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Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2α is a potent oncogenic stimulus, but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate KrasG12D and delete Hif2α solely within the pancreas. Surprisingly, loss of Hif2α in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of β-catenin and SMAD4. The relationship among HIF2α, β-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2α resulted in reduced β-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and β-catenin. Cancer Res; 73(15); 4781–90. ©2013 AACR.

Supplementry Figure 4 - PDF file 812K, HIF2� promotes B-catenin and Smad4 expression

Supplementary Figure 2 - PDF file 2100K, Normal pancreas development in Ptf1Cre;Hif2�f/f mice

Supplementary Figure 5 - PDF file 5613 K, Loss of Smad4 in PKH2 mPanINs

Supplementary Materials and Methods- PDF file 100K, Additional experimental procedures including Generation of Hif2�-floxed mouse line, Tissue processing and Immunostaining, Western Blot, and Small Interfering RNA transfection

Supplementary Figure 1 - PDF file 2170K, Generation of the Hif2�-floxed strain, and validation of Hif2� inactivation in the pancreas

Supplementary Tables S1-S2 - PDF file 73K, List of primary antibodies, along with the sources and working dilutions (S1); primers used in RT-PCR analyses (S2)

Supplementary Figure and Table Legends�- PDF file 93K, Legend for Supplemental Tables S1-S2 and Supplemental Figures S1-S5

Under normoxia, hypoxia inducible factor (HIF) α subunits are hydroxylated by PHDs (prolyl hydroxylase domain proteins) and subsequently undergo polyubiquitylation and degradation. Normal embryogenesis occurs under hypoxia, which suppresses PHD activities and allows HIFα to stabilize and regulate development. In this Primer, we explain molecular mechanisms of the oxygen-sensing pathway, summarize HIF-regulated downstream events, discuss loss-of-function phenotypes primarily in mouse development, and highlight clinical relevance to angiogenesis and tissue repair.

Tight junctions (TJs) form the structural basis of retinal pigment epithelium (RPE) barrier functions. Although oxidative stress contributes to age-related macular degeneration, it is unclear how RPE TJ integrity is controlled by redox balance. In this study, we investigated the protective roles of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor, and heme oxygenase-1 (HO1), a heme-degrading enzyme encoded by the NRF2 target gene HMOX1.ARPE19 cell cultures and mice, including wild-type, Nrf2-/-, and RPE-specific NRF2-deficient mice, were treated with chemicals that impose oxidative stress or impact heme metabolism. In addition, NRF2 and HO1 expression in ARPE19 cells was knocked down by siRNA. TJ integrity was examined by anti-zonula occludens-1 staining of cultured cells or flatmount RPE tissues from mice. RPE barrier functions were evaluated by transepithelium electrical resistance in ARPE19 cells and immunofluorescence staining for albumin or dextran in eye histological sections.TJ structures and RPE barrier functions were compromised due to oxidant exposure and NRF2 deficiency but were rescued by HO1 inducer. Furthermore, treatment with HO1 inhibitor or heme precursor is destructive to TJ structures and RPE barrier properties. Interestingly, both NRF2 and HO1 were upregulated under oxidative stress, probably as an adaptive response to mitigate oxidant-inflicted damages.Our data indicate that the NRF2-HO1 axis protects TJ integrity and RPE barrier functions by driving heme degradation.

In mice, retinal vascular and astrocyte networks begin to develop at birth, expanding radially from the optic nerve head (ONH) towards the retinal periphery. The retinal vasculature grows towards the periphery ahead of differentiated astrocytes, but behind astrocytic progenitor cells (APCs) and immature astrocytes. Endothelial cell specific Vegfr-2 disruption in newborn mice not only blocked retinal vascular development but also suppressed astrocytic differentiation, reducing the abundance of differentiated astrocytes while causing the accumulation of precursors. By contrast, retinal astrocytic differentiation was accelerated by the exposure of wild-type newborn mice to hyperoxia for 24 hours, or by APC specific deficiency in hypoxia inducible factor (HIF)−2α, an oxygen labile transcription factor. These findings reveal a novel function of the retinal vasculature, and imply that in normal neonatal mice, oxygen from the retinal circulation may promote astrocytic differentiation, in part by triggering oxygen dependent HIF-2α degradation in astrocytic precursors.

Metabolic gene variants, smoking, and alcohol consumption are important upper digestive tract cancer (UDTC) risk factors. However, the gene-gene and gene-environment interactions remain unclear. A case-control study in a high incidence area for upper digestive tract cancer was conducted in China. DNA was extracted from buffy coat samples for PCR or PCR-restriction fragment length polymorphism. Smoking and alcohol drinking status was determined by questionnaires. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the associations. After adjusting for confounding factors, smoking increased esophageal cancer (EC), gastric cardia cancer (GCC) and gastric antral carcinoma (GAC) risk by 3.594, 4.658, and 3.999-fold, respectively. Alcohol consumption increased EC, GCC and GAC risk by 1.953, 2.442 and 1.765-fold, respectively. The cytochrome P4501A1 (CYP1A1) rs4646903 T>C polymorphism increased GCC risk, the cytochrome P4502E1 (CYP2E1) rs2031920 C>T polymorphism increased EC risk, while the GSTM1 null genotype decreased EC risk. An association existed between the following: CYP1A1 rs4646903 and smoking in EC, GCC and GAC; CYP1A1 rs4646903 and alcohol consumption in EC and GCC; CYP2E1 rs2031920 and smoking in EC, GCC and GAC and CYP2E1 rs2031920 and alcohol consumption in EC and GCC. No association was observed between CYP1A1 and CYP2E1. The glutathione S-transferase mu 1 (GSTM1) null genotype decreased EC risk (OR=0.510). Smoking/drinking are upper digestive tract cancer risk factors. The CYP1A1 rs4646903 and CYP2E1 rs2031920 polymorphisms were risk factors of GCC or EC, and the GSTM1 null genotype may serve a protective role against EC. The results of the present study indicated that gene-environment interactions increase the risk of UDTC.

Vascular pruning is crucial for normal development, but its underlying mechanisms are poorly understood. Here, we report that retinal vascular pruning is controlled by the oxygen-sensing mechanism in local astrocytes. Oxygen sensing is mediated by prolyl hydroxylase domain proteins (PHDs), which use O(2) as a substrate to hydroxylate specific prolyl residues on hypoxia inducible factor (HIF)-α proteins, labeling them for polyubiquitylation and proteasomal degradation. In neonatal mice, astrocytic PHD2 deficiency led to elevated HIF-2α protein levels, expanded retinal astrocyte population and defective vascular pruning. Although astrocytic VEGF-A was also increased, anti-VEGF failed to rescue vascular pruning. However, stimulation of retinal astrocytic growth by intravitreal delivery of PDGF-A was sufficient to block retinal vascular pruning in wild-type mice. We propose that in normal development, oxygen from nascent retinal vasculature triggers PHD2-dependent HIF-2α degradation in nearby astrocytic precursors, thus limiting their further growth by driving them to differentiate into non-proliferative mature astrocytes. The physiological limit of retinal capillary density may be set by astrocytes available to support their survival, with excess capillaries destined for regression. This article has an associated ‘The people behind the papers’ interview.

We quantified the serum levels of 34 cytokines/chemokines in 30 patients with SARS-CoV-2 infection. Elevated levels of IP-10 and IL-7 were detected in the acute and convalescent stages of the infection and were highly associated with disease severity.

Piwi-interacting RNAs (piRNAs) dysregulation occurs frequently in extensive cancers. However, there was no report about piRNA expression in esophageal cancer (EC). In this study, the expression levels of piR-823 and DNMT1, DNMT3A, DNMT3B were detected in 54 pairs of ESCC tissues and adjacent normal tissues using the quantitative real-time polymerase chain reaction method. Pearson's chi-squared test and receiver operating characteristic curves were established to evaluate the diagnostic and prognostic value of piR-823 in ESCC. Spearman's correlation analysis was used to evaluate the association between piR-823 and DNMTs. We found that piR-823 was significantly upregulated in ESCC tissues compared with matched normal tissues (P = 0.0213), the level of piR-823 was significantly associated with lymph node metastasis (P = 0.042). The ROC curve analysis of piR-823 expression level yielded an area under the ROC curve value of 0.713 (P = 0.0001). DNMT3B was upregulated in ESCC tissues compared with matched normal tissues (P = 0.0286). There was an obvious positive correlation between piR-823 and DNMT3B expression (r = 0.6420, P < 0.0001). In conclusion, for the first time, we provided evidence about piRNA expression in EC. piRNA-823 and DNMT3B were both upregulated in ESCC and positively correlated with each other, suggesting the tumor oncogenic role of piR-823 in ESCC to epigenetically induce aberrant DNA methylation through DNMT3B. In addition, piRNA-823 showed high specificity in detecting ESCC and higher piRNA-823 level indicated higher risk of lymph node metastasis, suggesting its diagnostic and prognostic biomarker potential.

To investigate the clinical characteristics and clinical prognostic factors of patients with acute lymphoblastic leukemia (ALL).Ninety-six ALL patients in our hospital from June 2012 to August 2014 were selected and their clinical data were collected. The related clinical data of patients were recorded, and the relation between clinical characteristics and therapeutic efficacy was analyzed. The COX analysis was used to reveal the risk factors affecting the patient's OS and DFS time.Among 96 ALL patients, 65 patients achieved complete remission (CR) after treatment. The age, immunophenotype, central nervous system leukemia (CNSL) and peripheral blood WBC count correlated with complete remission (P0.05). The age, WBC count, platelet level, immune typing and consolidation therapy were the prognostic factors (P0.05), the 2 year OS rate was influenced by age, WBC count, CD34 and consolidation therapy (P0.05), the 2 year DFS rate was influenced by age, CD34 and consolidation therapy (P0.05).Age, WBC counts, CD34 and consolidated treatment after remission are prognostic factors for ALL patients, which has guiding significance for clinical treatment of ALL.

In model of image-retrieval based on bag-of-features, a large number of information is lost during the process of quantizing the high-dimensional SIFT features as visual words. It leads to the teeming of errors matching feature points. To address this problem, this paper couples the color information into the BoF model as a complement to sift features, two different features are extracted to represent the same interest region and a visual pair is obtained by quantizing the descriptor pair with two independent codebooks. What’s more, we weight similarity degree of images by using the saliency area of image to decrease the semantic gap between low-level features and high-level expressions. We show that such an approach can significantly outperform matching results compared with traditional model of bag-of-features on Holiday dataset. Furthermore, our strategy of weighting based saliency further improved our performance in image-retrieval.

To explore the correlation of Th17 cell rate and IL-17 level with pathogenetis of multiple myeloma(MM).Forty-five cases of MM were enrolled in MM group, while 45 healthy volunteers were selected in control group. The rate of Th17 cells, levels of IL-17 and β2-microglobulin(β2-MG) in patients subgrouping according to ISS staging and treatment were detected by using flow cytometer and IL-17 assay kit. The correlation of Th17 cell rate and IL-17 level with MM was analyzed.The rate of Th17 cells and level of IL-17 in MM group were higher than those in control group(P0.05), the rate of Th17 cells and level of IL-17 in ISS III stage patients were higher than those in ISS I and II stage patients(P0.05); the rate of Th17 cells and level of IL-17 in ISS I and ISS II stage patients were not significant difference (P0.05); the rate of Th17 cells and level of IL-17 in firstly treated, retreated/refractory patients were significantly higher than those in patients with effective treatment(P0.05), while the rate of Th17 cells and level of IL-17 between firstly treated patients and retreated/refractory patients were not significant difference (P0.05). The Th17 rate and IL-17 level in MM patients positively correlated with β2-MG level (r=0.422, r=0.416, P0.05).The obvious increase of Th17 rate, IL-17 and β2-MG levels closely relates with pathogenesis of MM. The Th17 rate and IL-17 level may be used as important evidence for evaluation of ISS stage and therapeutic efficacy of MM.

Background: Our previous studies demonstrate that the major histocompatibility complex (MHC) is associated with the progression of esophageal squamous cell carcinoma (ESCC). HLA-DQA1, which belongs to the MHC Class II family, may be a potential biomarker in ESCC progression. However, the association between HLA-DQA1 and ESCC in high-incidence area of northern China has not been well characterized. The purpose of this study is to investigate the relationship of HLA-DQA1 expression with the progression and prognosis of ESCC. Methods: We analyzed the expression profiles of HLA-DQA1 in esophageal cancer (EC) samples in the TCGA database and validated HLA-DQA1 expression by immunohistochemistry, western blotting, and quantitative reverse-transcription polymerase chain reaction in matched EC and normal tissues, respectively. The correlation between HLA-DQA1 expression and clinicopathologic characteristics of ESCC was further analyzed. Result: Immunohistochemical analysis indicated that the expression level of HLA-DQA1 in ESCC tissues was significantly higher than the matched normal tissues (P 4 cm were associated with higher HLA-DQA1 expression levels. A prognostic significance of HLA-DQA1 was also found by the Log-rank method, in which high expression of HLA-DQA1 was correlated with a shorter overall survival time. The receiver operating characteristic (ROC) curve analysis yielded the area under the ROC curve value of 0.693. Univariate and multivariate analyses also suggest that high expression of HLA-DQA1 is a potential indicator for poor prognosis of ESCC. Conclusions: Our results demonstrate that HLA-DQA1 plays an important role in ESCC progression and may be a biomarker for ESCC diagnosis and prognosis, as well as a potential target for the treatment of patients with ESCC.

To study the clinical features of of patients with primary central nervous system lymphoma(PCNSL) and their influence on prognosis.Forty-two cases of PCNSL hospitallized in our hospital from January 2012 to December 2015 were selected, and the laboratory analysis, imaging examination, bone marrow analysis and pathological examination all were performed, 26 cases were treated by lumbar puncture combined with intrathecal injection of drugs (Ara C, dexamethason and methotrexate), 8 cases were treated by methotrexate combined with rituximab, 8 cases voluntanly abandon treatment after being diagnosed as PCNSL.Headache accrued in 12 cases, diplopia in 2 cases, dizziness in 6 cases, limb weakness in 10 cases, amnesia in 2 cases, inhibited speech in 4 cases.Out of 42 patients 4 cases of peripheral T cell lymphoma, 38 cases of B cell lymphoma; 30 cases of multiple lesions, 12 cases of solitary lesions, 8 cases of corpus callosum, 8 cases of thalamus, 8 cases of frontal lobe, parietal lobe, temporal lobe, thalamus and other lesions, 2 cases of hydrocephalus, 2 cases of cerebral hemorrhage; and the patients HIV were negative. 8 cases erythrocyte sedimentation rate were faster, IgG, IgE and IgM levels increased to varying degrees in 42 cases, and the blood routine, liver function and blood coagulation examinations showed normal; There was no significant difference in the influence of the lumbar injection, methotrexate dose, radiation therapy, and hematopoietic stem cell transplantation on survival time(P0.05); but there was significant difference in the influence of rituximab and number of lesions on survival time (P0.05); there were significant differences in the effects of age and protein content in cerebrospinal fluid on therapeutic effecacy(P0.05).There is no significant difference in the imaging examination and clinical manifestation between PCNSL and other intracranial tumors. The lumbar puncture is an effective way to identify, the age, cerebrospinal fluid protein and the number of lesions are the adverse factors influencing the prognosis.

The dynamic range of the luminance of the scenes surrounding us are mostly very wide in all time of a day. High performance cameras were designed to capture these luminance with longer digits in their pixels. However, conventional displays can only render pixels with eight bits per channel, making the devices the bottleneck among the whole pipeline. As an effort to narrow this gap, this paper presents an improved strategy based on existing tone reproduction algorithms. It aims to provide good luminance range compression while preserving fine details of the contents. Experiments demonstrate that the presented algorithm can be successfully applied to the rendition of both natural and synthesized scenes, with high dynamic range or low radiance.

To explore the clinical value of arsenious acid (H3AsO3) for treating patients with acute promyelocytic leukemia (APL).A total of 86 patients with APL were randomly divided into experimental group (43 cases) and control group (43 cases). The control group was treated by all trans retinoic acid combined with chemotherapy, the experimental group were treated by arsenous acid on the basis of the control group.The overall response rate (ORR) in experimental group (100.00%) was significantly higher than that in control group (88.37%) (P0.05). The time of returm to complete remission in experimental group (30.86 ± 4.34) was better than that in control group (42.42 ± 7.10) d (P0.05). The time of return to normal levels of peripheral WBC count (20.86 ± 9.28) × 10⁹/L, hemoglobin count (68.62 ± 14.97) g/L and thrombocyte count in experimental group obviously less than that in control group (P0.05). The rates of high white blood syndrome (HWBS), disseminated intravascular coagulation (DIC) in experimental group were lower than that in control group (P0.05). The survival rates of 2 and 3 years in experimental group were higher than that in control group (P0.05). The recurrence rate after treatment in experimental group was lower than that in control group (P0.05). The application of arsenious acid was main factor for patients survival (P0.05).Arsenious acid can improve the clinical efficacy for the patients with acute promyelocytic leukemia, and reduce the complication, therefore it is worthy of application in clinic.