Neutrophils and monocyte toll like receptors 2 and 4 expression in preterm versus term delivery.

Pregnancy results in an increase in immune cells, especially monocytes, which enhances the innate immune system. The increase of inflammatory cytokines in pregnant women's amniotic fluid, can cause uterine contraction, is linked to preterm labor. These inflammatory responses are controlled by Toll-like receptors (TLRs), which are largely expressed on neutrophils and monocytes. This study aimed to determine the role of neutrophils and monocyte subsets, as well as their expression of TLR-2 and TLR-4 in women with preterm and full-term delivery. The study involved a total of 74 women, comprising of 29 preterm labor, 25 full-term labor, and 20 non-pregnant women. The distribution of three monocyte subsets, namely (CD14++CD16-), (CD14+CD16+), and (CD14-/dim CD16++) was measured. Also, the expression of TLR2 and TLR4 in monocytes and neutrophils was analyzed using flow cytometry. Non-classical monocytes and intermediate monocytes were significantly higher in the preterm group than the control and full-term groups (p=0.041, p=0.043, and p=0.004, p= 0.049, respectively). Women in the preterm group showed significantly TLR2 expression on nonclassical monocytes compared to the control and full-term groups (p=0.002, and p=0.010, respectively). Also, preterm group expression of TLR4 was significantly higher in classical monocytes and nonclassical monocytes in comparison to the control group (p=0.019, and p≤0.0001, respectively). Besides, TLR4 expression was significantly up regulated in the preterm group compared to full-term in non-classical monocyte subset (p < 0.0001). Moreover, the expression of TLR-4 in neutrophils from the preterm group was statistically higher than expression from the full-term labor and control groups (p < .0001 for both). Such findings highlight the important role of monocyte subsets and neutrophils in activating the innate immune system and initiating strong pro-inflammatory responses that induce preterm labor. Additionally, TLR4 and TLR2 expressions on non-classical monocytes may be used as a marker to assess the probability of preterm labor.

Could the Crosstalk Between Myeloid-Derived-Suppressor Cells and Regulatory T Cells Have a Role in Beta-Thalassemia?

Background: Secondary iron overload, alloimmunization, and increased risk of infection are common complications in patients with transfusion-dependent thalassemia (TDT). Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) play an essential role in preventing excessive immune response. This research aimed to study the interaction between Tregs and MDSCs in TDT patients and to evaluate the association of these cell types with disease severity. Methods: This case-control study included 26 patients with TDT and 23 healthy, age- and sex-matched controls. All patients were investigated for complete blood count (CBC), serum ferritin, and flow cytometric analysis of peripheral blood to detect Tregs, MDSCs, and MDSC subsets. Results: A significant increase was observed in the frequencies of Tregs and MDSCs, particularly monocytic MDSCs (MO-MDSCs), in TDT patients compared with controls. The frequencies of these cells showed a direct association with ferritin level and total leukocyte count and an inverse association with hemoglobin level. Furthermore, a positive correlation was observed between Tregs and each of the total MDSCs and MO-MDSCs. Conclusions: Levels of Tregs and MDSCs increased in TDT and may probably have a role in suppressing the active immune systems of TDT patients.

Effect of 17-Hydroxyprogesterone Caproate on Interleukin-6 and Tumor necrosis factor-alpha in expectantly managed early-onset preeclampsia.

The study aimed to evaluate the effect of 17 hydroxy progesterone (17-OHPC) on interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in expectantly managed early-onset preeclampsia (PE). A randomized open-label controlled study included women who were diagnosed as early-onset PE if they assigned to expectant management according to the American College of Obstetricians and Gynecologists (ACOG) 2013 criteria for diagnosis of severity of PE. Patients were randomized into Group A (40 patients) received 17-OHPC 250 mg intra-muscular at admission and every 7 days thereafter and Group B (40 patients) was given the usual conservative measures of early-onset PE as a control group. Blood samples were obtained from all participants for measurements of TNF-α and IL-6 levels at admission and repeated at termination of pregnancy. The primary outcome was the mean difference between TNF-α and IL-6 levels before and after treatment in both groups. TNF-α and IL-6 levels at admission were not different between the two groups. However, there was a significant difference concerning these inflammatory biomarkers within the same group at admission and at termination (p < 0.001), with significant decline of IL-6 and TNF-α level in the 17-OHPC treated group and significant rise of IL-6 and TNF-α in the control group. There was a strong positive correlation between systolic blood pressure (SBP) at admission and TNF-α level (r= 0.867, p=0.017), and moderately positive significant correlation between diastolic blood pressure (DBP) at admission and TNF-α (r=0.610, p < 0.001). There was a mild positive significant correlation between IL-6 levels and SBP (r= 0.231, p=0.039), and DBP (r= 0.203, p= 0.041) at admission. In conclusion, 17-OHPC has no effect in improving maternal or neonatal outcomes in conservatively managed early onset PE, although it alters the inflammatory markers levels (IL-6 and TNF-α) that could improve the pathogenesis of PE.

Maternal urinary vascular endothelial growth factor (VEGF) versus N.T. pro brain natriuretic peptide (NT-pro BNP) as novel biomarkers for placental accreta spectrum (PAS): A case-control study.

This study planned to compare the predictive ability of maternal urinary vascular endothelial growth factor (VEGF) versus N-terminal pro B-type natriuretic peptide (NT-pro BNP) for prediction of placenta accreta spectrum (PAS). This was a prospective case-control study carried out in a tertiary university hospital. It included pregnant women between 37-39 weeks. The study included 50 pregnant women classified in two groups. Group (Ι, n=25) were pregnant women with PAS, and group (II, n=25) women with uncomplicated pregnancies, as controls. Urine samples were collected, and quantitative analyses of VEGF and NT-pro BNP were performed by ELISA. VEGF was assessed with a cut point of 215.6 pg/ml and NT-pro BNP with a cut point of 182.2 pg/ml to predict the condition of PAS. Both biomarkers were good predictors of PAS with the area under the ROC curve (AUC) equal to (0.871 and 0.904), respectively. However, maternal urinary VEGF levels could predict PAS better than NT-pro BNP (OR=9.967, 95%CI 2.032-48.879, p=0.005) versus (OR=8.066, 95% CI 1.520 - 42.811, p=0.014) in NT-pro BNP. In conclusion, third trimester urinary levels of both VEGF and NT-pro BNP appear to be s crucially good predictors for PAS. However, VEGF is superior to NT-pro BNP in predicting women with PAS. These biomarkers present promising candidates as they can help to detect patients at high probability of PAS. They can be assessed by non-invasive, simple, and low-cost procedures.

Prognostic factors affecting infantile medulloblastoma outcomes in the molecular era: a 12-year single-center experience from Egypt.

Aims: To assess the clinical, pathological and molecular characteristics (Sonic hedgehog and group 3/4 molecular subtypes expression) and treatment modalities for infantile medulloblastoma in correlation with outcomes. Materials & methods: A retrospective study of 86 medulloblastoma patients (≤3 years) was conducted. M0 patients <2.5 years received four cycles of chemotherapy followed by focal radiotherapy (FRT) and chemotherapy. Between 2007 and 2015, Metastatic patients <2.5 years received craniospinal irradiation (CSI) after the end of chemotherapy. After 2015, metastatic patients <2.5 years received CSI postinduction. Results: The hazard ratio for death was significantly higher in the FRT (HR = 2.8) group compared with the CSI group (hazard ratio = 1). Metastatic disease significantly affected the overall survival of the Sonic hedgehog group and the overall survival and event-free survival of group 3/4. Conclusion: Metastatic disease had a significant impact on outcomes. FRT is not effective in treating infantile medulloblastoma.

This study aimed to analyze the management of and prognostic factors affecting the outcomes of 86 young children (<3 years of age at presentation) diagnosed with medulloblastoma, an aggressive brain tumor that is commonly seen in this age group. All children had surgical operations aiming at resecting their tumors, followed by chemotherapy and irradiation. Study results showed that disease disseminated into the nervous system was associated with poorer outcomes compared with localized disease. Administration of local irradiation to the primary tumor site in the brain only, without exposing the spinal cord to radiotherapy, was associated with a higher risk of death.

Evaluation of diagnostic performance of a rapid antigen test in diagnosing COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is our time's major global health crisis and the greatest health challenge. Reverse transcription-polymerase chain reaction (RT-PCR) test for severe acute respiratory syndrome coronavirus (SARS-CoV-2) is the gold standard technique for diagnosis of symptomatic cases and asymptomatic carriers. By 2020, antigen rapid tests have been approved for use in Covid-19 testing by regulatory bodies all over the world owing to their benefits as they are rapid and cost effective. This work aimed to determine the diagnostic sensitivity and accuracy of the SARS-CoV-2 rapid antigen test in the detection of SARS-CoV-2 infection compared to RT-PCR data. The study included 111 symptomatic COVID-19 patients and 20 control subjects. Of the 111 study patients, 91 patients (81.98%) were positive by RT-PCR and 20 patients negative. The BIOZEK antigen COVID-19 Ag rapid test device was evaluated using sera from the 111 symptomatic COVID-19 patients. Of the 91 RT-PCR positive patients, 81 (90.1%) were positive by the antigen rapid diagnostic test (Ag-RDT). The control subjects were negative by both tests. The overall sensitivity, specificity, PPV, NPV, and accuracy of the Ag-RDT were 91.11%, 100%, 100%, 68.9%, and 91.8%, respectively and these increased as the level of viremia increased. In conclusion, the used Ag-RDT showed high sensitivity and accuracy for detecting of a SARS-CoV-2 infection, especially when the viral load was high. However, the test lacks sensitivity particularly in those with low viral load.

Assessment of COVID -19 associated coagulopathy and multiple hemostatic markers: a single center study in Egypt.

BACKGROUND: Coagulopathy is still a serious pattern of coronavirus-19 disease. We aimed to evaluate COVID-19-associated coagulopathy and multiple hemostatic markers in Egyptian patients. In addition, to assess coagulation acute phase reactants and its effect on the outcome. METHODS: The study included 106 COVID-19 patients, and 51 controls. All patients were positive for COVID-19 infection by nasopharyngeal swab for detection of viral RNA by real-time PCR. In addition to baseline data and radiological findings, the coagulation profile was done with special attention to Fibrinogen, D-dimer, Factor VIII, von Willebrand factor (VWF), Protein C, Protein S, Antithrombin III (ATIII) and Lupus anticoagulant (LA)-1 and 2. RESULTS: The results showed significantly higher VWF, D-dimer, and LA1 (screening) and LA2 (confirmation) in patients than a control group. Significantly higher D-dimer FVIII, VWF and LA1-2 were detected in the severe group. ATIII had high diagnostic accuracy in severity prediction. We found a significantly higher international randomized ratio (INR) and VWF among patients with thrombotic events. For prediction of thrombosis; VWF at cutoff > 257.7 has 83.3% sensitivity and 83.3% specificity. CONCLUSION: Patients with COVID-19 infection are vulnerable to different forms of coagulopathy. This could be associated with poor outcomes. D-Dimer is a chief tool in diagnosis, severity evaluation but not thrombosis prediction. Early screening for this complication and its proper management would improve the outcome.

Surgical outcome of children with medulloblastoma: a retrospective study of a 405-patient series from Children's Cancer Hospital Egypt (CCHE-57357).

PURPOSE: To analyze the impact of increasing the extent of resection (EOR) on the survival rates and on the surgical outcome of children with medulloblastoma. METHODS: A series of consecutive 405 children operated for medulloblastoma between July 2007 and April 2018 was identified. The details of pre-operative data, surgical interventions, post-operative complications, and survival rates were analyzed. RESULTS: The Kaplan-Meier (KM) analysis showed no advantage of gross total resection (GTR) over near and subtotal resection regarding over all (OS) (p=0.557) and progression free survival (PFS) (p=0.146). In the same time, increasing the EOR was not associated with higher morbidity. Tumor dissemination at onset correlated to worse OS (KM: p=0.003, OR 1.999, 95% CI: 1.242-3.127; p = 0.004) and PFS (KM: p<0.001, Cox: OR 2.171, 95% CI: 1.406-3.353; p<0.001). OS was significantly affected in patients < 3 years old (KM: p=0.011, OR 2.036, 95% CI: 1.229-3.374; p = 0.006), while PFS was worse among patients who had pre-op seizures (KM: p=0.036, Cox: OR 2.852, 95% CI: 1.046-7.773; p=0.041) or post-op pseudomeningocele (KM: p=0.021, Cox: OR 2.311, 95% CI: 1.123-4.754; p=0.023). CONCLUSIONS: Although surgical excision of medulloblastoma is the standard of care, there was no significant benefit for GTR over near or subtotal resection on the OS or PFS rates that are mainly influenced by the patient's age and tumor dissemination. However, GTR should be targeted, as it is not associated with increased incidence of mutism or other surgery-related complications.

Design and Synthesis of New CDK2 Inhibitors Containing Thiazolone and Thiazolthione Scafold with Apoptotic Activity.

Cyclin dependent kinase 2 (CDK2) inhibition is a well-established strategy for treating cancer. Different series of novel thiazolone (1, 7-9) together with fused thiazolthione (2-6, and 10) derivatives were designed, then synthesized and evaluated for their biological inhibitory activity against CDK2. Additionally, the cytotoxicity of the new compounds was explored against breast and colon cancer cell lines. The novel thiazolone and the fused thiazolthione derivatives exhibited potent CDK2/cyclin A2 inhibitory effect of an IC50 values ranging 105.39-742.78 nM. Amongst them compounds 4 and 6 revealed highest IC50 of 105.39 and 139.27 nM, respectively. Most compounds showed significant inhibition on both breast cancer and colon cancer cell lines with IC50 range 0.54-5.26 and 0.83-278 µM, respectively. Further investigations involved flow cytometry analysis on MCF-7 cancer cell line for compounds 5 and 7 which resulted in arrest cell-cycle at two phases Pre G1/G2-M and re-enforced apoptosis via activation of caspase-7. Molecular modeling simulation of the designed compounds revealed that they were well fitted into CDK2 active site and their complexes were stabilized through the essential hydrogen bonding. Three dimensional quantitative structure activity relationship (3D QSAR) pharmacophore, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were also carried out showing proper pharmacokinetic and drug-likeness which aided in the prediction of the structure requirements responsible for the observed antitumor activity.

Discovery of pyrano[2,3-d]pyrimidine-2,4-dione derivatives as novel PARP-1 inhibitors: design, synthesis and antitumor activity.

Poly(ADP-ribose) polymerases-1 (PARP-1) are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death. In this study, we report the synthesis of a novel series of pyrano[2,3-d]pyrimidine-2,4-dione analogues as potential inhibitors against PARP-1. All the newly synthesized compounds were evaluated for their inhibitory activity towards PARP-1 and examined for their anti-proliferative activity against MCF-7 and HCT116 human cancer cell lines. The synthesized compounds showed promising activity where compounds S2 and S7 emerged as the most potent PARP-1 inhibitors with an IC50 value of 4.06 ± 0.18 and 3.61 ± 0.15 nM, respectively compared to that of Olaparib 5.77 nM and high cytotoxicity against MCF-7 with IC50 2.65 ± 0.05 and 1.28 ± 1.12 µM, respectively (Staurosporine 7.258 µM). Compound S8 remarkably showed the highest cell growth inhibition against MCF-7 and HCT116 with an IC50 value of 0.66 ± 0.05 and 2.76 ± 0.06 µM, respectively. Furthermore, molecular docking of the compounds into the PARP-1 active site was performed to explore the probable binding mode. Finally, most of the synthesized compounds were predicted to have good pharmacokinetics properties in a theoretical kinetic study.

Effect of Combined HCV Therapy on Natural Killer Cell Activity.

Hepatitis C virus (HCV) is a major health problem all over the world with the highest prevalence reported in Egypt. Various treatment regimens have been developed over the last years. Interferon (IFN) based regimen was the standard of care regimen and then the IFN-free therapies were emerged. Host innate immunity through the activity of natural killer (NK) cell is one of the major players in competing infections and tumors, by producing perforin and granzymes that cause cytolysis of target cells, or by the production of various cytokines such as natural interferon gamma. Natural cytotoxicity receptors (NCRs), including Nkp30, Nkp44 and Nkp46, are a group of activating receptors that almost have restricted expression on the surface of NK cells and their density correlates with NK cytotoxicity. The role of these cells is not fully elucidated in patients with chronic HCV infection either treatment-naive or treatment experienced. Therefore, this study aimed to investigate the change that occurs in NK cell activity and cytotoxicity in response to successful elimination of HCV from blood after triple therapy with PEG-IFN-α, ribavirin and sofosbuvir. A total of 56 (50 male: 6 female) HCV patients with mean age of 41.6± 12.1 years were included in this study. They were divided into two groups: treatment naive group (20 patients) and the sustained virologic response (SVR) group (36 patients). All patients were investigated for their NK cell profile, NCRs, perforin and granzyme B expression by flow cytometry. Data was expressed as mean fluorescence intensity (MFI). Results revealed significant increase in MFI of granzyme B (P=0.001) and decrease in MFI of NKp30 (P=0.042) in the SVR group as compared to treatment naïve group. These findings indicated that triple therapy of HCV (IFN, Ribavirin and Sofosbuvir) effected NK activation and cytotoxicity.