Search

Naglaa S Elabd,1 Shimaa E Soliman,2 Moamena S Elhamouly,1 Suzy F Gohar,3 Ayman Elgamal,4 Mahmoud Magdy Alabassy,5 Haitham A Soliman,5 Abdelnaser A Gadallah,6 Osama D Elbahr,7 Ghada Soliman,3 Amany A Saleh2 1Tropical Medicine Department, Faculty of Medicine - Menoufia University, Menoufia, Egypt; 2Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 3Clinical Oncology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 4Fellow of Tropical Medicine Department, Faculty of Medicine - Menoufia University, Menoufia, Egypt; 5General Medicine Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 6Internal Medicine Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 7Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, EgyptCorrespondence: Naglaa S Elabd, Tropical Medicine, Faculty of Medicine - Menoufia University- Egypt, Cairo, Egypt, Tel +201092304322, Email naglaa_elabd@yahoo.comBackground: 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.Keywords: CRC, expression, lncRNA, overall survival, progression-free survival

Safaa I Tayel,1 Shimaa E Soliman,1 Iman A Ahmedy,2 Mohamed Abdelhafez,3 Aly M Elkholy,3 Amira Hegazy,4 Nashwa M Muharram1 1Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, 32511, Egypt; 2Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, 32511, Egypt; 3Hematology Unit, Department of Internal Medicine, Faculty of Medicine, Menoufia University, Shebin El-Kom, 32511, Egypt; 4Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, 32511, EgyptCorrespondence: Safaa I Tayel, Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt, Email drsafaa_tayel@yahoo.comBackground: 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.Keywords: acute myeloid leukemia, CircRNAs, CircANXA2, circ0075001, circFBXW7

Pseudopapilledema caused by optic disc drusen (ODD) mimics the appearance of papilledema and usually presents as a diagnostic challenge. A young boy with known Chiari malformation type 1 (CM-1) was referred to the pediatric ophthalmology clinic for eye assessment to exclude papilledema due to elevated intracranial pressure (ICP). Despite the ophthalmic examination revealing bilateral optic disc elevation, multimodal imaging techniques such as fundus autofluorescence, optical coherence tomography (OCT), and B-scan ultrasonography are recommended to confirm the distinction between bilateral ODD causing pseudopapilledema and papilledema secondary to elevated ICP. Accidental coexistent papilledema mimickers like ODD need to be considered in patients with CM-1 before making a diagnosis of papilledema to avoid unnecessary invasive procedures. There was no evidence that the presence of ODD excludes the possibility of future optic nerve head changes due to elevated ICP. The multidisciplinary consensus decided on annual ophthalmology follow-ups using multimodal imaging to detect any subtle optic nerve head changes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alkhayat et al.)

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., Competing Interests: Competing interests: There is no competing of the interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We present a groundbreaking and versatile approach to multi-mode rainbow trapping in photonic crystal waveguides (PCWs), overcoming long-standing limitations in photonic device design. Our innovative semi-bilayer PC design, formed by stacking two PCs, enables the realization of new photonic modes that were previously inaccessible, leading to enhanced device flexibility, improved performance, and increased resilience to defects and imperfections. By meticulously engineering a chirped PC within the PCW, we achieve multi-mode light trapping at distinct positions for different frequencies along the waveguide, effectively creating a rainbow of light. This study paves the way for efficient and robust trapping and demultiplexing of multiple wavelengths, opening up new avenues for on-chip nanophotonic applications. Moreover, the realization of ultra-high-quality (Q) factor Fano resonances within the waveguide cavity unveils unprecedented possibilities for designing on-chip nanophotonic devices. The diverse array of Fano resonances holds immense potentials for developing novel optical filters, switches, and lasers with exceptionally low thresholds. Our proposed structure offers a more compact, efficient, and robust solution for multi-wavelength photonic device applications.

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.

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.

Objective: The primary aim of this study was to identify the frequency of death, metastasis, enucleation, and use of external beam radiation therapy (EBRT) among retinoblastoma patients. The secondary aim was to determine whether any events were associated with suboptimal clinical management to identify areas for clinical care improvement., Methods: Patients diagnosed with retinoblastoma between January 1, 2000, and December 31, 2015, at The Hospital for Sick Children were included. Medical records of eligible patients underwent a comprehensive 2-part review. First, a chart review collected diagnostic details, treatment course, and occurrence of 4 events: death, metastasis, use of EBRT, and enucleation. Next, events were reviewed in detail, and a multidisciplinary committee reached consensus on cases managed suboptimally., Results: The study included 209 patients (292 eyes). There were 8 deaths, 11 metastases, 177 enucleations (143 primary, 34 secondary), and 8 uses of EBRT. Thirteen patients were reviewed by the multidisciplinary committee, which confirmed that 5 of these patients had events associated with suboptimal clinical management. Three patients developed metastases leading to death (misdiagnosis and mismanagement of trilateral retinoblastoma [1], parental refusal of enucleation [1], and inaccurate histopathology after primary enucleation [1]). One patient developed extraocular extension related to scleral invasion following aggressive focal therapy. One patient underwent secondary enucleation for a Group B eye related to mismanagement of a treatment complication., Discussion: Deaths, metastases, and enucleations with documented instances of suboptimal care highlighted a need to enhance medical team and patient communication, histopathology interpretation, laser treatment guidelines, and trilateral retinoblastoma management. Routine clinical audit of retinoblastoma management can identify areas for clinical practice change., (Copyright © 2021 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To highlight prevalence, spectrum of anomalies, and outcome of ophthalmic involvement in PHACES syndrome (posterior fossa malformations, infantile hemangiomas, arterial, cardiac, eye, and sternal anomalies)., Methods: A retrospective, noncomparative, single-institution observational case series of children with PHACES was conducted from 2000 to 2019. Data on ocular presentations, interventions and visual outcomes were collected. Primary outcome measures were the frequency and spectrum of ocular involvement. Secondary outcomes were final visual acuity, long-term ocular sequelae, and frequency of surgical interventions., Results: A total of 43 infants had PHACES, of whom 29 (67%) had periocular infantile facial hemangiomas (IFH) and 6 (14%) had primary ocular anomalies that were always ipsilateral to the IFH. Five patients (12%) met ocular PHACES-specific diagnostic criteria, including optic nerve (3), retinal vascular (1) and lenticular (2) anomalies. Non-PHACES-specific abnormalities were Peters anomaly (1), persistent pupillary membranes (2), dysmorphic optic nerves (1), and iris/choroidal hemangiomas (2). IFH-related periocular abnormalities were frequent: ptosis (29), proptosis (9), strabismus (6). Surgery was required in 8 of the 29 children: (strabismus [6], entropion [2], ptosis [2], and optical iridectomy [1]), all of whom had orbital/conjunctival hemangioma (P = 0.03). Final visual acuity (follow-up, 8.7 years) ranged between 20/20 and 20/80 in 26 of 29 patients. All patients with visual acuity worse than 20/200 (3/29 [10%]) had structural anomalies., Conclusions: Two-thirds of infants with PHACES have periocular IFH causing vision compromising complications of amblyopia and strabismus. Structural ocular anomalies exist in 1 of 7 patients and are always ipsilateral to the IFH. Long-term ophthalmic monitoring and management is required, and the majority of patients obtain good visual outcomes., (Copyright © 2022 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the risk of patients with an early diagnosis of heritable retinoblastoma being diagnosed with TRb (or pineoblastoma) asynchronously in a later stage and its effect on screening., Methods: We updated the search (PubMed and Embase) for published literature as performed by our research group in 2014 and 2019. Trilateral retinoblastoma (TRb) patients were eligible for inclusion if identifiable as unique and the age at which TRb was diagnosed was available. The search yielded 97 new studies. Three new studies and eight new patients were included. Combined with 189 patients from the previous meta-analysis, the database included 197 patients. The main outcome was the percentage of asynchronous TRb in patients diagnosed before and after preset age thresholds of 6 and 12 months of age at retinoblastoma diagnosis., Results: Seventy-nine per cent of patients with pineoblastoma are diagnosed with retinoblastoma before the age of 12 months. However, baseline MRI screening at time of retinoblastoma diagnosis fails to detect the later diagnosed pineal TRb in 89% of patients. We modelled that an additional MRI performed at the age of 29 months picks up 53% of pineoblastomas in an asymptomatic phase. The detection rate increased to 72%, 87% and 92%, respectively, with 2, 3 and 4 additional MRIs., Conclusions: An MRI of the brain in heritable retinoblastoma before the age of 12 months misses most pineoblastomas, while retinoblastomas are diagnosed most often before the age of 12 months. Optimally timed additional MRI scans of the brain can increase the asymptomatic detection rate of pineoblastoma., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

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., (© 2021. Royal Academy of Medicine in Ireland.)

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.

Objective: To determine the role of iodine-125 plaque radiotherapy (IPR) as a secondary treatment for localized (solitary or multiple) residual (partially regressed) or recurrent (regrowth after ≥6 months stability) retinoblastoma in the era of systemic and/or regional chemotherapy., Design: A single-institute retrospective, noncomparative, interventional case series managed between July 2014 and June 2019., Participants: Thirteen consecutive eyes of 12 patients with 14 residual or recurrent retinoblastoma tumors treated with IPR. Patients who had to follow up <1 year post-IPR were excluded except for those who had enucleation., Methods: Data collected included pre-IPR treatments, tumor characteristics at IPR, and post-IPR anatomical outcome (local tumor control and globe salvage) and functional outcome (radiation complications)., Results: Local tumor control was achievable in 12 of 14 tumors. Local recurrences were observed in 2 of 5 tumors that exhibited fish-flesh regression after IPR (p = 0.04). Globe salvage was possible in 11 eyes (12 tumors). Only 2 eyes were legally blind and the remaining 9 eyes had vision >20/125. Radiation-induced complications included radiation retinopathy (4/11), radiation papillopathy (1/11), diffuse vitreous hemorrhage (4/11). Eyes with fish-flesh-regressed tumours tended to show more complications, but were statistically insignificant (p = 0.09, Fisher exact test). There was no association of time to IPR (early <6 months vs late >6 months) with occurrence of tumor recurrence or complications (p > 0.05)., Conclusion: IPR offers satisfactory local tumor control and globe salvage in localized recurrent/residual retinoblastoma. Fish-flesh tumor regression after IPR should be closely monitored for further recurrences., (Copyright © 2021 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is a chronic autoimmune illness with a growing prevalence in many populations. Few studies have examined genetic predisposition to SLE, so we aimed to examine the clinical impact of the genetic polymorphisms MECP2 rs2734647and TIRAP rs8177374 on the outcomes and therapeutic precision of SLE with and without nephritis. This study included 110 SLE patients-divided into 63 with lupus nephritis (LN), and 47 without nephritis-and 100 controls. Laboratory measurements including CRP, ESR, ACR, CBC, anti-ds-DNA, vitamin A, C3, and C4 were carried out, along with genotyping of MECP2 rs2734647and TIRAP rs8177374 by real-time PCR and sequencing. Treg %, vitamin A, C3, and C4 were lower, whereas Th17 % was higher, in patients vs. controls ( p < 0.001). The T allele of MECP2 rs2734647 was higher in LN than in non-nephritis and control subjects. Moreover, the T allele of TIRAP rs8177374 was higher in LN than in non-nephritis and control subjects. The MECP2 and TIRAP genes could play a role in predisposition to SLE, and can also predict disease progress to nephritis, helping to personalize medicine.

Background: Sepsis is still the main etiology of mortality in pediatric intensive care units (PICUs). Therefore, we performed this study to evaluate the value of procollagen Type III amino-terminal propeptide (PIIINP) as a biomarker for sepsis severity diagnosis and mortality., Method: A prospective study was carried out on 170 critically ill children admitted into the PICU and 100 controls. The performed clinical examinations included calculation of the pediatric risk of mortality. Serum PIIINP was withdrawn from patients at admission and from the controls., Results: PIIINP level was significantly more increased in sepsis, severe sepsis, and septic shock than among the controls ( p < 0.001). PIIINP was significantly higher in severe sepsis and septic shock (568.3 (32.5-1304.7) and 926.2 (460.6-1370), respectively) versus sepsis (149.5 (29.6-272.9)) ( p < 0.001). PIIINP was significantly increased in non-survivors (935.4 (104.6-1370)) compared to survivors (586.5 (29.6-1169)) ( p < 0.016). ROC curve analysis exhibited an area under the curve (AUC) of 0.833 for PIIINP, which is predictive for sepsis, while the cut-off point of 103.3 ng/mL had a sensitivity of 88% and specificity of 82%. The prognosis of the AUC curve for PIIINP to predict mortality was 0.651; the cut-off of 490.4 ng/mL had a sensitivity of 87.5% and specificity of 51.6%., Conclusions: PIIINP levels are increased in sepsis, with significantly higher levels in severe sepsis, septic shock, and non-survivors, thus representing a promising biomarker for pediatric sepsis severity and mortality.

Cholera caused by Vibrio cholerae O139 could reemerge, and proactive development of an effective O139 vaccine would be prudent. To define immunoreactive and potentially immunogenic carbohydrate targets of Vibrio cholerae O139, we assessed immunoreactivities of various O-specific polysaccharide (OSP)-related saccharides with plasma from humans hospitalized with cholera caused by O139, comparing responses to those induced in recipients of a commercial oral whole-cell killed bivalent (O1 and O139) cholera vaccine (WC-O1/O139). We also assessed conjugate vaccines containing selected subsets of these saccharides for their ability to induce protective immunity using a mouse model of cholera. We found that patients with wild-type O139 cholera develop IgM, IgA, and IgG immune responses against O139 OSP and many of its fragments, but we were able to detect only a moderate IgM response to purified O139 OSP-core, and none to its fragments, in immunologically naive recipients of WC-O1/O139. We found that immunoreactivity of O139-specific polysaccharides with antibodies elicited by wild-type infection markedly increase when saccharides contain colitose and phosphate residues, that a synthetic terminal tetrasaccharide fragment of OSP is more immunoreactive and protectively immunogenic than complete OSP, that native OSP-core is a better protective immunogen than the synthetic OSP lacking core, and that functional vibriocidal activity of antibodies predicts in vivo protection in our model but depends on capsule thickness. Our results suggest that O139 OSP-specific responses are not prominent following vaccination with a currently available oral cholera vaccine in immunologically naive humans and that vaccines targeting V. cholerae O139 should be based on native OSP-core or terminal tetrasaccharide. IMPORTANCE Cholera is a severe dehydrating illness of humans caused by Vibrio cholerae serogroup O1 or O139. Protection against cholera is serogroup specific, and serogroup specificity is defined by O-specific polysaccharide (OSP). Little is known about immunity to O139 OSP. In this study, we used synthetic fragments of the O139 OSP to define immune responses to OSP in humans recovering from cholera caused by V. cholerae O139, compared these responses to those induced by the available O139 vaccine, and evaluated O139 fragments in next-generation conjugate vaccines. We found that the terminal tetrasaccharide of O139 is a primary immune target but that the currently available bivalent cholera vaccine poorly induces an anti-O139 OSP response in immunologically naive individuals.

Background and Aim: Gastric Cancer (GC) is a leading cause of morbidity and mortality worldwide, particularly in developing nations, only a few suitable gastric cancer serum biomarkers with acceptable sensitivity and specificity exist. This work aims to highlight and uncover miR-30a-5p and miR-182-5p's diagnostic roles regarding gastric cancer and their roles in predicting prognosis., Methods: 148 patients participated in this study. Groups I, II, and III had 47 patients with GC, 54 patients with benign gastric lesions, and 47 apparently healthy subjects of coincided age and gender as controls , respectively. All participants were clinically evaluated and subjected to CBC, serum CEA, and CA19-9 by ELISA, and real-time PCR tests of miR-30a-5p and miR-182-5p., Results: MiR30a-5p and miR-182-5p were down regulated in gastric cancer patients in Group I more than Groups II and III (P < 0.001). ROC curve analysis revealed that miR30a-5p had better AUC, sensitivity, and specificity (0.961%, 93.62%, and 90.74%respectively). When miR-182-5p was gathered with CEA and CA19-9, specificity raised to 98.15% and PPV to 97.6%. Lower miR-30a-5p levels are linked with the presence of distant metastases, advanced TNM stage, and degree of pathological differentiation of tumors in GC patients (p = 0.034, 0.019, 0.049) respectively. According to the multivariate analysis, miR30a-5p expression level could be an independent predictor of GC., Conclusion: Our results exhibited that miRNAs, miR-30a-5p and miR182-5p, gene expression have a diagnostic power and can identify patients with GC. MiR-30a-5p displayed the highest diagnostic specificity and sensitivity. Besides other known tumor markers, they could offer simple noninvasive biomarkers that predict gastric cancer., (© 2021 The Authors.)

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.

Retinoblastoma is the most common pediatric intraocular cancer. Rarely, it may develop in adults, with different clinical and imaging characteristics that make the diagnosis a challenge. We present a case of a white retinal tumor in a 42-year-old woman that progressed slowly over 3 years and on enucleation an undifferentiated tumor was found without a conclusive diagnosis. Molecular analysis identified RB1 pathogenic variant that confirmed retinoblastoma diagnosis in this discordant clinicopathologic presentation of the tumor.

Background: Congenital heart diseases (CHDs) are the leading cause of infant deaths worldwide. The relationship between angiotensin-converting enzyme (ACE) gene polymorphism and CHDs is not clear. The aim of this work is to assess the presence of an association between ACE I/D polymorphism and CHD in Egyptian population., Subjects and Methods: Seventy CHD cases and 70 controls were incorporated in this study. DNA was isolated from their peripheral blood, and then ACE I/D gene polymorphism was tested by polymerase chain reaction (PCR)., Results: There was no significant difference among the frequencies of the DD, II, and DI genotypes in patients and controls (26 [37.1%], 37 [53.3%], and 4 [5.7%], 5 [6.7%]), 40 (57.2%), 28 (40%), respectively (p value = 1 and OR [95% CI] = 1.1). There was no significant difference between D allele (DD + DI) and II genotype distribution among patients and controls (p value = 1 and OR [95% CI] = 1.2 [0.3-2.9]). Moreover, there was no difference between I allele (II + DI) and DD frequency (p value = 0.2 and OR [95% CI] = 0.6 [0.3-1.2])., Conclusions: ACE I/D gene polymorphism might not be a risk factor of CHD in Egyptian children. Additional widespread studies are needed to affirm these data., (© 2020 Wiley Periodicals, Inc.)

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.

Topic: To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms., Clinical Relevance: Approximately 45% of patients with retinoblastoma-those with a germline RB1 pathogenic variant-are at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued., Methods: We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus., Results: One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9-29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P = 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb. The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively., Conclusions: Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Invisible retinoblastoma tumors are now detected with screening for retinal tumors in at-risk neonates (those inheriting RB1 pathogenic alleles from affected parents) using handheld OCT. Laser photocoagulation is challenging, requiring exact localization of a tumor invisible to indirect ophthalmoscopy and standard imaging. We describe OCT-guided localization and photocoagulation of these invisible tumors with 1-year follow-up., Design: Retrospective, noncomparative, single-institutional, observational case series., Participants: Children with any clinically invisible retinoblastoma tumor that was detected on OCT posterior pole screening., Methods: OCT revealed round homogeneous invisible tumors within the inner nuclear layer. Software calipers placed beside anatomic retinal landmarks (branched/curved vessels, fovea, or optic disc) mapped the tumor location and extent. A single laser (532 nm) burn flagged the location, and OCT evaluated the tumor-laser burn relationship; laser treatment was then continued in the correct location. Post-laser OCT ensured complete treatment., Main Outcome Measures: Accuracy (frequency of geographic miss and skip areas), effectiveness (recurrence rate), and burden (scar size and characteristics at final follow-up) of laser treatment., Results: Eleven new invisible posterior pole tumors in 7 eyes of 5 children were treated by this technique. Localization and tumor-laser burn relationships were accurate in 11 of 11 tumors (100%, 95% confidence interval [CI], 49.9-100), and all showed swelling and hyper-reflectiveness of the tumor in post-laser OCT. Two photocoagulation sessions (2 weeks apart) were sufficient to successfully manage 9 of 11 tumors (82%, 95% CI, 37.4-100) with resulting permanent flat scars. One tumor (9%, 95% CI, 0.2-50.6) developed OCT-detected subclinical recurrences within 3 months, treated by 1 laser session. No treatment scar showed gliosis, foveal involvement, or retinal traction at 1-year follow-up. Scar expansion occurred in 1 tumor (9%, 95% CI, 0.2-50.6), and all scars (100%, 95% CI, 49.9-100) showed pigmentary changes., Conclusions: The OCT-guided localization and photocoagulation technique is valuable in achieving precision results in managing invisible new retinoblastoma tumors. This technique shows a potential to improve outcomes of secondary prevention screening for retinoblastoma., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Attempted eye salvage for unilateral (cT2b/group D) retinoblastoma may risk tumor spread compared with primary enucleation. Identification of clinical features predictive of low histopathologic risk support safe trial salvage., Design: Retrospective, noncomparative single-institutional observational case series., Participants: Children with unilateral cT2b/group D retinoblastoma managed with primary enucleation at the Hospital for Sick Children, Toronto, Canada, January 2008 through February 2018., Methods: Data included clinical features (intraocular pressure, optic nerve obscuration, macular involvement, tumor seeding, and serous retinal detachment [RD] >1 quadrant), timing to enucleation, histopathologic features, and follow-up., Main Outcome Measures: Primary outcome was low-risk (LR; pT1/pT2) versus high-risk (HR; pT3/pT4) histopathologic features with clinicopathologic correlations. Secondary outcomes were positive predictive (probability that certain clinical features would predict LR histopathologic features) and negative predictive values (probability that absence of these clinical features would predict HR histopathologic features)., Results: Thirty-eight eyes were eligible and showed vitreous seeding and normal intraocular pressure. The median diagnosis to enucleation interval was 4 days (range, 0-14 days). Histopathologic analysis diagnosed 4 (10.5%) HR and 34 (89.5%) LR eyes. High-risk eyes demonstrated massive choroidal invasion (4/38) or trans-scleral, extraocular, and postlaminar optic nerve invasion (1/38). Clinical findings included macular involvement (31/38), complete optic nerve obscuration (27/38), and RD (28/38). The proportion of eyes with HR histopathologic features was 13% (4/31; 95% confidence interval [CI], 1%-25%) with macular involvement, 15% (4/27; 95% CI, 1%-28%) with complete optic nerve obscuration, and 14% (4/28; 95% CI, 1%-27%) with RD. The predictability of LR histopathologic features was 100% with macular sparing (7/7; 95% CI, 47%-100%), optic nerve visibility (10/10; 95% CI, 63%-100%), and less than 1 quadrant of RD (10/10; 95% CI, 63%-100%). In 1 child lacking all 3 clinical LR predictive features with HR histopathologic features (pT3a), metastases developed and the patient died; other children are alive and well (mean follow-up, 65 months)., Conclusions: Presence of macular sparing, optic nerve visibility, less than 1 quadrant of RD, or a combination thereof predicted LR histopathologic features at primary enucleation, suggesting safe trial eye salvage. No clinical sign predicted HR histopathologic features., (Copyright © 2019 American Academy of Ophthalmology. All rights reserved.)

Background/aims: To assess tumour control, vision and anatomical visual potential in eyes with perifoveal retinoblastoma treated by sequential photocoagulation from the antifoveal tumour edge inwards, avoiding treatment near the fovea. Patients were monitored for tumour control, foveal and perifoveal anatomy at each treatment session by optical coherence tomography (OCT) and treated for amblyopia when the other eye had better vision., Methods: Eyes with perifoveal retinoblastoma treated between 1 January 2011 and 31 May 2017 with laser therapy after chemotherapy for juxtafoveal (fovea clear of tumour but <3000 µm from tumour edge) or foveolar retinoblastoma (tumour underlying fovea) were retrospectively reviewed for tumour control without recurrence, anatomical success (foveal pit preservation and/or restoration with ≥500 µm perifoveal retina free of tumour and scar) and functional success (acceptable (>0.1 decimal) or good (>0.3 decimal) visual acuity (VA))., Results: Twenty-two eyes (14 juxtafoveal, 8 foveolar tumours) of 20 patients (19 bilateral, 1 familial and 11 females) were included. No juxtafoveal tumour had tumour recurrence, and 13/14 patients showed foveal pit preservation with ≥500 µm of perifoveal retina tumour free. Foveolar tumours had significant worse anatomical outcomes: failure to restore foveal pit or perifoveal retina (8/8, p=0.001) and tumour recurrences (5/8, p=0.001). Functional success with acceptable VA was achieved in 12/14 juxtafoveal and 5/8 foveal tumours eyes (p=0.01). Amblyopia therapy data were insufficient to evaluate impact on VA., Conclusions: Anatomical visual potential and functional vision were better in juxtafoveal than foveolar retinoblastoma treated with foveal-sparing laser photocoagulation guided by OCT. The role of amblyopia therapy requires a prospective study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Oligosaccharides equipped with amine-containing linkers can be conjugated to carrier proteins using squaric acid chemistry. In a two-step process, a squarate derivative of such oligosaccharide is formed first, which is followed by its reaction with a protein carrier. Monitoring of the conjugation reaction is achieved by SELDI-TOF-MS or MALDI-TOF-MS. This experimentally simple procedure yields desired glycoconjugates in high yields and with reproducible hapten-protein ratios.

Background: Non-small cell lung cancer (NSCLC) is leading cause of cancer related death and the survival rate for patients with NSCLC remain poor so early diagnosis of NSCLC represents the best opportunity for cure. Cell-free DNA (cf-DNA) is extracellular nucleic acids found in cell-free plasma/serum of humans, given the recent approval of a liquid biopsy in lung cancer, the use of circulating tumor DNA as a novel non-invasive diagnostic and prognostic biomarker is promising., Objectives: Studying whether the concentrations of circulating Cell Free DNA in serum can be used as a diagnostic and prognostic biomarker for NSCLC patients., Method: This study was carried out on 140 subjects included 60 patients with non small cell lung cancer,40 patients with Chronic Obstructive Pulmonary Disease (COPD) and 40 healthy controls. Quantitative analysis of serum circulating cf-DNA was done b y AlU-based quantitative real time PCR. Serum level of CEA was measured by ELISA., Results: NSCLC patients demonstrated significantly higher values of each of ALU 215, ALU 247, and DNA integrity than both COPD patients and controls. On ROC curve analysis, the total accuracy of ALU 247, ALU 115, DNA integrity (92.1%, 83.6%, 56.4%) at cutoff points (325, 565 & 0.48) respectively. On combining both DNA integrity and CEA, improved sensitivity to 93.3% was noted. For NSCLC patients, ALU 115 & ALU 247 increased significantly with more advanced stage and highest level was noticed in metastatic patients. Regarding survival there was better overall survival among patients with low DNA integrity., Conclusion: Serum cf-DNA concentrations and integrity index may be valuable tool in early diagnosis of NSCLC and prediction of prognosis of those patients.

A child with bilateral familial retinoblastoma underwent staging MRI brain and orbit which identified subtle leptomeningeal enhancement, thus prompting an MRI whole body, which revealed a retroperitoneal mass, confirmed on laparoscopic biopsy to be neuroblastoma. This is the first reported case of these two rare embryonal non-central nervous system tumors occurring concurrently. The cause of this concurrence is unknown despite their pathogenic similarities with a chance of 4 cases per 10 billion children aged 1-4 years. Incidental neuroblastomas in infants can regress spontaneously but this child underwent systemic chemotherapy for his retinoblastoma that may have caused regression of the neuroblastoma.

Background and Aim: Increasing prevalence of neonatal sepsis in recent years catch attention to early prevention and management. Vitamin D receptor (VDR) polymorphism can modulate VDR expression level that greatly influences immunity and susceptibility to microbial infections. We aimed to investigate the association of VDR polymorphism at FokI, rs2228570 T/C, and TaqI, rs731236 C/T gene with serum 25-hydroxyvitamin D level and risk of neonatal sepsis., Methods: This work carried on 160 subjects classified into 80 cases (40 mothers and their 40 septic neonates) and 80 healthy controls (40 volunteer mothers and their 40 healthy neonates). Genotyping of VDR polymorphisms were assayed by real-time PCR and serum 25-hydroxyvitamin D level and hs-CRP were measured by ELISA., Results: Vitamin D deficiency was observed in mothers of cases compared with healthy ones (p = <0.001) and in septic neonates versus healthy ones (p = <0.001). Septic neonates had much higher VDR FokI TT genotype (p = 0.014) and T allele (p = 0.003) versus healthy ones. TT genotype and T allele could increase the risk of sepsis with OR 95% CI [4.804 (1.4-16.4)] and [2.786 (1.4-5.7)] respectively while VDR TaqI showed no association with sepsis. There was a strong LD between FokI and TaqI in sepsis cases. In sepsis, T/T genotype at FokI had significantly lower vitamin D (p = <0.001)., Conclusion: Vitamin D deficiency in mothers/neonates is a risk factor for neonatal sepsis. VDR FokI T allele had lower 25-hydroxyvitamin D level that may predispose to sepsis hazards., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A concise synthesis of a branched trisaccharide, α-l-Dig-(1 → 3)-[α-l-Eva-(1 → 4)]-β-d-Fuc, corresponding to saccharomicin B, has been developed via reagent-controlled α-selective glycosylations. Starting from the d-fucose acceptor, l- epi-vancosamine was selectively installed using 2,3-bis(2,3,4-trimethoxyphenyl)cyclopropene-1-thione/oxalyl bromide mediated dehydrative glycosylation. Following deprotection, l-digitoxose was installed using the AgPF 6 /TTBP thioether-activation method to produce the trisaccharide as a single α-anomer. This highly functionalized trisaccharide can potentially serve as both a donor and an acceptor for the total synthesis of the antibiotic saccharomicin B.

Background: Children with retinoblastoma treated with carboplatin chemotherapy risk moderate to severe, irreversible hearing loss. Based on published evidence, we hypothesized that ototoxicity risk is associated with clinical parameters and variants in candidate genes in drug metabolism pathways (methyltransferases [thiopurine S-methyltransferase, TPMT] and [catechol-O-methyltransferase, COMT], and drug transporter ABCC3)., Procedure: We retrospectively reviewed clinical records of patients with retinoblastoma treated with carboplatin chemotherapy regarding age (at diagnosis and chemotherapy initiation), chemotherapy sessions (cycles number, drug doses, and cumulative carboplatin dose), and hearing loss (defined as ototoxicity ≥grade 2 by at least one classification system). Blood samples were genotyped for genetic variants in TPMT (rs12201199, rs1800460), COMT (rs4646316, rs9332377), and ABCC3 (rs1051640) by quantitative PCR and confirmed by allele-specific PCR. Univariate statistical tests, receiver-operating characteristic analysis, and Kaplan-Meier curves were used to examine the association between hearing loss, clinical factors, and variants in candidate genes., Results: Audiometric data and stored DNA were available for 71 patients with retinoblastoma (88% carried an RB1 pathogenic variant allele). Median carboplatin cumulative dose was 1,400 mg/m 2 (260-5,148 mg/m 2 ). Ototoxicity occurred in 18 patients (25%), strongly associated with age at diagnosis (P = 0.01) and age at chemotherapy initiation (OR = 4.99, P = 0.008). The highest likelihood ratio of hearing loss was associated with chemotherapy initiation <4.25 months of age. Ototoxicity was not associated with any tested genetic variants., Conclusions: We observed a 25% prevalence of ototoxicity in patients with retinoblastoma treated with carboplatin, higher than previously published. Age at chemotherapy initiation was associated with carboplatin-induced ototoxicity, with children <4.25 months of age at highest risk., (© 2018 Wiley Periodicals, Inc.)

Background/aim: There is no doubt that colorectal cancer (CRC) poses a major threat to public health worldwide, and despite improvement in managements, prognosis still remains an irritating question with no definite answer. Being a fundamental player in cancer metabolism, glucose transporter 1 (GLUT1) could be utilized as a prognostic biomarker that could fuel development of new treatment strategies. The aim of this study was to assess the validity of GLUT1 expression as a prognostic biomarker and to elucidate to what extent it is immersed in poor clinical outcome among CRC patients., Patients and Methods: GLUT1 expression in peripheral blood specimens was analyzed by quantitative real-time polymerase chain reaction in 47 CRC patients and 20 healthy controls., Results: There was significantly elevated GLUT1 expression in peripheral blood of CRC patients than in controls (P < 0.001). The cutoff value of 0.605 provided 98% sensitivity and 100% specificity. There were significantly higher values of GLUT1 expression in patients under 50 years (P = 0.003), performance status 2 (P = 0.009), stage IV (P < 0.001), and presence of metastasis (P < 0.001). GLUT1 expression showed nonsignificant association with overall survival (P = 0.068), while tumor stage (P = 0.01) and metastasis (P = 0.009) were significantly associated with lower overall survival., Conclusion: GLUT1 is sensitive and specific marker for CRC. It is overexpressed in young age patients, poor performance status, and stage IV patients. Although this was not statistically significant, GLUT 1 showed higher expression level in patients with lesser survival.

Purpose: Assess the role of handheld optical coherence tomography (OCT) in guiding management decisions during diagnosis, treatment, and follow-up of eyes affected by retinoblastoma., Design: Retrospective, noncomparative, single-institution case series., Participants: All children newly diagnosed with retinoblastoma from January 2011 to December 2015 who had an OCT session during their active treatment at The Hospital for Sick Children (SickKids) in Toronto, Canada. The OCT sessions for fellow eyes of unilateral retinoblastoma without any suspicious lesion and those performed more than 6 months after the last treatment were excluded., Methods: Data collected included age at presentation, sex, family history, RB1 mutation status, 8th edition TNMH cancer staging and International Intraocular Retinoblastoma Classification (IIRC), and number of OCT sessions per eye. Details of each session were scored for indication-related details (informative or not) and assessed for guidance (directive or not), diagnosis (staging changed, new tumors found or excluded), treatment (modified, stopped, or modality shifted), or follow-up modified., Main Outcome Measures: Frequency of OCT-guided management decisions, stratified by indication and type of guidance (confirmatory vs. influential)., Results: Sixty-three eyes of 44 children had 339 OCT sessions over the course of clinical management (median number of OCT scans per eye, 5; range, 1-15). The age at presentation and presence of a heritable RB1 mutation significantly correlated with an increased number of OCT sessions. Indications included evaluation of post-treatment scar (55%) or fovea (16%), and posterior pole scanning for new tumors (11%). Of all sessions, 92% (312/339) were informative; 19 of 27 noninformative sessions had large, elevated lesions; of these, 14 of 19 were T2a or T2b (IIRC group C or D) eyes. In 94% (293/312) of the informative sessions, OCT directed treatment decisions (58%), diagnosis (16%), and follow-up (26%). Optical coherence tomography influenced and changed management from pre-OCT clinical plans in 15% of all OCT sessions and 17% of directive sessions., Conclusions: Optical coherence tomography improves the accuracy of clinical evaluation in retinoblastoma management., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate knowledge of retinoblastoma inheritance among parents of children with familial retinoblastoma, and to compare this to timing of eye examination for at-risk children, disease severity at diagnosis, treatment burden, and outcome., Methods: A retrospective review of familial retinoblastoma cases that presented at Alexandria Main University Hospital was performed. Primary outcome measures were parental knowledge of familial retinoblastoma (disease, heritability) and subsequent action (early screening or not) and their impact on tumor burden (classification at diagnosis, potential threat to vision, ocular salvage, and life), treatment burden, and treatment success (avoidance of enucleation and irradiation)., Results: Twenty-three eyes of 13 familial retinoblastoma cases were included. Probands were parents in 9 (69%) and older siblings in 4 (31%) cases. At time of diagnosis of the first affected children, none (0%) of the parental probands knew that newborns should be screened, in contrast to all parents with a child proband (4/4, 100%; p = 0.004). Early eye screening was significantly associated with lower tumor burden (p = 0.03), lower treatment burden (p = 0.04), higher rate of ocular salvage (p = 0.01), and better visual outcome (p = 0.01)., Conclusion: Parental knowledge of retinoblastoma nature and heritability is crucial to good patient outcomes, but translating this knowledge into appropriate action (i.e. screening of at-risk children) is still deficient.

Objective: To evaluate the clinical presentation of retinoblastoma in Alexandria, Egypt, correlate the timing of accurate diagnosis with the presence of advanced disease and identify causes of delayed presentation., Methods: Retrospective noncomparative single institution study reviews demographic and clinical data of all new children with retinoblastoma presenting to Alexandria Main University ocular oncology clinic (OOC) from January 2012 to June 2014. Diagnosis time was from initial parental complaint to retinoblastoma diagnosis and referral time was from retinoblastoma diagnosis to presentation to the Alexandria OCC. Delayed Diagnosis and referral were counted if >2 weeks. Advanced presentation is defined as clinical TNMH (8th edition) staging of cT2 or cT3 (international intraocular retinoblastoma classification group D or E) in at least one eye or the presence of extra-ocular disease (cT4)., Results: Seventy eyes of 47 children were eligible: 52% unilateral, 7% with family history and 96% presented with leukocorea. Sixty-four percent of children had advanced intraocular disease and none had extra-ocular disease. Delayed presentation occurred in 58% of children and was significantly associated with advanced disease in both unilaterally and bilaterally affected children (p = 0.003, 0.002 respectively). The delay in diagnosis was more in unilateral cases while the delay in referral was more in bilateral cases. The main cause of delayed presentation in unilateral retinoblastoma was misdiagnosis (30%) while parental shopping for second medical opinion (30%) was the main cause in bilateral children., Conclusions: Delayed diagnosis is a problem affecting retinoblastoma management. Better medical education and training, health education and earlier screening are recommended to achieve earlier diagnosis.

Retinoblastoma is the prototype genetic cancer: in one or both eyes of young children, most retinoblastomas are initiated by biallelic mutation of the retinoblastoma tumor suppressor gene, RB1, in a developing retinal cell. All those with bilateral retinoblastoma have heritable cancer, although 95% have not inherited the RB1 mutation. Non-heritable retinoblastoma is always unilateral, with 98% caused by loss of both RB1 alleles from the tumor, whereas 2% have normal RB1 in tumors initiated by amplification of the MYCN oncogene. Good understanding of retinoblastoma genetics supports optimal care for retinoblastoma children and their families. Retinoblastoma is the first cancer to officially acknowledge the seminal role of genetics in cancer, by incorporating "H" into the eighth edition of cancer staging (2017): those who carry the RB1 cancer-predisposing gene are H1; those proven to not carry the familial RB1 mutation are H0; and those at unknown risk are HX. We suggest H0* be used for those with residual <1% risk to carry a RB1 mutation due to undetectable mosaicism. Loss of RB1 from a susceptible developing retinal cell initiates the benign precursor, retinoma. Progressive genomic changes result in retinoblastoma, and cancer progression ensues with increasing genomic disarray. Looking forward, novel therapies are anticipated from studies of retinoblastoma and metastatic tumor cells and the second primary cancers that the carriers of RB1 mutations are at high risk to develop. Here, we summarize the concepts of retinoblastoma genetics for ophthalmologists in a question/answer format to assist in the care of patients and their families., (Copyright 2017 Asia-Pacific Academy of Ophthalmology.)

Purpose: To compare overall outcomes of conventional postnatal screening of familial retinoblastoma and prenatal RB1 mutation identification followed by planned early-term delivery., Design: Retrospective, observational study., Participants: Twenty children with familial retinoblastoma born between 1996 and 2014 and examined within 1 week of birth., Methods: Cohort 1 included spontaneously delivered neonates examined within 1 week of birth and confirmed postnatal to carry their family's RB1 mutant allele. Cohort 2 included infants identified by amniocentesis to carry their family's RB1 mutant allele, and therefore scheduled for early-term delivery (36-38 weeks' gestation). Treatment for retinoblastoma was performed at the Hospital for Sick Children, Toronto, Canada., Main Outcome Measures: Age at first tumor in each eye, eye stage, treatments given, ocular salvage, treatment success (defined as avoidance of enucleation, external-beam irradiation, or both), visual outcome, number of anesthetics, pregnancy or delivery complications, and estimated treatment burden., Results: Vision-threatening tumors were present at birth in 4 of 8 infants in cohort 1 and in 3 of 12 infants in cohort 2. Eventually, all infants demonstrated tumors in both eyes. At the first treatment, 1 of 8 infants in cohort 1 had eyes in stage cT1a/cT1a or cT1a/cT0 (smallest and least vision-threatening tumors), compared with 8 of 12 infants in cohort 2 (P = 0.02). Null RB1 germline alleles induced earlier tumors than low-penetrance alleles (P = 0.03). Treatment success was achieved in 3 of 8 children in cohort 1 compared with 11 of 12 children in cohort 2 (P = 0.002). Acceptable vision (better than 0.2 decimal) was achieved for 8 of 16 eyes in cohort 1 compared with 21 of 24 eyes in cohort 2 (P = 0.014). Useful vision (better than 0.1, legal blindness) was achieved for 8 of 9 children in cohort 1 compared with 12 of 12 children in cohort 2. There were no complications related to early-term delivery. Median follow-up was 5.6 years, cohort 1 and 5.8 years, cohort 2., Conclusions: When a parent had retinoblastoma, prenatal molecular diagnosis with early-term delivery increased the likelihood of infants born with no detectable tumors, better vision outcomes, and less invasive therapy. Prenatal molecular diagnosis facilitates anticipatory planning for both the child and family., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The first chemical synthesis of the complete protective O-antigen of a human-disease-causing pathogenic bacterium is described. The synthesis involved a protecting-group strategy that facilitated the regioselectivity of the key transformations, stereoselective glycosylation reactions, and enabled the one-step global deprotection of the completely assembled, fully protected, phosphorylated hexasaccharide by hydrogenation/hydrogenolysis. The final amino-group-functionalized, linker-equipped antigen was obtained in a form ready for conjugation to suitable carriers, for example, proteins, to yield immunogens., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Importance: Intra-arterial chemotherapy has emerged as a treatment for intraocular retinoblastoma and has been quickly adopted by centers worldwide., Objective: To conduct a systematic review and attempt a meta-analysis to summarize the reported outcomes of intra-arterial chemotherapy., Evidence Review: In January 2015, we performed comprehensive searches in Medline, Embase, Cochrane, and Web of Science from inception through January 2015, including any peer-reviewed English-language publication that described outcomes related to toxicity or efficacy in at least 4 patients., Findings: From a total of 208 identified publications, 28 met inclusion criteria. Twelve reports with discernable nonduplicative information were included, reporting 655 patients, 757 eyes, and 2350 catheterizations. All were single-arm case series, and 67% (8 of 12) were retrospective. Across all studies, globe salvage was achieved for 502 (66%) of all eyes. Most common reported toxicities were chorioretinal atrophy and vascular occlusions. There were at least 13 reports of children with metastases. After publication, 7 additional children had metastases. The 4 different classification systems used challenged the comparison of disease severity at presentation. Visual outcome was not addressed in most studies. Meta-analyses were not possible because no study had a comparative group. Assessment of risk of bias was not possible because no validated tool for single-arm studies was available., Conclusions and Relevance: Intra-arterial chemotherapy is a promising new treatment associated with high rates of globe salvage. However, the literature is limited by the predominance of retrospective case series, absence of comparison groups, short median follow-up, heterogeneous definitions and tumor classifications, and frequent duplicate reporting. Metastases have been observed, and long-term follow-up is needed. Until the results of clinical, prospective studies are available, it is recommended that intra-arterial chemotherapy be offered selectively among other options, with fully informed discussion about all possible risks, benefits, and uncertainties.

A new pathway to the tetrasaccharide α-Colp-(1→2)-4,6-P-β-d-Galp-(1→3)-[α-Colp-(1→4)]-β-d-GlcpNAc-1-(OCH2CH2)3NH2 has been developed. Glycosylation of 8-azido-3,6-dioxaoctyl 4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-β-d-glucopyranoside with 3,4,6-tri-O-acetyl-2-O-bromoacetyl-α-d-galactopyranosyl bromide afforded the β-linked disaccharide. Debromoacetylation followed by reductive opening of the benzylidene acetal afforded the disaccharide diol acceptor. Halide-assisted glycosylation with 2,4-di-O-benzyl-α-colitosyl bromide gave the 1,2-cis-coupling product. Deacetylation followed by regioselective phosphorylation gave isomeric (R,S)-(P)-4(II),6(II)-cyclic phosphates, which were globally deprotected by one-step catalytic (Pd/C) hydrogenation/hydrogenolysis. The target tetrasaccharide, obtained in high overall yield, is amenable for conjugation to proteins.

Purpose: To identify the socioeconomic and psychosocial impacts of clinical treatment decisions for advanced unilateral intraocular retinoblastoma., Design: Retrospective observational case series., Setting: institutional study at Alexandria Main University Hospital., Study Population: records of 66 unilateral retinoblastoma cases treated from May 2005 to May 2013 were retrospectively reviewed. Sixty cases were eligible (International Intraocular Retinoblastoma Classification [IIRC] group C, D or E)., Procedures: two treatment groups were compared: enucleation vs. salvage treatment. Salvage treatment eyes were further subdivided based on IIRC group. Six socioeconomic parameters (financial burden, financial impact, psychological, social, medical and tumor impacts) were scored. Parameter scores ranged from 0 to 3, for overall score range 0 (no adverse impact) to 18 (severe adverse impact)., Main Outcome Measures: derived Socioeconomic scores were correlated with treatment and outcomes., Results: The enucleation group (28 eyes) had a median overall Socioeconomic score of 4/18, significantly lower than the salvage treatment group (32 eyes), median score 11/18 (P<0.01). Socioeconomic score varied with IIRC group. Attempted eye salvage failed in 25 children, due to uncontrolled tumor (44%) and socioeconomic impact of cumulative therapies (56%). Treatment duration and Socioeconomic score were higher for the 5 children in the salvage treatment group who developed metastatic disease compared to those without metastasis (P<0.01)., Conclusions: The socioeconomic and psychosocial impacts of attempted ocular salvage for unilateral intraocular retinoblastoma are severe, in comparison to primary enucleation. Primary enucleation is a good treatment for unilateral retinoblastoma., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

N-Bromosuccinimide-mediated 4,6-O-benzylidene ring opening in 8-azido-3,6-dioxaoctyl 4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-β-D-glucopyranoside afforded the corresponding 4-O-benzoyl-6-bromo-6-deoxy analogue, which was coupled with 3,4,6-tri-O-acetyl-2-O-benzyl-α-D-galactopyranosyl chloride to give the 1,2-cis α-linked disaccharide as the major product. Conventional hydroxyl group manipulation in the latter and products of further conversions gave the desired, functionalized disaccharide α-D-GalpA-(1→3)-β-D-QuipNAc. The rare, foregoing sequence forms the downstream end in the O-specific polysaccharide of both Vibrio cholerae O22 and O139. Halide-assisted glycosylation at 4(I)-OH in 8-azido-3,6-dioxaoctyl 6-O-benzyl-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2-trichloroacetamido-β-D-glucopyranoside, obtained by regioselective reductive opening of the acetal ring in the parent 4(I),6(I)-O-benzylidene derivative, with 2,4-di-O-benzyl-α-colitosyl bromide, gave exclusively the α-linked trisaccharide. The latter was sequentially deacetylated and selectively benzylated to give 8-azido-3,6-dioxaoctyl 2,4-di-O-benzyl-3,6-dideoxy-α-L-xylo-hexopyranosyl-(1→4)-[3-O-benzyl-β-D-galactopyranosyl-(1→3)]-6-O-benzyl-2-deoxy-2-trichloroacetamido-β-D-glucopyranoside. Subsequent selective phosphorylation of the triol, thus obtained, with 2,2,2-trichloroethyl phosphorodichloridate afforded isomeric (R,S)-(P)-4(II),6(II)-cyclic phosphates, which were both obtained in crystalline form and fully characterized. Each of the latter was globally deprotected by catalytic (Pd/C) hydrogenation/hydrogenolysis to give the desired, amino-functionalized, spacer-equipped, phosphorylated upstream trisaccharide fragment of the O-PS of V. cholerae O139.