The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL-derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is overexpressed in approximately 15% of adult and high-risk pediatric B-ALL that lack MLL, TCF3, TEL, and BCR/ABL rearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with the IGH locus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-offunction mutation that promotes constitutive dimerization and cytokine independent growth. A mutually exclusive subset harbors activating mutations in JAK2. In fact, all 22 B-ALLs with mutant JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 as the key scaffold for mutant JAK2 signaling in B-ALL. Expression of WT CRLF2 with mutant JAK2 also promotes cytokine independent growth that, unlike CRLF2 Phe232Cys or ligand-induced signaling by WT CRLF2, is accompanied by JAK2 phosphorylation. Finally, cells dependent on CRLF2 signaling are sensitive to small molecule inhibitors of either JAKs or protein kinase C family kinases. Together, these findings implicate CRLF2 as an important factor in B-ALL with diagnostic, prognostic, and therapeutic implications.uring the past decade, studies using oligonucleotide arrays and high-throughput sequencing have identified several genetic and transcriptional aberrations in B-cell acute lymphoblastic leukemia (B-ALL) (1), leading to three conceptual advances. First, genes involved in normal B-cell development (e.g., PAX5, IKZF1) are frequently mutated in B-ALL (1-3). Second, B-ALL is highly heterogeneous and can exist as multiple, genetically distinct clones within the same individual (1, 4). Third, B-ALL transcriptional profiles cluster based on characteristic chromosomal rearrangements, hereafter defined as rearrangements of TEL, MLL, TCF3, and BCR/ABL (5-8).However, one third of B-ALL cases lack characteristic rearrangements (9). Transcriptional profiles from a subset of these leukemias cluster with profiles from BCR/ABL-expressing B-ALL (3, 5), suggesting that the former harbor cryptic alterations in tyrosine kinase signaling. Supporting this notion, mutations in JAKs were recently identified in a small percentage of pediatric B-ALL and approximately 20% of ALL in children with Down syndrome (10-14).Upon ligand binding to a type I cytokine receptor, JAKs phosphorylate substrates including STATs, which in turn affect the transcription of progrowth and antiapoptotic factors (15). JAK enzymatic activity requires interaction with a cytokine receptor, which is believed to se...
BackgroundToxoplasmosis is an important zoonotic parasitic disease worldwide. In immune competent individuals, Toxoplasma gondii preferentially infects tissues of central nervous systems, which might be an adding factor of certain psychiatric disorders. Congenital transmission of T. gondii during pregnancy has been regarded as a risk factor for the health of newborn infants. While in immune-compromised individuals, the parasite can cause life-threatening infections. This study aims to investigate the prevalence of T. gondii infection among clinically healthy individuals and patients with psychiatric disorders in China and to identify the potential risk factors related to the vulnerability of infection in the population.MethodsSerum samples from 2634 healthy individuals and 547 patients with certain psychiatric disorders in Changchun and Daqing in the northeast, and in Shanghai in the south of China were examined respectively for the levels of anti-T. gondii IgG by indirect ELISA and a direct agglutination assay. Prevalence of T. gondii infection in the Chinese population in respect of gender, age, residence and health status was systematically analyzed.ResultsThe overall anti-T. gondii IgG prevalence in the study population was 12.3%. In the clinically healthy population 12.5% was sero-positive and in the group with psychiatric disorders 11.3% of these patients were positive with anti-T. gondii IgG. A significant difference (P = 0.004) was found between male and female in the healthy population, the seroprevalence was 10.5% in men versus 14.3% in women. Furthermore, the difference of T. gondii infection rate between male and female in the 20-19 year's group was more obvious, with 6.4% in male population and 14.6% in female population.ConclusionA significant higher prevalence of T. gondii infection was observed in female in the clinically healthy population. No correlation was found between T. gondii infection and psychiatric disorders in this study. Results suggest that women are more exposed to T. gondii infection than men in China. The data argue for deeper investigations for the potential risk factors that threat the female populations.
h Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3␣ gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating. Plasmodium vivax has the widest geographical distribution among the four human-infecting species, stretching from the Korean Peninsula to northern Argentina. An estimated 2.48 billion people lived at risk of P. vivax malaria in 2010, of which a large majority was in Central and Southeast Asia (1). Each year, P. vivax infects an estimated 130 to 391 million people (2, 3). Past eradication campaigns have witnessed the resilience of vivax malaria to control efforts. In areas where P. vivax and P. falciparum are coendemic, intensified control efforts have led to major changes in malaria epidemiology, and the problem of vivax malaria has become more prominent (4). With emerging global interests in malaria elimination (5), many nations in which vivax malaria is endemic will inevitably face greater challenges for the control and elimination of this parasite. For example, among the 34 malariaeliminating countries, 26 have malaria burdens mainly or solely due to P. vivax (4).The relative resilience of vivax malaria may be attributed to the formation of dormant hypnozoites in the livers of patients. These hypnozoites awaken in the weeks and months following a primary attack and cause new attacks, called relapses. Thus, treatment of P. vivax malaria requires drugs that target both the ...
YAP1 is overexpressed in numerous cancers, but its molecular mechanism in the carcinogenesis and clinic significance in tumor diagnosis and prognosis remains to be determined. We attempted to analyze the clinicopathologic significance of YAP1 expression and the correlation of the YAP1 levels with the progression, metastasis and prognosis of patients with gastric carcinoma. By immunohistochemistry, we determined YAP1 expression in 214 of primary gastric carcinoma (GC), 167 of matched normal gastric mucosa, 40 of chronic atrophic gastritis, 11 of dysplasia and 73 of intestinal metaplasia. The positive rate of YAP1 in gastric carcinoma was significantly higher than that in normal gastric mucosa, chronic atrophic gastritis and intestinal metaplasia. In the gastric cancers with lymph node metastasis, the positive rate of YAP1 was much higher than that in the group without lymph node metastasis. Moreover, gastric cancer patients with YAP1 overexpression demonstrated poorer prognosis than those with YAP1 negative staining. Finally, multivariate analysis of 191 patients with gastric carcinoma indicated that YAP1 overexpression, the invasion depth and lymph node metastasis were high hazard factors for gastric carcinoma. Our results demonstrated that YAP1 overexpression is correlated to the progression, lymph node metastasis and poor prognosis of gastric carcinoma, suggesting that overexpression of YAP1 might be an adjuvant factor for predicting lymph node metastasis, and a useful biomarker for the diagnosis and prediction of prognosis in patients with gastric cancers.
Water is one of the most widespread impurities and contaminants for pharmaceuticals and chemical products. A simple, fast and reliable water assay method is of high significance for the pharmaceutical and chemical manufacturing industries. In this work, lanthanide metal–organic framework Eu-dipicolinic acid/2-aminophthalic acid (Eu-DPA/PTA-NH2) was prepared as a double-color ratiometric fluorescent water sensor, which shows ultrasensitive (limit of detection 0.01% v/v) and linear broad-range (0–100% v/v) response to water. An innovative analytical device based on a one-to-two logic gate was constructed by using the water content and the two fluorescence responses as the input and output signals, respectively. The direct analysis of water content can be achieved by the four output types, NOT (0, 1), PASS 0 (0, 0), PASS 1 (1, 1), and YES (1, 0). Importantly, the metal–organic framework (MOF)-loaded fiber paper was prepared as a microsensor, and a water assay tube was designed for rapid water detection of solid pharmaceuticals via ratiometric chromaticity, coupled with a portable visual determination device. The paper-based microsensor is response-rapid (20 s), long-term stable (at least 30 days), and can achieve the accurate (relative error <9.8%) visual assay of trace water in solid pharmaceuticals. To our knowledge, this is the first time to report an MOF-based double-color ratiometric fluorescent water sensor, a water analytical logic device, and a paper-based water microsensor for point-of-care visual water assay in solid samples via ratiometric chromaticity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.