Opportunities for targeted therapies: trametinib as a therapeutic approach to canine oral squamous cell carcinomas.

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. OSCCs have significant upregulation of the RAS-RAF-MEK-MAPK signaling axis, and we had previously hypothesized that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. Here, we demonstrate that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several COSCC cell lines established from current patient tumor samples. We further show clinical evidence that the drug is able to cause significant tumor regression in some patients with spontaneously occurring COSCC. Given the limited treatment options available and the high rate of owner rejection of these offered options, these findings provide new hope that more acceptable treatment options may soon enter the veterinary clinic.

Overcoming Barriers Associated with Oral Delivery of Differently Sized Fluorescent Core-Shell Silica Nanoparticles.

Oral delivery, while a highly desirable form of nanoparticle-drug administration, is limited by challenges associated with overcoming several biological barriers. Here, the authors study how fluorescent and poly(ethylene glycol)-coated (PEGylated) core-shell silica nanoparticles sized 5 to 50 nm interact with major barriers including intestinal mucus, intestinal epithelium, and stomach acid. From imaging fluorescence correlation spectroscopy studies using quasi-total internal reflection fluorescence microscopy, diffusion of nanoparticles through highly scattering mucus is progressively hindered above a critical hydrodynamic size around 20 nm. By studying Caco-2 cell monolayers mimicking the intestinal epithelia, it is observed that ultrasmall nanoparticles below 10 nm diameter (Cornell prime dots, [C' dots]) show permeabilities correlated with high absorption in humans from primarily enhanced passive passage through tight junctions. Particles above 20 nm diameter exclusively show active transport through cells. After establishing C' dot stability in artificial gastric juice, in vivo oral gavage experiments in mice demonstrate successful passage through the body followed by renal clearance without protein corona formation. Results suggest C' dots as viable candidates for oral administration to patients with a proven pathway towards clinical translation and may generate renewed interest in examining silica as a food additive and its effects on nutrition and health.

Condoms on Campus: Understanding College Students' Embarrassment, Self-Efficacy, and Beliefs About Distribution Programs.

BACKGROUND: Condom distribution programs are a structural-level intervention implemented on college campuses to reduce sexually transmitted infections and unplanned pregnancies. Understanding students' beliefs about these programs and attitudes that can affect condom use is critical. METHODS: Students at 6 different universities (n = 2809) completed items related to beliefs about campus condom distribution programs and their personal condom embarrassment and condom self-efficacy levels. Surveys were completed both in classroom and online. T Tests and analysis of variance were used to examine differences based on demographics. Logistic regression was used to examine predictors of condom use. RESULTS: College students support the distribution of condoms on campus (97.4%) but express moderate levels of embarrassment in condom acquisition and possession (mean, 19.37). Lower rates of embarrassment were reported for condom negotiation (mean, 9.13) and actual condom use (mean, 8.48). Lower overall rates of embarrassment were reported by condom users, men and individuals in relationships compared with noncondom users, women, and single individuals. Heterosexual students were more embarrassed than bisexual students about acquiring condoms and negotiating condom use. Condom users, men, and individuals in relationships had higher rates of condom self-efficacy compared with nonusers, women, and single students. There were no differences in self-efficacy based on sexual orientation. Embarrassment about acquiring and actual use of condoms, condom self-efficacy and demographics were all significant predictors of condom use. CONCLUSIONS: Campus condom distribution programs are supported by college students. Interventions to address embarrassment and increase condom self-efficacy need to be tailored to different students based on gender, experience with condoms, and relationship status.

An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection.

Zika virus (ZIKV), an arbovirus transmitted by mosquitoes, was identified as a cause of congenital disease during a major outbreak in the Americas in 2016. Vaccine design strategies relied on limited available isolate sequence information due to the rapid response necessary. The first-generation ZIKV mRNA vaccine, mRNA-1325, was initially generated and, as additional strain sequences became available, a second mRNA vaccine, mRNA-1893, was developed. Herein, we compared the immune responses following mRNA-1325 and mRNA-1893 vaccination and reported that mRNA-1893 generated comparable neutralizing antibody titers to mRNA-1325 at 1/20th of the dose and provided complete protection from ZIKV challenge in non-human primates. In-depth characterization of these vaccines indicated that the observed immunologic differences could be attributed to a single amino acid residue difference that compromised mRNA-1325 virus-like particle formation.

Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas.

Activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs) are characterized by constitutive activation of nuclear factor κB driven by the B-cell receptor (BCR) and Toll-like receptor (TLR) pathways. However, BCR-pathway-targeted therapies have limited impact on DLBCLs. Here we used >1,100 DLBCL patient samples to determine immune and extracellular matrix cues in the lymphoid tumour microenvironment (Ly-TME) and built representative synthetic-hydrogel-based B-cell-lymphoma organoids accordingly. We demonstrate that Ly-TME cellular and biophysical factors amplify the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signalling pathways in ABC-DLBCL cells, which reduce the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Combinatorial inhibition of multiple aberrant signalling pathways induced higher antitumour efficacy in lymphoid organoids and implanted ABC-DLBCL patient tumours in vivo. Our studies define the complex crosstalk between malignant ABC-DLBCL cells and Ly-TME, and provide rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.

Evaluation of Athlete Monitoring Tools across 10 Weeks of Elite Youth Basketball Training: An Explorative Study.

The growth of sport science technology is enabling more sporting teams to implement athlete monitoring practices related to performance testing and load monitoring. Despite the increased emphasis on youth athlete development, the lack of longitudinal athlete monitoring literature in youth athletes is concerning, especially for indoor sports such as basketball. The aim of this study was to evaluate the effectiveness of six different athlete monitoring methods over 10 weeks of youth basketball training. Fourteen state-level youth basketball players (5 males and 9 females; 15.1 ± 1.0 years) completed this study during their pre-competition phase prior to their national basketball tournament. Daily wellness and activity surveys were completed using the OwnUrGoal mobile application, along with heart rate (HR) and inertial measurement unit (IMU) recordings at each state training session, and weekly performance testing (3x countermovement jumps [CMJs], and 3x isometric mid-thigh pulls [IMTPs]). All of the athlete monitoring methods demonstrated the coaching staff's training intent to maintain performance and avoid spikes in workload. Monitoring IMU data combined with PlayerLoad™ data analysis demonstrated more effectiveness for monitoring accumulated load (AL) compared to HR analysis. All six methods of athlete monitoring detected similar trends for all sessions despite small-trivial correlations between each method (Pearson's correlation: -0.24 < r < 0.28). The use of subjective monitoring questionnaire applications, such as OwnUrGoal, is recommended for youth sporting clubs, given its practicability and low-cost. Regular athlete education from coaches and support staff regarding the use of these questionnaires is required to gain the best data.

Cardiometabolic Phenotypic Differences in Male Offspring Born to Obese Preeclamptic-Like BPH/5 Mice.

Preeclampsia (PE) is a hypertensive disorder of pregnancy occurring in approximately 10% of women worldwide. While it is life threatening to both the mother and baby, the only effective treatment is delivery of the placenta and fetus, which is often preterm. Maternal obesity is a risk factor for PE, and the effects of both on offspring are long standing with increased incidence of cardiometabolic disease in adulthood. Obese BPH/5 mice spontaneously exhibit excessive gestational weight gain and late-gestational hypertension, similar to women with PE, along with fetal growth restriction and accelerated compensatory growth in female offspring. We hypothesized that BPH/5 male offspring will demonstrate cardiovascular and metabolic phenotypes similar to BPH/5 females. As previously described, BPH/5 females born to ad libitum-fed dams are overweight with hyperphagia and increased subcutaneous, peri-renal, and peri-gonadal white adipose tissue (WAT) and cardiomegaly compared to age-matched adult female controls. In this study, BPH/5 adult male mice have similar body weights and food intake compared to age-matched control mice but have increased inflammatory subcutaneous and peri-renal WAT and signs of cardiovascular disease: left ventricular hypertrophy and hypertension. Therefore, adult male BPH/5 do not completely phenocopy the cardiometabolic profile of female BPH/5 mice. Future investigations are necessary to understand the differences observed in BPH/5 male and female mice as they age. In conclusion, the impact of fetal programming due to PE has a transgenerational effect on both male and female offspring in the BPH/5 mouse model. The maternal obesogenic environment may play a role in PE pregnancy outcomes, including offspring health as they age.

ST-Elevation Myocardial Infarction in a 23-Year-Old Female: The Mystery of Thrombus Formation.

Acute ST-elevation myocardial infarction (STEMI) is rarely seen in young adults, however, when encountered, the underlying cause is either a genetic condition leading to early-onset coronary artery disease (CAD), an acquired pro-thrombotic condition, or an idiopathic condition like spontaneous coronary artery dissection (SCAD). Our case describes a healthy 23-year-old female who presented with sudden onset severe angina and was found to have a laminated thrombus in the left anterior descending coronary artery (LAD), with no evidence of intraluminal dissection or plaque rupture. Although the underlying etiology of thrombus formation remains unknown, coronavirus disease 2019 (COVID-19) related thrombotic event is the prime suspect. In addition, another culprit that cannot be excluded is phentermine-induced coronary vasospasm, a commercially available medication for weight loss. This report addresses current literature on acute coronary syndromes in young adults and reviews the potential etiologies for coronary artery thrombosis, which led to a near-fatal acute coronary syndrome in our patient.

A Validated Smartphone-based Electrocardiogram Reveals Severe Bradyarrhythmias during Immobilizing Restraint in Mice of Both Sexes and Four Strains.

Mouse handling and restraint affect behavior, physiology, and animal welfare, yet little information is available on how various mouse restraint methods affect cardiovascular parameters. We validated the use of a smartphone-based ECG sys- tem in mice by performing simultaneous smartphone and telemetry ECG recordings in conscious, restrained mice and in anesthetized mice. We observed that mice held in standard immobilizing restraint ("scruffing") experienced severe bradycardia. Mice of both sexes and 4 different strains (BALB/cJ, C57BL/6J, DBA/2J, and FVB/nJ) were restrained by 3 handlers using 3 different restraint methods: light restraint; 3-finger restraint, which creates a dorsal transverse fold of skin; and the standard immobilizing restraint, which creates a dorsal longitudinal fold of skin that results in a crease on the ventral neck. Regardless of the handler, immobilizing restraint, but not 3-finger restraint, produced severe bradycardia with irregular rhythm in all 4 strains and both sexes, with an average decrease in heart rate of 31%, or 211 bpm, and a maximal decrease of 79%, or 542 bpm. When evaluated using telemetry, immobilizing restraint produced severe arrhythmias such as junctional and ventricular escape rhythms, and second- and third-degree atrioventricular block. Sinus pauses were observed for an average of 4 min, but up to 6.8 min after release from immobilizing restraint. Atropine administration to C57BL/6J mice attenuated immobilizing restraint-induced bradycardia, supporting the hypothesis that pressure on cervical baroreceptors during stretching of the neck skin results in a vagally-mediated reflex bradycardia. Because of these profound cardiovascular effects, we recommend using the light or 3-finger restraint and avoiding or minimizing the use of immobilization restraint while handling mice.

Brown adipose tissue is associated with cardiometabolic health.

White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear1,2. Here we retrospectively categorized 134,529 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values. The beneficial effects of BAT were more pronounced in individuals with overweight or obesity, indicating that BAT might play a role in mitigating the deleterious effects of obesity. Taken together, our findings highlight a potential role for BAT in promoting cardiometabolic health.

Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.

Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual targeting of EZH2 and Bcl-2 is a rational therapeutic approach. We hypothesized that EZH2 and Bcl-2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the Bcl-2 inhibitor venetoclax in DLBCL cells, 3-dimensional lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells and 3-dimensional lymphoma organoids that harbor an EZH2 mutation and an IGH/BCL2 translocation but not in wild-type cells. Tazemetostat treatment results in upregulation of proapoptotic Bcl-2 family members and priming of mitochondria to BH3-mediated apoptosis, which may sensitize cells to venetoclax. The combination of tazemetostat and venetoclax was also synergistic in vivo. In DLBCL PDXs, short-course combination therapy resulted in complete remissions that were durable over time and associated with superior overall survival compared with either drug alone.

Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity.

We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical entities with antimycobacterial activity driven via a noncovalent inhibition of the decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1). The representative compounds from the new scaffold reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent DprE1 inhibition and antimycobacterial activity. A representative compound from the benzimidazole series demonstrated good efficacy in a murine model of tuberculosis. Furthermore, molecular modeling of the BI scaffold suggests plausible modes of binding in the active site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series.

Predictors of Universal Catheter Failure in Transradial Coronary Angiography.

BACKGROUND: Use of a universal diagnostic catheter may decrease procedural time and catheter-exchange related spasm when compared with a dual-catheter strategy. The aim of this study was to identify preprocedural predictors of failure to complete a coronary angiogram with a universal catheter alone. METHODS: Consecutive patients (n = 782) who underwent a right transradial/transulnar coronary angiogram with a single operator were retrospectively reviewed. Multivariable predictors of failure to complete the procedure with a universal catheter alone were identified using logistic regression analysis and presented as odds ratio (OR) and 95% confidence interval (CI). RESULTS: Of the study population (n = 558), a total of 216 (38.7%) required exchange to a coronary-specific catheter (44.4% for right coronary artery alone, 25.5% for left coronary artery alone, 30.1% for both) and 342 (61.3%) underwent angiography with a universal catheter alone. Patients who required a catheter exchange were more likely to have the following characteristics compared with patients who underwent an angiogram with a universal catheter alone: age >75 years (27.3% vs 16.4%; P<.01), female sex (34.3% vs 23.1%; P<.01), diabetes mellitus (50.0% vs 38.3%; P<.01), hypertension (88.0% vs 74.6%; P<.001), and chronic kidney disease (29.2% vs 17.8%; P<.01). After multivariable adjustment, age ≫75 years (OR, 1.92; 95% CI, 1.21-3.04), female sex (OR, 1.94; 95% CI, 1.20-3.14), hypertension (OR, 2.08; 95% CI, 1.22-3.57), and chronic kidney disease (OR, 1.58; 95% CI, 1.01-2.46) predicted failure of a universal catheter alone to complete angiography. CONCLUSION: Consideration may be given to use an initial dual-catheter strategy if one or more of the following are present: elderly age, female sex, hypertension, and chronic kidney disease.

Subfornical organ insulin receptors tonically modulate cardiovascular and metabolic function.

Insulin acts within the central nervous system through the insulin receptor to influence both metabolic and cardiovascular physiology. While a major focus has been placed on hypothalamic regions, participation of extrahypothalamic insulin receptors in cardiometabolic regulation remains largely unknown. We hypothesized that insulin receptors in the subfornical organ (SFO), a forebrain circumventricular region devoid of a blood-brain barrier, are involved in metabolic and cardiovascular regulation. Immunohistochemistry in mice revealed widespread insulin receptor-positive cells throughout the rostral to caudal extent of the SFO. SFO-targeted adenoviral delivery of Cre-recombinase in insulin receptorlox/lox mice resulted in sufficient ablation of insulin receptors in the SFO. Interestingly, when mice were maintained on a normal chow diet, deletion of SFO insulin receptors resulted in greater weight gain and adiposity, relative to controls, independently of changes in food intake. In line with this, ablation of insulin receptors in the SFO was associated with marked hepatic steatosis and hypertriglyceridemia. Selective removal of SFO insulin receptors also resulted in a lower mean arterial blood pressure, which was primarily due to a reduction in diastolic blood pressure, whereas systolic blood pressure remained unchanged. Cre-mediated targeting of SFO insulin receptors did not influence heart rate. These data demonstrate multidirectional roles for insulin receptor signaling in the SFO, with ablation of SFO insulin receptors resulting in an overall deleterious metabolic state while at the same time maintaining blood pressure at low levels. These novel findings further suggest that alterations in insulin receptor signaling in the SFO could contribute to metabolic syndrome phenotypes.

The Condom Fairy program: A novel mail-order service for condoms and sexual health supplies.

Objective: In recent years college health professionals have used a variety of innovative strategies to increase availability and accessibility of condoms and safer sex products. The purpose of this study is to evaluate the efficacy and efficiency of a mail-order delivery program titled the Condom Fairy. Participants: Seven hundred thirty-three students (63.4% women, 86.1% heterosexual, and 59.2% Caucasian) completed a questionnaire assessing their overall experience with the program. Methods: Participants completed a 60 item questionnaire 30 days after receiving condoms and safer sex products. Results: Overall, 46,980 condoms were distributed over a six semester period. Almost all of the participants (97.4%) reported they ordered male condoms while 58.0% ordered sexual lubricant, 11.1% female condoms, and 10.2% latex dams. Nearly than three-quarters (73.9%) of participants reported they used the condoms provided. Conclusions: Findings support the implementation of innovative mail-in condom and safer sex product programs on college campuses.

Celecoxib restores angiogenic factor expression at the maternal-fetal interface in the BPH/5 mouse model of preeclampsia.

Preeclampsia (PE), a hypertensive disease of pregnancy, is a leading cause of fetal and maternal morbidity/mortality. Early angiogenic and inflammatory disturbances within the placenta are thought to underlie the development of the maternal PE syndrome and poor pregnancy outcomes. However, the exact etiology remains largely unknown. Here, we use the BPH/5 mouse model of PE to elucidate the way in which inflammation early in pregnancy contributes to abnormal expression of angiogenic factors at the maternal-fetal interface. We have previously described improvement in maternal hypertension and fetal growth restriction in this model after treatment with the anti-inflammatory cyclooxygenase-2 (Cox2) specific inhibitor celecoxib. To further characterize the mechanisms by which celecoxib improves poor pregnancy outcomes in BPH/5 mice, we determined expression of angiogenic factors and complement pathway components after celecoxib. In BPH/5 implantation sites there was increased hypoxia inducible factor-1α ( Hif1α), heme oxygenase-1 ( Ho-1), and stem cell factor ( Scf) mRNA concomitant with elevated prostaglandin synthase 2 ( Ptgs2), encoding Cox2, and elevated VEGF protein. Angiopoietin 1 ( Ang1), tunica interna endothelial cell kinase-2 receptor ( Tie2), complement factor 3 ( C3), and complement factor B ( CfB) were increased in midgestation BPH/5 placentae. Whereas BPH/5 expression levels of VEGF, Ang1, and Tie2 normalized after celecoxib, placental C3 and CfB mRNA remained unchanged. However, celecoxib did reduce the pregnancy-specific circulating soluble fms-like tyrosine kinase-1 (sFlt-1) rise in BPH/5 mice at midgestation. These data show that elevated Cox2 during implantation contributes to placental angiogenic factor imbalances in the BPH/5 mouse model of PE.

Missed opportunities for catch-up human papillomavirus vaccination among university undergraduates: Identifying health decision-making behaviors and uptake barriers.

BACKGROUND: Suboptimal adolescent human papillomavirus (HPV) vaccine rates in the US highlight the need for catch-up vaccination. When teenagers enter college, there may be a shift in healthcare decision-making from parents and guardians to the students themselves. Little is known about factors influencing college students' healthcare decision-making processes. STUDY DESIGN: We evaluated HPV vaccine decision-making among 18-to-26-year-old college students through a self-administered, anonymous, cross-sectional survey. This survey was distributed to a sample of men and women in classroom settings at two universities. Categorical data comparisons were conducted using Chi-square and Fisher's exact tests. Multivariate Poisson regression was used to model initiation of HPV vaccine and compute prevalence ratios while controlling for key influential covariates at the 0.05 alpha level. RESULTS: A total of 527 students participated (response proportion=93.1%). Overall, 55.8% of participants received the HPV vaccine. Encouraging conversations with doctors and/or parents/guardians were identified as one of the most influential factors to increase vaccine uptake. Among students who received encouragement from both a doctor and parent, 95.8% received the vaccine. Campaigns about cancer prevention were viewed as more influential than those that focus on preventing genital warts. Approximately one-third of students indicated they didn't know where to get the HPV vaccine. Women were more likely to report that their parents would not let them get the HPV vaccine compared to men (26.7% vs. 2.3%). The majority of students (77.3%) indicated their parents were sometimes, equally, or mostly involved in making decisions about receiving vaccines (other than flu). CONCLUSION: Students' decision-making is greatly influenced by their parents; therefore, interventions for this population should work to increase students' control over decision-making while also addressing parental concerns.

Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia.

Preeclampsia (PE), a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity and mortality. Although the etiology is unknown, PE is thought to be caused by defective implantation and decidualization in pregnancy. Pregnant blood pressure high (BPH)/5 mice spontaneously develop placentopathies and maternal features of human PE. We hypothesized that BPH/5 implantation sites have transcriptomic alterations. Next-generation RNA sequencing of implantation sites at peak decidualization, embryonic day (E)7.5, revealed complement gene up-regulation in BPH/5 vs. controls. In BPH/5, expression of complement factor 3 was increased around the decidual vasculature of E7.5 implantation sites and in the trophoblast giant cell layer of E10.5 placentae. Altered expression of VEGF pathway genes in E5.5 BPH/5 implantation sites preceded complement dysregulation, which correlated with abnormal vasculature and increased placental growth factor mRNA and VEGF164 expression at E7.5. By E10.5, proangiogenic genes were down-regulated, whereas antiangiogenic sFlt-1 was up-regulated in BPH/5 placentae. We found that early local misexpression of VEGF genes and abnormal decidual vasculature preceded sFlt-1 overexpression and increased complement deposition in BPH/5 placentae. Our findings suggest that abnormal decidual angiogenesis precedes complement activation, which in turn contributes to the aberrant trophoblast invasion and poor placentation that underlie PE.-Sones, J. L., Merriam, A. A., Seffens, A., Brown-Grant, D.-A., Butler, S. D., Zhao, A. M., Xu, X., Shawber, C. J., Grenier, J. K., Douglas, N. C. Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia.

Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain.

Nonalcoholic fatty liver disease (NAFLD), characterized by an excess accumulation of hepatic triglycerides, is a growing health epidemic. While ER stress in the liver has been implicated in the development of NAFLD, the role of brain ER stress - which is emerging as a key contributor to a number of chronic diseases including obesity - in NAFLD remains unclear. These studies reveal that chemical induction of ER stress in the brain caused hepatomegaly and hepatic steatosis in mice. Conversely, pharmacological reductions in brain ER stress in diet-induced obese mice rescued NAFLD independent of body weight, food intake, and adiposity. Evaluation of brain regions involved revealed robust activation of ER stress biomarkers and ER ultrastructural abnormalities in the circumventricular subfornical organ (SFO), a nucleus situated outside of the blood-brain-barrier, in response to high-fat diet. Targeted reductions in SFO-ER stress in obese mice via SFO-specific supplementation of the ER chaperone 78-kDa glucose-regulated protein ameliorated hepatomegaly and hepatic steatosis without altering body weight, food intake, adiposity, or obesity-induced hypertension. Overall, these findings indicate a novel role for brain ER stress, notably within the SFO, in the pathogenesis of NAFLD.