Predictors of lateral lymph node metastasis and skip metastasis in patients with papillary thyroid microcarcinoma.

Background: Papillary thyroid microcarcinoma (PTMC) is characterized by its favorable prognosis and potential for active surveillance (AS) as a management option. However, the presence of cervical lymph node (LN) metastasis, especially lateral LN metastasis, significantly impacts management and prognosis. Previous studies have focused on post-surgery risk factors for cervical LN metastasis. This study aims to identify predictors of lateral LN metastasis by analyzing pre-operative ultrasonographic findings alongside clinicopathological factors. Methods: A retrospective review of medical records was conducted for patients with PTMC who underwent surgery at Chonnam National University Hwasun Hospital between 2004 and 2013. This is a case-control study that compares patients with lateral LN metastasis (N1b) to age- and sex-matched patients without LN metastasis (N0). Subgroup analysis was performed to evaluate risk factors of skip metastasis. Results: The study included 90 patients with PTMC with lateral LN metastasis (N1b) and 268 age- and sex-matched patients without LN metastasis (N0). The mean age was 49.3 years, and female patients were dominant in both groups. Structural recurrences of 4.4% (4/90) were observed only in the N1b group. The N1b group exhibited a higher frequency of upper lobe tumor location compared to the N0 group (38.9% vs. 16.0%, p < 0.001). There was no significant difference in the locations with the presence of invasion to adjacent organs. A higher proportion of non-parallel shape was observed in the N1b group than the N0 group (80.0% vs. 66.0%, p = 0.013). There were no differences in echogenicity, sonographic feature, margin, and AP diameter of the thyroid gland between the two groups. In multivariate analysis, independent risk factors for lateral LN metastasis included extrathyroidal extension, multiplicity, upper lobe tumor location, and non-parallel shape. Skip metastasis in patients with PTMC was associated with upper lobe tumor location. Conclusion: Detailed ultrasound examinations, evaluating tumor location, number, orientation, and the presence of ETE, are crucial in accurately predicting lateral LN metastasis especially when primary tumor was in the upper lobe to avoid missing skip metastasis. These evaluations can help guide the decision between AS and immediate surgery in patients with PTMC.

Trisomy 21-driven metabolite alterations are linked to cellular injuries in Down syndrome.

Down syndrome (DS) arises from a genetic anomaly characterized by an extra copy of chromosome 21 (exCh21). Despite high incidence of congenital diseases among DS patients, direct impacts of exCh21 remain elusive. Here, we established a robust DS model harnessing human-induced pluripotent stem cells (hiPSCs) from mosaic DS patient. These hiPSC lines encompassed both those with standard karyotype and those carrying an extra copy of exCh21, allowing to generate isogenic cell lines with a consistent genetic background. We unraveled that exCh21 inflicted disruption upon the cellular transcriptome, ushering in alterations in metabolic processes and triggering DNA damage. The impact of exCh21 was also manifested in profound modifications in chromatin accessibility patterns. Moreover, we identified two signature metabolites, 5-oxo-ETE and Calcitriol, whose biosynthesis is affected by exCh21. Notably, supplementation with 5-oxo-ETE promoted DNA damage, in stark contrast to the protective effect elicited by Calcitriol against such damage. We also found that exCh21 disrupted cardiogenesis, and that this impairment could be mitigated through supplementation with Calcitriol. Specifically, the deleterious effects of 5-oxo-ETE unfolded in the form of DNA damage induction and the repression of cardiogenesis. On the other hand, Calcitriol emerged as a potent activator of its nuclear receptor VDR, fostering amplified binding to chromatin and subsequent facilitation of gene transcription. Our findings provide a comprehensive understanding of exCh21's metabolic implications within the context of Down syndrome, offering potential avenues for therapeutic interventions for Down syndrome treatment.

Establishment and verification of the first prognostic nomograms in locally advanced thyroid cancer based on the analysis of clinical and follow-up information on 2396 patients.

Background and objectives: The purpose of this research was to develop and validate the first prognostic nomograms for 3-, 5-, and 10-year cancer-specific survival (CSS) and overall survival (OS) in patients diagnosed with locally advanced thyroid cancer (LATC) by evaluating independent predictors of prognosis in a population of LATC patients. Methods: Demographics, clinicopathologic characteristics, treatment, and follow-up of 2396 LATC patients in the surveillance, epidemiology, and end results database from 2004 to 2015 were retrospectively analyzed and compared with patients with LATC according to staging. We randomized all LATC patients into training and validation groups in a 7:3 ratio. Cox regression analyses helped us to derive independent prognostic factors for LATC patients. According to these results, we established and validated the first prognostic nomograms and risk stratification. Results: In our research, the clinical information of LATC patients was compared and significant differences were found in the relevant variables including CSS and OS (P < 0.05), with CSS of 82.0 % and 49.0 %, and OS of 70.6 % and 40.0 %, respectively. Cox regression analyses showed that age at diagnosis, tumor diameter, presence of DM, extrathyroidal extension sites, histological type, thyroidectomy scope, radiotherapy status, and chronological sequence of radiotherapy and surgery were observably correlated with CSS in LATC patients, and in addition to the above factors, gender, marital status, and chemotherapy status were also observably correlated with OS in LATC patients. The prognostic predictive power of the above factors is visualized by the Kaplan-Meier survival curve. The concordance index of nomograms for CSS and OS were 0.933, 0.925, and 0.926 (CSS), 0.918, 0.909, and 0.906 (OS), respectively, and the time-dependent receiver operating characteristic curve, area under curve, calibration curve and decision curve analysis curve indicate that the nomograms have good discriminatory ability, accuracy and clinical applicability in both the training and validation groups. Conclusions: In these findings, we drawed a conclusion that there were significant differences in clinical information between patients with T4a and T4b LATC, and we established and validated the first prognostic nomograms and risk stratification of CSS and OS for LATC patients at 3, 5, and 10 years, which will help clinicians to individualize their postoperative treatment and individualized follow-up.

Three-dimensional ultrasound-based radiomics nomogram for the prediction of extrathyroidal extension features in papillary thyroid cancer.

Purpose: To develop and validate a three-dimensional ultrasound (3D US) radiomics nomogram for the preoperative prediction of extrathyroidal extension (ETE) in papillary thyroid cancer (PTC). Methods: This retrospective study included 168 patients with surgically proven PTC (non-ETE, n = 90; ETE, n = 78) who were divided into training (n = 117) and validation (n = 51) cohorts by a random stratified sampling strategy. The regions of interest (ROIs) were obtained manually from 3D US images. A larger number of radiomic features were automatically extracted. Finally, a nomogram was built, incorporating the radiomics scores and selected clinical predictors. Receiver operating characteristic (ROC) curves were performed to validate the capability of the nomogram on both the training and validation sets. The nomogram models were compared with conventional US models. The DeLong test was adopted to compare different ROC curves. Results: The area under the receiver operating characteristic curve (AUC) of the radiologist was 0.67 [95% confidence interval (CI), 0.580-0.757] in the training cohort and 0.62 (95% CI, 0.467-0.746) in the validation cohort. Sixteen features from 3D US images were used to build the radiomics signature. The radiomics nomogram, which incorporated the radiomics signature, tumor location, and tumor size showed good calibration and discrimination in the training cohort (AUC, 0.810; 95% CI, 0.727-0.876) and the validation cohort (AUC, 0.798; 95% CI, 0.662-0.897). The result suggested that the diagnostic efficiency of the 3D US-based radiomics nomogram was better than that of the radiologist and it had a favorable discriminate performance with a higher AUC (DeLong test: p < 0.05). Conclusions: The 3D US-based radiomics signature nomogram, a noninvasive preoperative prediction method that incorporates tumor location and tumor size, presented more advantages over radiologist-reported ETE statuses for PTC.

Gi/o GPCRs drive the formation of actin-rich tunneling nanotubes in cancer cells via a Gßγ/PKCα/FARP1/Cdc42 axis.

The functional association between stimulation of G-protein-coupled receptors (GPCRs) by eicosanoids and actin cytoskeleton reorganization remains largely unexplored. Using a model of human adrenocortical cancer cells, here we established that activation of the GPCR OXER1 by its natural agonist, the eicosanoid 5-oxo-eicosatetraenoic acid, leads to the formation of filopodia-like elongated projections connecting adjacent cells, known as tunneling nanotube (TNT)-like structures. This effect is reduced by pertussis toxin and GUE1654, a biased antagonist for the Gßγ pathway downstream of OXER1 activation. We also observed pertussis toxin-dependent TNT biogenesis in response to lysophosphatidic acid, indicative of a general response driven by Gi/o-coupled GPCRs. TNT generation by either 5-oxo-eicosatetraenoic acid or lysophosphatidic acid is partially dependent on the transactivation of the epidermal growth factor receptor and impaired by phosphoinositide 3-kinase inhibition. Subsequent signaling analysis reveals a strict requirement of phospholipase C ß3 and its downstream effector protein kinase Cα. Consistent with the established role of Rho small GTPases in the formation of actin-rich projecting structures, we identified the phosphoinositide 3-kinase-regulated guanine nucleotide exchange factor FARP1 as a GPCR effector essential for TNT formation, acting via Cdc42. Altogether, our study pioneers a link between Gi/o-coupled GPCRs and TNT development and sheds light into the intricate signaling pathways governing the generation of specialized actin-rich elongated structures in response to bioactive signaling lipids.

Theoretical study on the radical scavenging activity of gallic acid.

The global descriptors of the chemical activity: ionization potential IP, electron affinity EA, chemical potential µ, absolute electronegativity χ, molecular hardness η and softness S, electrophilicity index ω, electro-donating ω-, electro-accepting ω+ powers as well as Ra and Rd indexes for gallic acid (GA) in the gas phase and water medium have been determined. To this aim, the HOMO and LUMO energies were calculated using the DFT method at the B3LYP, M06-2X, LC-ωPBE, BHandLYP, ωB97XD/cc-pVQZ theory levels using C-PCM, IEF-PCM and SMD solvation models, enabling more accurate descriptor calculations than those carried out so far. Quantum-chemical computations were also applied to investigate the GA structure and thermodynamic parameters characterizing its radical scavenging properties. To this aim, the full optimization of the neutral GA and its radical, cationic and anionic forms in vacuum and water medium has been performed, and then the bond dissociation enthalpy BDE, adiabatic ionization potential AIP, proton dissociation enthalpy PDE, proton affinity PA, electron transfer enthalpy ETE, gas phase acidity Hacidity and free Gibbs acidity Gacidity in water have been determined. The calculations revealed that GA in vacuum scavenges free radicals via hydrogen atom transfer (HAT), whereas in water (polar) medium by sequential proton loss electron transfer (SPLET). Analysis of the global activity descriptors of GA indicates that only B3LYP method combined with different solvation models satisfactory reproduces LUMO-HOMO energies and provides the smallest value of the total electron energy of GA. Among the parameters of chemical activity, the indexes Ra and Rd are the most independent of the computational method and the solvation model used. They can be recommended as a reliable source of information on the antioxidant activity of chemical compounds.

5-Oxo-ETE/OXER1: A Link between Tumor Cells and Macrophages Leading to Regulation of Migration.

Chronic inflammation is an important factor in the development of cancer. Macrophages found in tumors, known as tumor associated macrophages (TAMs), are key players in this process, promoting tumor growth through humoral and cellular mechanisms. 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), an arachidonic acid metabolite, has been described to possess a potent chemoattractant activity for human white blood cells (WBCs). The biological actions of 5-oxo-ETE are mediated through the GPCR 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor (OXER1). In addition, we have previously reported OXER1 as one of the membrane androgen receptors with testosterone antagonizing 5-oxo-ETE's actions. OXER1 is highly expressed in inflammatory cells and many normal and cancer tissues and cells, including prostate and breast cancer, promoting cancer cell survival. In the present study we investigate the expression and role of OXER1 in WBCs, THP-1 monocytes, and THP-1 derived macrophages, as well as its possible role in the interaction between macrophages and cancer cells (DU-145 and T47D). We report that OXER1 is differentially expressed between WBCs and macrophages and that receptor expression is modified by LPS treatment. Our results show that testosterone and 5-oxo-ETE can act in an antagonistic way affecting Ca2+ movements, migration, and cytokines' expression in immune-related cells, in a differentiation-dependent manner. Finally, we report that 5-oxo-ETE, through OXER1, can attract macrophages to the tumor site while tumor cells' OXER1 activation in DU-145 prostate and T47D breast cancer cells, by macrophages, induces actin cytoskeletal changes and increases their migration.

Survey of Korean head and neck surgeons and endocrinologists for the surgical extent of 1.5 and 2.5 cm papillary thyroid carcinoma.

Background: The surgical extent of 1-4 cm papillary thyroid carcinoma (PTC) is controversial. We aimed to determine the current trend in the extent of thyroidectomy and prophylactic central neck dissection (pCND) for 1.5 and 2.5 cm PTC, which are the most clinically controversial sizes. Methods: The questionnaire was sent to 342 Korean Society of Head and Neck Surgery and 160 one branch of Korean Endocrine Society members from June to July 2021 by e-mail. A questionnaire included extent of thyroidectomy [hemithyroidectomy (Hemi) vs. total thyroidectomy (TT)] and pCND according to the tumor location and degree of extrathyroidal extension (ETE) at 1.5 or 2.5 cm PTC. We compared the proportion of respondents' preference for each scenario. Results: Fifty-seven of 342 surgeons and twenty-seven of 160 endocrinologists responded to the questionnaire. At 1.5 and 2.5 cm PTC without ETE, both groups preferred Hemi, and there was no difference between the groups. When 1.5 or 2.5 cm PTC with anterior minimal ETE was suspected, the preference for Hemi by endocrinologists was significantly lower than that by surgeons (P<0.05). When anterior and posterior gross ETE were suspected, TT was preferred in both groups. When anterior gross ETE was suspected, the preference for Hemi by endocrinologists was significantly lower than that by surgeons (P<0.05). There was no difference between the groups in the posterior gross ETE. Surgeons preferred Hemi and endocrinologists preferred TT for a 1.5 cm PTC located in the isthmus. The pCND showed a similar pattern in both groups according to the size and location of the tumor and the degree of ETE. The proportion of Hemi did not differ between high-experience and low-experience endocrinologists. Also, there was no significant difference in preference for surgical extent between low-volume and high-volume surgeons. Conclusions: TT was frequently preferred in tumors with a large size or gross ETE, and pCND was frequently preferred in cases of suspected gross ETE. This study shows as the extent of thyroid surgery may differ between endocrinologists and surgeons and this could be confusing to patient and affect the patient outcomes. Therefore, multidisciplinary approach considering the extent of surgery for thyroid cancer is recommended.

Predictive value of ultrasonic features and microscopic extrathyroidal extension in the recurrence of PTC.

PURPOSE: To determine the clinical value of ultrasonic features, especially extrathyroidal extension (ETE), in the prediction of PTC recurrence. METHOD: A total of 863 patients with PTC confirmed by pathological examinations from January 2012 to August 2018 were selected in this study, including 59 cases of recurrence. The Cox-proportional hazards regression analysis and Kaplan-Meier method were adopted to determine the relationship between the variables and recurrence free survival (RFS). RESULTS: The recurrence rate of PTC is 6.8 %. Tumor maximum diameter, margin, multifocality, microcalcifications, ETE and preoperative lymph node metastasis were valuable predictive factors in univariate survival analysis. Tumor larger than 20 mm, multifocality and lateral cervical lymph node metastasis were independent risk factors for PTC recurrence, and lymph node metastasis has the highest hazard ratio (HR). Preoperative lateral cervical lymph node metastasis was more often found in the gross and extensive ETE groups. Microscopic ETE has little value in predicting PTC recurrence and has no correlation with preoperative cervical lymph node metastasis. CONCLUSIONS: Tumor maximum diameter >20 mm, multifocality and lateral cervical lymph node metastasis were independent risk factors for PTC recurrence. Preoperative lateral cervical lymph nodes should be carefully examined when gross ETE and extensive ETE were detected. Microscopic ETE has no impact on preoperative cervical lymph node metastasis or tumor recurrence.

Two Theorems and Important Insight on How the Preferred Mechanism of Free Radical Scavenging Cannot Be Settled. Comment on Pandithavidana, D.R.; Jayawardana, S.B. Comparative Study of Antioxidant Potential of Selected Dietary Vitamins; Computational Insights. Molecules 2019, 24, 1646.

Totally ignoring that the five enthalpies of reaction­bond dissociation enthalpy (BDE), adiabatic ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE)­characterizing the three free radical scavenging mechanisms­direct hydrogen atom transfer (HAT), sequential electron transfer proton transfer (SET-PT), and stepwise proton loss electron transfer (SPLET)­are not independent of each other, a recent publication on the antioxidant activity of dietary vitamins compared various vitamins and "found" different quantities, which should be strictly equal by virtue of energy conservation. Aiming to clarify this point, as well as to avoid such mistakes in future studies and to unravel errors in the previous literature, in the present paper we formulate two theorems that any sound results on antioxidation should obey. The first theorem states that the sums of the enthalpies characterizing the individual steps of SET-PT and SPLET are equal: IP+PDE = PA+ETE (=H2). This is a mathematical identity emerging from the fact that both the reactants and the final products of SET-PT and SPLET are chemically identical. The second theorem, which is also a mathematical identity, states that H2 − BDE = IPH > 0, where IPH is the ionization potential of the H-atom in the medium (e.g., gas or solvent) considered. Due to their general character, these theorems may/should serve as necessary sanity tests for any results on antioxidant activity, whatever the method employed in their derivation. From a more general perspective, they should represent a serious word of caution regarding attempts to assign the preferred free radical scavenging pathway based merely on thermochemical descriptors.

Diagnostic Accuracy of Ultrasound in Predicting Extrathyroidal Extension and Its Relation to Body Mass Index in a North American Population.

Detection of extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) influences treatment plan and surgical aggressiveness. Ultrasound (US) is the long-standing preoperative imaging method of choice. Recent literature from Asia suggests US accuracy to be influenced by patient characteristics, such as body mass index (BMI). Here, we examine the effect of BMI on the accuracy of US at a North American tertiary referral center. A total of 204 PTC-confirmed patients were retrospectively read by a radiologist blinded to surgical pathology findings. The radiologist recorded multiple sonographic features, including ETE, loss of echogenic capsule, nodule vascularity, capsular abutment, and bulging of contour. When considering all patients, the ultrasonographic feature with the best overall performance was loss of echogenic capsule (diagnostic odds ratio (DOR) = 4.48, 95% confidence interval (CI) = 1.86-10.78). Sub-group analysis by patient BMI found that area under the curve (AUC) for sonographic features was greater in non-obese BMI patients (0.71 ± 0.06) when compared with obese patients (0.43 ± 0.05; p = 0.001). Overall, US diagnostic performance was significantly better in non-obese (DOR = 3.70, 95%CI = 1.53-8.94) patients when compared to those who were obese (DOR = 1.12, 95%CI = 0.62-2.03; p = 0.03). Loss of the echogenic capsule did not differ between the two cohorts with respect to DOR (p = 0.51), specificity (p = 0.52), or sensitivity (p = 0.09). Our work suggests that the diagnostic value of ETE detection by US is impaired in obese patients. Considering that loss of the echogenic capsule did not differ with respect to diagnostic performance, specificity, nor sensitivity between non-obese and obese patients, it could be considered the most important predictor of US-determined ETE.

Case Report: Necrotizing fasciitis caused by Staphylococcus aureus positive for a new sequence variant of exfoliative toxin E.

Objectives: Necrotizing fasciitis (NF) caused by S. aureus is a rare, aggressive and rapidly progressing superficial fascia infection with a high mortality rate. The aim of this study was to identify virulence-related genes from a complete genome sequence of a methicillin-susceptible S. aureus (MSSA) isolate recovered from a monomicrobial case of NF. Materials and methods: The MSSA isolate UMCG579 was cultured from a pus collection from the subcutis of a patient with NF. The genome of isolate UMCG579 was sequenced using MinION (Oxford Nanopore) and MiSeq (illumina) platforms. Results: The genome of the UMCG579 isolate was composed of a 2,741,379 bp chromosome and did not harbor any plasmids. Virulence factor profiling identified multiple pore-forming toxin genes in the UMCG579 chromosome, including the Panton-Valentine leukocidin (PVL) genes, and none of the superantigen genes. The UMCG579 isolate harbored a new sequence variant of the recently described ete gene encoding exfoliative toxin (type E). A search in the GenBank database revealed that the new sequence variant (ete2) was exclusively found among isolates (n = 115) belonging to MLST CC152. While the majority of S. aureus ete-positive isolates were recovered from animal sources, S. aureus ete2-positive isolates originated from human carriers and human infections. Comparative genome analysis revealed that the ete2 gene was located on a 8777 bp genomic island. Conclusion: The combination of two heterogeneously distributed potent toxins, ETE2 and PVL, is likely to enhance the pathogenic ability of S. aureus isolates. Since anti-virulence therapies for the treatment of S. aureus infections continue to be explored, the understanding of specific pathogenetic mechanisms may have an important prophylactic and therapeutic value. Nevertheless, the exact contribution of ETE sequence variants to S. aureus virulence in NF infections must be determined.

Extrathyroidal Extension Prediction of Papillary Thyroid Cancer With Computed Tomography Based Radiomics Nomogram: A Multicenter Study.

Objectives: To develop and validate a Computed Tomography (CT) based radiomics nomogram for preoperative predicting of extrathyroidal extension (ETE) in papillary thyroid cancer (PTC) patients. Methods: A total of 153 patients were randomly assigned to training and internal test sets (7:3). 46 patients were recruited to serve as an external test set. A radiologist with 8 years of experience segmented the images. Radiomics features were extracted from each image and Delta-radiomics features were calculated. Features were selected by using one way analysis of variance and the least absolute shrinkage and selection operator in the training set. K-nearest neighbor, logistic regression, decision tree, linear-support vector machine (linear -SVM), gaussian-SVM, and polynomial-SVM were used to build 6 radiomics models. Next, a radiomics signature score (Rad-score) was constructed by using the linear combination of selected features weighted by their corresponding coefficients. Finally, a nomogram was constructed combining the clinical risk factors with Rad-scores. Receiver operating characteristic (ROC) curve, decision curve analysis (DCA), and calibration curve were performed on the three sets to evaluate the nomogram's performance. Results: 4 radiomics features were selected. The six models showed the certain value of radiomics, with area under the curves (AUCs) from 0.642 to 0.701. The nomogram combining the Rad-score and clinical risk factors (radiologists' interpretation) showed good performance (internal test set: AUC 0.750; external test set: AUC 0.797). Calibration curve and DCA demonstrated good performance of the nomogram. Conclusion: Our radiomics nomogram incorporating the radiomics and radiologists' interpretation has utility in the identification of ETE in PTC patients.

Metabolism of anti-inflammatory OXE (oxoeicosanoid) receptor antagonists by nonhuman primates.

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is the only product of the proinflammatory 5-lipoxygenase pathway with potent chemoattractant effects for human eosinophils, suggesting an important role in eosinophilic diseases such as asthma. 5-Oxo-ETE, acting through its selective OXE receptor, induces dermal eosinophilia in both humans and monkeys. To block its effects, we designed selective indole-based OXE antagonists containing hexyl (S-230) or phenylhexyl (S-C025 and S-Y048) side chains, which inhibit allergen-induced dermal and pulmonary inflammation in monkeys, suggesting that they may be useful therapeutic agents in humans. In this study we identified two metabolic pathways for the phenylhexyl-containing antagonists in liver microsomes: benzylic and N-methyl hydroxylation, resulting in ω-hydroxy, ω-oxo, and NH-containing products with reduced potencies that were identified by mass spectrometry and comparison with synthetic standards. Products of both pathways were also identified in monkey plasma following oral administration of S-C025 and S-Y025, but were less abundant than the α-hydroxy metabolites that we previously identified. Interestingly, the α-hydroxy compounds were not detected in microsomal incubations, suggesting a different origin. The relative rates of metabolism of these antagonists were S-230 >> S-C025 > S-Y048, which may help to explain the differences in their plasma half-lives (S-230 < S-C025 < S-Y048). In conclusion, S-C025 and S-Y048 are metabolized by liver microsomes by benzylic and N-methyl hydroxylation but not by α-hydroxylation, whereas all three pathways exist in vivo. Addition of a phenyl group to the hexyl side chain of these antagonists dramatically reduced their rates of metabolism, which would explain their prolonged in vivo half-lives.

Ceramide kinase regulates acute wound healing by suppressing 5-oxo-ETE biosynthesis and signaling via its receptor OXER1.

The sphingolipid, ceramide-1-phosphate (C1P), has been shown to promote the inflammatory phase and inhibit the proliferation and remodeling stages of wound repair via direct interaction with group IVA cytosolic phospholipase A2, a regulator of eicosanoid biosynthesis that fine-tunes the behaviors of various cell types during wound healing. However, the anabolic enzyme responsible for the production of C1P that suppresses wound healing as well as bioactive eicosanoids and target receptors that drive enhanced wound remodeling have not been characterized. Herein, we determined that decreasing C1P activity via inhibitors or genetic ablation of the anabolic enzyme ceramide kinase (CERK) significantly enhanced wound healing phenotypes. Importantly, postwounding inhibition of CERK enhanced the closure rate of acute wounds, improved the quality of healing, and increased fibroblast migration via a "class switch" in the eicosanoid profile. This switch reduced pro-inflammatory prostaglandins (e.g., prostaglandin E2) and increased levels of 5-hydroxyeicosatetraenoic acid and the downstream metabolite 5-oxo-eicosatetraenoic acid (5-oxo-ETE). Moreover, dermal fibroblasts from mice with genetically ablated CERK showed enhanced wound healing markers, while blockage of the murine 5-oxo-ETE receptor (oxoeicosanoid receptor 1) inhibited the enhanced migration phenotype of these cell models. Together, these studies reinforce the vital roles eicosanoids play in the wound healing process and demonstrate a novel role for CERK-derived C1P as a negative regulator of 5-oxo-ETE biosynthesis and the activation of oxoeicosanoid receptor 1 in wound healing. These findings provide foundational preclinical results for the use of CERK inhibitors to shift the balance from inflammation to resolution and increase the wound healing rate.

Association between HIV clinic caseloads and viral load suppression in New York City.

The relationship between HIV patient caseload and a clinic's ability to achieve viral load suppression (VLS) in their HIV patient population is not understood. The New York City Department of Health and Mental Hygiene (NYCDOHMH) administered a survey to clinics providing HIV care to people living with HIV (PLWH) in NYC in 2016. Clinics were stratified by quartiles of HIV patient caseload and dichotomized by whether ≥85% (n = 36) or <85% (n = 74) of their patients achieved VLS. Multivariable logistic regression adjusted for confounders of age, sex, ethnicity, and race. Provider to patient ratios (PPR) were calculated for each clinic as staffing full time equivalents per 100 HIV patients.

Targeting the OXE receptor with a selective antagonist inhibits allergen-induced pulmonary inflammation in non-human primates.

BACKGROUND AND PURPOSE: The 5-lipoxygenase product, 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid), is a potent chemoattractant for eosinophils and neutrophils. However, little is known about its pathophysiological role because of the lack of a rodent ortholog of the oxoeicosanoid (OXE) receptor. The present study aimed to determine whether the selective OXE receptor antagonist S-Y048 can inhibit allergen-induced pulmonary inflammation in a monkey model of asthma. EXPERIMENTAL APPROACH: Monkeys sensitized to house dust mite antigen (HDM) were treated with either vehicle or S-Y048 prior to challenge with aerosolized HDM, and bronchoalveolar (BAL) fluid was collected 24 h later. After 6 weeks, animals that had initially been treated with vehicle received S-Y048 and vice versa for animals initially treated with S-Y048. Eosinophils and neutrophils in BAL and lung tissue samples were evaluated, as well as mucus-containing cells in bronchi. KEY RESULTS: HDM significantly increased the numbers of eosinophils, neutrophils, and macrophages in BAL fluid 24 h after challenge. These responses were all significantly inhibited by S-Y048, which also reduced the numbers of eosinophils and neutrophils in lung tissue 24 h after challenge with HDM. S-Y048 also significantly reduced the numbers of bronchial epithelial cells staining for mucin and MUC5AC after antigen challenge. CONCLUSION AND IMPLICATIONS: This study provides the first evidence that 5-oxo-ETE may play an important role in inducing allergen-induced pulmonary inflammation and could also be involved in regulating MUC5AC in goblet cells. OXE receptor antagonists such as S-Y048 may useful therapeutic agents in asthma and other eosinophilic as well as neutrophilic diseases.

Enhanced OXER1 expression is indispensable for human cancer cell migration.

OXER1 is a recently identified receptor, binding the arachidonic acid metabolic product 5-oxo-ETE, considered an inflammatory receptor, implicated in chemoattraction of circulating mononuclear cells, Ca2+ surge in neutrophils, inflammation and cancer. Recently, we have shown that OXER1 is also a membrane androgen receptor in various cancer tissues. It was reported that the presence of OXER1 in leucocytes and the production and release of 5-oxo-ETE by wounded tissues is a wound sensing mechanism, leading to lymphocyte attraction. In view of the similarity of hallmarks of cancer and wound healing, we have explored the role of OXER1 and its endogenous ligand in the control of cell migration of human cancer epithelial cells (DU-145, T47D and Hep3B), mimicking the activation/migration phase of healing. We show that OXER1 is up-regulated only at the leading edge of the wound and its expression is up-regulated by its ligand 5-oxo-ETE, in a time-related manner. Knock-down of OXER1 or inhibition of 5-oxo-ETE synthesis led to decreased migration of cells and a prolongation of healing, in culture prostate cancer cell monolayers, with a substantial modification of actin cytoskeleton and a decreased filopodia formation. Inhibition of cell migration is a phenomenon mediated by Gßγ OXER1 mediated actions. These results provide a novel mechanism of OXER1 implication in cancer progression and might be of value for the design of novel OXER1 antagonists.

Psychiatric Admissions of Children and Adolescents Across School Periods and Daylight-Saving Transitions.

OBJECTIVES: This study sought to examine fluctuations in admissions to a child and adolescent inpatient psychiatry unit in relation to school breaks, school starts, as well as time change transitions in and out of Daylight-Saving Time (DST). METHODS: Five years (2012-2017) of youth inpatient admissions to a pediatric hospital in Ontario were retrieved (n=2,498). A sub-sample was grouped weekly, starting on the Sunday of each week for a total of 260 weekly time bins. The number of admissions during in and out of school periods, school starts in the fall and winter semester, and time change transitions were compared. RESULTS: Admissions were significantly higher during school periods as opposed to out of school periods, and significantly increased from prior- to post-school starts. No significant difference in admission rates were found in and out of DST changes. Weekly time series analyses for DST changes and monthly time series analyses for school starts did not identify a significant seasonality in admissions. CONCLUSIONS: These findings suggest that school periods and school onset may be significant stressors associated with an increased rate of psychiatric admissions. The presence of potential compensating factors is proposed to explain the lack of relationship between pedopsychiatric admissions and time change transitions.

OBJECTIFS: La présente étude visait à examiner les fluctuations des hospitalisations dans une unité psychiatrique pour enfants et adolescents relativement aux congés scolaires, aux retours en classe, ainsi qu'aux transitions à l'entrée et au sortir de l'heure d'été. MÉTHODES: Cinq ans (2012­2017) d'hospitalisations de jeunes patients dans un hôpital psychiatrique de l'Ontario ont été récupérés (n = 2 498). Un sous-échantillon a été assemblé chaque semaine, débutant le dimanche de chaque semaine pour un total de 260 plages horaires hebdomadaires. Le nombre d'hospitalisations durant les périodes scolaires et en dehors, les retours en classe à l'automne et au semestre d'hiver et les transitions du changement de temps a été comparé. RÉSULTATS: Les hospitalisations étaient significativement plus élevées durant les périodes scolaires par opposition aux périodes non scolaires, et augmentaient significativement d'avant le retour en classe à l'après retour en classe. Aucune différence significative des taux d'hospitalisation n'a été constatée à l'entrée ou à la sortie de l'heure d'été. Les analyses des séries de plages hebdomadaires pour les changements de l'heure d'été et les analyses des séries de temps mensuelles pour les retours en classe n'ont pas identifié de saisonnalité significative des hospitalisations. CONCLUSIONS: Ces résultats suggèrent que les périodes scolaires et le début de l'école peuvent être des stresseurs significatifs associés à un taux accru d'hospitalisations psychiatriques. La présence de facteurs de compensation potentiels est proposée pour expliquer l'absence de relation entre les hospitalisations pédopsychiatriques et les transitions du changement de l'heure d'été.