Sunitinib has been associated with several cardiotoxic effects such as cardiac fibrosis. The present study was designed to explore the role of interleukin (IL)-17 in sunitinib-induced myocardial ...fibrosis (MF) in rats and whether its neutralization and/or administration of black garlic (BG), a form of fermented raw garlic (
L.), could extenuate this adverse effect. Male Wistar albino rats received sunitinib (25 mg/kg three times a week, orally) and were co-treated with secukinumab (3 mg/kg, subcutaneously, three times total) and/or BG (300 mg/kg/day, orally) for four weeks. Administration of sunitinib induced significant increase in cardiac index, cardiac inflammatory markers, and cardiac dysfunction that were ameliorated by both secukinumab and BG, and to a preferable extent, with the combined treatment. Histological examination revealed disruption in the myocardial architecture and interstitial fibrosis in cardiac sections of the sunitinib group, which were reversed by both secukinumab and BG treatments. Both drugs and their co-administration restored normal cardiac functions, downregulated cardiac inflammatory cytokines, mainly IL-17 and NF-κB, along with increasing the MMP1/TIMP1 ratio. Additionally, they attenuated sunitinib-induced upregulation of the OPG/RANK/RANKL axis. These findings highlight another new mechanism through which sunitinib can induce interstitial MF. The current results propose that neutralizing IL-17 by secukinumab and/or supplementation with BG can be a promising therapeutic approach for ameliorating sunitinib-induced MF.
Abstract
Objectives
Patients with clonal cytopenia of undetermined significance (CCUS) are at increased risk of developing myeloid neoplasia (MN). We evaluated whether a simple flow cytometry ...immunophenotyping (FCIP) assay could differentiate the risk of development of MN in patients with CCUS.
Methods
Bone marrow aspirates were assessed by FCIP panel in a cohort of 80 patients identified as having CCUS based on next-generation sequencing or cytogenetics from March 2015 to May 2020, with available samples. Flow cytometric assay included CD13/HLA-DR expression pattern on CD34-positive myeloblasts; CD13/CD16 pattern on maturing granulocytic precursors; and aberrant expression of CD2, CD7, or CD56 on CD34-positive myeloblasts. Relevant demographic, comorbidity, and clinical and laboratory data, including the type and extent of genetic abnormalities, were extracted from the electronic health record.
Results
In total, 17 (21%) patients with CCUS developed MN over the follow-up period (median survival follow-up, 28 months 95% confidence interval, 19-31). Flow cytometry immunophenotyping abnormalities, including the aberrant pattern of CD13/HLA-DR expression, as detected at the time of the diagnosis of CCUS, were significantly associated with risk of developing MN (hazard ratio, 2.97; P = .006). Additional FCIP parameters associated with the development of MN included abnormal expression of CD7 on myeloblasts and the presence vs absence of any FCIP abnormality.
Conclusions
A simple FCIP approach that includes assessment of CD13/HLA-DR pattern on CD34-positive myeloblasts can be useful in identifying patients with CCUS at higher risk of developing MN.
DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as ...a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes t(8;21), n=27 and inv(16), n=40, mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.
•Isolated and comutated DDX41 myeloid neoplasms have different characteristics.•DDX41-mutated AML has a relatively favorable outcome comparable to core binding factor AML.
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The main objective of this study was to develop a soluble product of the practically insoluble curcumin (CMN) to treat colorectal cancer more effectively than with pure CMN. To improve the solubility ...of CMN, various hydrophilic carriers of skimmed milk powder (SMP), polyvinylpyrrolidone (PVP), and mannitol (MNT) were utilized to prepare solid dispersion (SD) binary complexes. The prepared complexes were characterized in terms of their aqueous solubility and in vitro drug release and analyzed by Fourier transform infrared spectrophotometry, powder X‐ray diffractometry, scanning electron microscopy, dynamic light scattering, and the novel dyeing test. Based on this characterization, the best SD complex was optimized using the Box–Behnken design (RSM‐BBD). These results showed that the solubility of CMN was greatly improved in combination with SMP. The SD of CMN with SMP produced significantly improved solubility (0.646 ± 0.024 mg/ml) and dissolution (54.94 ± 3.21% at 5 min). Further, solid‐state characterization revealed that the complex exhibited intermolecular inclusion of the drug and carrier. Also, the complex did not undergo any chemical modification owing to its amorphous form, and the novel dye test showed better coloring impact, indicating the solubility of CMN. The in vitro cytotoxicity of the complex showed that 50% inhibition (IC50) of SW480 and Caco‐2 cells was achieved at a considerably lower concentration than that of pure CMN. Flow cytometry analysis confirmed that the cell cycle arrest was at G2/M phase (43.26% and 65.14%), and DNA fragmentation analysis investigation confirmed that the complex induced more DNA damage during apoptosis.
Developing a soluble product of the practically insoluble curcumin (CMN) to treat colorectal cancer more effectively than with pure CMN. Skimmed milk powder (SMP) used a solubility as well as cytotoxicity enhancer. Soluble CMN tremendously enhanced the solubility and cytotoxicity on human adenocarcinoma cells.
Hepatitis C virus (HCV) is the leading cause of liver fibrosis and hepatocellular carcinoma (HCC). At present, there is no predictive biomarker for the patients at high risk of developing HCC. In ...this study, we examined the association between single-nucleotide polymorphisms (SNPs) in 3 innate immunity genes 2'-5'oligoadenylate synthetase 1 (OAS1) rs10774671, interleukin 28B (IL28B) rs12979860, and low molecular mass polypeptide 7 (LMP-7) at codon 49 besides cytomegalovirus (CMV) coinfection and susceptibility to HCC in genotype 4 (GT4) chronically infected Egyptian patients. SNPs were determined using restriction fragment length polymorphism analysis in DNA from HCC patients (n = 34) and compared with either controls (n = 70) or patients with early grades of liver fibrosis (n = 49). Our results demonstrated that patients bearing the genetic combination consisting of LMP-7 CA/AA OR 4.75, 95% confidence interval (CI) 1.443-15.631, P = 0.007 and IL28B rs12979860 CT/TT (OR 6.00, 95% CI 1.603-22.455, P = 0.004) and positive for CMV viremia (OR 3.11, 95% CI 1.151-8.412, P = 0.02) were more likely to have HCC. However, OAS1 rs10774671 does not seem to contribute to the development of HCC. Binary regression analysis indicated that HCC risk significantly increases with the presence of each unfavorable genotype (LMP-7 CA/AA, IL28B rs12979860 CT/TT), when accompanied by the existence of CMV coinfection (probability of HCC risk is 0.8 for combined factors versus 0.14, 0.07, and 0.07 for individual factor IL28B, LMP-7, and CMV; respectively). These data suggest that the 2 SNPs and the coinfection in concert have potential in predicting the risk of HCC development in patients infected with HCV GT4.
We report our experience with percutaneous nephrolithotomy in a pediatric population in which primary as well as recurrent stone episodes are frequent and the need for less invasive procedures is ...imperative.
Percutaneous nephrolithotomy was performed in 60 children 3 to 13 years old (average age 6), including 44 boys (73.3%) and 16 girls (26.7%). There was a single obstructing renal calculus in 43 patients, while 17 had multiple calculi. The procedure was performed in 1 stage in 49 patients, and it was staged with preliminary nephrostomy in 11 who presented with calculous anuria and elevated serum creatinine. Normal saline was used as an irrigant and perioperatively serum electrolytes were measured to monitor fluid absorption in 18 patients. Stones were extracted intact from 40 patients (66.6%) and ultrasonic lithotripsy was performed in 20 (33.3%).
Of the 60 patients 50 (83.3%) were rendered stone-free at 1 session. Incomplete stone clearance at 1 session was due to intraoperative bleeding requiring blood transfusion, extravasation, multiple stones that were inaccessible via 1 tract, displacement of stone fragments into an inaccessible calix and insignificant residual fragments less than 3 mm. in 2 cases each. During followup of 3 months to 6 years (average 1 year) no late complications were noted.
Percutaneous nephrolithotomy is a safe and relatively efficacious mode of managing pediatric renal calculi. Although higher success rates are achieved in adults, caution should be exercised in children, in whom diligent attempts at stone clearance in 1 session may be made at the expense of safety.
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