential therapeutic target for human PDAC treatment.

Comparison of "Lumipulse anti-Treponema pallidum" and "Architect Syphilis TP" and further examination.

BACKGROUND: Syphilis is a sexually transmitted disease caused by Treponema pallidum (TP) infection. In recent years, diagnostic reagents with fully automated immunoassay instruments have become mainstream. However, these positive screening tests with high sensitivity, which are performed with full automation, need confirmation by Treponema pallidum particle agglutination (TPPA) to be judged as positive. METHODS: We evaluated the diagnostic performance of Lumipulse G TP-N assay (Lumi-TP, Fujirebio Inc) in 223 preselected TP-positive samples and 1041 TP-negative samples, compared it with that of the TP gold standard test (TPPA) and Architect Syphilis TP test (Archi-TP, Abbott). RESULTS: The concordance rates for the results for the positive and negative samples between Lumi-TP and TPPA were 100%. On the other hand, the rates for the results between Archi-TP and TPPA were 100% for positive samples and 99.14% (1032/1041) for negative samples. Correlation tendency and rate between Archi-TP and Lumi-TP were 2.549 and 0.841 in positive specimens up to 160 detected values in Lumi-TP. However, the detection value of Archi-TP reached a plateau when it exceeded about 40. Furthermore, according to the comparison of each value obtained from Archi-TP and Lumi-TP with the strength of the staining of each line in the immune-chromatography assay kit, ESPLINE TP (Fujirebio Inc) for TP major antigens, Tp15-17 and TpN47, it was found that Lumi-TP obtained higher values than Archi-TP, particularly for TpN 47. CONCLUSIONS: Lumi-TP has high specificity and is useful not only for screening but also for determining the amount of anti-TP antibodies.

MicroRNA hsa-miR-623 directly suppresses MMP1 and attenuates IL-8-induced metastasis in pancreatic cancer.

Matrix metalloproteinase­1 (MMP1) participates in the metastasis of pancreatic cancer, and its expression can be regulated by endogenous microRNAs (miRs/miRNAs) and exogenous inflammatory factors. Whether miRNAs that potentially modulate MMP1 expression can also attenuate the pro­metastatic effects of its inducer on pancreatic cancer is yet to be completely elucidated. In the present study, a systematic analysis including in silico and bioinformatics analyses, a luciferase reporter assay and an RNA electrophoretic mobility shift assay (EMSA), were used to investigate the interaction between miRNAs and MMP1 mRNA. In addition, wound­healing assays, Transwell assays and xenograft nude mouse models were implemented to investigate the antitumor activities exerted by candidate miRNAs. As a result, hsa­miR­623 was screened as a candidate miRNA that interacts with the MMP1 transcript, and an inverse correlation between the expression of hsa­miR­623 and MMP1 was observed in human pancreatic cancer tissue samples. The EMSA confirmed that hsa­miR­623 was able to directly bind to its cognate target within the 3'­untranslated region of the MMP1 transcript. In addition, transfection of hsa­miR­623 mimics into PANC­1 and BXPC­3 cell lines markedly inhibited the expression of MMP1 at the mRNA and protein levels, and attenuated IL­8­induced MMP1 expression. hsa­miR­623 also decreased IL­8­induced epithelial­mesenchymal transition in PANC­1 and BXPC­3 cells via the underlying mechanism of inhibition of ERK phosphorylation. Consequently, hsa­miR­623 inhibited pancreatic cancer cell migration and invasion in vitro and metastasis in vivo. The results of the present study suggest that hsa­miR­623 represents a novel adjuvant therapeutic target to prevent metastasis in pancreatic cancer.

Secreted Frizzled-Related Protein 2 Is Associated with Disease Progression and Poor Prognosis in Breast Cancer.

PURPOSE: Secreted frizzled-related protein 2 (sFRP2) is a secreted protein associated with cancer drug resistance and metastasis. However, few studies have reported serum sFRP2 levels in breast cancer. We evaluated serum sFRP2 as a potential biomarker for breast cancer. METHODS: Serum sFRP2 concentrations were detected in 274 breast cancer patients along with 147 normal healthy controls by enzyme-linked immunosorbent assay (ELISA). Diagnostic significance was evaluated by area under the curve (AUC) analysis and the Youden index. Prognostic significance was determined by Kaplan-Meier survival method and univariate and multivariate Cox proportional hazard regression model analyses. RESULTS: Serum sFRP2 was elevated in breast cancer patients compared to normal healthy controls (P < 0.001). The sensitivity of sFRP2 in diagnosing breast cancer was 76.9% at a specificity of 76.6%. Elevated serum sFRP2 levels are associated with primary tumor size, TNM stage, and lymph node metastases. The Kaplan-Meier curves showed a significant association of serum sFRP2 with progression-free survival. The multivariate Cox analysis confirmed that high serum sFRP2 was an independent prognostic factor for poor prognosis (HR = 3.89, 95% CI = 1.95-7.68, P = 0.001). CONCLUSIONS: In conclusion, serum sFRP2 may serve as a potential biomarker for breast cancer diagnosis and prognostic evaluation.

Tumor-driven like macrophages induced by conditioned media from pancreatic ductal adenocarcinoma promote tumor metastasis via secreting IL-8.

Tumor-associated macrophages (TAMs) are abundant population of inflammatory cells which play an essential role in remodeling tumor microenvironment and tumor progression. Previously, we found the high density of TAMs was correlated with lymph node metastasis and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Therefore, this study was designed to investigate the mechanisms of interaction between TAMs and PDAC. THP-1 monocytes were the exposure to conditioned media (CM) produced by PDAC cells; then, monocyte recruitment and macrophage differentiation were assessed. CM from PDAC attracted and polarized THP-1 monocytes to tumor-driven like macrophages. mRNA expression cytokine profiling and ELISA identified the IL-8 secretion was increasing in tumor-driven like macrophages, and STAT3 pathway was involved. Addition of exogenous recombinant human IL-8 promoted PDAC cells motility in vitro and metastasis in vivo via upregulating Twist expression, which mediated epithelial-mesenchymal transition in cancer cells. What is more, IL-8 expression level in tumor stroma by immunohistochemical analysis was related to lymph node metastasis, the number of tumor CD68 but not CD163 positive macrophages and patient outcome. Taken together, these findings shed light on the important interplay between cancer cells and TAMs in tumor microenvironment and suggested that IL-8 signaling might be a potential therapeutic target for PDAC.

MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells.

The molecular mechanism of perineural invasion (PNI) is unclear, and insufficient detection during early-stage PNI in vivo hampers its investigation. We aimed to identify a cytokine paracrine loop between pancreatic ductal adenocarcinoma (PDAC) cells and nerves and established a noninvasive method to monitor PNI in vivo. Methods: A Matrigel/ dorsal root ganglia (DRG) system was used to observe PNI in vitro, and a murine sciatic nerve invasion model was established to examine PNI in vivo. PNI was assessed by MRI with iron oxide nanoparticle labeling. We searched publicly available datasets as well as obtained PDAC tissues from 30 patients to examine MMP1 expression in human tumor and non-tumor tissues. Results: Our results showed that matrix metalloproteinase-1 (MMP1) activated AKT and induced protease-activated receptor-1 (PAR1)-expressing DRG to release substance P (SP), which, in turn, activated neurokinin 1 receptor (NK1R)-expressing PDAC cells and enhanced cellular migration, invasion, and PNI via SP/NK1R/ERK. In animals, hind limb paralysis and a decreased hind paw width were observed approximately 20 days after inoculation of cancer cells in the perineurium. MMP1 silencing with shRNA or treatment with either a PAR1 or an NK1R antagonist inhibited PNI. MRI detected PNI as early as 10 days after implantation of PDAC cells. PNI also induced PDAC liver metastasis. Bioinformatic analyses and pathological studies on patient tissues corroborated the clinical relevance of these findings. Conclusion: In this study, we provided evidence that the MMP1/PAR1/SP/NK1R paracrine loop contributes to PNI during the early stage of primary tumor formation. Furthermore, we established a sensitive and non-invasive method to detect nerve invasion using iron oxide nanoparticles and MRI.

Serum human epididymis secretory protein 4 as a potential biomarker of renal fibrosis in kidney transplantation recipients.

BACKGROUND: Renal fibrosis remains an important cause of kidney allograft failure. The objective of this study was to evaluate the performance of serum human epididymis secretory protein 4 (HE4) as a biomarker for renal fibrosis in kidney transplant recipients. METHODS: A total of 103 kidney transplantation patients were enrolled in this study, and serum HE4 concentrations were detected using the chemiluminescent microparticle immunoassay. Renal biopsy was carried out, and histological findings were assessed by immunohistochemistry. RESULTS: Median serum HE4 concentrations were significantly increased in kidney transplant recipients (186.2 pmol/l, interquartile range [IQR] 125.6-300.2) compared with control subjects (34.3 pmol/l, IQR 30.4-42.3, p < 0.0001). Meanwhile, serum HE4 concentrations were significantly increased along with disease severity (p < 0.0001). In addition, we found serum HE4 concentrations to be strongly correlated with the severity of fibrosis (IF/TA 0, 1, 2, and 3: 114.3, 179.0, 197.8, and 467.8 pmol/l, respectively; p < 0.0001) and serum HE4 concentrations significantly correlated with HE4 tissue expression concentrations in renal biopsy. CONCLUSIONS: Serum HE4 was increased in kidney transplant recipients with decreased kidney function and renal fibrosis and was correlated with the severity of the disease, suggesting that HE4 has the potential to be used as a novel clinical biomarker for evaluating kidney function and predicting renal fibrosis in kidney transplant recipients.

KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer.

Oncogenic KRAS plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. However, the mechanism has not been clearly elucidated. RKIP is a tumor repressor, and loss of RKIP has been shown in PDAC. Here, we found that KRAS expression was inversely correlated with RKIP expression in PDAC fresh tissue regardless of the KRAS mutant status. The negative correlation between KRAS and RKIP was further confirmed in our PDAC tissue microarray. KRAS overexpression and RKIP downregulation were associated with poor clinical outcomes. Knockdown or overexpression of KRAS in PDAC cell lines robustly increased or decreased, respectively, RKIP protein and mRNA levels. Furthermore, the MAPK-ERK pathway was involved in the regulation of RKIP. KRAS-regulated RKIP expression, which in turn affected the expression of pivotal epithelial-mesenchymal transition (EMT) and apoptosis factors. The biological function of the KRAS-RKIP axis was demonstrated in human pancreatic cancer cells in vitro and in vivo. KRAS knockdown increased RKIP expression and inhibited metastasis and chemoresistance. Moreover, the feature of metastasis and chemoresistance was rescued in the KRAS-knockdown cells through the inhibition of RKIP by RNA interference. In conclusion, our studies demonstrate how KRAS inhibits the tumor suppressor RKIP, thus offering novel justification for targeting RKIP as a strategy to overcome KRAS-induced tumor metastasis and chemoresistance in PDAC.

Evaluation of serum CCL18 as a potential biomarker for ovarian cancer.

BACKGROUND: Early detection and differentiation diagnosis of a pelvic mass (PM) is crucial in improving the prognosis of patients with epithelial ovarian cancer (EOC). C-C motif chemokine ligand 18 (CCL18) was reported as a chemokine-mediated tumor-related inflammation that can be detected in serum and may correlate with cancer patients' prognosis. OBJECTIVE: We performed this study to investigate the relationship between CCL18 levels and clinical characteristics of EOC patients, and to explore their diagnostic and prognostic values. METHODS: CCL18 serum concentrations were detected by ELISA in 187 patients with EOC, 126 patients with benign PMs, and 118 healthy controls. CCL18 serum levels were analyzed in the context of patients' clinicopathological information, and ROC analyses were performed to determine the effect of CCL18 on distinguishing benign and malignant PMs. The ability of CCL18 to serve as an EOC biomarker was compared with CA125. Further survival analyses were carried out to assess the prognostic value of CCL18 in EOC patients. RESULTS: Mean serum CCL18 levels were elevated in benign PM patients and were even higher in EOC patients than in healthy controls; furthermore, high CCL18 expression was associated with worse International Federation of Gynecology and Obstetrics (FIGO) staging and predicted a poorer survival of the patient. When compared with CA125, although the sensitivity and negative predictive values (NPV) of serum CCL18 were lower, its specificity and positive predictive values (PPV) were higher. CONCLUSIONS: Serum CCL18 was elevated in patients with EOC and could serve as a new tumor biomarker, which also predicted a poor survival of the patient.

Development and Validation of a Serum Biomarker Panel for the Detection of Esophageal Squamous Cell Carcinoma through RNA Transcriptome Sequencing.

Serum tumor markers for the diagnosis of esophageal squamous cell carcinoma (ESCC) have low sensitivity. This study aims to identify new serum markers for ESCC diagnosis from RNA sequencing (RNA-seq) data. RNA-seq was performed using six pairs of ESCC and matched normal tissues. The candidates for ESCC were screened from the differentially expressed genes. The candidates were analyzed by ELISA from the serum of a test group and a validation group. Real-time PCR, Western blotting and immunohistochemistry were used to detect the expression of the candidates in tumor cell lines and tumor tissues. Ten genes were selected from the RNA-seq data. Serum levels of ADAM12, CHI3L1, MMP13 and SPP1 were significantly higher in the ESCC patients than in the healthy controls. A diagnostic model combining CHI3L1, MMP13, and SPP1 was established. The area under the curve (AUC) values for serum CHI3L1, MMP13, and SPP1 and the diagnostic model for discriminating ESCC patients from controls were 0.732, 0.881, 0.661 and 0.928, respectively. In the validation cohort, the AUC values were 0.753, 0.789, 0.696 and 0.843, respectively. Moreover, the AUC of the model for classifying patients with early ESCC was 0.918 in the test group and 0.857 in the validation group. Overexpression of CHI3L1, MMP13 and SPP1 was observed in the tumor cell lines and tissues. The diagnostic model composed of CHI3L1, MMP13 and SPP1 discriminates ESCC patients with high sensitivity. Our data highlight the potential of this diagnostic model for the noninvasive diagnosis of ESCC.

Impacts of increasing typhoons on the structure and function of a subtropical forest: reflections of a changing climate.

Due to their destructive and sporadic nature, it is often difficult to evaluate and predict the effects of typhoon on forest ecosystem patterns and processes. We used a 21-yr record of litterfall rates to explore the influence of typhoon frequency and intensity, along with other meteorological variables, on ecosystem dynamics in a subtropical rainforest. Over the past half century there has been an increasing frequency of strong typhoons (category 3; >49.6 m s-1; increase of 1.5 typhoons/decade) impacting the Fushan Experimental Forest, Taiwan. At Fushan strong typhoons drive total litterfall mass with an average of 1100 kg ha-1 litterfall typhoon-1. While mean typhoon season litterfall has been observed to vary by an order of magnitude, mean litterfall rates associated with annual leaf senescence vary by <20%. In response to increasing typhoon frequency, total annual litter mass increased gradually over the 21-year record following three major typhoons in 1994. Monthly maximum wind speed was predictive of monthly litterfall, yet the influence of precipitation and temperature was only evident in non-typhoon affected months. The response of this subtropical forest to strong typhoons suggests that increasing typhoon frequency has already shifted ecosystem structure and function (declining carbon sequestration and forest stature).

Co-delivery of microRNA-21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer therapy.

Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining downregulation of target genes with chemotherapy drugs, is expected to improve therapeutic effects. Therefore, we developed a combined therapy of microRNA-21 antisense oligonucleotides (ASO-miR-21) and gemcitabine (Gem) using a targeted co-delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. Polyethylene glycol-polyethylenimine-magnetic iron oxide NPs were used to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single-chain variable fragment (scFvCD44v6 ) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR-21 by ASO resulted in upregulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of epithelial-mesenchymal transition, which inhibited the proliferation and induced the clonal formation, migration, and invasion of pancreatic cancer cells in vitro. The co-delivery of ASO-miR-21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFvCD44v6 -PEG-polyethylenimine/ASO-magnetic iron oxide NP/Gem accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. Magnetic resonance imaging was used to observed tumor homing of NPs. These results imply that the combination of miR-21 gene silencing and Gem therapy using an scFv-functionalized NP carrier exerted synergistic antitumor effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.

A Nomogram based on Inflammatory Factors C-Reactive Protein and Fibrinogen to Predict the Prognostic Value in Patients with Resected Non-Small Cell Lung Cancer.

Purpose: This study aimed to develop an effective nomogram for predicting survival in surgically treated non-small cell lung cancer patients. Methods: We retrospectively evaluated 856 NSCLC in this study. Cox regression analyses were performed to identify significant prognostic factors for developing a nomogram to predict overall survival (OS). The discriminative ability was assessed with the concordance index (C-index). Results: On multivariate analysis of the 856 cohort, independent factors for survival were CRP, fibrinogen, tumor status, nodal status, distant metastasis and clinical stage, which were entered into the nomogram. The C-index of the established nomogram 0.720 (95% CI: 0.671-0.769) was higher than that of the seventh edition TNM staging system 0.689 (95% CI: 0.668-0.709) for predicting OS (P < 0.05). Compared with patients with low CRP levels (< 8.6 g/L) and low fibrinogen levels (< 3.7 g/L), patients with high CRP and fibrinogen levels had shorter OS. Subgroup analyses revealed that the nomogram was a favorable prognostic parameter in stage I-IV NSCLC (P < 0.05). Conclusion: A nomogram integrating CRP and fibrinogen, which could be convenient and feasible to obtain from the serum preoperatively, may assist in risk stratification for individual patient with resected NSCLC.

Ultrasound assisted, thermally activated persulfate oxidation of coal tar DNAPLs.

The feasibility of ultrasound assisted, thermally activated persulfate for effective oxidation of twenty 2-6 ringed coal tar PAHs in a biphasic tar/water system and a triphasic tar/soil/water system were investigated and established. The results indicate that ultrasonic assistance, persulfate and elevated reaction temperature are all required to achieve effective oxidation of coal tar PAHs, while the heating needed can be provided by ultrasonic induced heating as well. Further kinetic analysis reveals that the oxidation of individual PAH in the biphasic tar/water system follows the first-order kinetics, and individual PAH oxidation rate is primary determined by the mass transfer coefficients, tar/water interfacial areas, the aqueous solubility of individual PAH and its concentration in coal tar. Based on the kinetic analysis and experimental results, the contributions of ultrasound, persulfate and elevated reaction temperature to PAHs oxidation were characterized, and the effects of ultrasonic intensity and oxidant dosage on PAHs oxidation efficiency were investigated. In addition, the results indicate that individual PAH degradability is closely related to its reactivity as well, and the high reactivity of 4-6 ringed PAHs substantially improves their degradability.

Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro.

It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.