Tracking the therapeutic efficacy of a ketone mono ester and ß-hydroxybutyrate for ulcerative colitis in rats: New perspectives.

Ulcerative colitis (UC) is an inflammatory condition that affects the colon's lining and increases the risk of colon cancer. Despite ongoing research, there is no identified cure for UC. The recognition of NLRP3 inflammasome activation in the pathogenesis of UC has gained widespread acceptance. Notably, the ketone body ß-hydroxybutyrate inhibits NLRP3 demonstrating its anti-inflammatory properties. Additionally, BD-AcAc 2 is ketone mono ester that increases ß-hydroxybutyrate blood levels. It has the potential to address the constraints associated with exogenous ß-hydroxybutyrate as a therapeutic agent, including issues related to stability and short duration of action. However, the effects of ß-hydroxybutyrate and BD-AcAc 2 on colitis have not been fully investigated. This study found that while both exogenous ß-hydroxybutyrate and BD-AcAc 2 produced the same levels of plasma ß-hydroxybutyrate, BD-AcAc 2 demonstrated superior effectiveness in mitigating dextran sodium sulfate-induced UC in rats. The mechanism of action involves modulating the NF-κB signaling, inhibiting the NLRP3 inflammasome, regulating antioxidant capacity, controlling tight junction protein expression and a potential to inhibit apoptosis and pyroptosis. Certainly, BD-AcAc 2's anti-inflammatory effects require more than just increasing plasma ß-hydroxybutyrate levels and other factors contribute to its efficacy. Local ketone concentrations in the gastrointestinal tract, as well as the combined effect of specific ketone bodies, are likely to have contributed to the stronger protective effect observed with ketone mono ester ingestion in our experiment. As a result, further investigations are necessary to fully understand the mechanisms of BD-AcAc 2 and optimize its use.

Recurrent Fever with Oral Lesions in Egyptian Children: A Familial Mediterranean Fever Diagnosis Not to Be Missed.

OBJECTIVES: the aim of this study was to describe the genetic and clinical features of familial Mediterranean fever (FMF) in a group of Egyptian children. MATERIALS AND METHODS: This cross-sectional observational study included 65 children diagnosed with FMF according to the (Eurofever/PRINTO) classification criteria. The complete blood count (CBC), and acute phase reactants such as Serum amyloid A (SAA), and C-reactive protein (CRP) were all measured during the febrile episode. Mutation analysis for the MEFV gene was carried out for all subjects. RESULTS: A total of 65 patients with FMF were included in the study. The first clinical manifestation was recurrent fever in all patients. Recurrent oral lesions accompanied fever in 63% of cases, abdominal pain in 31%, and musculoskeletal pain in 6%. The mean SAA level was 162.5 ± 85.78 mg/L. MEFV mutations were detected in 56 patients (86%). Among these patients, 6 (10.7%) were homozygous, while 44 (78.6%) were heterozygous. The most frequently observed mutation was E148Q 24 (37.5%), followed by M694I 18 (32.1%), and V726A 13 (20.3%). Half of the patients with oral lesions were E148Q positive, however abdominal pain was found to be higher in the patients with the M694I mutation. CONCLUSION: Recurrent fever with oral lesions could be an important atypical presentation of FMF in Egyptian children that should not be ignored and/or missed.

Salivary Interleukin-6 and C-Reactive Protein/Mean Platelet Volume Ratio in the Diagnosis of Late-Onset Neonatal Pneumonia.

Neonatal pneumonia is a serious respiratory infectious disease with a high rate of case fatality in developing countries. Salivary cytokines could serve as interesting noninvasive markers in the diagnosis of neonatal pneumonia. The aim was to assess the diagnostic role of salivary and serum interleukin-6 (IL-6), C-reactive protein/mean platelet volume (CRP/MPV) ratio, and the combination of these markers in the diagnosis of late-onset neonatal pneumonia in full-term neonates. Seventy full-term neonates, 35 with late-onset neonatal pneumonia and 35 controls, were enrolled in this prospective case-control study. Complete blood count (CBC), salivary and serum IL-6, and CRP concentrations were measured for all the study subjects. The sensitivity, specificity, positive predictive value, and negative predictive value of salivary IL-6, serum IL-6, and CRP/MPV ratio for the diagnosis of late-onset neonatal pneumonia were determined. At the cutoff point of >34 pg/ml, salivary IL-6 showed 82.86% sensitivity and 91.43% specificity. CRP/MPV ratio showed a sensitivity of 97.14% and specificity of 85.71% at a cutoff value > 0.88. The combination of salivary IL-6 and CRP/MPV ratio improved the sensitivity and specificity to 100%. The current study shows for the first time that both salivary IL-6 and CRP/MPV ratio are suitable markers for the diagnosis of late-onset neonatal pneumonia in full-term neonates.

Salivary and Serum Interleukin-10, C-Reactive Protein, Mean Platelet Volume, and CRP/MPV Ratio in the Diagnosis of Late-Onset Neonatal Sepsis in Full-Term Neonates.

Salivary markers could serve as potential noninvasive markers in the diagnosis of neonatal infections. We aimed to investigate the diagnostic role of salivary and serum interleukin 10 (IL-10), C-reactive protein (CRP), mean platelet volume (MPV), and CRP/MPV ratio in the diagnosis of late-onset neonatal sepsis in full-term neonates. Seventy full-term neonates were enrolled in this prospective case-control study, 35 with late-onset neonatal sepsis, and 35 controls. Salivary IL-10, serum IL-10, and CRP concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Complete blood (CBC) count was measured by an automated blood cell counter. The salivary IL-10, serum IL-10, CRP, MPV, and CRP/MPV ratio levels were much higher in neonates with late-onset sepsis than in control (220 ± 150 vs. 18 ± 9 pg/ml, P < 0.001), (316 ± 198 vs. 23.7 ± 14 pg/ml, P < 0.001), (78.2 ± 34 vs. 3.3 ± 1.7 mg/L, P < 0.001), (11.2 ± 0.9 vs. 8.6 ± 0.4 fL), and (7.08 ± 3.3 vs. 0.4 ± 0.2, P < 0.001), respectively. At the cutoff point of >31 pg/ml, salivary IL-10 showed 97.1% sensitivity and 94.3% specificity. Serum IL-10 at a cutoff value of ≥33.6 pg/ml had a sensitivity of 97.1% and specificity of 80%. MPV showed a sensitivity of 100% and specificity of 94.4% at a cutoff value ≥ 9.2 fL. CRP/MPV ratio showed a sensitivity of 100% and specificity of 97.1% at a cutoff value > 0.9. Salivary and serum IL-10 showed a positive correlation with CRP and CRP/MPV ratio in septic neonates. The current study shows for the first time that both salivary IL-10 and CRP/MPV showed statistically significant differences between neonates with late-onset sepsis and controls. Accordingly, salivary IL-10 could serve as a potential noninvasive biomarker for the diagnosis of late-onset sepsis in full-term neonates.

The Eleanor ncRNAs activate the topological domain of the ESR1 locus to balance against apoptosis.

MCF7 cells acquire estrogen-independent proliferation after long-term estrogen deprivation (LTED), which recapitulates endocrine therapy resistance. LTED cells can become primed for apoptosis, but the underlying mechanism is largely unknown. We previously reported that Eleanor non-coding RNAs (ncRNAs) upregulate the ESR1 gene in LTED cells. Here, we show that Eleanors delineate the topologically associating domain (TAD) of the ESR1 locus in the active nuclear compartment of LTED cells. The TAD interacts with another transcriptionally active TAD, which is 42.9 Mb away from ESR1 and contains a gene encoding the apoptotic transcription factor FOXO3. Inhibition of a promoter-associated Eleanor suppresses all genes inside the Eleanor TAD and the long-range interaction between the two TADs, but keeps FOXO3 active to facilitate apoptosis in LTED cells. These data indicate a role of ncRNAs in chromatin domain regulation, which may underlie the apoptosis-prone nature of therapy-resistant breast cancer cells and could be good therapeutic targets.

Lead: a hidden "untested" risk in neonatal blood transfusion.

BACKGROUND: Neonates may be exposed to lead (Pb) through blood transfusions from donors. Pb exposure has neurological, cardiovascular, renal, and other adverse effects. The study aimed to (i) determine the blood lead levels (BLLs) in different blood product units (whole blood, packed red blood cells (pRBCs), platelets, and plasma transfused to neonates) and (ii) estimate the proportion of units with high BLLs. METHODS: Residual blood from blood bank bags that were used for neonatal transfusion were collected: 25 samples from each type of blood product except for whole blood (10 samples). The Pb analysis was performed using the atomic absorption method. The study was conducted at the Suez Canal University Hospital, Egypt. RESULTS: The mean of BLL in pRBCs, platelets, plasma, and whole blood were 136, 199, 108, and 130 µg/L, respectively; 60% contained Pb above 50 µg/L. The highest BLLs were in platelet units. CONCLUSIONS: The present study showed for the first time that platelets and plasma in addition to whole blood and pRBCs used for neonatal transfusions are sources of Pb. Re-evaluation of the guidelines is mandatory for the safety of the neonates. Long-term neurodevelopment assessment of neonates exposed to high Pb is warranted.

Maternal and neonatal vitamin D deficiency and transient tachypnea of the newborn in full term neonates.

AIM: To investigate the association between maternal and neonatal serum 25-hydroxyvitamin D (25-OHD) levels and development of transient tachypnea of the newborn (TTN) in full term infants. METHODS: This was a prospective case-control study carried out on 30 neonates with TTN and their mothers and 30 control neonates and their mothers. Levels of 25-OHD were measured in maternal and neonatal blood samples that were obtained in the first 12-24 h of postnatal age. RESULTS: Both maternal and neonatal 25-OHD levels in the TTN group were significantly lower compared to the control group (P=0.0001). A negative correlation was observed between neonatal 25-OHD level and average hospital stay (P=0.0001). CONCLUSION: We observed that lower maternal and neonatal vitamin 25-OHD levels were associated with TTN development in full term infants.

Correlation between histone acetylation and expression of Notch1 in human lung carcinoma and its possible role in combined small-cell lung carcinoma.

Combined small-cell lung carcinoma (cSCLC) is composed of small-cell lung carcinoma (SCLC) admixed with non-small-cell lung carcinoma (NSCLC). Evaluating the molecular differences between SCLC and NSCLC could lead to a better understanding of the pathogenesis of such neoplasms. Therefore, in this study, we investigated the correlation between histone acetylation and Notch1 expression in lung carcinoma. Using chromatin immunoprecipitation (ChIP) assay, we measured the level of acetylated histone H3 around the promoter region of Notch1 in SCLC and NSCLC cells. We then treated SCLC cells with trichostatin A (TSA) and characterized the level of histone H3 acetylation at Notch1. In addition, TSA-treated cells were injected into immune-compromised mice, for analysis of the ex vivo tumor xenograft phenotype. The level of acetylated histone H3 surrounding the Notch1 promoter was lower in lung cancer cells not expressing Notch1. Tumors originated from TSA-treated SCLC cells occasionally formed an epithelial-like glandular arrangement of cells; with Notch1 expression and decreased expression of neuroendocrine (NE) markers. Histone deacetylation around the promoter region of Notch1 inhibits Notch1 protein expression in SCLC and the restoration of Notch1 expression in SCLC leads to the concurrent appearance of epithelial-like areas within the SCLC, which could provide a possible mechanism for histogenesis of cSCLC.

Roles of long noncoding RNAs in chromosome domains.

The cell nucleus is highly organized and functionally compartmentalized. Double-stranded naked DNA is complexed with core histones and assembled into nucleosomes and chromatin, which are surrounded by nuclear domains composed of RNAs and proteins. Recently, three-dimensional views of chromosome organization beyond the level of the nucleosome have been established and are composed of several layers of chromosome domains. Only a small portion of the human genome encodes proteins; the majority is pervasively transcribed into noncoding RNAs whose functions are under intensive investigation. Importantly, the questions of how nuclear retained noncoding RNAs play roles in orchestrating the chromatin structure that have been addressed. We discuss the novel noncoding RNA clusters, Eleanors, which are derived from a large chromatin domain. They accumulate at the site of their own transcription to form RNA clouds in the nucleus, and they activate gene expression in the chromatin domain. Noncoding RNAs have emerging roles in genome regulation that are integrated into the spatial organization of chromatin and the nucleus. WIREs RNA 2017, 8:e1384. doi: 10.1002/wrna.1384 For further resources related to this article, please visit the WIREs website.

A cluster of noncoding RNAs activates the ESR1 locus during breast cancer adaptation.

Estrogen receptor-α (ER)-positive breast cancer cells undergo hormone-independent proliferation after deprivation of oestrogen, leading to endocrine therapy resistance. Up-regulation of the ER gene (ESR1) is critical for this process, but the underlying mechanisms remain unclear. Here we show that the combination of transcriptome and fluorescence in situ hybridization analyses revealed that oestrogen deprivation induced a cluster of noncoding RNAs that defined a large chromatin domain containing the ESR1 locus. We termed these RNAs as Eleanors (ESR1 locus enhancing and activating noncoding RNAs). Eleanors were present in ER-positive breast cancer tissues and localized at the transcriptionally active ESR1 locus to form RNA foci. Depletion of one Eleanor, upstream (u)-Eleanor, impaired cell growth and transcription of intragenic Eleanors and ESR1 mRNA, indicating that Eleanors cis-activate the ESR1 gene. Eleanor-mediated gene activation represents a new type of locus control mechanism and plays an essential role in the adaptation of breast cancer cells.