Targeting tissue-resident memory CD8+ T cells in the kidney is a potential therapeutic strategy to ameliorate podocyte injury and glomerulosclerosis

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Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

Methodological advances in the design of peptide-based vaccines

The tremendous advances in genomics, recombinant DNA technology, bioengineering and nanotechnology, in conjunction with the development of high-end computations, have been instrumental in the process of rational design of peptide-based vaccines. The use of peptide vaccines was limited owing to their inherent instability when systemically administered; however, advanced formulation techniques have been developed for their systemic delivery, thereby overcoming their degradation, clearance, cellular uptake and off-target effects. With the rise of sophisticated immunological predictors and experimental techniques, several methodological advances have occurred in this field. This review examines contemporary methods to identify and optimize epitopes, engineer their immunogenic properties and develop their safe and efficient delivery into the host.     

Comment on “Outcomes of curative liver resection for hepatocellular carcinoma in patients with cirrhosis”

The present letter to the editor is in response to the research “Outcomes of curative liver resection for hepatocellular carcinoma in patients with cirrhosis” by Elshaarawy et al in World J Gastroenterol 2021; 13(5): 424–439. The preoperative assessment of the liver reserve function in hepatocellular carcinoma (HCC) patients with cirrhosis is crucial, and there is no universal consensus on how to assess it. Based on a retrospective study, Elshaarawy et al investigated the impact of various classical clinical indicators on liver failure and the prognosis after hepatectomy in HCC patients with cirrhosis. We recommend that we should strive to explore new appraisal indicators, such as the indocyanine green retention rate at 15 min.     

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

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The Yield of Multimodal Computed Tomography among Emergency Department Patients with Suspected Large Vessel Occlusion Stroke

Objectives: Endovascular therapy (EVT) improves outcomes for appropriately selected acute ischemic stroke patients. Guidelines suggest rapid acquisition of noninvasive vascular imaging to screen suspected ischemic stroke patients for large vessel occlusion (LVO) and candidacy for EVT. We sought to quantify the yield of an LVO stroke screening process in an undifferentiated emergency department (ED) suspected stroke population as well as identify predictors of successful EVT. Methods: We identified a cohort of consecutive ED patients who received CT angiography and brain perfusion (CTA/P) imaging to determine candidacy for EVT during 2016. In keeping with the guidelines at that time, hospital protocol directed physicians to obtain CTA/P studies if time from the onset of symptoms was less than or equal to 6 hours, and the National Institute of Health Stroke Scale (NIHSS) more than or equal to 6 or if recommended by the consulting stroke neurologist. Final discharge diagnoses, EVT attempts, and successful reperfusion (TICI 2b or better) were recorded. Yield of CTA/P was compared among patients based on NIHSS and duration of symptoms. Results: Over a 12-month period, 406 suspected stroke patients were screened with CTA/P; 273 (67%) received a final diagnosis of ischemic stroke. Among cases screened, 53 (13%) underwent attempted EVT; 35 (9%) achieved successful reperfusion. Only 1 of 113 (1%) patients with an NIHSS less than 6 was successfully treated with EVT compared to 34 of 285 (12%) with higher NIHSS (p = 0.001). The probability of successful EVT declined with increasing symptom duration (p = 0.009 for trend). In multivariable analysis, NIHSS more than or equal to 6 was associated with successful EVT (odds ratio [OR] 4.0 [1.6 to 9.9]) but presentation within 6 hours of onset was not (OR 2.3 [0.8 to 6.7]). Conclusions: EVT candidates were common among suspected stroke patients screened with CTA/P in the ED, however, patients with NIHSS less than 6 rarely received successful EVT.     

NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15¹3 and NUDT15¹2 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15¹3 and NUDT15¹2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.