Advances in imaging and cell-labeling techniques have greatly enhanced our understanding of developmental and neurobiological processes. Among vertebrates, zebrafish is uniquely suited for in vivo ...imaging owing to its small size and optical translucency. However, distinguishing and following cells over extended time periods remains difficult. Previous studies have demonstrated that Cre recombinase-mediated recombination can lead to combinatorial expression of spectrally distinct fluorescent proteins (RFP, YFP and CFP) in neighboring cells, creating a 'Brainbow' of colors. The random combination of fluorescent proteins provides a way to distinguish adjacent cells, visualize cellular interactions and perform lineage analyses. Here, we describe Zebrabow (Zebrafish Brainbow) tools for in vivo multicolor imaging in zebrafish. First, we show that the broadly expressed ubi:Zebrabow line provides diverse color profiles that can be optimized by modulating Cre activity. Second, we find that colors are inherited equally among daughter cells and remain stable throughout embryonic and larval stages. Third, we show that UAS:Zebrabow lines can be used in combination with Gal4 to generate broad or tissue-specific expression patterns and facilitate tracing of axonal processes. Fourth, we demonstrate that Zebrabow can be used for long-term lineage analysis. Using the cornea as a model system, we provide evidence that embryonic corneal epithelial clones are replaced by large, wedge-shaped clones formed by centripetal expansion of cells from the peripheral cornea. The Zebrabow tool set presented here provides a resource for next-generation color-based anatomical and lineage analyses in zebrafish.
An important feature shared by many cancer cells is drastically altered metabolism that is critical for rapid growth and proliferation. The distinctly reprogrammed metabolism in cancer cells makes it ...possible to manipulate the levels of metabolites for cancer treatment. Citrate is a key metabolite that bridges many important metabolic pathways. Recent studies indicate that manipulating the level of citrate can impact the behaviors of both cancer and immune cells, resulting in induction of cancer cell apoptosis, boosting immune responses, and enhanced cancer immunotherapy. In this review, we discuss the recent developments in this emerging area of targeting citrate in cancer treatment. Specifically, we summarize the molecular basis of altered citrate metabolism in both tumors and immune cells, explore the seemingly conflicted growth promoting and growth inhibiting roles of citrate in various tumors, discuss the use of citrate in the clinic as a novel biomarker for cancer progression and outcomes, and highlight the new development of combining citrate with other therapeutic strategies in cancer therapy. An improved understanding of complex roles of citrate in the suppressive tumor microenvironment should open new avenues for cancer therapy.
This study investigates an AR (autoregressive)-filtered version of several conventional diagnostic tests for cross-sectional dependence in large mixed panels when both N and T are large, including ...the adjusted Lagrangian Multiplier test (LM), the cross-section dependence test (CD), and the Schott test. We show that conventional tests of cross-sectional dependence based on Pearson correlation coefficients could diverge if the components are not all I(0) processes and the modified tests possess the asymptotical normality property. The distinctive feature of these new tests is their ease of implementation, even though the exact time series properties of each component of a mixed panel are unknown or unobservable in practice. Simulations show that the AR-filtered version of the CD test (CD
AR
) performs well relative to the other testing procedures in the finite sample and computation time, especially for those cases with a large cross-sectional dimension. Given the good statistical properties of CD
AR
test, we also propose to use it as an early warning indicator for market risk or crisis.
Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity.
ASNase (
) substitution was approved in 2011 for ...allergic reactions.
has, however, been intermittently unavailable because of drug supply issues. The impact of
substitution or complete ASNase discontinuation is unknown.
Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute NCI standard risk SR: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to
but receiving all doses versus not receiving all ASNase doses.
We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio HR, 1.5; 95% CI, 1.2 to 1.9;
= .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with
substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6;
= .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6;
= .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7;
= .03).
Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of
shortages.
Tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) inhibitors are among the most potent treatments for inflammatory arthropathies including rheumatoid arthritis, psoriasis, and ...spondyloarthropathies. The availability of these biologic agents have revolutionized the management of these conditions and improved patient outcomes. Though generally safe, these biologics may contribute to the induction or exacerbation of colitis. This paradoxical colitis has been observed in patients on TNF-α inhibitor etanercept and IL-17 inhibitors (secukinumab and ixekizumab). We report a case of a 46-year-old female with psoriasis and psoriatic arthritis who presented with gastrointestinal symptoms after treatment with etanercept and IL-17 inhibitors. She was later diagnosed with paradoxical indeterminate colitis that was masked and treated by subsequent biologics given for her RA and psoriatic arthritis. In this report, we will discuss the importance of considering paradoxical colitis in the differential diagnosis for patients even several years after TNF-α/IL-17 inhibitor initiation and explain why careful consideration must be made when initiating these colitis-inducing agents to treat patients with inflammatory disorders.
Background
Evidence suggests that early‐onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been ...performed.
Methods
Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re‐reviewed to perform a morphologic‐molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next‐generation sequencing data.
Results
A higher rate of CDH1 mutations (22.2% of early‐onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early‐onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early‐onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild‐type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high‐penetrance genes (CDH1 and APC) and moderate‐penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers.
Conclusions
Early‐onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate‐penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.
Early‐onset gastric cancers have distinct genomic alterations, such as CDH1 mutations, but share with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. The histologic classification and the CDH1 mutation status correlate with overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate‐penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.
This paper proposes a novel and intuitive indicator to measure market systemic risk. This risk indicator is established by the understanding of market’s needs for risk diversification through ...cross-border investment and its impact on the stability of global financial system as a whole. We formulate the risk indicator based on a measure of cross-sectional dependence that is robust to persistent and long-memory stochastic processes. In an analysis of 14 global equity markets and 10 hedging assets from January 1999 to December 2021, we demonstrate the usefulness of our indicator by showing its ability of accurately tracking international market fluctuations and its out-of-sample performance for predicting the U.S. equity market. We further analyze the impact of the U.S. macroeconomics news on market systemic risk, with the objectiveness of both measuring the change of market systemic risk and understanding how it links to various macroeconomic factors. In particular, we find that, in the long-run, monetary policy actions have a steady impact on market systemic risk regardless of whether policy changes are expected.
•Novel, easy-to-compute measure of market systemic risk.•Accurate tracking of international market fluctuations.•Improved prediction of U.S. equity market using systemic risk indicator.•Impact of U.S. macroeconomics news on market systemic risk.•Long-term effects of expected and unexpected monetary policy on systemic risk.
More anesthesiologists are routinely using transesophageal echocardiography (TEE) during liver transplant surgery, but the effects on patient outcome are unknown. Transplant anesthesiologists are ...therefore uncertain if they should undergo additional training and adopt TEE. In response to these clinical questions, the Society for the Advancement of Transplant Anesthesia appointed experts in liver transplantation and who are certified in TEE to evaluate all available published evidence on the topic. The aim was to produce a summary with greater explanatory power than individual reports to guide transplant anesthesiologists in their decision to use TEE. An exhaustive search recovered 51 articles of uncontrolled clinical observations. Topics chosen for this study were effectiveness and safety because they were a major or minor topic in all articles. The pattern of clinical use was a common topic and was included to provide contextual information. Summarized observations showed effectiveness as the ability to make a new and unexpected diagnosis and to direct the choice of clinical management. These were reported in each stage of liver transplant surgery. There were observations that TEE facilitated rapid diagnosis of life‐threatening conditions difficult to identify with other types of monitoring commonly used in the operating room. Real‐time diagnosis by TEE images made anesthesiologists confident in their choice of interventions, especially those with a high risk of complications such as use of anticoagulants for intracardiac thrombosis. The summarized observations in this systematic review suggest that TEE is an effective form of monitoring with a safety profile similar to that in cardiac surgery patients.
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