The tumor suppressor Annexin A6 increases the sensitivity towards anti-cancer drugs targeting the EGFR/Ras/MAPK pathway

Sustained EGFR/Ras/MAPK signaling is associated with various cancers. Hence, blocking EGFR and its downstream effectors has become an established target in anti-cancer therapeutics. However, targeted agents face several challenges which limit their clinical use such as inter-patient variation, mutation, and resistance. Therefore, the identification of biomarkers that could predict the treatment outcome in cancer patients is crucial. Annexin A6 (AnxA6) is a calcium-dependent membrane binding protein with potential tumor suppressor properties. It was shown to bind and promote the involvement of p120GAP and protein kinase Cα (PKCα), two negative regulators of the EGFR/Ras/MAPK pathway, in the signal termination of this cascade. Increasing evidence points at the involvement of scaffold proteins, like AnxA6, in the sensitivity of cancer cells towards anti-cancer drugs. In this study, we examined the influence of single and combinatorial treatments targeting the EGFR/Ras/MAPK signaling cascade on the oncogenic proliferation of A431 cells in the presence and absence of AnxA6. Using A431wt cells, which lack endogenous AnxA6, and A431-A6 cells, a well characterized cell line which stably overexpress AnxA6, we investigated clonogenic growth in the presence of the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, the EGFR-targeted monoclonal antibody cetuximab, the MEK1/2 inhibitor PD98059, and the PKCα inhibitors BIM-I and Gö 6976 via clonogenic and MTS assays. We found that treating the cells with TKIs, MEK1/2 or PKCα inhibitors was able to effectively reduce colony and cell growth more than the individual drugs, and this inhibition was more pronounced in AnxA6 overexpressing cells. Furthermore, combinatorial treatment of A431 cancer cells with TKIs together with MEK1/2 inhibitors was more effective in cells expressing AnxA6. The data presented here suggest AnxA6 as a possible biomarker that could predict treatment outcome in EGFR-related cancers

Evaluating the performance of two rapid antigen detection tests in diagnosis of SARS- COV- 2 infection

Background:Rapid antigen detection tests for SARS-CoV-2 infection could promote the clinical and public health policies to handle the COVID-19 pandemic. Rapid antigen detection and molecular approaches could expand entry to checking and initial evidence of issues and playing an essential role in public health managing choices that may decrease the transmission. Objectives: We evaluated the diagnostic accurateness of couple of rapid antigen recognition tests equated with the molecular-based assays for verdict of SARS-CoV-2 infection. Methods: The 100 nasopharyngeal swabs were verified by the SARS-CoV-2 RT-PCR kit as a gold standard for COVID-19 recognition. SARS‐CoV‐2 antigen (Ag) was evaluated in the nasopharyngeal swabs using iFlash and UNICELL-2019-nCoV antigen methods. The iFlash-2019-nCoV antigen assay, which is a chemiluminescent immunoassay (CLIA), was used to qualitatively determine the nucleocapsid protein antigen, where the other one was used to identify the nucleocapsid protein antigen by lateral flow immunofluorescent test. Results: Out of the 100 samples, 62% were positive by RT-PCR. Amongst 62 confirmed COVID-19 cases, 43 (69.4%) were positive by iFlash and 40 samples (64.5%) were positive by the UNICELL-2019-nCoV antigen assay. The specificity of both I Flash-2019-nCoV antigen assay & UNICELL-2019-nCoV antigen assay with RT-PCR were 100% and sensitivity were 69.35 and 64.52%, respectively. This sensitivity was augmented to 100% compared with the PCR with Ct-value of ≤25 and specificity of 80.28 and 84.51%, respectively. Conclusion: Antigen detection rapid diagnostic tests may be motivating in the initial stage of the infection when the viral load is elevated, and the risk of SARS‐CoV‐2 transmission be high

Rhamnolipids nano-micelles as a potential hand sanitizer

COVID-19 is a pandemic disease caused by the SARS-CoV-2, which continues to cause global health and economic problems since emerging in China in late 2019. Until now, there are no standard antiviral treatments. Thus, several strategies were adopted to minimize virus transmission, such as social distancing, face covering protection and hand hygiene. Rhamnolipids are glycolipids produced formally by Pseudomonas aeruginosa and as biosurfactants, they were shown to have broad antimicrobial activity. In this study, we investigated the antimicrobial activity of rhamnolipids against selected multidrug resistant bacteria and SARS-CoV-2. Rhamnolipids were produced by growing Pseudomonas aeruginosa strain LeS3 in a new medium formulated from chicken carcass soup. The isolated rhamnolipids were characterized for their molecular composition, formulated into nano-micelles, and the antibacterial activity of the nano-micelles was demonstrated in vitro against both Gram-negative and Gram-positive drug resistant bacteria. In silico studies docking rhamnolipids to structural and non-structural proteins of SARS-CoV-2 was also performed. We demonstrated the efficient and specific interaction of rhamnolipids with the active sites of these proteins. Additionally, the computational studies suggested that rhamnolipids have membrane permeability activity. Thus, the obtained results indicate that SARS-CoV-2 could be another target of rhamnolipids and could find utility in the fight against COVID-19, a future perspective to be considered

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

AER-075

Anticipating the potential future changes of airport design and expansion along with city planning for the purpose of bringing the two entities in closer alignment with one another is the main purpose of this book. By conducting a timeline analysis of five different US cities and their airports, conclusions were drawn from tracking the relationship between the growth patterns of both. This allowed for a discovery of methods to increase connectivity with one another. These conclusions were followed by an overview of the jet industry and its possible future impacts on the way airports are designed, considering future adaptations of airports to new design and technology concepts in aerospace. The concept of ”integration through fragmentation” is explored in the final two chapters. Architectural fragmentations of airport programs and their integration into urban design/planning were applied to three cities - from the five previously selected- in order to; give readers a closer vision and understanding of how the concept might work. Possible variations of “fragmentation” design decisions were simulated in response to each city’s driving forces. The application time of the proposed concept considered by this book is the year 2075, the ideas consider a long-range of planning and work with a mixture of hard data and hypothetical scenarios. This project predicts that by 2075, new building, security and aircraft technologies will enable a fragmenting of airport programs and a reintegration of them with city future master plans to simultaneously address the needs of both cities and airports.https://digitalscholarship.unlv.edu/arch_grad_capstones/1004/thumbnail.jp

Response to MEK inhibitor in small cell neuroendocrine carcinoma of the cervix with a KRAS mutation

• Molecular testing may play a role in the determination of targeted therapy treatment options. • Targeted therapy provides treatment options for recurrent cervical cancer. • MEK inhibitor is a treatment option for recurrent cervical cancer in a patient with KRAS mutation

Clinico-laboratory outcomes of plasma transfusion in the Egyptian’s pediatric intensive care units—a prospective observational study

Abstract Background Despite the paucity of data supporting their indications, plasma transfusions (PT) are regularly administered for critically ill patients (CIP) in pediatric intensive care units (PICU). The aim of this study was to identify the actual indications for PT in the Egyptian’s PICUs and determine to what extent it affects the clinic-laboratory outcomes for CIP. Methods A prospective observational study was conducted for 6 months on 180 CIP in PICUs of Cairo University Hospital who received plasma for at least one time during their length of stay (LOS). Full history, examination, and investigations were obtained from the medical records. Results Plasma was transfused in 64.4% of the studied population to support moderate and severe critical illness identified by multiple organ dysfunction score (MODS). Meanwhile, subjective-based physician conceptions accounted for 12.8% of all indications for plasma transfusion. PT in CIP was associated with a significant reduction in platelet count, prothrombin time, partial thromboplastin time, and international normalized ratio with p-value < 0.001, while there was a significant increase in hemoglobin level with p-value < 0.001. A statistically positive correlation exists between the time interval between admission and 1st PT and LOS with a p-value < 0.001 being shorter with earlier transfusion. Of the 180 patients enrolled in this study, seventy patients (38.9%) died, while 110 patients (61.1%) survived. A statistically significant increase in mechanical ventilation (MV) (p = 0.004), total number of PT (p < 0.001), and MODS score (p < 0.001) were recorded in dead CIP compared with survivors. Conclusion Moderate and severe critical illness identified by MODS was the most frequent cause for PT in the Egyptian’s PICUs. Early, precise, and objectively based PT has a strong role in improving the outcomes in CIP

Binary ethosomes for the enhanced topical delivery and antifungal efficacy of ketoconazole

This work aimed to prepare ketoconazole-loaded ethosomes and binary ethosomes to improve its skin delivery and antifungal efficacy. A 32 factorial design was used to optimize the ethosomes and formulate ketoconazole-loaded binary ethosomes. Ethosomes and binary ethosomes were evaluated for particle size, polydispersity index, zeta potential, percent drug entrapment efficiency, drug release, skin permeation and deposition and antifungal efficacy. The ethosomes particle size ranged from 78.99±16.72 to 321.53±10.41 nm and decreased by increasing phospholipid and ethanol concentrations. The polydispersity index values were in the range of 0.17±0.01 to 0.49 ± 0.04. The percent drug entrapment efficiency ranged from 36.09±2.66 to 95.89±0.19 and increased by increasing phospholipid concentration while ethanol concentration had the opposite effect. The binary ethosomes had smaller size but similar drug entrapment efficiency and zeta potential compared with the ethosomes. They had significantly higher percent drug release (∼96%) and permeation (∼95%) through rat skin compared with the ethosomes (93% and 90%, respectively). Binary ethosomes and ethosomes had, respectively 1.9 and 1.8-fold higher drug skin permeation and 5.3- and 5.6-fold higher drug deposition in the epidermis/dermis compared with the drug suspension. The antifungal efficacy of the drug-loaded ethosomes and binary ethosomes were similar to the drug hydroalcoholic solution. Collectively, these results confirm the potential of these nanocarriers to enhance drug efficacy given their small size, sustained drug release and enhanced skin permeability