Anti-inflammatory control of human skin keratinocytes by targeting nuclear transport checkpoint.

Background: In the two common inflammatory skin diseases, Atopic Dermatitis (AD) and Psoriasis (Ps), keratinocytes (KCs) respond to immune insults through activation of proinflammatory transcription factors (TFs) and their translocation to the cell's nucleus. Therein, the TFs induce expression of genes encoding mediators of skin inflammation. The Nuclear Transport Checkpoint Inhibitors (NTCIs) were developed to regulate nuclear translocation of activated TFs, the essential step of inflammatory response.

Association of serum 25-hydroxyvitamin D concentration with all-cause and cause-specific mortality in hypertensive patients.

Background And Aims: To examine the association of serum 25-hydroxyvitamin D [25(OH)D] with all-cause mortality and disease-specific mortality in patients with hypertension.

Methods And Results: This cohort study included US adults in the National Health and Nutrition Examination Survey from 2007 to 2018. All-cause mortality and cause-specific mortality outcomes were determined by association with National Death Index records.

Event-triggered tracking control for switched nonlinear systems.

In this paper, we study the output tracking control problem based on the event-triggered mechanism for cascade switched nonlinear systems. Firstly, an integral controller based on event-triggered conditions is designed, and the output tracking error of the closed-loop system can converge to a bounded region under the switching signal satisfying the average dwell time. Secondly, it is proved that the proposed minimum inter-event interval always has a positive lower bound and the Zeno behavior is successfully avoided during the sampling process.

Activation of thousands of genes in the lungs and kidneys by sepsis is countered by the selective nuclear blockade.

The steady rise of sepsis globally has reached almost 49 million cases in 2017, and 11 million sepsis-related deaths. The genomic response to sepsis comprising multi-system stage of raging microbial inflammation has been reported in the whole blood, while effective treatment is lacking besides anti-microbial therapy and supportive measures. Here we show that, astoundingly, 6,237 significantly expressed genes in sepsis are increased or decreased in the lungs, the site of acute respiratory distress syndrome (ARDS).

Genomic control of inflammation in experimental atopic dermatitis.

Atopic Dermatitis (AD) or eczema, a recurrent allergic inflammation of the skin, afflicts 10-20% of children and 5% adults of all racial and ethnic groups globally. We report a new topical treatment of AD by a Nuclear Transport Checkpoint Inhibitor (NTCI), which targets two nuclear transport shuttles, importin α5 and importin β1. In the preclinical model of AD, induced by the active vitamin D analog MC903 (calcipotriol), NTCI suppressed the expression of keratinocyte-derived cytokine, Thymic Stromal Lymphopoietin (TSLP), the key gene in AD development.

Single-cell RNA sequencing reveals the role of immune-related autophagy in spinal cord injury in rats.

Spinal cord injury refers to damage to the spinal cord due to trauma, disease, or degeneration; and the number of new cases is increasing yearly. Significant cellular changes are known to occur in the area of spinal cord injury. However, changes in cellular composition, trajectory of cell development, and intercellular communication in the injured area remain unclear.

SRC Family Kinase Inhibition Targets YES1 and YAP1 as Primary Drivers of Lung Cancer and as Mediators of Acquired Resistance to ALK and Epidermal Growth Factor Receptor Inhibitors.

Purpose: The identification of novel oncogenic driver alterations and novel mechanisms of acquired resistance (AR) is the key for further development of personalized therapy. The current study investigates the potential role of amplification as a primary driver of tumorigenesis and of amplifications as mediators of AR to ALK and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).

Methods: Models of ectopic expression were established and characterized for YES1 and YAP1 in human bronchial epithelial cells and fusion-positive (ALK+) and -mutant lung adenocarcinoma cell lines.

The phosphate-solubilizing ability of and its effects on the growth of in phosphate-limiting conditions.

Microbes in soil can degrade insoluble inorganic and organic phosphorus, which are components of the soil phosphorus cycle and play an important role in plant growth. is a pioneer tree species used for afforestation in southern China and grows in poor, acidic soil. A shortage of available phosphorus in soil limits the growth of To alleviate this situation, it is necessary to improve soil fertility.

Monitoring Therapeutic Response and Resistance: Analysis of Circulating Tumor DNA in Patients With ALK+ Lung Cancer.

Introduction: Despite initial effectiveness of ALK receptor tyrosine kinase inhibitors (TKIs) in patients with ALK+ NSCLC, therapeutic resistance will ultimately develop. Serial tracking of genetic alterations detected in circulating tumor DNA (ctDNA) can be an informative strategy to identify response and resistance. This study evaluated the utility of analyzing ctDNA as a function of response to ensartinib, a potent second-generation ALK TKI.

Incidence and Outcomes of C5 Palsy and Axial Pain After Open-Door Laminoplasty or Laminectomy and Fusion: A Meta-Analysis.

Objective: C5 palsy and axial pain are significant factors affecting the quality of life after posterior cervical surgery; however, there has been no clear and supportive conclusion on which method is more suitable in a certain case. As a result, we compare the clinical outcomes, complication rates, and anatomical changes between open-door laminoplasty (ODL) and laminectomy and fusion (LF) for cervical spondylotic myelopathy. This is a systematic literature review and meta-analysis.

On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation.

Purpose: The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with -mutant lung cancer. Despite the development of highly selective third-generation inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in screens.

CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism.

CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44 cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the ability to self-regenerate when transplanted into immune-deficient mice. However, the exact role of CD44 in cancer stem cells remains unclear in part because CD44 exists in various isoforms due to alternative splicing.

PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner.

Background/aims: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells.

amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics.

In ∼30% of patients with -mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in an -mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen were , a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1.

Cracking the Code of Resistance across Multiple Lines of ALK Inhibitor Therapy in Lung Cancer.

In the setting of recent exciting clinical results and numerous ongoing trials, Gainor and colleagues explored mechanisms of acquired resistance to first- and second-generation ALK inhibitors in ALK-rearranged non-small cell lung cancer and found that an increased frequency and distinct spectrums of resistance mutations emerged with the more potent second-generation inhibitors. Their findings have important and immediate clinical implications as the resistance mutations detected impart differential sensitivities to available ALK inhibitors, thereby highlighting the need for sequential biopsies with molecular testing to determine the most effective treatment strategy upon disease progression. Cancer Discov; 6(10); 1084-6.

The adaptor CRADD/RAIDD controls activation of endothelial cells by proinflammatory stimuli.

A hallmark of inflammation, increased vascular permeability, is induced in endothelial cells by multiple agonists through stimulus-coupled assembly of the CARMA3 signalosome, which contains the adaptor protein BCL10. Previously, we reported that BCL10 in immune cells is targeted by the "death" adaptor CRADD/RAIDD (CRADD), which negatively regulates nuclear factor κB (NFκB)-dependent cytokine and chemokine expression in T cells (Lin, Q., Liu, Y.

Interaction of the transcription start site core region and transcription factor YY1 determine ascorbate transporter SVCT2 exon 1a promoter activity.

Transcription of the ascorbate transporter, SVCT2, is driven by two distinct promoters in exon 1 of the transporter sequence. The exon 1a promoter lacks a classical transcription start site and little is known about regulation of promoter activity in the transcription start site core (TSSC) region. Here we present evidence that the TSSC binds the multifunctional initiator-binding protein YY1.

CpG methylation at the USF-binding site mediates cell-specific transcription of human ascorbate transporter SVCT2 exon 1a.

SVCT2 (sodium-vitamin C co-transporter 2) is the major transporter mediating vitamin C uptake in most organs. Its expression is driven by two promoters (CpG-poor exon 1a promoter and CpG-rich exon 1b promoter). In the present study, we mapped discrete elements within the proximal CpG-poor promoter responsible for exon 1a transcription.

Regulation of the human ascorbate transporter SVCT2 exon 1b gene by zinc-finger transcription factors.

The sodium-dependent vitamin C transporter (SVCT) 2 is crucial for ascorbate uptake in metabolically active and specialized tissues. This study focused on the gene regulation of SVCT2 exon 1b, which is ubiquitously expressed in human and mouse tissues. Although the human SVCT2 exon 1b promoter does not contain a classical TATA box, we found that it does contain a functional initiator that binds Yin Yang-1 (YY1) and interacts with upstream Sp1/Sp3 elements in the proximal promoter region.

Transfer of ascorbic acid across the vascular endothelium: mechanism and self-regulation.

To determine how ascorbic acid moves from the bloodstream into tissues, we assessed transfer of the vitamin across the barrier generated by EA.hy926 endothelial cells when these were cultured on semipermeable filter supports. Ascorbate transfer from the luminal to the abluminal compartment was time dependent, inhibited by anion channel blockers and by activation of protein kinase A, but was increased by thrombin.

Cobalt-induced oxidant stress in cultured endothelial cells: prevention by ascorbate in relation to HIF-1alpha.

Endothelial cells respond to hypoxia by decreased degradation of hypoxia-inducible factor 1alpha (HIF-1alpha), accumulation of which leads to increased transcription of numerous proteins involved in cell growth and survival. Ascorbic acid prevents HIF-1alpha stabilization in many cell types, but the physiologic relevance of such effects is uncertain. Given their relevance for angiogenesis, endothelial cells in culture were used to evaluate the effects of ascorbate on HIF-1alpha expression induced by hypoxia and the hypoxia mimic cobalt.

Macrophage differentiation increases expression of the ascorbate transporter (SVCT2).

To determine whether macrophage differentiation involves increased uptake of vitamin C, or ascorbic acid, we assessed the expression and function of its transporter SVCT2 during phorbol ester-induced differentiation of human-derived THP-1 monocytes. Induction of THP-1 monocyte differentiation by phorbol 12-myristate 13-acetate (PMA) markedly increased SVCT2 mRNA, protein, and function. When ascorbate was present during PMA-induced differentiation, the increase in SVCT2 protein expression was inhibited, but differentiation was enhanced.

[Preparation of the polypeptide antibody against human transcriptional factors TFDP1 and TFDP3].

Aim: To prepare the polyclonal antibody against human transcriptional factors DP3(TFDP3) and DP1(TFDP1) and identify their reactivity and specificity.

Methods: Two totally different peptides between TFDP1 and TFDP3 were chosen as antigens to inoculate rabbits. The proteins from HEK293 cells were transiently transfcted with eukaryotic expression vectors of TFDP1 and TFDP3.

Ascorbic acid uptake and regulation of type I collagen synthesis in cultured vascular smooth muscle cells.

Background/aims: Vascular smooth muscle cells contribute both to the structure and function of arteries, but are also involved in pathologic changes that accompany inflammatory diseases such as atherosclerosis. Since inflammation is associated with oxidant stress, we examined the uptake and cellular effects of the antioxidant vitamin ascorbic acid in cultured A10 vascular smooth muscle cells.

Methods/results: A10 cells concentrated ascorbate against a gradient in a sodium-dependent manner, most likely on the sodium-dependent vitamin C transporter type 2 (SVCT2) ascorbate transporter, which was present in immunoblots of cell extracts.