Effect of MUC16 Blockade using the Humanized AR9.6 Antibody in Patient Derived Organoid Models of PDAC

Pancreatic Ductal Adenocarcinoma (PDAC) represents nearly 90% of all pancreatic cancer cases. 49,830 of the 62,210 patients diagnosed in 2022 are estimated to succumb to the malignancy. Early diagnosis of the disease is uncommon as most patients present with symptoms when the cancer is late-stage and metastatic. This decreases the likelihood of successful surgical resection and increases the dependency on standard of care chemotherapy leads to which is met with therapeutic resistance, demonstrated by the 5-year post-diagnosis survival rate of a mere 11.5%. Mucin-16, a heavy glycosylated transmembrane protein is overexpressed in more than 65% PDAC cases. AR9.6 is an anti-MUC16 antibody that has been recently humanized after evidence of its therapeutic potential was found in an orthotopic study utilizing the murine version of the antibody. The HuAR9.6 antibody efficiently binds MUC16 expressed on tumor cells, and can both inhibit downstream oncogenic signaling and elicit tumor killing by signaling the immune system to the tumor. In this project, we used RNA sequencing to evaluate the MUC16 mediated transcriptomic changes by using the humanized AR9.6 antibody in patient-derived organoid models of PDAC. To begin this study, organoids were developed using tumor cells from a primary PDAC tumor with a high MUC16 profile obtained from rapid autopsy patient #142 from the Rapid Autopsy Program at UNMC. The organoids were then treated in triplicates using a monoclonal antibody HuIgG as an isotype control due to its lack of specificity, and the test arm of study, HuAR9.6. These samples were treated with 40 ug/mL of the antibodies for a 24-hour period, post which RNA isolation was performed. RNA sequencing and subsequent Gene Ontology and KEGG enrichment analysis revealed a downregulation of genes involved in the Hippo signaling pathway, fat digestion and absorption and TGF-β signaling. Based on this gene expression profiling, we hypothesize that HuAR9.6 can slow tumor progression by downregulating the Hippo and TGF-β signaling pathways. In the future, we aim to robustly validate these results at the level of the proteome and assess if these results can be reproduced in multiple patient samples with the hope to translate this antibody to the clinic to be used in PDAC patients who have a high MUC16 expression.https://digitalcommons.unmc.edu/surp2022/1038/thumbnail.jp

Staphylococcus aureus bacteraemia at two academic hospitals in Johannesburg

Objectives and methods. Staphylococcus aureus bacteraemia (SAB) remains a major problem worldwide. A retrospective study of patients with SAB seen from November 1999 to October 2002 was conducted at two academic hospitals in Johannesburg to determine mortality rates (death within 14 days of submission of blood culture) in patients bacteraemic with methicillin-sensitive (MSSA) and resistant S. aureus (MRSA) and to identify risk factors associated with mortality. Results. Of 449 patients with SAB, 104 (23.2%) died within 14 days of clinically suspected SAB. Of the 204 patients who acquired SAB in hospital, 6 patients died within 2 days, 39 between 2 and 14 days, and 41 more than 14 days after onset of SAB. One hundred and five patients (23.4%) had MRSA bacteraemia, 21 (20%) originating from the community. The MRSA bacteraemia rate among patients with hospital-acquired infection was 41.1%, significantly higher (p < 0.0001) than the 10.3% community-acquired MRSA bacteraemia. Thirty-five (33.3%) of the 105 patients with MRSA bacteraemia died within 14 days, compared with 69 (20.1%) of 344 MSSA patients (p = 0.0048). Admission to the intensive care unit (ICU) was significantly associated with mortality (p < 0.001) – 30 of 79 patients admitted to ICU died (38%). Among 222 patients whose HIV status was known, 117 (52.7%) were positive, and of these 32 died (27.4%), a rate not significantly higher than that among HIVseronegative patients (18 of 105 patients, p = 0.69). Conclusions. Compared with MSSA, MRSA was shown to be significantly associated with mortality. Stay in ICU and infection with strains resistant to oxacillin, ofloxacin and rifampicin were highly significant predictors for mortality. South African Medical Journal Vol. 96(8) 2006: 714-71

Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase

Many natural organic compounds with pharmaceutical applications, including antibiotics (chlortetracycline and vancomycin), antifungal compounds (pyrrolnitrin), and chemotherapeutics (salinosporamide A and rebeccamycin) are chlorinated. Halogenating enzymes like tryptophan 7-halogenase (PrnA) and tryptophan 5-halogenase (PyrH) perform regioselective halogenation of tryptophan. In this study, the conformational dynamics of two flavin-dependent tryptophan halogenasesPrnA and PyrHwas investigated through molecular dynamics simulations, which are in agreement with the crystallographic and kinetic experimental studies of both enzymes and provide further explanation of the experimental data at an atomistic level of accuracy. They show that the binding sites of the cofactor-flavin adenine dinucleotide and the substrate do not come into close proximity during the simulations, thus supporting an enzymatic mechanism without a direct contact between them. Two catalytically important active site residues, glutamate (E346/E354) and lysine (K79/K75) in PrnA and PyrH, respectively, were found to play a key role in positioning the proposed chlorinating agent, hypochlorous acid. The changes in the regioselectivity between PrnA and PyrH arise as a consequence of differences in the orientation of substrate in its binding site

Health outcomes of a subsidised fruit and vegetable program for Aboriginal children in northern New South Wales

Objective: To evaluate the impact of a fruit and vegetable subsidy program on short-term health outcomes of disadvantaged Aboriginal children.Design, setting and participants: A before-and-after study involving clinical assessments, health record audits and blood testing of all children aged 0&ndash;17 years (n = 167) from 55 participating families at baseline and after 12 months at three Aboriginal community-controlled health services in New South Wales. All assessments were completed between December 2008 and September 2010.Intervention: A weekly box of subsidised fruit and vegetables linked to preventive health services and nutrition promotion at an Aboriginal Medical Service.Main outcome measures: Change in episodes of illness, health service and emergency department attendances, antibiotic prescriptions and anthropometry.Results: There was a significant decrease in oral antibiotics prescribed (&minus; 0.5 prescriptions/year; 95% CI, &minus; 0.8 to &minus; 0.2) during 12 months of participation in the program compared with the 12 months before the program. The proportion of children classified as overweight or obese at baseline was 28.3% (38/134) and the proportion in each weight category did not change (P = 0.721) after 12 months. A small but significant increase in mean haemoglobin level (3.1 g/L; 95% CI, 1.4&ndash;4.8 g/L) was shown, although the proportion with iron deficiency (baseline, 41%; follow-up, 37%; P = 0.440) and anaemia (baseline, 8%; follow-up, 5%; P = 0.453) did not change significantly.Conclusion: This fruit and vegetable subsidy program was associated with improvements in some indicators of short-term health status among disadvantaged Aboriginal children. A controlled trial is warranted to investigate the sustainability and feasibility of healthy food subsidy programs in Australia

A high anticholinergic burden is associated with a history of falls in the previous year in middle-aged women:findings from the Aberdeen Prospective Osteoporosis Screening Study

APOSS was funded by the Grampian Osteoporosis Trust. A.D.A. received an Aberdeen Summer Research Scholarship supported by the funding from the Grampian Osteoporosis Trust Charity. The funder has no role in design, analysis, interpretation and reporting of the work presented. We gratefully acknowledge the Steering Committee of APOSS for permission to conduct this research.Peer reviewedPostprin

Money Market Funds, Shadow Banking and Systemic Risk in United Kingdom

Shadow banking entities have been repeatedly charged with the breaking up of the recent financial crises. This paper examines the contribution of the money market funds, an important part of the shadow banking entities, to the systemic risk in United Kingdom by using the CoVaR methodology (Adrian and Brunnermeier, 2016). Using a sample of 143 money market funds, continuously listed between 2005Q4 and 2013Q4, we investigate the impact of institutional corporate variables on the systemic risk. Our results show that liquidity mismatch increases the average systemic risk over the whole period, but decreases the risk during the Great Financial Depression

Identifying Key Predictors of Cognitive Dysfunction in Older People Using Supervised Machine Learning Techniques: Observational Study

Background: Machine learning techniques, specifically classification algorithms, may be effective to help understand key health, nutritional, and environmental factors associated with cognitive function in aging populations. Objective: This study aims to use classification techniques to identify the key patient predictors that are considered most important in the classification of poorer cognitive performance, which is an early risk factor for dementia. Methods: Data were used from the Trinity-Ulster and Department of Agriculture study, which included detailed information on sociodemographic, clinical, biochemical, nutritional, and lifestyle factors in 5186 older adults recruited from the Republic of Ireland and Northern Ireland, a proportion of whom (987/5186, 19.03%) were followed up 5-7 years later for reassessment. Cognitive function at both time points was assessed using a battery of tests, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), with a score Results: In the classification of a low RBANS score ( Conclusions: The results suggest that it may be possible for a health care professional to make an initial evaluation, with a high level of confidence, of the potential for cognitive dysfunction using only a few short, noninvasive questions, thus providing a quick, efficient, and noninvasive way to help them decide whether or not a patient requires a full cognitive evaluation. This approach has the potential benefits of making time and cost savings for health service providers and avoiding stress created through unnecessary cognitive assessments in low-risk patients

A cross-sectional investigation of back pain beliefs and fear in physiotherapy and sport undergraduate students.

Background Although low back pain (LBP) beliefs have been well investigated in mainstream healthcare discipline students, the beliefs within sports-related study students, such as Sport and Exercise Science (SES), Sports Therapy (ST), and Sport Performance and Coaching (SPC) programmes have yet to be explored. This study aims to understand any differences in the beliefs and fear associated with movement in students enrolled in four undergraduate study programmes–physiotherapy (PT), ST, SES, and SPC. Method 136 undergraduate students completed an online survey. All participants completed the Tampa Scale of Kinesiophobia (TSK) and Back Beliefs Questionnaire (BBQ). Two sets of two-way between-subjects Analysis of Variance (ANOVA) were conducted for each outcome of TSK and BBQ, with the independent variables of the study programme, study year (1st, 2nd, 3rd), and their interaction. Results There was a significant interaction between study programme and year for TSK (F(6, 124) = 4.90, P < 0.001) and BBQ (F(6, 124) = 8.18, P < 0.001). Post-hoc analysis revealed that both PT and ST students had lower TSK and higher BBQ scores than SES and SPC students particularly in the 3rd year. Conclusions The beliefs of clinicians and trainers managing LBP are known to transfer to patients, and more negative beliefs have been associated with greater disability. This is the first study to understand the beliefs about back pain in various sports study programmes, which is timely, given that the management of injured athletes typically involves a multidisciplinary team

Corridor Volatility Risk and Expected Returns

This paper examines the pricing of volatility risk using SPX corridor implied volatility. We decompose model-free implied volatility into various components using different segments of the cross-section of out-of-the money put and call option prices. We find that only model-free volatility computed from the cross-section of out-of-the-money call option prices carries a significant negative risk premium in the cross-section of stock returns and subsumes all relevant information for forecasting future volatility. Our empirical results provide strong evidence that SPX out-of-the money put option prices do not contain useful information for pricing aggregate volatility risk in the cross-section of stock returns