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Journal of Hematology & Oncology Oct 2022Besides featured glucose consumption, recent studies reveal that cancer cells might prefer "addicting" specific energy substrates from the tumor microenvironment (TME);...
BACKGROUND
Besides featured glucose consumption, recent studies reveal that cancer cells might prefer "addicting" specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear.
METHODS
Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved.
RESULTS
We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-κB, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD.
CONCLUSION
Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD.
Topics: Adenocarcinoma; Cancer-Associated Fibroblasts; Cytokines; Gene Expression Regulation, Neoplastic; Glucose; Glutamine; Humans; In Situ Hybridization, Fluorescence; Large Neutral Amino Acid-Transporter 1; Luciferases; Lung; Lung Neoplasms; NF-kappa B; RNA, Long Noncoding; Tumor Microenvironment
PubMed: 36209111
DOI: 10.1186/s13045-022-01359-4 -
JAMA Network Open Apr 2023Thyroid storm is the most severe form of thyrotoxicosis, with high mortality, and is treated with propylthiouracil and methimazole. Some guidelines recommend...
IMPORTANCE
Thyroid storm is the most severe form of thyrotoxicosis, with high mortality, and is treated with propylthiouracil and methimazole. Some guidelines recommend propylthiouracil over methimazole, although the difference in outcomes associated with each treatment is unclear.
OBJECTIVE
To compare outcomes associated with use of propylthiouracil vs methimazole for the treatment of thyroid storm.
DESIGN, SETTING, AND PARTICIPANTS
This comparative effectiveness study comprised a large, multicenter, US-based cohort from the Premier Healthcare Database between January 1, 2016, and December 31, 2020. It included 1383 adult patients admitted to intensive or intermediate care units with a diagnosis of thyroid storm per International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and treated with either propylthiouracil or methimazole. Analyses were conducted from July 2022 to February 2023.
EXPOSURE
Patients received either propylthiouracil or methimazole for treatment of thyroid storm. Exposure was assigned based on the initial thionamide administered.
MAIN OUTCOMES AND MEASURES
The primary outcome was the adjusted risk difference of in-hospital death or discharge to hospice between patients treated with propylthiouracil and those treated with methimazole, assessed by targeted maximum likelihood estimation.
RESULTS
A total of 1383 patients (656 [47.4%] treated with propylthiouracil; mean [SD] age, 45 [16] years; 473 women [72.1%]; and 727 [52.6%] treated with methimazole; mean [SD] age, 45 [16] years; 520 women [71.5%]) were included in the study. The standardized mean difference for age was 0.056, and the standardized mean difference for sex was 0.013. The primary composite outcome occurred in 7.4% of of patients (102 of 1383; 95% CI, 6.0%-8.8%). A total of 8.5% (56 of 656; 95% CI, 6.4%-10.7%) of patients who initiated propylthiouracil and 6.3% (46 of 727; 95% CI, 4.6%-8.1%) who initiated methimazole died in the hospital (adjusted risk difference, 0.6% [95% CI, -1.8% to 3.0%]; P = .64). There were no significant differences in duration of organ support, total hospitalization costs, or rates of adverse events between the 2 treatment groups.
CONCLUSION AND RELEVANCE
In this comparative effectiveness study of a multicenter cohort of adult patients with thyroid storm, no significant differences were found in mortality or adverse events in patients who were treated with propylthiouracil or methimazole. Thus, current guidelines recommending propylthiouracil over methimazole for treatment of thyroid storm may merit reevaluation.
Topics: Adult; Humans; Female; Middle Aged; Methimazole; Propylthiouracil; Thyroid Crisis; Antithyroid Agents; Critical Illness; Hospital Mortality
PubMed: 37067797
DOI: 10.1001/jamanetworkopen.2023.8655 -
Medicine Jan 2020Cerebral palsy (CP) is a common disability in children featured with pathological gait and limb function limitation due to muscle weakness. Improving limb function and...
BACKGROUND
Cerebral palsy (CP) is a common disability in children featured with pathological gait and limb function limitation due to muscle weakness. Improving limb function and quality of life is currently considered to be highlighted. Physiotherapy is a chief component of rehabilitation for children with CP, correcting gait and improve walking capacity through muscle strength training. Standard rehabilitation programs for CP have not been determined. Core stability training (CST), which coordinates limb balance via trunk control, is widely used in sports competition. And it is gradually introduced into the rehabilitation of children with cerebral palsy with a positive impact on the patients' gait performance. By screening published literatures, this study aims to conduct a meta-analysis to systematically evaluate the effectiveness and safety of CST in gait of children with CP.
METHODS
Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) on CST in the treatment of children with CP were searched from 6 databases. Moreover, the reference lists of conference papers and included literatures will be manually searched to avoid omissions. Literature screening and data extraction were performed independently by 2 researchers. RCTs carry out the risk of bias analysis evaluation from seven aspects through the Cochrane Collaboration's risk of bias tool. Fixed or random effect model will be performed to analyze the outcomes. When higher heterogeneity occurs (I > 50%), the sensitivity or subgroup analysis will also be conducted to find potential factors. And the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach is used for assessing the quality of evidence.
RESULTS
The study will evaluate the effect of CST on gait of children with CP from multiple outcomes, including walking speed, endurance, stride length, and safety.
CONCLUSION
Based on evidence-based medicine, the conclusion of this study can demonstrate the effectiveness and safety of CST in gait correction for children with CP.
PROSPERO REGISTRATION NUMBER
PROSPERO CRD 42019134094.
Topics: Biomechanical Phenomena; Cerebral Palsy; Child; Clinical Trials as Topic; Exercise Therapy; Female; Humans; Male; Methylthiouracil; Muscle Strength; Research Design; Meta-Analysis as Topic; Systematic Review as Topic
PubMed: 31914039
DOI: 10.1097/MD.0000000000018609 -
PloS One 2023The purpose of this meta-analysis was to assess the safety of the anti-thyroid drugs (ATDs) propylthiouracil (PTU) and methimazole (MMI) in the treatment of... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The purpose of this meta-analysis was to assess the safety of the anti-thyroid drugs (ATDs) propylthiouracil (PTU) and methimazole (MMI) in the treatment of hyperthyroidism during pregnancy.
METHOD
From inception until June 2, 2022, all available studies were searched in PubMed, Web of Science, Cochrane, EBSCO, Embase, Scopus, and CNKI.
RESULT
Thirteen articles satisfying the inclusion criteria were examined. Our meta-analysis indicated that pregnant women treated with MMI had a higher risk of congenital anomalies than those treated with PTU (OR 0.80, 95%CI 0.69-0.92, P = 0.002, I2 = 41.9%). Shifting between MMI and PTU during pregnancy did not reduce the risk of birth defects compared to PTU alone (OR 1.18, CI 1.00 to 1.40, P = 0.061, I2 = 0.0%). There were no statistically significant differences in hepatotoxicity (OR 1.54, 95%CI 0.77-3.09, P = 0.221, I2 = 0.0%) or miscarriage (OR 0.89, 95%CI 0.72-1.11, P = 0.310, I2 = 0.0%) between PTU and MMI exposure.
CONCLUSION
The study confirmed propylthiouracil is a safer alternative to methimazole for treating hyperthyroidism in pregnant women, and it is appropriate to treat maternal thyroid disease with PTU during the first trimester of pregnancy. However, it is not clear whether switching between propylthiouracil and methimazole is a better option than treating PTU alone during pregnancy. Further studies on this matter may be needed to develop new evidence-based guidelines for the treatment of pregnant women with hyperthyroidism.
Topics: Female; Pregnancy; Humans; Methimazole; Propylthiouracil; Antithyroid Agents; Hyperthyroidism; Abortion, Spontaneous; Pregnancy Complications
PubMed: 37205692
DOI: 10.1371/journal.pone.0286097 -
Mayo Clinic Proceedings. Innovations,... Jun 2020An understanding of the molecular basis of liver regeneration will open new horizons for the development of novel therapies for chronic liver failure. Such therapies... (Review)
Review
An understanding of the molecular basis of liver regeneration will open new horizons for the development of novel therapies for chronic liver failure. Such therapies would solve the drawbacks associated with liver transplant, including the shortage of donor organs, long waitlist time, high medical costs, and lifelong use of immunosuppressive agents. Regeneration after partial hepatectomy has been studied in animal models, particularly fumarylacetoacetate hydrolase-deficient ( ) mice and pigs. The process of regeneration is distinctive, complex, and well coordinated, and it depends on the interplay among several signaling pathways (eg, nuclear factor κβ, Notch, Hippo), cytokines (eg, tumor necrosis factor α, interleukin 6), and growth factors (eg, hepatocyte growth factor, epidermal growth factor, vascular endothelial growth factor), and other components. Furthermore, endocrinal hormones (eg, norepinephrine, growth hormone, insulin, thyroid hormones) also can influence the aforementioned pathways and factors. We believe that these endocrinal hormones are important hepatic mitogens that strongly induce and accelerate hepatocyte proliferation (regeneration) by directly and indirectly triggering the activity of the involved signaling pathways, cytokines, growth factors, and transcription factors. The subsequent induction of cyclins and associated cyclin-dependent kinase complexes allow hepatocytes to enter the cell cycle. In this review article, we comprehensively summarize the current knowledge regarding the roles and mechanisms of these hormones in liver regeneration. Articles used for this review were identified by searching MEDLINE and EMBASE databases from inception through June 1, 2019.
PubMed: 32542223
DOI: 10.1016/j.mayocpiqo.2020.02.001 -
Endocrinology Jun 2021Iodothyronine deiodinases are enzymes capable of activating and inactivating thyroid hormones (THs) and have an important role in regulating TH action in tissues... (Review)
Review
Iodothyronine deiodinases are enzymes capable of activating and inactivating thyroid hormones (THs) and have an important role in regulating TH action in tissues throughout the body. Three types of deiodinases (D1, D2, and D3) were originally defined based on their biochemical characteristics. Cloning of the first complementary DNAs in the 1990s (Dio1 in rat and dio2 and dio3 in frog) allowed to confirm the existence of 3 distinct enzymes. Over the years, increasing genomic information revealed that deiodinases are present in all chordates, vertebrates, and nonvertebrates and that they can even be found in some mollusks and annelids, pointing to an ancient origin. Research in nonmammalian models has substantially broadened our understanding of deiodinases. In relation to their structure, we discovered for instance that biochemical properties such as inhibition by 6-propyl-2-thiouracil, stimulation by dithiothreitol, and temperature optimum are subject to variation. Data from fish, amphibians, and birds were key in shifting our view on the relative importance of activating and inactivating deiodination pathways and in showing the impact of D2 and D3 not only in local but also whole body T3 availability. They also led to the discovery of new local functions such as the acute reciprocal changes in D2 and D3 in hypothalamic tanycytes upon photostimulation, involved in seasonal rhythmicity. With the present possibilities for rapid and precise gene silencing in any species of interest, comparative research will certainly further contribute to a better understanding of the importance of deiodinases for adequate TH action, also in humans.
Topics: Animals; Animals, Laboratory; Anura; Biomedical Research; Birds; Fishes; History, 20th Century; History, 21st Century; Iodide Peroxidase; Rats; Thyroid Hormones; Vertebrates
PubMed: 33606002
DOI: 10.1210/endocr/bqab039 -
Expert Opinion on Therapeutic Targets Jul 2020Coronary artery disease (CAD) poses significant morbidity and mortality globally. Despite significant advances in treatment interventions, residual cardiovascular risks... (Review)
Review
INTRODUCTION
Coronary artery disease (CAD) poses significant morbidity and mortality globally. Despite significant advances in treatment interventions, residual cardiovascular risks remain unchecked. Recent clinical trials have shed light on the potential therapeutic benefits of targeting anti-inflammatory pathways. Myeloperoxidase (MPO) plays an important role in atherosclerotic plaque formation and destabilization of the fibrous cap; both increase the risk of atherosclerotic cardiovascular disease and especially CAD.
AREAS COVERED
This article examines the role of MPO in the pathogenesis of atherosclerotic CAD and the mechanistic data from several key therapeutic drug targets. There have been numerous interesting studies on prototype compounds that directly or indirectly attenuate the enzymatic activities of MPO, and subsequently exhibit atheroprotective effects; these include aminobenzoic acid hydrazide, ferulic acid derivative (INV-315), thiouracil derivatives (PF-1355 and PF-06282999), 2-thioxanthines derivative (AZM198), triazolopyrimidines, acetaminophen, N-acetyl lysyltyrosylcysteine (KYC), flavonoids, and alternative substrates such as thiocyanate and nitroxide radical.
EXPERT OPINION
Future investigations must determine if the cardiovascular benefits of direct systemic inhibition of MPO outweigh the risk of immune dysfunction, which may be less likely to arise with alternative substrates or MPO inhibitors that selectively attenuate atherogenic effects of MPO.
Topics: Animals; Anti-Inflammatory Agents; Coronary Artery Disease; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Peroxidase; Plaque, Atherosclerotic
PubMed: 32336171
DOI: 10.1080/14728222.2020.1762177 -
Nature Protocols Aug 2019Analysis of cell-type-specific transcriptomes is vital for understanding the biology of tissues and organs in the context of multicellular organisms. In this Protocol...
Analysis of cell-type-specific transcriptomes is vital for understanding the biology of tissues and organs in the context of multicellular organisms. In this Protocol Extension, we combine a previously developed cell-type-specific metabolic RNA labeling method (thiouracil (TU) tagging) and a pipeline to detect the labeled transcripts by a novel RNA sequencing (RNA-seq) method, SLAMseq (thiol (SH)-linked alkylation for the metabolic sequencing of RNA). By injecting a uracil analog, 4-thiouracil, into transgenic mice that express cell-type-specific uracil phosphoribosyltransferase (UPRT), an enzyme required for 4-thiouracil incorporation into newly synthesized RNA, only cells expressing UPRT synthesize thiol-containing RNA. Total RNA isolated from a tissue of interest is then sequenced with SLAMseq, which introduces thymine to cytosine (T>C) conversions at the sites of the incorporated 4-thiouracil. The resulting sequencing reads are then mapped with the T>C-aware alignment software, SLAM-DUNK, which allows mapping of reads containing T>C mismatches. The number of T>C conversions per transcript is further analyzed to identify which transcripts are synthesized in the UPRT-expressing cells. Thus, our method, SLAM-ITseq (SLAMseq in tissue), enables cell-specific transcriptomics without laborious FACS-based cell sorting or biochemical isolation of the labeled transcripts used in TU tagging. In the murine tissues we assessed previously, this method identified ~5,000 genes that are expressed in a cell type of interest from the total RNA pool from the tissue. Any laboratory with access to a high-throughput sequencer and high-power computing can adapt this protocol with ease, and the entire pipeline can be completed in <5 d.
Topics: Animals; Female; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Organ Specificity; Pentosyltransferases; Sequence Analysis, RNA; Thiouracil; Transcriptome
PubMed: 31243395
DOI: 10.1038/s41596-019-0179-x -
Journal of Molecular and Cellular... Nov 2021Subclinical hypothyroidism and low T3 syndrome are commonly associated with an increased risk of cardiovascular disease (CVD) and mortality. We examined effects of T3 on...
Subclinical hypothyroidism and low T3 syndrome are commonly associated with an increased risk of cardiovascular disease (CVD) and mortality. We examined effects of T3 on T-tubule (TT) structures, Ca mobilization and contractility, and clustering of dyadic proteins. Thyroid hormone (TH) deficiency was induced in adult female rats by propyl-thiouracil (PTU; 0.025%) treatment for 8 weeks. Rats were then randomized to continued PTU or triiodo-L-thyronine (T3; 10 μg/kg/d) treatment for 2 weeks (PTU + T3). After in vivo echocardiographic and hemodynamic recordings, cardiomyocytes (CM) were isolated to record Ca transients and contractility. TT organization was assessed by confocal microscopy, and STORM images were captured to measure ryanodine receptor (RyR2) cluster number and size, and L-type Ca channel (LTCC, Ca1.2) co-localization. Expressed genes including two integral TT proteins, junctophilin-2 (Jph-2) and bridging integrator-1 (BIN1), were analyzed in left ventricular (LV) tissues and cultured CM using qPCR and RNA sequencing. The T3 dosage used normalized serum T3, and reversed adverse effects of TH deficiency on in vivo measures of cardiac function. Recordings of isolated CM indicated that T3 increased rates of Ca release and re-uptake, resulting in increased velocities of sarcomere shortening and re-lengthening. TT periodicity was significantly decreased, with reduced transverse tubules but increased longitudinal tubules in TH-deficient CMs and LV tissue, and these structures were normalized by T3 treatment. Analysis of STORM data of PTU myocytes showed decreased RyR2 cluster numbers and RyR localizations within each cluster without significant changes in Ca1.2 localizations within RyR clusters. T3 treatment normalized RyR2 cluster size and number. qPCR and RNAseq analyses of LV and cultured CM showed that Jph2 expression was T3-responsive, and its increase with treatment may explain improved TT organization and RyR-LTCC coupling.
Topics: Animals; Calcium; Calcium Channels, L-Type; Calcium Signaling; Cells, Cultured; Disease Models, Animal; Female; Gene Expression; Heart Ventricles; Hypothyroidism; Membrane Proteins; Myocytes, Cardiac; Rats; Ryanodine Receptor Calcium Release Channel; Sarcolemma; Sarcomeres; Treatment Outcome; Triiodothyronine; Ventricular Function
PubMed: 34175303
DOI: 10.1016/j.yjmcc.2021.06.010