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Background: Skin diseases are common, especially in the developing countries. Mental health disorders are prevalent among those with skin diseases and affect their life and their treatment. Anxiety is one of the psychiatric disorders, and its symptoms were found among the patients with skin diseases. This survey analysis aimed to explore the prevalence and factors associated with anxiety among patients with skin diseases. Methodology: A self-administered structured questionnaire was distributed in outpatient clinics among adult patients, who were suffering from anxiety with common skin disease. The questionnaire included questions regarding socio-demographics, perceived stigma, social support, and anxiety. Data analysis was done through Statistical Package for the Social Science program version 22. Results: Patients with facial skin diseases were significantly the highest sufferers of anxiety among all patients with skin diseases (p-value < 0.001). Also, Eczema patients were significantly the most anxious and worried about their disease (p-value < 0.001). While Acne constituted a significant majority of those who were unable to stop or control their worries, to worry about different issues, to have problems in relaxing more than half days, and to be easily annoyed every day compared to other patients (p-value < 0.001). Conclusion: Patients with dermatological diseases have a high level of anxiety and worry, especially with acne and skin disease affecting visible areas like the face. Further studies are required in Saudi Arabia to explore the true estimates of this problem.

This study aimed to evaluate the supplementation (of drinking water) effects of L-Carnitine (LC) and/or calf thymus extract (TE) on immunity, antioxidant, duodenal histomorphometric, growth, and economic performance of Japanese quail. Six hundred, one day old unsexed quail were divided into four groups, the control group (G1) received plain drinking water, while G2, G3, and G4 were supplemented with LC and/or TE, respectively. The treated groups recorded a significant (p < 0.05) improvement in the final body weight, weight gain, feed conversion ratio, phagocytic activity %, phagocytic index, lymphocytes %, and plasma glutathione level compared to the G1. On the other hand, these supplementations significantly lower the mortality rate %, heterophil %, H/L ratio and plasma malondialdehyde level of the supplemented groups relative to G1. The supplemented groups recorded a non-significant increase in duodenal histomorphometric parameters (villous height, villous width, surface area, and crypt depth) relative to G1. Generally, LC and/or TE improve the values of economic profile (total returns, net profit, total return/total costs %, etc.) in treated groups compared to the control one. In conclusion, L-carnitine supplementation was more effective than TE or their combination with TE in the immunological, anti-oxidative, growth, and economic performance.

Kaff-e-Maryam (Anastatica hierochuntica L.) is extensively used to treat a range of health problems, most notably to ease childbirth and alleviate reproductive system-related disorders. This study aimed to evaluate the effect of A. hierochuntica ethanolic (KEE), and aqueous (KAE) extracts on CCl4-induced oxidative stress and nephrotoxicity in rats using the biochemical markers for renal functions and antioxidant status as well as histopathological examinations of kidney tissue. A. hierochuntica contained 67.49 mg GAE g−1 of total phenolic compounds (TPC), 3.51 µg g−1 of total carotenoids (TC), and 49.78 and 17.45 mg QE g−1 of total flavonoids (TF) and total flavonols (TFL), respectively. It resulted in 128.71 µmol of TE g−1 of DPPH-RSA and 141.92 µmol of TE g−1 of ABTS-RSA. A. hierochuntica presented superior antioxidant activity by inhibiting linoleic acid radicals and chelating oxidation metals. The HPLC analysis resulted in 9 and 21 phenolic acids and 6 and 2 flavonoids in KEE and KAE with a predominance of sinapic and syringic acids, respectively. Intramuscular injection of vit. E + Se and oral administration of KEE, KAE, and KEE + KAE at 250 mg kg−1 body weight significantly restored serum creatinine, urea, K, total protein, and albumin levels. Additionally, they reduced malondialdehyde (MOD), restored reduced-glutathione (GSH), and enhanced superoxide dismutase (SOD) levels. KEE, KAE, and KEE + KAE protected the kidneys from CCl4-nephrotoxicity as they mainly attenuated induced oxidative stress. Total nephroprotection was about 83.27%, 97.62%, and 78.85% for KEE, KAE, and KEE + KAE, respectively. Both vit. E + Se and A. hierochuntica extracts attenuated the histopathological alteration in CCl4-treated rats. In conclusion, A. hierochuntica, especially KAE, has the potential capability to restore oxidative stability and improve kidney function after CCl4 acute kidney injury better than KEE. Therefore, A. hierochuntica has the potential to be a useful therapeutic agent in the treatment of drug-induced nephrotoxicity.

Simple Summary β-escin, a component of horse chestnut seed extract, was first identified as an inhibitor of ovarian cancer (OvCa) adhesion/invasion in our high-throughput screening program using a three-dimensional organotypic model assembled from primary human cells and extracellular matrix. The goal of the study presented here is to determine if β-escin and structurally-similar compounds have a therapeutic potential against OvCa metastasis. β-escin and cardiac glycosides inhibit ovarian cancer adhesion/invasion to the omental microenvironment in vivo, and β-escin inhibits ovarian cancer metastasis in the prevention and intervention setting. Additionally, β-escin was found to decrease the stemness of ovarian cancer cells, inhibit extracellular matrix production in the tumor microenvironment, and inhibit HIF1α stability in ovarian cancer cells and the tumor microenvironment. This study reveals that the natural compound β-escin has therapeutic potential because of its ability to prevent OvCa dissemination by targeting both cancer and stromal cells in the OvCa tumor microenvironment. Abstract The high mortality of OvCa is caused by the wide dissemination of cancer within the abdominal cavity. OvCa cells metastasize to the peritoneum, which is covered by mesothelial cells, and invade into the underlying stroma, composed of extracellular matrices (ECM) and stromal cells. In a study using a three-dimensional quantitative high-throughput screening platform (3D-qHTS), we found that β-escin, a component of horse chestnut seed extract, inhibited OvCa adhesion/invasion. Here, we determine whether β-escin and structurally similar compounds have a therapeutic potential against OvCa metastasis. Different sources of β-escin and horse chestnut seed extract inhibited OvCa cell adhesion/invasion, both in vitro and in vivo. From a collection of 160 structurally similar compounds to β-escin, we found that cardiac glycosides inhibited OvCa cell adhesion/invasion and proliferation in vitro, and inhibited adhesion/invasion and metastasis in vivo. Mechanistically, β-escin and the cardiac glycosides inhibited ECM production in mesothelial cells and fibroblasts. The oral administration of β-escin inhibited metastasis in both OvCa prevention and intervention mouse models. Specifically, β-escin inhibited ECM production in the omental tumors. Additionally, the production of HIF1α-targeted proteins, lactate dehydrogenase A, and hexokinase 2 in omental tumors was blocked by β-escin. This study reveals that the natural compound β-escin has a therapeutic potential because of its ability to prevent OvCa dissemination by targeting both cancer and stromal cells in the OvCa tumor microenvironment.

Background Burnout is defined as a syndrome resulting from chronic workplace stress that has not been successfully managed. It is characterised by feelings of energy depletion or exhaustion, increased mental distance from one’s job and reduced professional efficacy. The COVID-19 pandemic has created unexpected demands on healthcare systems worldwide and they have experienced numerous stressors. As the coping is one of the stressors management strategies that may affect burnout, this is a descriptive cross-sectional study aimed to estimate the frequency and level of burnout and its association with coping strategies among physicians and nurses in Saudi Arabia during the COVID-19 Pandemic using Copenhagen Burnout Inventory and Brief-COPE. Results Overall, 403 healthcare providers were recruited (85 physicians, 318 nurses). Personal, work-related and client-related burnout were detected among 67.5%, 68% and 58.3% of the respondents, respectively. The mean score for adaptive coping was (27.6 ± 10.3, median: 29 IQR: 14.0) out of 48, and the mean score for maladaptive coping was (14.2 ± 6.81, median: 14 IQR: 8.0) out of 36. Some factors associated with burnout were participants’ age group, professional position, number of family members and years of experience in the medical field. The personal, work-related and client-related burnout had inverse correlations with the overall adaptive coping category. Conclusion The frequency of burnout during the COVID-19 pandemic, particularly among nurses, was significant. Burnout was also frequent among both the younger age group and those with fewer years of experience. Some predictors were identified as having a close person infected with COVID-19, being assigned to treat COVID-19 patients, longer working hours, having sleeping hours affected by the pandemic and experiencing verbal or physical abuse from patients. In addition to a significant correlation between the adaptive coping category and the three burnout dimensions.

The Na+/K+-ATPase (NKA) complex is the master regulator of membrane potential and a target for anti-cancer therapies. Here, we investigate the effect of drug-induced oxidative stress on NKA activity. The natural product, plumbagin increases oxygen radicals through inhibition of oxidative phosphorylation. As a result, plumbagin treatment results in decreased production of ATP and a rapid increase in intracellular oxygen radicals. We show that plumbagin induces apoptosis in canine cancer cells via oxidative stress. We use this model to test the effect of oxidative stress on NKA activity. Using whole-cell patch-clamp electrophysiology we demonstrate that short-term exposure (4 min) to plumbagin results in 48% decrease in outward current at +50 mV. Even when exogenous ATP was supplied to the cells, plumbagin treatment resulted in 46% inhibition of outward current through NKA at +50 mV. In contrast, when the canine cancer cells were pre-treated with the oxygen radical scavenger, N-acetylcysteine, the NKA inhibitory activity of plumbagin was abrogated. These experiments demonstrate that the oxidative stress-causing agents such as plumbagin and its analogues, are a novel avenue to regulate NKA activity in tumors.

Monitoring tissue composition could be persistent for many medical applications. Bioimpedance may be useful for monitoring several cardiovascular parameters such as cardiac output, stroke volume, blood pressure and heart rate. In addition, it could be useful for diagnosing the mitral insufficiency, stenosis, and other valvular heart diseases. The purpose of this study is to use the bioimpedance signal to determine the heart rate. This study involved 51 volunteers (28 male, 23 female) ranging from 20 to76 years. A current of 1 mA at 30 kHz was injected through two outer electrodes placed on the subject’s left arm and then the impedance was collected using two inner electrodes placed between the former outer electrodes. The acquired bioimpedance signal was pre-processed and used to identify the peaks and calculated the average interval. Thus, heart rates of each subject were calculated and then compared with actual measurement from FUZZY model MP3 digital blood pressure monitor. The results showed high correlation, 95.44 %, between the calculated heart rates and measurements. The various clinical applications of bioimpedance will help further promote the technique and several parameters can be determined using the electrical bioimpedance approach.

Very few studies have been concerned with assessing the prevalence of burnout and depressive symptoms, especially during an infectious outbreak on non-frontline health care workers, such as a psychiatrist. In such instances, the role of psychiatrists and other mental health providers as a source of psychological support to the public and frontline workers is indispensable and valuable. This study aims to assess the prevalence of burnout and depressive symptoms, and their correlation, during the COVID-19 pandemic among psychiatry residents in Saudi Arabia. A total of 121 out of 150 psychiatry residents in Saudi Arabia completed the Maslach Burnout Inventory and Patient’s Health Questionnaire for the assessment of burnout and depressive symptoms. Burnout symptoms were found in 27.3%, and another 27.3% reported having depression symptoms. In addition, 16.5% reported having both burnout and depressive symptoms, with a significant relationship between them. Participants in the first 2 years of training and having a history of receiving mental health treatment in the past 2 years were at higher risk. The need is urgent to increase investment in mental health services and to construct a plan to reduce this risk of burnout and depression among psychiatrists by developing preventative strategies to prevent burnout and promote wellness is more important than ever.

Currently, antiviral drugs and/or vaccines are not yet available to treat or prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we narrated the available data, from credible publishers, regarding the possible role of polyphenols and natural extracts-containing polyphenols in the prevention of coronavirus disease 2019 (COVID-19), and their immune-boosting properties. It was revealed that polyphenols could be considered as promising biologically active substances for the prevention of COVID-19. The underlying potential mechanism behind this action is mostly due to the antiviral activities and the immune-regulation functions of polyphenols against COVID-19-infections. Antivirus polyphenolic-based medications can mitigate SARS-CoV-2-enzymes, which are vital for virus duplication and infection. It was also found that triterpenoid, anthraquinone, flavonoids, and tannins are possible keys to scheming antiviral therapies for inhibiting SARS-CoV-2-proteases. The identified pharmacophore structures of polyphenols could be utilized in the explanation of novel anti-COVID-19 designs. The advantage of using mixtures containing polyphenols is related to the high-safety profile without having major side-effects, but further randomized controlled trials are required in the upcoming studies., Highlights • Polyphenols possess many potential health benefits, including antiviral effects. • Polyphenols consider promising bioactive substances for COVID-19 prevention. • Polyphenol-rich foods will be helpful during the COVID-19's treatment. • Polyphenols assist as blocking agent for protease's enzymatic activity of COVID-19.

Background: The objective was to evaluate the level of awareness regarding systemic lupus erythematosus (SLE) among the general population in the Al-Qassim region, Kingdom of Saudi Arabia (KSA).Methods: This was a cross-sectional study carried out between March and April 2021 and conducted among the general population at Al-Qassim region, KSA. A valid pre-tested electronic questionnaire was distributed through social media among the targeted population that included socio-demographic characteristics and questionnaires measuring awareness, attitude and their belief about SLE. All statistical analyses were performed using SPSS version 26.Results: A total of 377 participants were enrolled. The most common age group was more than 40 years old (39%), with slightly females (52.5%) than males. The prevalence of participants who had heard about SLE was 52.5%. Of those who have heard about SLE, a poor level of awareness was detected among 69.2% of participants, while 30.8% were at a good level. Factors associated with an increased level of awareness were having diagnosed been with SLE and those who indicated their doctor as their sources of SLE information.Conclusions: The awareness of the general population in the Al-Qassim region regarding SLE was insufficient. Obtaining SLE information from their doctor and having been diagnosed with SLE are associated with better awareness. We propose that awareness campaigns should be promoted.

Background Th appropriate placement and size selection of mitral prostheses in transcatheter mitral valve implantation (TMVI) is critical, as encroachment on the left ventricular outflow tract (LVOT) may lead to flow obstruction. Recent advances in computed tomography (CT) can be employed for pre-procedural planning of mitral prosthetic valve placement. This study aims to develop patient-specific computational fluid dynamics models of the left ventricle (LV) in the presence of a mitral valve prosthesis to investigate blood flow and LVOT pressure gradient during systole. Methods Patient-specific computational fluid dynamics simulations of TMVI with varied cardiac anatomy and insertion angles were performed (n = 30). Wide-volume full cycle cardiovascular CT images prior to TMVI were used as source anatomical data (n = 6 patients). Blood movement was governed by Navier-Stokes equations and the LV endocardial wall deformation was derived from each patient's CT images. Results The computed pressure gradients in the presence of the mitral prosthesis compared well with clinically measured gradients. Analysis of the effects of prosthetic valve angulation, aorto-mitral annular angle, ejection fraction, LV size and new LVOT area (neo-LVOT) after TMVI in silico revealed that the neo-LVOT area (p < 0.001) was the most significant factor affecting LVOT pressure gradient. Angulation of the mitral valve can substantially mitigate LVOT gradient. Conclusions Computational fluid dynamics simulation is a promising method to aid in pre-TMVI planning and understanding the factors underlying LVOT obstruction.

The first case of COVID-19 originated in Wuhan, China, after which it spread across more than 200 countries. By 21 July 2020, the rapid global spread of this disease had led to more than 15 million cases of infection, with a mortality rate of more than 4.0% of the total number of confirmed cases. This study aimed to predict the prevalence of COVID-19 and to investigate the effect of awareness and the impact of treatment in Saudi Arabia. In this paper, COVID-19 data were sourced from the Saudi Ministry of Health, covering the period from 31 March 2020 to 21 July 2020. The spread of COVID-19 was predicted using four different epidemiological models, namely the susceptible&ndash, infectious&ndash, recovered (SIR), generalized logistic, Richards, and Gompertz models. The assessment of models&rsquo, fit was performed and compared using four statistical indices (root-mean-square error (RMSE), R squared (R2), adjusted R2 (&nbsp, Radj2), and Akaike&rsquo, s information criterion (AIC)) in order to select the most appropriate model. Modified versions of the SIR model were utilized to assess the influence of awareness and treatment on the prevalence of COVID-19. Based on the statistical indices, the SIR model showed a good fit to reported data compared with the other models (RMSE = 2790.69, R2 = 99.88%, Radj2 = 99.98%, and AIC = 1796.05). The SIR model predicted that the cumulative number of infected cases would reach 359,794 and that the pandemic would end by early September 2020. Additionally, the modified version of the SIR model with social distancing revealed that there would be a reduction in the final cumulative epidemic size by 9.1% and 168.2% if social distancing were applied over the short and long term, respectively. Furthermore, different treatment scenarios were simulated, starting on 8 July 2020, using another modified version of the SIR model. Epidemiological modeling can help to predict the cumulative number of cases of infection and to understand the impact of social distancing and pharmaceutical intervention on the prevalence of COVID-19. The findings from this study can provide valuable information for governmental policymakers trying to control the spread of this pandemic.

Atovaquone is a FDA-approved antimalarial agent that has also shown potent anticancer properties. In the current study, we demonstrate that atovaquone is a prime candidate for treatment of high-grade serous ovarian cancer. We have tested atovaquone against a panel of ovarian cancer cells lines and shown that this drug inhibits proliferation and induces apoptosis at IC50 concentrations between 10-20 microM. Exposure to atovaquone results in increased apoptosis as indicated by an increase in cleaved caspase 3 and other relevant apoptotic markers. Additionally, our data also suggest that atovaquone is able to reactivate p53. Inhibition of p53 attenuates the cytotoxicity of atovaquone. However, the primary event that occurs in atovaquone-treated cells is the rapid surge in intracellular oxygen radicals. Imaging cytometry experiments conclusively demonstrate that the oxygen radical surge originates in the mitochondria. The oxidative stress caused by atovaquone is responsible for DNA damage and p53 activation. The atovaquone-induced oxygen radical surge also leads to damage to the Na+/K+-ATPase, perturbing the ability of the cancer cells to maintain an optimal membrane potential. This increase in oxygen radicals occurs because atovaquone targets the oxidative phosphorylation pathway in the mitochondria and blocks electron transport. Measurements conducted on the Seahorse analyzer show decreased consumption of oxygen and lower levels of ATP in the atovaquone-treated cells. In the malarial parasite, atovaquone targets mitochondrial complex III. In ovarian cancer cells, supplying succinate did not reverse atovaquone-induced inhibition of oxidative phosphorylation. On the other hand, when cells were supplemented with the substrate for complex IV, the oxygen consumption rate normalized in atovaquone-exposed cells. These experiments suggest that atovaquone is likely inhibiting complex I-III of mitochondria. Atovaquone is a naphthoquinone with significant structural similarity with the electron transporter ubiquinone. In silico modeling experiments indicate that atovaquone can bind to the ubiquinone binding pocket on complexes I-III. Based on these experiments, we propose that atovaquone is competing with ubiquinone to inhibit efficient electron transport and thereby increasing the intracellular oxygen radicals. Ovarian tumor-bearing mice tolerated prolonged treatment with Mepron®, the clinical formulation of atovaquone. Daily treatment of ID8 tumor-bearing C57BL/6 mice with atovaquone for 3-4 weeks resulted in a significant decrease in tumor growth. Additionally, we also show decreased proliferation of human ovarian tumors treated ex vivo with atovaquone. These experiments indicate that atovaquone can be used as a safe and effective drug for chemoprevention and chemotherapy of ovarian tumors. Citation Format: Arvinder Kapur, Mildred Felder, Yousef Alharbi, Allegra Cappuccini, Bikash Pattnaik, Lisa Barroilhet, Manish Patankar. Antimalarial agent, atovaquone, inhibits cancer cell proliferation by targeting oxidative phosphorylation and is a candidate for chemoprevention and chemotherapy of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B36.

With their role in connecting disease-associated antigens to the cellular immune response, antibodies hold considerable promise as therapeutic agents. This chapter discusses three classes of therapeutic antibodies that have been developed for use in ovarian cancer therapy. The first includes antibodies selected against tumor-associated antigens such as MUC16/CA125, mesothelin, epithelial cell adhesion molecule, and folate receptor α‎. Antibodies in the second class target proteins such as CTLA-4 and PD1 that act as immune response checkpoint receptors. The third class of antibodies target secreted factors that promote tumor growth: targets in this class include vascular endothelial growth factor, cytokines, and chemokines. The development of each of these is described. The chapter also discusses the complications presented by soluble antigens, which serve to limit the applicability of antigens (such as MUC16/CA125) that are both cell-surface associated and circulating and the prospects for the combination of antibody-based immunotherapy and chemotherapy.

Aerobic glycolysis is an important metabolic adaptation in tumors. However, there is mounting evidence that oxidative phosphorylation (OXPHOS) also contributes to metabolism in cancer cells. Therefore, agents targeting OXPHOS can serve as novel anticancer agents. We will present data on small molecule agents that inhibit the proliferation of ovarian and other cancer cells by inhibiting mitochondrial electron transport. We have focused our attention on citral, plumbagin, curcumin, cinnamaldehyde, piperlongumine, perillaldehyde, nonenal and other naturally occurring agents. All of these molecules share a common molecular epitope, the unsaturated carbonyl that participates in redox reactions. Cancer cells treated with these agents show a marked decrease in oxygen consumption rate and an increase in extracellular acidification. The redox ratio (NADH/FAD) and cellular ATP levels also decrease in response to these small molecule agents. In our search for additional and more potent OXPHOS inhibitors we have discovered that the FDA-approved anti-malarial drug atovaquone is an efficient inhibitor of electron transport in ovarian cancer cells. Chronic administration of atovaquone decreases the growth of ID8 tumors in C57BL/6 mice. Investigation in to the mechanism of action of the unsaturated carbonyl compounds indicates that their initial effect in cancer cells is the immediate and substantial rise in oxygen radicals as a result of OXPHOS inhibition. This increase in reactive oxygen causes extensive oxidative damage leading to DNA strand breaks. Subsequently, we have observed activation of p53-mediated apoptosis. These experiments are suggesting that inhibition of OXPHOS and the subsequent increase in intracellular oxygen radicals can result in the reactivation of the tumor suppressive responses of at least a subset of the p53 mutants. Additionally, our studies also indicate that the oxidative stress occurring as a result of OXPHOS inhibition directly leads to inhibition of ion transport through the Na+/K+-ATPase. As a result of this inhibition, cancer cells are unable to maintain a normal membrane potential. Studies are currently underway to determine if the inability to maintain membrane potential also contributes to apoptotic cancer cell death induced by these unsaturated carbonyl-containing compounds. Oxidative stress caused by these compounds leads to an increase in superoxide dismutase, catalase and glutathione synthesis via the activation of Nrf-2. Inhibition of Nrf-2 results in an increase in the potency of the unsaturated carbonyl compounds. We are therefore examining Nrf-2 increase as a form of chemoresistance mechanism that likely impinges on the anti-cancer activity of the unsaturated carbonyl compounds. These studies are allowing us to develop medicinal chemistry-based approaches to develop novel molecules with increased potency and targetability as OXPHOS inhibitors for the treatment of ovarian cancer. Citation Format: Arvinder Kapur, Amruta Nayak, Mildred Felder, Allegra Cappucini, Spencer Ericksen, Yousef Alharbi, Bikash Pattnaik, Lisa Barroilhet, and Manish S. Patankar. TARGETING OVARIAN TUMORS WITH OXPHOS INHIBITORS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-103.

Plumbagin and atovaquone are chemotoxic to ovarian, breast and other tumors. Both molecules inhibit oxidative phosphorylation causing a rapid increase in intracellular oxygen radicals and apoptosis. Oxidative stress is also known to inhibit the activity of Na+/K+-ATPase (NKA), the ion channel that maintains the membrane potential. Here, we investigate if the oxidative stress mediated by plumbagin and atovaquone also leads to inhibition of NKA activity. We confirm that plumbagin and atovaquone inhibit proliferation of three human (OVCAR-3, SKOV-3 and TYKNu) and one mouse (ID8) ovarian cancer cell lines. Using SKOV-3 and OVCAR-3 as models for ovarian cancer, we demonstrate that oxygen radical scavenger, N-acetylcysteine (NAC) attenuated the cytotoxicity of plumbagin and atovaquone. Using whole cell patch clamping we demonstrate that plumbagin and atovaquone inhibit outward and inward current flowing through NKA in SKOV-3 and OVCAR-3. Both drugs decrease cellular ATP. Providing exogenous ATP (5 mM) in the pipet solution used during patch clamping did not recover NKA activity in the plumbagin or atovaquone treated SKOV-3 and OVCAR-3 cells. However, pretreatment of the cells with NAC completely abrogated the NKA inhibitory activity of plumbagin and atovaquone. Exposure of the SKOV-3 cells to either of the drugs for 1-2 h resulted in a significant decrease in the expression of NKA. We conclude that oxidative stress caused by plumbagin and atovaquone degrades NKA and hence the membrane potential cannot be optimally maintained. Evaluation of compounds that induce oxidative stress should therefore consider contribution of NKA inhibition to the cytotoxic activity of such agents. Citation Format: Yousef Alharbi, Arvinder Kapur, Mildred Felder, Lisa Barroilhet, Bikash Pattnaik, Manish S. Patankar. Plumbagin and atovaquone inhibit Na+/K+-ATPase through the generation of oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 891.

Background: Delay in seeking medical care has many negative effects on the patient’s condition and medical cost, and it reduces the potential benefits of early interventions. Delay in seeking medical care, which is affected by many factors, is a common global problem. This study aimed to study the prevalence and causes of delay in seeking medical care in Al-Madina, Saudi Arabia. Method: This research was a cross-sectional study conducted among Al-Madina population using a self-administrated questionnaire which was only administered when the inclusion and exclusion criteria for the study have been met by the participants. The questionnaire collected the demographic characteristics and information about the prevalence and the reasons of delaying in seeking medical care in Al-Madina, Saudi Arabia. Results: The study included 441 subjects out of which 61.9% were females while 38.1% were males. Seventy-eight and point two percent had university education level. Only 27.4% of participants always seek medical care as soon as they feel they need it. Delayed seeking medical care due to a financial impediment was stated by 26.1% of the subjects. Merely 25.2% had health insurance. The language was the most important criteria when choosing health service providers for 42% of patients. Severe pain forces 40.1% of participants to seek medical care, while moderate pain drives only 4.3% to seek medical care while 58.9% seek medical care when the pain or discomfort increases with time. Conclusion: There was a high prevalence of delay in seeking medical care among Al-Medina population, Saudi Arabia. Economic factors and lack of health insurance are among the main obstacles in seeking medical care. Acute pain serves as the principal reason in seeking medical care among Al- Madina population.

The correct placement of mitral prostheses in transcatheter mitral valve replacement (TMVR) is crucial, since any obstruction of the left ventricular outflow tract (LVOT) by the mitral device may decrease the LVOT area, leading to flow obstruction. Recent advances in patient-specific modelling based

Cardiac glycosides (CG) are potent inhibitors of Na+/K+-ATPase (NKA), inducing apoptosis through the inhibition of ion current. We developed a synthetic CG, CEN09-106, with enhanced cytotoxic potential over conventional CGs such as oubain and others. For specific delivery to the tumor, CEN09-106 was conjugated through a stable chemical linker to antibodies targeted against cell surface proteins that form complexes with NKA. Due to this molecular design CEN09-106 is locally presented to the tumor and inhibits NKA activity. Internalization of CEN09-106 is not required for its cytotoxicity, and hence we refer to this family of antibody-CG complexes as extracellular drug conjugates (EDC). Ovarian tumors overexpress FXYD5, a modulator of NKA activity. We have developed EDC1 to target FXYD5. Here, we demonstrate the ability of EDC1 to target ovarian tumors and confirm its mechanism of action. First, we compared the activity of oubain, CEN09-106, and EDC1 in cell viability assays. While the potency of oubain was approximately 1-10 mM, CEN09-106 and EDC1 both had IC50 between 1-2.5 nM when tested against OVCAR-5, OV2008, and SKOV3 cells. Expression of FXYD5 in these cell lines was confirmed by flow cytometry. The inhibition of cell viability was attributed to apoptosis induced by CEN09-106 and EDC1 as measured by increase in cleaved caspase3 and annexin V binding and decrease in Bcl-2 expression. CEN09-106 and EDC1 also inhibited viability of the cisplatin-resistant C13 (IC50 ~2.5 nM) cells. Whole-cell patch-clamp recording of cancer cells revealed NKA ionic current in SKOV-3 and OV2008 cells after inhibition of majority of the cell surface ion transporters and channels. Outward ion current detected in SKOV3 and OV2008 prior to treatment with CEN09-106 and EDC1 was in the range of 500-1000 pA. Upon treatment with CEN09-106 and EDC1 (2.5 nM, each), the current in these two cell lines decreased to only 200-400 pA, a 60-75% decrease. In vivo administration of EDC1 in nonhuman primates established its low general toxicity profile. In vivo studies in xenograft mouse models are currently under way and are showing promising results with significant inhibition of SKOV3 and OV2008 tumors when CEN09-106 and EDC1 were administered intraperitoneally. In ongoing work, we are screening additional platinum-sensitive and -resistant ovarian cancer lines for their responses to EDC1. These basic and translational studies will serve as the foundation to demonstrate the clinical value of EDC1 in the treatment of patients with ovarian tumors. Citation Format: Yousef Alharbi, Arvinder Kapur, Jim Prudent, David Marshall, Mildred felder, Bikash Pattnaik, Manish Patankar. Antibody-conjugated cardiac glycosides: Potent agents for treatment of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B11.