Livedo racemosa associated with central venous catheter use in a newborn.

Livedo racemosa (LRac) refers to violaceous, red, or blue netlike mottling of the skin in an irregular pattern caused by circulatory abnormalities. Central venous catheters (CVC) are widely used in neonates who require intensive care to offer steady intravenous access. CVCs are covered with a hydrophilic polymer gel that reduces friction between the sheath and the vessel wall, thereby minimizing vascular spasm, irritation, and aneurysm formation. However, the introduction of foreign material into the vein carries a risk of embolization. Recently, LRac was reported as a cutaneous manifestation of hydrophilic polymer gel embolization (HPE) in adults. We present a case of LRac in a newborn that developed following CVC insertion and resolved spontaneously after the catheter was removed.

A single dose of aminophylline administration during therapeutic hypothermia; does it make a difference in glomerular filtration rate?

Aminophylline has been demonstrated to be effective in improving renal functions of the infants suffering from acute kidney injury (AKI) due to perinatal asphyxia. We aimed to evaluate the effect of a single-dose aminophylline on estimated glomerular filtration rate (eGFR), urine output (UO), and incidence and severity of AKI according to the pediatric-modified RIFLE and neonatal RIFLE criteria in newborns with perinatal asphyxia under therapeutic hypothermia. This was a single-center, retrospective cohort study including newborns (gestational age ≥36 weeks) who underwent therapeutic hypothermia due to hypoxic ischemic encephalopathy between 2016 and 2019. Demographic and clinical data were obtained from electronic medical records and patient files. Two patient groups were established: aminophylline group and control group which were only under therapeutic hypothermia. Twenty-one newborns were in the aminophylline group and 13 newborns were in the control group. Our study revealed that on the third day of life (DOL), eGFR was significantly higher in the control group (p=0.025), but UO was significantly higher in the aminophylline group (p=0.021). In the aminophylline group, eGFR on the first DOL was higher than the value on the second DOL (p=0.017) while UO was higher on the second and third DOL compared to the first DOL (1-2 DOL p=0.006, and 1-3 DOL p=0.004). However, in the control group, there was no statistically significant difference in UO over the four DOL. Both groups were similar in the presence, severity, and outcome of AKI.Conclusion: This study demonstrated that aminophylline increases UO even in the infants under therapeutic hypothermia. However, the eGFR did not significantly increase in the aminophylline group. Understanding how therapeutic hypothermia affects pharmacokinetics may help us improve our results in future studies. What is known: • Therapeutic hypothermia (TH) reduces the incidence of acute kidney injury in asphyxiated newborns. • Aminophylline is effective in improving renal functions in asphyxiated newborns. What is new: • This is the first study evaluating the effect of a single dose of aminophylline on renal functions in newborns under TH. • A single dose of aminophylline administration in newborns under TH was associated with increased urine output especially on the third day of life. However, no significant increase was detected in glomerular filtration rate associated with aminophylline administration.

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish.

Phenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1H NMR and 13C NMR mass (ESI+) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1-28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1, 3, PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10, with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research.

CHRNA5 belongs to the secondary estrogen signaling network exhibiting prognostic significance in breast cancer.

PURPOSE: Cholinergic signals can be important modulators of cellular signaling in cancer. We recently have shown that knockdown of nicotinic acetylcholine receptor subunit alpha 5, CHRNA5, diminishes the proliferative potential of breast cancer cells. However, modulation of CHRNA5 expression in the context of estrogen signaling and its prognostic implications in breast cancer remained unexplored. METHODS: Meta-analyses of large breast cancer microarray cohorts were used to evaluate the association of CHRNA5 expression with estrogen (E2) treatment, estrogen receptor (ER) status and patient prognosis. The results were validated through RT-qPCR analyses of multiple E2 treated cell lines, CHRNA5 depleted MCF7 cells and across a breast cancer patient cDNA panel. We also calculated a predicted secondary (PS) score representing direct/indirect induction of gene expression by E2 based on a public dataset (GSE8597). Co-expression analysis was performed using a weighted gene co-expression network analysis (WGCNA) pipeline. Multiple other publicly available datasets such as CCLE, COSMIC and TCGA were also analyzed. RESULTS: Herein we found that CHRNA5 expression was induced by E2 in a dose- and time-dependent manner in breast cancer cell lines. ER- breast tumors exhibited higher CHRNA5 expression levels than ER+ tumors. Independent meta-analysis for survival outcome revealed that higher CHRNA5 expression was associated with a worse prognosis in untreated breast cancer patients. Furthermore, CHRNA5 and its co-expressed gene network emerged as secondarily induced targets of E2 stimulation. These targets were largely downregulated by exposure to CHRNA5 siRNA in MCF7 cells while the response of primary ESR1 targets was dependent on the direction of the PS-score. Moreover, primary and secondary target genes were uncoupled and clustered distinctly based on multiple public datasets. CONCLUSION: Our findings strongly associate increased expression of CHRNA5 and its co-expression network with secondary E2 signaling and a worse prognosis in breast cancer.

ZenoFishDb v1.1: A Database for Xenotransplantation Studies in Zebrafish.

Rapidly accumulating literature has proven feasibility of the zebrafish xenograft models in cancer research. Nevertheless, online databases for searching the current zebrafish xenograft literature are in great demand. Herein, we have developed a manually curated database, called ZenoFishDb v1.1 (https://konulab.shinyapps.io/zenofishdb), based on R Shiny platform aiming to provide searchable information on ever increasing collection of zebrafish studies for cancer cell line transplantation and patient-derived xenografts (PDXs). ZenoFishDb v1.1 user interface contains four modules: DataTable, Visualization, PDX Details, and PDX Charts. The DataTable and Visualization pages represent xenograft study details, including injected cell lines, PDX injections, molecular modifications of cell lines, zebrafish strains, as well as technical aspects of the xenotransplantation procedures in table, bar, and/or pie chart formats. The PDX Details module provides comprehensive information on the patient details in table format and can be searched and visualized. Overall, ZenoFishDb v1.1 enables researchers to effectively search, list, and visualize different technical and biological attributes of zebrafish xenotransplantation studies particularly focusing on the new trends that make use of reporters, RNA interference, overexpression, or mutant gene constructs of transplanted cancer cells, stem cells, and PDXs, as well as distinguished host modifications.