Endothelial HIF2α suppresses retinal angiogenesis in neonatal mice by upregulating NOTCH signaling.

Prolyl hydroxylase domain (PHD) proteins are oxygen sensors that use intracellular oxygen as a substrate to hydroxylate hypoxia-inducible factor (HIF) α proteins, routing them for polyubiquitylation and proteasomal degradation. Typically, HIFα accumulation in hypoxic or PHD-deficient tissues leads to upregulated angiogenesis. Here, we report unexpected retinal phenotypes associated with endothelial cell (EC)-specific gene targeting of Phd2 (Egln1) and Hif2alpha (Epas1).

Magnetic resonance imaging radiomics-based prediction of clinically significant prostate cancer in equivocal PI-RADS 3 lesions in the transitional zone.

Purpose: This bi-institutional study aimed to establish a robust model for predicting clinically significant prostate cancer (csPCa) (pathological grade group ≥ 2) in PI-RADS 3 lesions in the transition zone by comparing the performance of combination models.

Materials And Methods: This study included 243 consecutive men who underwent 3-Tesla magnetic resonance imaging (MRI) and ultrasound-guided transrectal biopsy from January 2020 and April 2022 which is divided into a training cohort of 170 patients and a separate testing cohort of 73 patients. T2WI and DWI images were manually segmented for PI-RADS 3 lesions for the mean ADC and radiomic analysis.

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions.

Tailless and hypoxia inducible factor-2α cooperate to sustain proangiogenic states of retinal astrocytes in neonatal mice.

Tailless (TLX, an orphan nuclear receptor) and hypoxia inducible factor-2α (HIF2α) are both essential for retinal astrocyte and vascular development. Tlx-/- mutation and astrocyte specific Hif2α disruption in Hif2αf/f/GFAPCre mice are known to cause defective astrocyte development and block vascular development in neonatal retinas. Here we report that TLX and HIF2α support retinal angiogenesis by cooperatively maintaining retinal astrocytes in their proangiogenic states.

Dependence of Retinal Pigment Epithelium Integrity on the NRF2-Heme Oxygenase-1 Axis.

Purpose: 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.

Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy.

Immunotherapy has become the breakthrough strategies for treatment of cancer in recent years. The application of messenger RNA in cancer immunotherapy is gaining tremendous popularity as mRNA can function as an effective vector for the delivery of therapeutic antibodies on immune targets. The high efficacy, decreased toxicity, rapid manufacturing and safe administration of mRNA vaccines have great advantages over conventional vaccines.

Oxygen-sensing mechanisms in development and tissue repair.

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.

Serum IP-10 and IL-7 levels are associated with disease severity of coronavirus disease 2019.

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.

piR-823 demonstrates tumor oncogenic activity in esophageal squamous cell carcinoma through DNA methylation induction via DNA methyltransferase 3B.

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.

Association between polymorphisms in the genes, and smoking, alcohol and upper digestive tract carcinomas in a high-incidence area of northern China.

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.

Developmental vascular pruning in neonatal mouse retinas is programmed by the astrocytic oxygen-sensing mechanism.

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 as a substrate to hydroxylate specific prolyl residues on hypoxia inducible factor (HIF)-α proteins, labeling them for polyubiquitylation and proteasomal degradation.

High expression of HLA-DQA1 predicts poor outcome in patients with esophageal squamous cell carcinoma in Northern China.

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.

[Analysis of Prognostic Factors for 96 Patients with Acute Lymphoblastic Leukemia].

Objective: To investigate the clinical characteristics and clinical prognostic factors of patients with acute lymphoblastic leukemia (ALL).

Methods: 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.

Retinal Angiogenesis Regulates Astrocytic Differentiation in Neonatal Mouse Retinas by Oxygen Dependent Mechanisms.

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.

[Correlation of Th17 Cells and IL-17 Level in Multiple Myeloma Patients with Pathogenesis of Multiple Myeloma].

Objective: To explore the correlation of Th17 cell rate and IL-17 level with pathogenetis of multiple myeloma(MM).

Methods: 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.

[Clinicopathological Features of Primary Central Nervous System Lymphoma and Their Influence on Prognosis of Desease].

Objective: To study the clinical features of of patients with primary central nervous system lymphoma(PCNSL) and their influence on prognosis.

Methods: 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.

Results: 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.

[Values of Detecting the Levels of β2-MG, TNF-α, CRP, IL-6 in the Patients with Multiple Myeloma].

Objective: To explore the values of detecting the serum levels of β2-MG, TNF-α, CRP, IL-6 in the patients with multiple myeloma.

Methods: A total of 40 patents with multiple myeloma were included in the experiment group, and 40 healthy volunteers were selected as the control group. The levels of β2-MG, TNF-α, CRP and IL-6 were detected and compared in 2 groups, the different durie-salmon (DS) stages of β2-MG, TNF-α, CRP and IL-6 in the experiment group were analyzed.

[Clinical Value of Arsenous Acid for Treating Patients with Acute Promyelocytic Leukemia].

Objective: To explore the clinical value of arsenious acid (H3AsO3) for treating patients with acute promyelocytic leukemia (APL).

Methods: 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.

Hematological, hepatic, and retinal phenotypes in mice deficient for prolyl hydroxylase domain proteins in the liver.

Prolyl hydroxylase domain (PHD) proteins catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor 1α and 2α, tagging them for pVHL-dependent polyubiquitination and proteasomal degradation. In this study, albumin Cre (Alb(Cre))-mediated, hepatocyte-specific triple disruption of Phd1, Phd2, and Phd3 (Phd(1/2/3)hKO) promoted liver erythropoietin (EPO) expression 1246-fold, whereas renal EPO was down-regulated to 6.7% of normal levels.

Hypoxia inducible factor-2α regulates the development of retinal astrocytic network by maintaining adequate supply of astrocyte progenitors.

Here we investigate the role of hypoxia inducible factor (HIF)-2α in coordinating the development of retinal astrocytic and vascular networks. Three Cre mouse lines were used to disrupt floxed Hif-2α, including Rosa26(CreERT2), Tie2(Cre), and GFAP(Cre). Global Hif-2α disruption by Rosa26(CreERT2) led to reduced astrocytic and vascular development in neonatal retinas, whereas endothelial disruption by Tie2(Cre) had no apparent effects.

Improved vascular survival and growth in the mouse model of hindlimb ischemia by a remote signaling mechanism.

Deficiencies in prolyl hydroxylase domain proteins (PHDs) may lead to the accumulation of hypoxia-inducible factor-α proteins, the latter of which activate local angiogenic responses by paracrine mechanisms. Here, we investigate whether a keratinocyte-specific PHD deficiency may promote vascular survival and growth in a distantly located ischemic tissue by a remote signaling mechanism. We generated mice that carry a keratinocyte-specific Phd2 knockout (kPhd2KO) and performed femoral artery ligation.

PanIN-specific regulation of Wnt signaling by HIF2α during early pancreatic tumorigenesis.

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.

Elevated vascular endothelial growth factor receptor-2 abundance contributes to increased angiogenesis in vascular endothelial growth factor receptor-1-deficient mice.

Background: Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is a potential therapeutic target for cardiovascular diseases, but its role in angiogenesis remains controversial. Whereas germline Vegfr-1(-/-) embryos die of abnormal vascular development in association with excessive endothelial differentiation, mice lacking only the kinase domain appear healthy.

Methods And Results: We performed Cre-loxP-mediated knockout to abrogate the expression of all known VEGFR-1 functional domains in neonatal and adult mice and analyzed developmental, pathophysiological, and molecular consequences.

[The clinical features and perioperational managements of craniopharyngiomas in posterior fossa].

Objective: To investigate the clinical features and perioperational managements of craniophayngiomas located in posterior fossa.

Methods: Nine patients with craniopharyngioma situated in posterior fossa were included in the study. The clinical manifestations, neuroimage features, operational treatment, and perioperational managments were retrospectively analyzed.