Background It has been discovered that Janus kinase 2 ( JAK2 ) exon12 mutations lead to the polycythemia vera (PV) phenotype, while somatic mutations of calreticulin ( CALR ) are associated with essential thrombocythemia (ET) or primary myelofibrosis. In this article, we report a case of ET with coexistence of JAK2 exon12 and CALR mutations. The objective of this study was to elucidate the pathogenicity mechanism of a JAK2 exon12 mutation ( JAK2 N533S) and the role of the coexistence of mutations on the hematological phenotype. Methods We designed a colony analysis of tumor cells obtained from this patient, and attempted to identify mutant genes using DNA from hair follicles. Mutation impairment prediction and conservative analysis were conducted to predict the mutation impairment and structure of JAK2 N533S. In addition, we conducted a functional analysis of JAK2 N533S by constructing Ba/F3 cell models. Results Three distinct tumor subclones, namely JAK2 N533S het+ / CALR type1 het + , JAK2 N533S het+ / CALR wt , and JAK2 N533S het+ / CALR type1 hom + , were identified from the 17 selected erythroid and 21 selected granulocyte colonies. The analysis of hair follicles yielded positive results for JAK2 N533S. According to the bioinformatics analysis, JAK2 N533S may exert only a minor effect on protein function. Functional studies showed that JAK2 N533S did not have a significant effect on the proliferation of Ba/F3 cells in the absence of interleukin-3 (IL-3), similar to wild-type JAK2 . Notably, there were no increased phosphorylation levels of JAK2 -downstream signaling proteins, including signal transducer and activator of transcription 3 (STAT3) and STAT5, in Ba/F3 cells harboring the JAK2 N533S. Conclusion Our study revealed that the JAK2 N533S het+ / CALR type1 het+ subclone was linked to a significant expansion advantage in this patient, indicating that it may contribute to the development of the ET phenotype. We further demonstrated that JAK2 N533S, as a noncanonical JAK2 exon12 mutation, is a germline mutation that may not exert an effect on cell proliferation and protein function. These results and the present body of available data imply that certain noncanonical JAK2 mutations are not gain-of-function mutations leading to the development of myeloproliferative neoplasms.
This paper focuses on the problem of exponential stability analysis of delayed cellular neural networks (DCNNs) with impulsive effects. The time delay is allowed to be time varying. By utilizing the piecewise linear property of the activation function of DCNNs and applying Razumikhin-type analysis techniques, two different types of delay-independent criteria for exponential stability of DCNNs with impulsive effects are derived in terms of linear matrix inequalities. The first of the two criteria can be used to design a reduced-order impulsive control law for unstable DCNNs. The other criterion shows that local stability of the equilibriums of the original DCNNs can still be retained under certain impulsive perturbation. Two numerical examples illustrated the efficiency of the proposed method.
In order to promote preclinical and clinical applications of photoacoustic imaging, novel photoacoustic contrast agents are highly desired for molecular imaging of diseases, especially for deep tumor imaging. Here, perylene-3,4,9,10-tetracarboxylic diiimide-based near-infrared-absorptive organic nanoparticles are reported as an efficient agent for photoacoustic imaging of deep brain tumors in living mice with enhanced permeability and retention effect.
Pathogenesis of chronically developing alveolar echinococcosis (AE) is characterized by a continuous, granulomatous, periparasitic infiltration of immune cells surrounding the metacestode of Echinococcus multilocularis (E.multilocularis) in the affected liver. A detailed cytokine and chemokine profile analysis of the periparasitic infiltrate in the liver has, however, not yet been carried out in a comprehensive way all along the whole course of infection in E. multilocularis intermediate hosts. We thus assessed the hepatic gene expression profiles of 18 selected cytokine and chemokine genes using qRT-PCR in the periparasitic immune reaction and the subsequent adjacent, not directly affected, liver tissue of mice from day 2 to day 360 post intra-hepatic injection of metacestode. DNA microarray analysis was also used to get a more complete picture of the transcriptional changes occurring in the liver surrounding the parasitic lesions. Profiles of mRNA expression levels in the hepatic parasitic lesions showed that a mixed Th1/Th2 immune response, characterized by the concomitant presence of IL-12α, IFN-γ and IL-4, was established very early in the development of E. multilocularis. Subsequently, the profile extended to a combined tolerogenic profile associating IL-5, IL-10 and TGF-β. IL-17 was permanently expressed in the liver, mostly in the periparasitic infiltrate; this was confirmed by the increased mRNA expression of both IL-17A and IL-17F from a very early stage, with a subsequent decrease of IL-17A after this first initial rise. All measured chemokines were significantly expressed at a given stage of infection; their expression paralleled that of the corresponding Th1, Th2 or Th17 cytokines. In addition to giving a comprehensive insight in the time course of cytokines and chemokines in E. multilocularis lesion, this study contributes to identify new targets for possible immune therapy to minimize E. multilocularis-related pathology and to complement the only parasitostatic effect of benzimidazoles in AE.
Fluorescence imaging in the second near-infrared window (NIR-II) is a new technique that permits visualization of deep anatomical features with unprecedented spatial resolution. Although attractive, effectively suppressing the interference signal of the background is still an enormous challenge for obtaining target-specific NIR-II imaging in the complex and dynamic physiological environment. Herein, dual-pathological-parameter cooperatively activatable NIR-II fluorescence nanoprobes (HISSNPs) are developed whereby hyaluronic acid chains and disulfide bonds act as the "double locks" to lock the fluorescence-quenched aggregation state of the NIR-II fluorescence dyes for performing ultrahigh specific imaging of tumors in vivo. The fluorescence can be lit up only when the "double locks" are opened by reacting with the "dual smart keys" (overexpressed hyaluronidase and thiols in tumor) simultaneously. In vivo NIR-II imaging shows that they reduce nonspecific activitation and achieve ultralow background fluorescence, which is 10.6-fold lower than single-parameter activatable probes (HINPs) in the liver at 15 h postinjection. Consequently, these "dual lock-and-key"-controlled HISSNPs exhibit fivefold higher tumor-to-normal tissue ratio than "single lock-and-key"-controlled HINPs at 24 h postinjection, attractively realizing ultrahigh specificity of tumor imaging. This is thought to be the first attempt at implementing ultralow background interference with the participation of multiple pathological parameters in NIR-II fluorescence imaging.
The incidence of rectal carcinoma (RC) has been increasing recently, and becomes the second most common digestive tumors besides gastric cancer, with a rise in the incidence of RC in younger populations. The early diagnosis and treatment are thus critical for the improvement of survival rate and life quality of patients. Stomatin-like protein 2 (SLP-2) is a type of membrane factor, which is generally found highly expressed in various tumors. Collagen and calcium-binding EGF domain (CCBE1) belongs to lymphatic tube genesis factor. The regulatory role of SLP-2 gene on CCBE1 expression in RC tumor and adjacent lymphatic tube tissues, however, has not been studied.52 RC patients were recruited, and tumor and adjacent lymphatic tube tissues were collected. Real-time PCR, western blotting and immunohistochemistry (IHC) staining were used to analyze SLP-2 and CCBE1 expressions. Human lymphatic endothelial cells (LECs) were cultured in vitro and were assigned to control, scramble, and SLP-2 siRNA group. MTT assay was used to detect cell proliferation, while caspase 3 activity was detected.SLP-2 and CCBE1 levels were significantly elevated in tumor lymphatic tissues, compared to that in adjacent tissues. Statistically positive correlation between SLP-1 and CCBE2 was found (p<0.05). The downregulation of SLP-2 by siRNA inhibited cell proliferation, elevated caspase3 activity, and decreased CCBE1 expression (p<0.05 compared to control group).SLP-2 is up-regulated in RC lymphatic tissues, and is positively correlated with the level of CCBE1, which provides the academic the basis for the development of medicine targeting SLP-2 in the anti-rectal carcinoma therapy.
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