SPT6 functions in transcriptional pause/release via PAF1C recruitment.

It is unclear how various factors functioning in the transcriptional elongation by RNA polymerase II (RNA Pol II) cooperatively regulate pause/release and productive elongation in living cells. Using an acute protein-depletion approach, we report that SPT6 depletion results in the release of paused RNA Pol II into gene bodies through an impaired recruitment of PAF1C. Short genes demonstrate a release with increased mature transcripts, whereas long genes are released but fail to yield mature transcripts, due to a reduced processivity resulting from both SPT6 and PAF1C loss. Unexpectedly, SPT6 depletion causes an association of NELF with the elongating RNA Pol II on gene bodies, without any observed functional significance on transcriptional elongation pattern, arguing against a role for NELF in keeping RNA Pol II in the paused state. Furthermore, SPT6 depletion impairs heat-shock-induced pausing, pointing to a role for SPT6 in regulating RNA Pol II pause/release through PAF1C recruitment.

A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals.

Catalytic-inactivating mutations within the Drosophila enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ∼80-amino-acid UTX stabilization domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential noncatalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations.

Transcriptional elongation control of hypoxic response.

The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation factor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C-terminal domain by its cyclin-dependent kinase component, CDK9. However, the signal and stress-specific roles of the various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear. Here, we identify and characterize the CDK9 complex required for transcriptional response to hypoxia. Contrary to previous reports, our data indicate that a CDK9 complex containing BRD4 but not AFF1/4 is essential for this hypoxic stress response. We demonstrate that BRD4 bromodomains (BET) are dispensable for the release of paused RNAPII at hypoxia-activated genes and that BET inhibition by JQ1 is insufficient to impair hypoxic gene response. Mechanistically, we demonstrate that the C-terminal region of BRD4 is required for Polymerase-Associated Factor-1 Complex (PAF1C) recruitment to establish an elongation-competent RNAPII complex at hypoxia-responsive genes. PAF1C disruption using a small-molecule inhibitor (iPAF1C) impairs hypoxia-induced, BRD4-mediated RNAPII release. Together, our results provide insight into potentially targetable mechanisms that control the hypoxia-responsive transcriptional elongation.

Surfactant protein D: a predictor for severity of community-acquired pneumonia in children.

BACKGROUND: Surfactant protein D (SP-D) is a promising biomarker proposed for the prediction of community-acquired pneumonia (CAP) severity. Therefore, we aimed to assess the role of SP-D in the prediction of CAP severity in pediatric patients. METHODS: A prospective cohort study was carried out at the Pediatric Intensive Care Unit (PICU) and wards of Menoufia University Hospital. We recruited 112 children admitted into wards with pneumonia (simple pneumonia) and 68 children admitted into PICU with severe pneumonia (PICU admitted). World Health Organization (WHO) classification and mortality predictive scores were calculated to determine the severity of pneumonia for the two groups, including the Pediatric Respiratory Severity Score (PRESS) and the Predisposition, Insult, Response, and Organ dysfunction modified Score (PIROm). SP-D was measured at admission. RESULTS: The SP-D level was significantly lower in patients with simple pneumonia than in patients with severe pneumonia (P < 0.001). SP-D was significantly higher among children with severe pneumonia, as determined by WHO, PRESS, and PIROm (P = 0.001). SP-D was significantly higher among children with mechanical ventilation, shock, hypoxia, sepsis, and mortality. Receiver operating characteristic curve analysis for SP-D showed that the area under the curve was 0.741 (P value < 0.001), with a sensitivity of 85.3% and a specificity of 44.6%. CONCLUSIONS: Serum SP-D level has a predictive value for the detection of community-acquired pneumonia severity in children. IMPACT: SP-D is a good predictor for the detection of CAP severity in hospitalized children. SP-D was correlated with severity scores and was associated with indicators of CAP severity, including mechanical ventilation, shock, hypoxia, sepsis, and mortality.

Analysis and Design of an X-Band Reflectarray Antenna for Remote Sensing Satellite System.

This paper presents the analysis and design of an X-band reflectarray. The proposed antenna can be used for a medium Earth orbit (MEO) remote sensing satellite system in the 8.5 GHz band. To obtain a nearly constant response along the coverage area of this satellite system, the proposed antenna was designed with a flat-top radiation pattern with a beam width of around 29° for the required MEO system. In addition, broadside pencil beam and tilted pencil beam reflectarrays were also investigated. The feeding element of the proposed reflectarray antennas is a Yagi-Uda array. The amplitude and phase distribution of the fields due to the feeding element on the aperture of the reflectarray antenna are obtained directly by numerical simulation without introducing any approximation. The required phase distribution along the aperture of the reflectarray to obtain the required flat-top radiation pattern is obtained using the genetic algorithm (GA) optimization method. The reflecting elements of the reflectarray are composed of stacked circular patches. This stacked configuration was found to be appropriate for obtaining a wide range of reflection phase shift, which is required to implement the required phase distribution on the reflectarray aperture. The antenna was fabricated and measured for verification.

Circulating miR-21-5p and miR-126-3p: diagnostic, prognostic value, and multivariate analysis in non-small-cell lung cancer.

One of the most recent of tumor molecular characterization approaches is the microRNA (miR) expression profile. No single marker is sufficiently accurate for clinical use. Numerous biomarkers panels were created for three main purposes: tumor subtype, classification and, early detection, and prediction of tumor responses to treatment and prognosis of patients. miR-21-5p and miR-126-3p have received special attention because of their relationship with many cancer sites such as lung cancer, colorectal cancer, and renal cell carcinoma. We aimed to study their diagnostic and prognostic utility in lung cancer patients. Serum carcinoembryonic antigen (CEA) level was measured using an enzyme-linked immunosorbent assay (ELISA) technique. The expression levels of miR-21-5p and miR-126-3p were determined by real-time PCR in 60 non small cell lung cancer (NSCLC) patients and 40 healthy controls to detect diagnostic utility. Moreover, it was correlated with all disease clinicopathological characters and patient survival. Higher miR-21-5p and lower miR-126-3p levels were found in lung cancer patients than in controls. The sensitivity of CEA and miR-21-5p and miR-126-3p were 78.3, 96.7, and 90% at cutoff points 7.5, 2.35, and 2.175, respectively to distinguish NSCLC patients from controls. On combining both miR-21-5p and miR-126-3p, an improvement of sensitivity to 97% was noted. For patients, miR-21-5P increased significantly with metastatic stage and the highest grade (GIII). There was significantly longer overall survival (OS) among patients with early stages, lower grades GI&II, low miR-21-5p, and high miR-126-3p. miR-126-3p and presence of metastasis, the last two factors were the independent factors affecting OS with a hazard ratio of 0.26 (95% CI: 0.06-1.09) and 3.64 (95% CI: 1.22-16.5), respectively. Circulating miR-21-5p and miR-126-3p may play a significant role in diagnosis and prognosis in NSCLC patients.

Neutrophil Cytosolic Factor-1 Genotyping in Acne Vulgaris.

Acne vulgaris (AV) is a very common inflammatory dermatosis. It has a complex pathogenesis in which oxidative stress plays an important role. Neutrophil cytosolic factor (NCF)-1 gene encodes for NCF1 protein which shares in reactive oxygen species (ROS) production. Copy number variation (CNV) is a type of genetic variance in which gene copies are duplicated or deleted. The current work aimed to detect the association between NCF1 CNV and NCF-1 genotypes and AV to explore their possible role in increased disease risk or influencing its clinical presentation. Twenty-five cases with AV and 25 age- and gender-matched healthy volunteers were selected. NCF1 CNV and genotypes were determined using quantitative real-time polymerase chain reaction. NCF1 copy number was significantly increased in patients compared to the control group (p = 0.02). Higher copy number increased the risk of occurrence of AV by about 4-fold. The NCF1 genotype was more prevalent in patients (72%) compared to NCF1B (24%) and NCF1C (4%) variants, while NCF1B and NCF1C variants (68%) were more prevalent in the control group. The NCF1B genotype decreased the risk of occurrence of AV by 0.2-fold. NCF1 was significantly associated with cases more than controls (p = 0.005). It increased the risk of occurrence of acne by 5.4-fold. There was significant association between NCF1 copy number and disease duration where higher number was associated with long disease duration (p = 0.03). Higher copy number was also associated with the NCF1 genotype (p = 0.01). This study suggests that increased copy number of NCF1 gene may be a predisposing factor for AV development. However, the presence of NCF1B and NCF1C variants lowers ROS production and subsequently decreases the risk of development of AV.

Evaluation of ASPM and TEF Gene Expressions as Potential Biomarkers for Bladder Cancer.

Bladder cancer is one of the most predominant tumors of the genitourinary tract. In addition to pathological findings, the molecular modifications that might affect tumorigenesis and tumor outcome should be considered when treating bladder cancer. Accordingly, we aimed to investigate the expression levels of both the ASPM and TEF genes in bladder cancer tissues and their value in disease prognosis. The expression levels of the ASPM and TEF genes were analyzed by quantitative real-time PCR (qRT-PCR) in 90 bladder cancer tissue specimens and 90 specimens of normal urinary bladder tissue taken away from the tumor site. The upregulation of ASPM expression and the downregulation of TEF expression were observed in bladder cancer tissues compared to adjacent normal tissues, and these levels were correlated with high-grade tumors, advanced stage disease and the presence of metastasis. Both genes had the ability to predict metastatic association with sensitivity (84.62%) and specificity (68.42%; *P < 0.001) for the ASPM gene and for the TEF gene with sensitivity (80.77%) and specificity (78.95%; *P < 0.001). Additionally, Kaplan-Meier survival analysis indicated that elevated ASPM expression levels and reduced TEF expression levels significantly correlated with decreased overall survival and progression-free survival. The current analysis concludes that ASPM and TEF expressions might be used as potential biomarkers in bladder cancer patients.

Potential value of circulatory microRNA122 gene expression as a prognostic and metastatic prediction marker for breast cancer.

Despite progress in terms of management, breast cancer still constitutes a major threat to health worldwide. Various microRNAs have been shown to play a fundamental role in tumor biology during development and progression. Therefore, our study was focused on investigating the role of circulating microRNA122 (miR-122) in breast cancer and its clinical utility as a potential easily accessible biomarker for use in the diagnostic and prognostic assessment of breast cancer. Determination of the serum CA15-3 and carcinoembryonic antigen levels was conducted using an enzyme-linked immunosorbent assay. The expression level of miR-122 was determined using real time PCR in 90 breast cancer patients and 60 healthy controls. Higher circulating miR-122 levels were found in breast cancer patients than in controls and higher miR-122 levels were observed in patients who experienced metastasis. Additionally, miR-122, at a cutoff > 2.2, had a sensitivity of 93.33% and a specificity of 90% when used to distinguish breast cancer patients from controls and was able to predict metastasis at a cutoff > 10.9 with a sensitivity of 95.83% and a specificity of 65.15%. Kaplan-Meier survival analysis revealed that high miR-122 expression is significantly associated with decreased overall survival and progression-free survival. This study concludes that circulatory miR-122 could be utilized as a diagnostic and prognostic biomarker in breast cancer patients.

Role of soluble urokinase plasminogen activator receptor in critically ill children with hospital-acquired pneumonia: an observational study in hospital with controls.

BACKGROUND: Diagnosing hospital-acquired pneumonia (HAP) (ventilator-associated pneumonia (VAP) and non-ventilator associated pneumonia (Non-VAP)) is still a hot issue. Soluble urokinase plasminogen activator receptor (suPAR) is prognostic in critically ill children with sepsis regarding mortality prediction. Our aim was to evaluate suPAR levels in children with HAP. METHODS: An observational, prospective study was conducted on 45 children diagnosed HAP (VAP and Non-VAP) and 40 healthy controls. Paediatric Sequential Organ Failure assessment Score (pSOFA) was assessed for each patient. Plasma suPAR levels were measured with ELISA on the day of diagnosis. RESULTS: On comparison levels of plasma suPAR for the children with HAP with the healthy control group, no statistically significant difference was observed (148 pg/mL (22.4-1939.7) and 184.4 pg/mL (31.6-1311.7), respectively, (p=0.32). suPAR was significantly increased in children with elevated pSOFA score on the day of diagnosis of pneumonia (p=0.034). suPAR was significantly increased in children with shock (p=0.005). suPAR levels was negatively correlated with oxygen saturation (rs=0.31,p=0.048). suPAR was not significantly correlated with C reactive protein. CONCLUSIONS: suPAR can be used as a predictor for severity of illness in children with HAP. We firmly know that plasma suPAR, a novel marker, could indicate the disease if carried out on larger patient groups.

Association between genetic variants of GRM7 (rs1396409 and rs9883258) and treatment outcomes in Schizophrenic Egyptian patients.

BACKGROUND AND AIM: This study evaluated the association between rs1396409 and rs9883258 and the risk of schizophrenia (SCZ) and treatment outcomes in Egyptian patients. METHODS: This study included 88 patients with SCZ and 88 healthy controls. Lipid profile was assayed. Genotyping of rs1396409 and rs9883258 polymorphisms was analyzed using real-time PCR. RESULTS: The rs1396409 AG genotype frequency was significantly associated with SCZ risk (p = 0.002). Also, significant increased risk of SCZ was observed under allelic (p = 0.001), dominant (p = 0.001) and overdominant (p = 0.001) genetic model of rs1396409. However, rs9883258 AA genotype revealed nonsignificant association with SCZ. Cases with the rs1396409AG genotype exhibited hypertriglyceridemia (p < 0.001) and hypercholesterolemia (p = 0.001). In total, 72.3% and 74.5% of the cases presented with rs1396409 AG have negative symptoms (p = 0.022) and exhibited poor drug response (p = 0.023), respectively; all cases with rs1396409 GG genotype attempted suicide (p = 0.002) and are drug-free (p = 0.003). SCZ patients with negative symptoms had hypercholesterolemia (p = 0.008) mainly low-density lipoproteins (LDLc) (p = 0.016), and those with cognitive symptoms presented with low level of high-density lipoprotein (HDLc) (p = 0.023). Moreover, the multivariate regression analysis revealed that both rs1396409 G allele and HDLc were predictors of SCZ (p = 0.003 and 0.001, resp.). CONCLUSION: The current study concluded that metabotropic glutamate receptor 7 (GRM7) rs1396409 AG could be a potential biomarker for SCZ diagnosis. It also revealed an independent association between the GRM7 rs1396409 G allele, HDLc and SCZ development.

Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.

The persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus on the release of positive transcription elongation factor b (P-TEFb) from sequestration by negative regulatory complexes, such as the 7SK complex and BRD4. Another major cellular reservoir of P-TEFb is in Super Elongation Complexes (SECs), which play broad regulatory roles in host gene expression. Still, it is unknown if the release of P-TEFb from SECs is a viable latency reversal strategy. Here, we demonstrate that the SEC is not required for HIV-1 replication in primary CD4+ T cells and that a small molecular inhibitor of the P-TEFb/SEC interaction (termed KL-2) increases viral transcription. KL-2 acts synergistically with other latency reversing agents (LRAs) to reactivate viral transcription in several cell line models of latency in a manner that is, at least in part, dependent on the viral Tat protein. Finally, we demonstrate that KL-2 enhances viral reactivation in peripheral blood mononuclear cells (PBMCs) from people living with HIV on suppressive ART, most notably in combination with inhibitor of apoptosis protein antagonists (IAPi). Taken together, these results suggest that the release of P-TEFb from cellular SECs may be a novel route for HIV-1 latency reactivation.

An in vivo "turning model" reveals new RanBP9 interactions in lung macrophages.

The biological functions of the scaffold protein Ran Binding Protein 9 (RanBP9) remain elusive in macrophages or any other cell type where this protein is expressed together with its CTLH (C-terminal to LisH) complex partners. We have engineered a new mouse model, named RanBP9-TurnX, where RanBP9 fused to three copies of the HA tag (RanBP9-3xHA) can be turned into RanBP9-V5 tagged upon Cre-mediated recombination. We created this model to enable stringent biochemical studies at cell type specific level throughout the entire organism. Here, we have used this tool crossed with LysM-Cre transgenic mice to identify RanBP9 interactions in lung macrophages. We show that RanBP9-V5 and RanBP9-3xHA can be both co-immunoprecipitated with the known members of the CTLH complex from the same whole lung lysates. However, more than ninety percent of the proteins pulled down by RanBP9-V5 differ from those pulled-down by RanBP9-HA. The lung RanBP9-V5 associated proteome includes previously unknown interactions with macrophage-specific proteins as well as with players of the innate immune response, DNA damage response, metabolism, and mitochondrial function. This work provides the first lung specific RanBP9-associated interactome in physiological conditions and reveals that RanBP9 and the CTLH complex could be key regulators of macrophage bioenergetics and immune functions.

Various Expressions of PIK3C2A and TXNIP Genes and Their Potential Role as Independent Risk Factors for Chronic Stable Angina and Acute Coronary Syndrome.

BACKGROUND AND AIM: Genetic factors play a significant role in the onset and progression of coronary artery disease (CAD). PIK3C2A may contribute to the development of acute coronary syndrome (ACS) by affecting blood glucose levels and oxidative stress. The expression levels of TXNIP were significantly higher in patients with unstable angina pectoris. However, the situation is different in ACS. In the current study, we aim to investigate the role of PIK3C2A and TXNIP as independent risk factors for chronic stable angina (CSA) and ACS. SUBJECTS AND METHODS: This study involved 215 subjects (60 patients with CSA, 55 patients with ACS, and 100 controls). All subjects were exposed for assaying gene expressions of PIK3C2A and TXNIP by quantitative real-time polymerase chain reaction. RESULTS: It was found that TXNIP was upregulated, whereas PIK3C2A was downregulated in patients with CAD compared to the control group. PIK3C2A was significantly downregulated in patients with ACS compared to that in patients with CSA (p < 0.001), but TXNIP was not (p = 0.7). TXNIP was significantly upregulated in STEMI-ACS patients compared to CSA (p = 0.045) and NSTEMI ACS (p = 0.046), among non-diabetic (p = 0.023) smokers (p = 0.036) with hypertension (p = 0.005) and hypercholesterolemia (p = 0.001). ROC (receiver operating characteristic) curve analysis revealed that PIK3C2A (0.981; p < 0.001; 98.18) was the most sensitive mRNA for discriminating ACS from control, followed by TXNIP (0.775; p < 0.001; 70.91). However, for discriminating ACS from CSA combined mRNAs, (PIK3C2A + TXNIP) (0.893; p < 0.001; 98.18) and PIK3C2A (0.892; p < 0.001; 81.82) are promising biomarkers. On the other hand, the most sensitive mRNA for differentiating CSA from control is mRNAs (PIK3C2A + TXNIP) (0.963; p < 0.001; 95), then TXINP (81.3; p < 0.001; 93.33), and finally, PIK3C2A (0.782; p < 0.001; 81.67). In the multivariate regression model, PIK3C2A ((p = 0.002), 0.118 (0.031-0.445)) and smoking status ((p = 0.034); 0.151 (0.026-0.866)) were independent variables for ACS. Moreover, PIK3C2A ((p < 0.013); 0.706 (0.614-0.812)), Hb ((p = 0.013); 0.525 (0.317-0.871)), and total cholesterol ((p = 0.04); 0.865 (0.784-0.955)) were significantly (p < 0.05) and independently related to the prognosis of CSA. Furthermore, PIK3C2A ((p = 0.002), 0.923 (0.877-0.971)), TXNIP ((p = 0.001); 2.809 (1.558-5.064)) the body weight ((p = 0.033); 1.254 (1.018-1.544)) were independently associated with CSA. CONCLUSIONS: Our study concluded that the dysregulated mRNA PIK3C2A and TXNIP gene expressions may be useful in diagnosis of CAD and prediction of ACS development.

Enhancing HIV-1 latency reversal through regulating the elongating RNA Pol II pause-release by a small-molecule disruptor of PAF1C.

The polymerase-associated factor 1 complex (PAF1C) is a key, post-initiation transcriptional regulator of both promoter-proximal pausing and productive elongation catalyzed by RNA Pol II and is also involved in transcriptional repression of viral gene expression during human immunodeficiency virus-1 (HIV-1) latency. Using a molecular docking-based compound screen in silico and global sequencing-based candidate evaluation in vivo, we identified a first-in-class, small-molecule inhibitor of PAF1C (iPAF1C) that disrupts PAF1 chromatin occupancy and induces global release of promoter-proximal paused RNA Pol II into gene bodies. Transcriptomic analysis revealed that iPAF1C treatment mimics acute PAF1 subunit depletion and impairs RNA Pol II pausing at heat shock-down-regulated genes. Furthermore, iPAF1C enhances the activity of diverse HIV-1 latency reversal agents both in cell line latency models and in primary cells from persons living with HIV-1. In sum, this study demonstrates that efficient disruption of PAF1C by a first-in-class, small-molecule inhibitor may have therapeutic potential for improving current HIV-1 latency reversal strategies.

Soluble urokinase plasminogen activator receptor: a novel biomarker of pediatric community-acquired and hospitalacquired pneumonia.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker in different clinical disorders but data in pediatric pneumonia is scarce. Our objective was to assess utility of suPAR in pediatric community-acquired and hospital-acquired pneumonia. METHODS: A prospective observational study including 120 hospitalized pneumonia patients and 55 healthy controls. Patients fell into two groups: community-acquired pneumonia (CAP) group (75 patients) and hospitalacquired pneumonia (HAP) group (45 patients). CAP severity scores were calculated, including Predisposition, Insult, Response, Organ dysfunction modified (PIROm) score and Pediatric Respiratory Severity (PRESS) Score. suPAR was measured to CAP patients on admission and to HAP patients on the day of pneumonia diagnosis. suPAR was also measured to controls. RESULTS: suPAR was higher among the whole patient cohort compared with controls (p < 0.001) and higher among CAP group compared with both controls (p < 0.001) and HAP group (p < 0.001). No significant difference was found between HAP and control groups. suPAR was higher among CAP patients with shock, PICU admission, mechanical ventilation, and death (p=0.013, 0.044, 0.019, 0.049 respectively). Among CAP patients, suPAR correlated with oxygen saturation, pulse rate, respiratory rate, PRESS, and PIROm. suPAR had area under Receiver Operating Characteristic Curve=0.68 for prediction of severe CAP. Among HAP group, suPAR was negatively correlated with oxygen saturation (rs=-0.31; p=0.048) and was higher among patients with shock (p=0.005) and among those with increased pediatric Sequential Organ Failure Assessment (pSOFA) score (p=0.034). CONCLUSIONS: suPAR is promising for diagnosing pediatric CAP but not HAP. suPAR predicted illness severity in both CAP and HAP but performed better in the former.

On-admission plasma levels of BNP, MR-proADM, and cTnI in pediatric heart failure: contributions to diagnosis, prognosis, and outcome.

BACKGROUND: The aim of this study is to evaluate the use of on-admission plasma levels of BNP, MR-proADM, and cTnI in diagnosing the clinical severity and progression of heart failure (HF) in children with CHD. Also, to correlate the levels of these biomarkers with the HF outcome (survival versus in-hospital mortality). RESULTS: A prospective cohort study conducted in period from January 2017 to March 2018. All children presenting with HF had a Ross score assessment, echocardiography, and on-admission plasma level assay of BNP, MR-proADM, and cTnI. Patients were followed clinically throughout their hospital stay. The discriminatory power of on-admission measurement of each biomarker was determined using the receiver-operating characteristic (ROC). The results showed a significantly high on-admission plasma level of the 3 biomarkers among CHD cohort children than healthy controls (p < 0.001). Linear correlation was noted between the 3 biomarkers with Ross score, ejection fraction, and duration of hospital stay. Furthermore, significant association between on-admission level of the 3 biomarkers (BNP, MR-proADM, and cTnI) with patient's in-hospital mortality (p = 0.0003, Beta coefficient = 0.842; p = 0.0495, Beta coefficient = 0.183; and p < 0.001, Beta coefficient = 0.635, respectively), with on-admission BNP (cut of point 507.13) predicting in-hospital mortality, with 95.5% sensitivity, 88% specificity. CONCLUSIONS: There is a high diagnostic value of measuring the on-admission levels of BNP, MR-proADM, and cTnI regarding the clinical severity and disease progression in the setting of pediatric heart failure, but the BNP level was more superior in prediction of the patients' outcome.

Deregulation of CircANXA2, Circ0075001, and CircFBXW7 Gene Expressions and Their Predictive Value in Egyptian Acute Myeloid Leukemia Patients.

Background: Acute myeloid leukemia (AML) is of heterogeneous pathogenesis and caused by alterations of multiple genes. CircRNAs act as oncogenes or tumor suppressors in numerous tumors and could be novel diagnostic and prognostic biomarkers. Few studies had incorporated circRNAs in AML. Aim of the Work: Assessment of circANXA2, circ0075001, and circFBXW7 gene expressions in AML patients. Evaluation of their relations with clinical, cytogenetic, and overall survival outcome to emphasize their diagnostic role and prognostic impact. Methods: This study was carried out on 120 subjects (66 AML patients and 54 controls). All subjects were subjected to gene expressions assay for circANXA2, circ0075001, circFBXW7 by quantitative real-time polymerase chain reaction. Results: Prominent overexpression of circANAX2 and circ0075001 in patients than control (P < 0.001), whereas circFBXW7 was markedly downregulated in patients than in control (P < 0.001). Moreover, circANXA2 with AUC 0.824, P <0.001, had a sensitivity of 74.24%, specificity 88.89% whereas circ0075001 with AUC 0.855, P < 0.001, had the highest sensitivity of 83.33% and specificity 79.63%, and circFBXW7 with AUC 0.826, P < 0.001, had a sensitivity of 75.76% and specificity 74.07% in the distinction of AML patients from controls. Additionally, we find out that high expression of circANXA2 and circ0075001 correlated significantly with splenomegaly, hepatomegaly, less differentiated FAB subtypes (M5, M7), short overall survival, and had an adverse cytogenetic pattern. Conclusion: CircANXA2, circ0075001, and circFBXW7 gene expressions could serve as potential diagnostic biomarkers for AML disease. Moreover, CircANXA2 and circ0075001 exert poor prognostic effects on AML patients.

Long Non-Coding RNAs ASB16-AS1 and AFAP1-AS1: Diagnostic, Prognostic Impact and Survival Analysis in Colorectal Cancer.

Background: We aimed to evaluate the diagnostic roles of AFAP1-AS1 and ASB16-AS1 in colorectal cancer and highlight their roles in predicting colorectal cancer patients' prognosis. Methods: In this case-control study, 146 participants were involved. Group I included 47 patients with CRC. Group II composed of 49 patients with benign lesions in the colon, and Group III included 50 apparently normal subjects of coincided age and gender as controls. All participants were subjected to clinical and endoscopic evaluations, CA19-9, CEA, and quantification of relative expression of lncRNAs ASB16-AS1 and AFAP1-AS1. Results: CRC patients had significantly elevated expression levels of both lncRNAs in tissue and plasma samples versus benign and control groups (p < 0.001). Despite the higher sensitivity of tissue samples results, the relative expression of both lncRNAs in plasma samples was very encouraging in the discrimination between patients with CRC versus control and benign groups. Furthermore, both lncRNAs could discriminate patients with early-stage CRC (stage I&II) from being colonic lesion and control groups with better sensitivity and specificity presented by ASB16-AS1 in tissue and plasma than results detailed by AFAP1-AS1. High expression levels of ASB16-AS1 in tissue and plasma and tissue lncRNA AFAP1-AS1 are significantly correlated with decreased overall survival (p < 0.001) and reduced progression-free (p < 0.001) compared to low expression in CRC patients. Conclusion: We propose the utilization of lncRNA ASB16-AS1 and lncRNA AFAP1-AS1 as biomarkers in diagnosis and prognosis estimation for CRC patients. Moreover, their value in early CRC patients may affect the assortment of target therapy and treatment protocols.

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis.

Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15-20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host's epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.