Optical Based Surface Plasmon Resonance Sensor for the Detection of the Various Kind of Cancerous Cell.

This research explores a novel biosensor design that exhibits much higher sensitivity compared to conventional biosensors. The biosensor's uniqueness originated from its innovative structure, which incorporates N-FK51A/Ag/AlON/BlueP materials, as well as its cutting-edge fabrication method. The refractive index component was considered when designing the SPR biosensor, which was developed from the angular analysis of the attenuated total reflection (ATR) approach for cancer detection. For instance, the resonance angle shifts by 15.57 deg when the refractive index changes from 1.360 to 1.401, demonstrating the sensor's responsiveness to variation in the refractive index. The sensitivities for skin (basal), cervical (HeLa), blood (Jurkat), adrenal gland (PC12), and breast (MDA-MB-231 and MCF-7) cancer cells were 197.65, 243.66, 255.36, 302.71, 372.57, and 416.85 deg/RIU, respectively. Also, the detection accuracy (DA), the figure of merit (FoM), and the quality factor were 0.37/deg, 155.94 (deg/RIU), and 26.71 RIU-1. We also examine the effects of substituting the noble, dielectric, 2D material layer with conventional biosensor materials for six cancers. Each time, the Ag/AION/BlueP layered structure performed best in distinguishing cancer cells from healthy cells. We also study the prism effects. The proposed biosensor, with a RI of 1.29-1.40, has a linear regression coefficient of R2 of 0.96094.

Comparative effectiveness and safety of eplerenone and spironolactone in patients with heart failure: a systematic review and meta-analysis.

BACKGROUND: Eplerenone and spironolactone, recognized as mineralocorticoid receptor antagonists (MRAs), have been reported to improve clinical prognosis among individuals diagnosed with heart failure (HF). However, the difference in the clinical effects between eplerenone and spironolactone in individuals with HF remains uncertain. We aimed to assess the impact of eplerenone compared to spironolactone on clinical outcomes within the HF population. METHODS: An extensive search was executed in several databases (PubMed, Web of Science, Scopus, Cochrane Library). All relevant studies evaluating eplerenone compared to spironolactone in patients with HF were included. Dichotomous data were pooled as Hazard ratio (HR) or Risk ratio (RR) with a 95% confidence interval (CI). Our main outcome was all-cause mortality. Secondary outcomes included death from cardiovascular causes, treatment withdrawal, and gynecomastia. RESULTS: Ten studies, comprising 21,930 HF individuals, were included in our investigation. Eplerenone showed a lower risk of all-cause mortality (HR = 0.78, 95%CI [0.64 to 0.94], P = 0.009) and cardiovascular mortality (HR = 0.54, 95%CI [0.39, 0.74], P = 0.0001) compared to spironolactone. Furthermore, eplerenone exhibited a reduced risk of treatment withdrawal (RR = 0.69, 95% CI [0.62, 0.78], P = 0.0001) and gynecomastia (RR = 0.07, 95% CI [0.02 to 0.31], P = 0.0001) than spironolactone. CONCLUSION: Eplerenone revealed lower all-cause and cardiovascular mortality events in comparison to spironolactone. Moreover, eplerenone was associated with lower gynecomastia and treatment withdrawal events compared to spironolactone. Further well-designed randomized controlled trials are still warranted better to identify the clinical differences between eplerenone and spironolactone. TRIAL REGISTRATION: Protocol registration: https://doi.org/10.17605/OSF.IO/VNMGK.

Nicotine inhalation and metabolism triggers AOX-mediated superoxide generation with oxidative lung injury.

With the increasing use of vaping devices that deliver high levels of nicotine (NIC) to the lungs, sporadic lung injury has been observed. Commercial vaping solutions can contain high NIC concentrations of 150 mM or more. With high NIC levels, its metabolic products may induce toxicity. NIC is primarily metabolized to form NIC iminium (NICI) which is further metabolized by aldehyde oxidase (AOX) to cotinine. We determine that NICI in the presence of AOX is a potent trigger of superoxide generation. NICI stimulated superoxide generation from AOX with Km = 2.7 µM and Vmax = 794 nmol/min/mg measured by cytochrome-c reduction. EPR spin-trapping confirmed that NICI in the presence of AOX is a potent source of superoxide. AOX is expressed in the lungs and chronic e-cigarette exposure in mice greatly increased AOX expression. NICI or NIC stimulated superoxide production in the lungs of control mice with an even greater increase after chronic e-cigarette exposure. This superoxide production was quenched by AOX inhibition. Furthermore, e-cigarette-mediated NIC delivery triggered oxidative lung damage that was blocked by AOX inhibition. Thus, NIC metabolism triggers AOX-mediated superoxide generation that can cause lung injury. Therefore, high uncontrolled levels of NIC inhalation, as occur with e-cigarette use, can induce oxidative lung damage.

Development and Enhancement of PCF-based Sensors for Terahertz-frequency Region Breast Cancer Cell Detection.

In today's medical research, breast cancer is a severe problem, so it is imperative to develop a reliable and efficient approach for identifying cancerous breast cells. PCF, with its exceptional sense-making abilities, simplifies and distinguishes that procedure. The research presents a unique structural hybrid PCF for detecting breast cancer cells using sensors based on PCF that are specifically built for the terahertz-frequency range. The improvement in sensor sensitivity and specificity in identifying cancer cells at these frequencies is a notable progress compared to conventional approaches, which could potentially result in earlier and more precise diagnosis. In our analysis, we discovered the most common malignancies in breast cancer. We investigate the features of the cancerous cell detector using the COMSOL-Multiphysics 5.6 software. This PCF detector achieves a Confinement Loss of 4.75 × 10-12 and 3.42 × 10-13 dB/m for Type-1 and Type-2 cancer cells, respectively, at 1.2 THz, as well as about 99.946% and 99.969% relative sensitivity. This sensor ensures the highest level of sensitivity for the identification of cancerous breast cells. This sensor's physical architecture is quite straightforward, making it simple to build using current manufacturing techniques. Therefore, it seems that this sensor will pave a new path for identifying and treating cancerous cells.

Dual Features, Compact Dimensions and X-Band Applications for the Design and Fabrication of Annular Circular Ring-Based Crescent-Moon-Shaped Microstrip Patch Antenna.

This study uses annular circular rings to create multi-band applications using crescent-shaped patch antennas. It is designed to be made up of five circular, annular rings nested inside of each other. Three annular rings are positioned and merged on top of the larger rings, with two annular rings set along the bottom of the feed line. The factors that set them apart, such as bandwidths, radiation patterns, gain, impedance, and return loss (RL), are analysed. The outcomes show how compact the multi-band annular ring antenna is. The proposed circular annular ring antenna has return losses of -33 dB and operates at two frequencies: 3.1 GHz and 9.3 GHz. This design is modelled and simulated using ANSYS HFSS. The outcomes of the simulation and the tests agree quite well. The X band and WLAN resonant bands have bandwidth capacities of 500 and 4300 MHz, respectively. Additionally, the circular annular ring antenna design is advantageous for most services at these operating bands.

Phosphodiesterase-5 inhibitors use and the risk of alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: The management of Alzheimer's disease (AD) poses considerable challenges, necessitating the pursuit of innovative therapeutic approaches. Recent research has spotlighted the promising role of phosphodiesterase type 5 inhibitors (PDE5Is) in reducing the prevalence of AD, utilizing their vasodilatory properties to suggest a potential neuroprotective effect. This meta-analysis and systematic review aims to assess the relationship between the use of PDE5Is and the risk of AD. METHODS: A detailed examination was carried out across several electronic databases till March 2024, including PubMed, Web of Science, Scopus, CENTRAL, and Embase. The focus was on identifying studies that compare the occurrence of AD among PDE5I users vs non-users. Through a random-effects model, pooled hazard ratios (HRs) were calculated, in alignment with guidelines from the Cochrane Handbook for Systematic Reviews and Meta-Analysis and the PRISMA standards. RESULTS: This analysis included six studies, cumulating a participant count of 8,337,313, involving individuals treated with sildenafil, tadalafil, and vardenafil, against a control group undergoing other or no treatments. The cumulative HR for AD risk among PDE5I users versus the control group was 0.53 (95% CI: 0.32-0.86, p = 0.008), signaling a markedly reduced likelihood of AD development in the PDE5I group. Particularly, sildenafil usage showed a significant risk reduction (HR: 0.46, 95% CI: 0.31-0.70, p < 0.001), while findings for tadalafil and vardenafil were not significant. Test of subgroup differences found no difference between male and female participants in the risk of AD. CONCLUSIONS: Our findings suggest that the use of PDE5Is is associated with a reduced risk of AD, highlighting its potential as a protective agent against neurodegenerative diseases. Given the very low quality of evidence and the heterogeneity among the included studies, further high-quality research is warranted to confirm these findings and elucidate the underlying mechanisms. Register number PROSPERO 2024: CRD42024522197.

Discoloration after revascularization using calcium phosphosilicate-based bioceramic versus mineral trioxide aggregate in necrotic immature permanent anterior teeth: A Randomized clinical trial.

Aim: The aim of the current study is to evaluate the effect of calcium phophosilicate-based bioceramic "Totalfill bioceramic putty" and white mineral trioxide aggregate (WMTA) as the coronal plug on discoloration after revascularization of necrotic immature permanent anterior teeth. Materials and Methods: This study was conducted on (48) necrotic young permanent central incisors in children ranging from 8 to 14 years old, that were randomly allocated to either Totalfill bioceramic (Group I = 24) or WMTA (Group II = 24) as the coronal plug. Two visits revascularization protocol was adopted in this study using 1.5% sodium hypochlorite, followed by 17% ethylenediaminetetraacetic acid, and ending with a saline flush as irrigation solution. The double antibiotic paste was used as intracanal medication. The blood clot was used as scaffold followed by the application of collagen membrane followed by coronal plud malterial. Finally, the access was sealed using resin composite restoration and composite restoration. Clinical assessment was conducted at 1, 3, 6, 9, and 12 months, while radiographic assessment was conducted at 6 and 12 months. Data were statistically analyzed using the Chi-squared test for intergroup comparisons and Cochran's Q test for intragroup comparison. Results: Clinically, Group I exhibited a success rate of 100%, whereas Group II exhibited a success rate of 85.7%. Radiographically, both materials showed a 90.5% success rate. There was no statistically significant difference between both materials for all assessed clinical and radiographic parameters at different follow-up periods. Conclusions: Both Totalfill bioceramic putty and WMTA can be used successfully as coronal plug in esthetic areas.

Prevalence of extended-spectrum beta-lactamase and molecular detection of blaTEM, blaSHV, and blaCTX-M genotypes among gram-negative Bacilli isolates from hospital acquired infections in pediatrics, one institutional study.

BACKGROUND: Gram-negative bacilli represents an important pathogen in hospital-acquired infections (HAIs) worldwide. The emergence of antibiotic resistance in these pathogens warrants attention for the proper management of infections. Extended-spectrum beta-lactamase (ESBL) resistance represents a major therapeutic problem in infections due to Gram-negative bacilli. The present study aimed to study the extended-spectrum beta-lactamase genes blaTEM, blaSHV, and blaCTX-M by multiplex polymerase reaction in isolated Gram-negative bacilli from HAIs in pediatric patients. METHODS: The study included one hundred-five isolates of Gram-negative bacilli from pediatric patients with different types of HAIs. The isolates were subjected to full microbiological identification, antibiotics susceptibility by disc diffusion method, the phenotypic study of ESBL, and the genetic study of ESBL genes by multiplex PCR. RESULTS: Fifty isolates of Gram-Negative bacilli showed ESBL activity by a phenotypic study by double disc diffusion method (50/105). All ESBL producers' isolates were positive by PCR for ESBL genes. The most frequent gene was blaTEM (64%), followed by blaSHV (30%) and CTX-M (22%). Mixed genes were found in 4 isolates (8%) for blaTEM and blaSHV, blaTEM and CTX-M. There was a significant association between PCR for ESBL genes and phenotypic ESBL detection (P = 0.001). There was significant detection of ESBL genes in E. coli (28%), followed by Enterobacter spp. (26%), Klebsiella spp. (24%), Serratia (14%), Pseudomonas spp. (6%) and Proteus (2%), P = 0.01. There Seventy percent of isolates positive for ESBL production had an insignificant association between MDR and PCR for ESBL genes (P = 0.23). CONCLUSION: The present study highlights the prevalence of ESBL activity among clinical isolates of Gram-negative bacilli isolated from hospital-acquired infections in pediatric patients. The most common gene responsible for this activity was blaTEM gee followed by blaSHV and blaCTX-M. There was a high prevalence of multiple antibiotic resistance among isolates with ESBL activity. The finding of the present study denotes the importance of screening extended beta-lactamase among Gram-negative bacilli associated with HAIs in pediatric patients.

Safety and feasibility of rotational atherectomy (RA) versus conventional stenting in patients with chronic total occlusion (CTO) lesions: a systematic review and meta-analysis.

BACKGROUND AND AIM: Interventional cardiologists face challenges in managing chronic total occlusion (CTO) lesions, with conflicting results when comparing rotational atherectomy (RA) to conventional PCI. This meta-analysis aims to provide a critical evaluation of the safety and feasibility of RA in CTO lesions. METHODS: PubMed, Scopus, Web of Science, Ovid, and Cochrane central library until April 2023 were searched for relevant studies. MACE was our primary outcomes, other outcomes were all cause of death, cardiac death, MI, and TVR. Also, we reported angiographic outcomes as technical success, procedural success, and procedural complications in a random effect model. The pooled data was analyzed using odds ratio (OR) with its 95% CI using STATA 17 MP. RESULTS: Seven studies comprising 5494 patients with a mean follow-up of 43.1 months were included in this meta-analysis. Our pooled analysis showed that RA was comparable to PCI to decrease the incidence of MACE (OR = 0.98, 95% CI [0.74 to 1.3], p = 0.9). Moreover, there was no significant difference between RA and conventional PCI in terms of other clinical or angiographic outcomes. CONCLUSION: Our study showed that RA had comparable clinical and angiographic outcomes as conventional PCI in CTO lesions, which offer interventional cardiologists an expanded perspective when addressing calcified lesions. PROSPERO REGISTRATION: CRD42023417362.

A comprehensive guide on the optimal timing of PCI in the setting of acute coronary syndrome: An updated meta-analysis.

BACKGROUND: Invasive revascularization is recommended for cohorts of patients with ST-elevation myocardial infarction (STEMI) and non-ST-elevation acute coronary syndrome (NSTE-ACS). However, the optimal timing of invasive revascularization is still controversial and no defined consensus is established. We aim to give a comprehensive appraisal on the optimal timing of invasive strategy in the heterogenous population of ACS. METHODS: Relevant studies were assessed through PubMed, Scopus, Web of science, and Cochrane Library from inception until April 2023. Major adverse cardiovascular events (MACE) and all-cause mortality were our primary outcomes of interest, other secondary outcomes were cardiac death, TVR, MI, repeat revascularization, recurrent ischemia, and major bleeding. The data was pooled as odds ratio (OR) with its 95% confidence interval (CI) in a random effect model using STATA 17 MP. RESULTS: A total of 26 studies comprising 21,443 patients were included in the analysis. Early intervention was favor to decrease all-cause mortality (OR = 0.79, 95% CI: 0.64 to 0.98, p = 0.03), when compared to delayed intervention. Subgroup analysis showed that early intervention was significantly associated with all-cause mortality reduction in only NSTE-ACS (OR = 0.83, 95% CI [0.7 to 0.99], p = 0.04). However, there was no significant difference between early and delayed intervention in terms of MACE, cardiac death, TVR, MI, repeat revascularization, recurrent ischemia, and major bleeding. CONCLUSION: An early intervention was associated with lower mortality rates compared to delayed intervention in NSTE-ACS with no significant difference in other clinical outcomes. PROSPERO registration: CRD42023415574.

A comparative analysis of deep neural network architectures for the dynamic diagnosis of COVID-19 based on acoustic cough features.

The study aims to assess the detection performance of a rapid primary screening technique for COVID-19 that is purely based on the cough sound extracted from 2200 clinically validated samples using laboratory molecular testing (1100 COVID-19 negative and 1100 COVID-19 positive). Results and severity of samples based on quantitative RT-PCR (qRT-PCR), cycle threshold, and patient lymphocyte numbers were clinically labeled. Our suggested general methods consist of a tensor based on audio characteristics and deep-artificial neural network classification with deep cough convolutional layers, based on the dilated temporal convolution neural network (DTCN). DTCN has approximately 76% accuracy, 73.12% in TCN, and 72.11% in CNN-LSTM which have been trained at a learning rate of 0.2%, respectively. In our scenario, CNN-LSTM can no longer be employed for COVID-19 predictions, as they would generally offer questionable forecasts. In the previous stage, we discussed the exactness of the total cases of TCN, dilated TCN, and CNN-LSTM models which were truly predicted. Our proposed technique to identify COVID-19 can be considered as a robust and in-demand technique to rapidly detect the infection. We believe it can considerably hinder the COVID-19 pandemic worldwide.

Poisoning-related emergency department visits: the experience of a Saudi high-volume toxicology center.

BACKGROUND: Acute poisoning is a major contributing factor to mortality and morbidity. There is a lack of research on the epidemiology of acute poisoning risk factors in Saudi Arabia. OBJECTIVES: Descriptive overview of poisoning cases at a tertiary care center. DESIGN: Descriptive, medical record review. SETTINGS: Tertiary care center in Riyadh. PATIENTS AND METHODS: From the electronic medical record system, we collected demographic information, medical history, and the poisoning history on all emergency department visits diagnosed as acute poisoning from January 2016 to January 2021. Patients were classed as children (<18 years old) or adults, and further classified by body mass index. MAIN OUTCOME MEASURES: Intensive care unit (ICU) admission, organ transplantation, and mortality were classified as poor outcomes. SAMPLE SIZE: 492 adults and 1013 children (<18 years old) were identified. RESULTS: The most frequent agent in poisoning for both groups was acetaminophen (n=52, 10.57% and n=100, 9.87%, respectively). The ICU admission rate was 6.7% and 4.8%, and the mortality rate 0.8% and 0.3%, respectively. The accidental poisoning rate was 57.7% among adults (n=284) and 67.6% among children (n=658). The suicide intention rate was 11.2% (n=55) and 7.4% (n=75) among adults and children, respectively. The management for both populations was nonspecific, involving observation, supportive measures, and symptomatic treatment. CONCLUSION: Although the ICU admission rates were consistent with reported data, the mortality rate was marginally lower. The pediatric predominance in the population implies a lack of caregiver education in the region regarding the safe storage of drugs and household products, as well as the use of child-resistant packaging. The high rate of accidental poisoning in both age groups should prompt further investment to promote public health education on the rational use and safe storage of toxic agents and self-protection. The high suicide intention rate needs to be investigated to develop multidisciplinary risk prevention strategies. LIMITATIONS: Single center, retrospective, small population size. CONFLICT OF INTEREST: None.

Electronic cigarette exposure causes vascular endothelial dysfunction due to NADPH oxidase activation and eNOS uncoupling.

We recently reported a mouse model of chronic electronic cigarette (e-cig) exposure-induced cardiovascular pathology, where long-term exposure to e-cig vape (ECV) induces cardiac abnormalities, impairment of endothelial function, and systemic hypertension. Here, we delineate the underlying mechanisms of ECV-induced vascular endothelial dysfunction (VED), a central trigger of cardiovascular disease. C57/BL6 male mice were exposed to ECV generated from e-cig liquid containing 0, 6, or 24 mg/mL nicotine for 16 and 60 wk. Time-dependent elevation in blood pressure and systemic vascular resistance were observed, along with an impairment of acetylcholine-induced aortic relaxation in ECV-exposed mice, compared with air-exposed control. Decreased intravascular nitric oxide (NO) levels and increased superoxide generation with elevated 3-nitrotyrosine levels in the aorta of ECV-exposed mice were observed, indicating that ECV-induced superoxide reacts with NO to generate cytotoxic peroxynitrite. Exposure increased NADPH oxidase expression, supporting its role in ECV-induced superoxide generation. Downregulation of endothelial nitric oxide synthase (eNOS) expression and Akt-dependent eNOS phosphorylation occurred in the aorta of ECV-exposed mice, indicating that exposure inhibited de novo NO synthesis. Following ECV exposure, the critical NOS cofactor tetrahydrobiopterin was decreased, with a concomitant loss of its salvage enzyme, dihydrofolate reductase. NADPH oxidase and NOS inhibitors abrogated ECV-induced superoxide generation in the aorta of ECV-exposed mice. Together, our data demonstrate that ECV exposure activates NADPH oxidase and uncouples eNOS, causing a vicious cycle of superoxide generation and vascular oxidant stress that triggers VED and hypertension with predisposition to other cardiovascular disease.NEW & NOTEWORTHY Underlying mechanisms of e-cig-induced vascular endothelial dysfunction are delineated. e-cig exposure activates and increases expression of NADPH oxidase and disrupts activation and coupling of eNOS, leading to a vicious cycle of superoxide generation and peroxynitrite formation, with tetrahydrobiopterin depletion, causing loss of NO that triggers vascular endothelial dysfunction. This process is progressive, increasing with the duration of e-cig exposure, and is more severe in the presence of nicotine, but observed even with nicotine-free vaping.

Spectrum of uropathogens and their susceptibility to antimicrobials in pregnant women: a retrospective analysis of 5-year hospital data.

OBJECTIVE: Urinary tract infections (UTI) are common during pregnancy. Identification of antimicrobial susceptibility patterns of microorganisms in pregnant women is important to select the most appropriate antimicrobial. We assessed common uropathogens in pregnant women with UTI and antimicrobial susceptibility, to guide empirical antibiotic selection. METHODS: In this retrospective study, we analyzed mid-stream urine culture and antibiotic susceptibility data from pregnant women who attended Jordan University Hospital during 2014 to 2018. Data were collected from patients' charts and urine cultures, and sensitivity results were extracted from the laboratory electronic system. We calculated descriptive statistics and determined correlations among pathogens and antibiotics. RESULTS: We examined 612 positive urine cultures from 559 pregnant women, including 163 (29.2%) inpatients. Escherichia coli (29.4%) was the most frequently identified microorganism, followed by coagulase-negative staphylococci (CoNS) (21.6%). All bacterial isolates were sensitive to aztreonam, chloramphenicol, fosfomycin, ofloxacin, pefloxacin, piperacillin, and colistin sulfate; 87.5% were sensitive to amikacin. Only 15.79%, 18.93%, and 17.91% were sensitive to oxacillin, nalidixic acid, and erythromycin, respectively. CONCLUSION: E. coli and CoNS were the most commonly identified microorganisms in this study. We found increased antibiotic resistance in Enterobacter species. The chosen antimicrobial therapy in pregnancy should be determined by sensitivity/resistance and fetomaternal safety.

Highly Sensitive Twin Resonance Coupling Refractive Index Sensor Based on Gold- and MgF2-Coated Nano Metal Films.

A plasmonic material-coated circular-shaped photonic crystal fiber (C-PCF) sensor based on surface plasmon resonance (SPR) is proposed to explore the optical guiding performance of the refractive index (RI) sensing at 1.7-3.7 µm. A twin resonance coupling profile is observed by selectively infiltrating liquid using finite element method (FEM). A nano-ring gold layer with a magnesium fluoride (MgF2) coating and fused silica are used as plasmonic and base material, respectively, that help to achieve maximum sensing performance. RI analytes are highly sensitive to SPR and are injected into the outmost air holes of the cladding. The highest sensitivity of 27,958.49 nm/RIU, birefringence of 3.9 × 10-4, resolution of 3.70094 × 10-5 RIU, and transmittance dip of -34 dB are achieved. The proposed work is a purely numerical simulation with proper optimization. The value of optimization has been referred to with an experimental tolerance value, but at the same time it has been ensured that it is not fabricated and tested. In summary, the explored C-PCF can widely be eligible for RI-based sensing applications for its excellent performance, which makes it a solid candidate for next generation biosensing applications.

STING Activated Tumor-Intrinsic Type I Interferon Signaling Promotes CXCR3 Dependent Antitumor Immunity in Pancreatic Cancer.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a lethal chemoresistant cancer that exhibits early metastatic spread. The highly immunosuppressive PDA tumor microenvironment renders patients resistant to emerging immune-targeted therapies. Building from our prior work, we evaluated stimulator of interferon genes (STING) agonist activation of PDA cell interferon-α/ß-receptor (IFNAR) signaling in systemic antitumor immune responses. METHODS: PDA cells were implanted subcutaneously to wild-type, IFNAR-, or CXCR3-knockout mice. Tumor growth was monitored, and immune responses were comprehensively profiled. RESULTS: Human and mouse STING agonist ADU-S100 reduced local and distal tumor burden and activated systemic antitumor immune responses in PDA-bearing mice. Effector T-cell infiltration and inflammatory cytokine and chemokine production, including IFN-dependent CXCR3-agonist chemokines, were elevated, whereas suppressive immune populations were decreased in treated tumors. Intratumoral STING agonist treatment also generated inflammation in distal noninjected tumors and peripheral immune tissues. STING agonist treatment of type I IFN-responsive PDA tumors engrafted to IFNAR-/- recipient mice was sufficient to contract tumors and stimulate local and systemic T-cell activation. Tumor regression and CD8+ T-cell infiltration were abolished in PDA engrafted to CXCR3-/- mice treated with STING agonist. CONCLUSIONS: These data indicate that STING agonists promote T-cell infiltration and counteract immune suppression in locally treated and distant tumors. Tumor-intrinsic type I IFN signaling initiated systemic STING-mediated antitumor inflammation and required CXCR3 expression. STING-mediated induction of systemic immune responses provides an approach to harness the immune system to treat primary and disseminated pancreatic cancers.

Long-term electronic cigarette exposure induces cardiovascular dysfunction similar to tobacco cigarettes: role of nicotine and exposure duration.

Electronic cigarette (e-cig) vaping (ECV) has been proposed as a safer alternative to tobacco cigarette smoking (TCS); however, this remains controversial due to a lack of long-term comparative studies. Therefore, we developed a chronic mouse exposure model that mimics human vaping and allows comparison with TCS. Longitudinal studies were performed to evaluate alterations in cardiovascular function with TCS and ECV exposure durations of up to 60 wk. For ECV, e-cig liquid with box-mod were used and for TCS, 3R4F-cigarettes. C57/BL6 male mice were exposed 2 h/day, 5 days/wk to TCS, ECV, or air control. The role of vape nicotine levels was evaluated using e-cig-liquids with 0, 6, or 24 mg/mL nicotine. Following 16-wk exposure, increased constriction to phenylephrine and impaired endothelium-dependent and endothelium-independent vasodilation were observed in aortic segents, paralleling the onset of systemic hypertension, with elevations in systemic vascular resistance. Following 32 wk, TCS and ECV induced cardiac hypertrophy. All of these abnormalities further increased out to 60 wk of exposure, with elevated heart weight and aortic thickness along with increased superoxide production in vessels and cardiac tissues of both ECV and TCS mice. While ECV-induced abnormalities were seen in the absence of nicotine, these occurred earlier and were more severe with higher nicotine exposure. Thus, long-term vaping of e-cig can induce cardiovascular disease similar to TCS, and the severity of this toxicity increases with exposure duration and vape nicotine content.NEW & NOTEWORTHY A chronic mouse exposure model that mimics human e-cigarette vaping and allows comparison with tobacco cigarette smoking was developed and utilized to perform longitudinal studies of alterations in cardiovascular function. E-cigarette exposure led to the onset of cardiovascular disease similar to that with tobacco cigarette smoking. Impaired endothelium-dependent and endothelium-independent vasodilation with increased adrenergic vasoconstriction were observed, paralleling the onset of systemic hypertension and subsequent cardiac hypertrophy. This cardiovascular toxicity was dependent on exposure duration and nicotine dose.

Mitochondria-targeted magnolol inhibits OXPHOS, proliferation, and tumor growth via modulation of energetics and autophagy in melanoma cells.

INTRODUCTION: Melanoma is an aggressive form of skin cancer for which there are no effective drugs for prolonged treatment. The existing kinase inhibitor antiglycolytic drugs (B-Raf serine/threonine kinase or BRAF inhibitors) are effective for a short time followed by a rapid onset of drug resistance. PRESENTATION OF CASE: Here, we show that a mitochondria-targeted analog of magnolol, Mito-magnolol (Mito-MGN), inhibits oxidative phosphorylation (OXPHOS) and proliferation of melanoma cells more potently than untargeted magnolol. Mito-MGN also inhibited tumor growth in murine melanoma xenografts. Mito-MGN decreased mitochondrial membrane potential and modulated energetic and mitophagy signaling proteins. DISCUSSION: Results indicate that Mito-MGN is significantly more potent than the FDA-approved OXPHOS inhibitor in inhibiting proliferation of melanoma cells. CONCLUSION: These findings have implications in the treatment of melanomas with enhanced OXPHOS status due to metabolic reprogramming or drug resistance.

Chronic cigarette smoke exposure triggers a vicious cycle of leukocyte and endothelial-mediated oxidant stress that results in vascular dysfunction.

Although there is a strong association between cigarette smoking exposure (CSE) and vascular endothelial dysfunction (VED), the underlying mechanisms by which CSE triggers VED remain unclear. Therefore, studies were performed to define these mechanisms using a chronic mouse model of cigarette smoking (CS)-induced cardiovascular disease mirroring that in humans. C57BL/6 male mice were subjected to CSE for up to 48 wk. CSE impaired acetylcholine (ACh)-induced relaxation of aortic and mesenteric segments and triggered hypertension, with mean arterial blood pressure at 32 and 48 wk of exposure of 122 ± 6 and 135 ± 5 mmHg compared with 99 ± 4 and 102 ± 6 mmHg, respectively, in air-exposed mice. CSE led to monocyte activation with superoxide generation in blood exiting the pulmonary circulation. Macrophage infiltration with concomitant increase in NADPH oxidase subunits p22phox and gp91phox was seen in aortas of CS-exposed mice at 16 wk, with further increase out to 48 wk. Associated with this, increased superoxide production was detected that decreased with Nox inhibition. Tetrahydrobiopterin was progressively depleted in CS-exposed mice but not in air-exposed controls, resulting in endothelial nitric oxide synthase (eNOS) uncoupling and secondary superoxide generation. CSE led to a time-dependent decrease in eNOS and Akt expression and phosphorylation. Overall, CSE induces vascular monocyte infiltration with increased NADPH oxidase-mediated reactive oxygen species generation and depletes the eNOS cofactor tetrahydrobiopterin, uncoupling eNOS and triggering a vicious cycle of oxidative stress with VED and hypertension. Our study provides important insights toward understanding the process by which smoking contributes to the genesis of cardiovascular disease and identifies biomarkers predictive of disease.NEW & NOTEWORTHY In a chronic model of smoking-induced cardiovascular disease, we define underlying mechanisms of smoking-induced vascular endothelial dysfunction (VED). Smoking exposure triggered VED and hypertension and led to vascular macrophage infiltration with concomitant increase in superoxide and NADPH oxidase levels as early as 16 wk of exposure. This oxidative stress was accompanied by tetrahydrobiopterin depletion, resulting in endothelial nitric oxide synthase uncoupling with further superoxide generation triggering a vicious cycle of oxidative stress and VED.

Prevalence of Gastroesophageal Reflux Disease in Saudi Arabia.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common chronic gastrointestinal tract disease. The incidence is higher in Asian and Arab countries. In Saudi Arabia, there are few studies that have assessed the prevalence of GERD among some cities' communities. Hence, this study aims to study the prevalence of GERD among the general population of Saudi Arabia. METHODS: A cross-sectional study was designed to determine the prevalence of GERD among the community of Saudi Arabia. The sample was randomly gathered through self-administered validated GERD questionnaire (GerdQ) to diagnose GERD, during the period from November to December 2016. The sociodemographic data was assessed for all participants. The data were analysed using Statistical Package for Social Sciences version 21.0 (SPSS); the t-test was used to assess the association of GERD and sociodemographic data. RESULTS: The sample was comprised of 2,043 participants. Female and male were 51.8% and 48.2%, respectively. Mean age was 29.6 years with the standard deviation of 10.5 years. The GERD prevalence was 28.7%. It was found statistically significant among divorced/widow (34.9%, P = 0.003). In contrast, there was no association between GERD's prevalence and gender, age, residence status, education level, occupation, and blood group (P > 0.05). CONCLUSIONS: The prevalence of GERD among Saudi population is higher than that in Western countries and East Asia. It affects divorced/widow, obese and those with a sedentary lifestyle. It is advocated that national programs and educational campaigns for prevention of this disease and its complications should be established.