Re-irradiation of recurrent head and neck cancers using pulsed reduced dose rate radiotherapy: An institutional series.

PURPOSE/OBJECTIVE(S): Pulsed reduced dose rate (PRDR) radiation (RT) is a re-irradiation (Re-RT) technique that potentially overcomes dose/volume constraints in the setting of previous RT. There is minimal data for its use for recurrent or secondary primary head and neck squamous cell carcinoma (HNSCC). In this study, we report preliminary data from our institution of a consecutive cohort of HNSCC patients who received PRDR Re-RT. MATERIALS/METHODS: Nine patients received PRDR Re-RT from August 2020 to January 2023 and had analyzable data. Intensity modulated RT was used for treatment delivery and a wait time between 20 cGy arc/helical deliveries was used to achieve the effective low dose rate. Data collected included patient demographic information, prior interventions, diagnosis, radiation therapy dose and fractionation, progression free survival, overall survival, and toxicity rates. RESULTS: The median time to PRDR-RT from completion of initial RT was 13 months (range, 6-50 months). All but one patient underwent salvage surgery prior to PRDR-RT. The median follow-up after Re-RT was 7 months. The median OS from PRDR-RT was 7 months (range, 1-32 months). Median PFS was 7 months (range, 1-32 months). One patient (11.1 %) had acute grade 3 toxicity, and two patients (22.2 %) had late grade 3 toxicities. There were no grade 4+ toxicities. CONCLUSION: PRDR Re-RT is a feasible treatment strategy for patients with recurrent or second primary HNSCC. Initial findings from this retrospective review suggest reasonable survival outcomes and potentially improved toxicity; prospective data is needed to establish the safety and efficacy of this technique.

A Prospective Study Measuring Resident and Faculty Contour Concordance: A Potential Tool for Quantitative Assessment of Residents' Performance in Contouring and Target Delineation in Radiation Oncology Residency.

PURPOSE/OBJECTIVE(S): Accurate target delineation (ie, contouring) is essential for radiation treatment planning and radiotherapy efficacy. As a result, improving the quality of target delineation is an important goal in the education of radiation oncology residents. The purpose of this study was to track the concordance of radiation oncology residents' contours with those of faculty physicians over the course of 1 year to assess for patterns. MATERIALS/METHODS: Residents in postgraduate year (PGY) levels 2 to 4 were asked to contour target volumes that were then compared to the finalized, faculty physician-approved contours. Concordance between resident and faculty physician contours was determined by calculating the Jaccard concordance index (JCI), ranging from 0, meaning no agreement, to 1, meaning complete agreement. Multivariate mixed-effect models were used to assess the association of JCI to the fixed effect of PGY level and its interactions with cancer type and other baseline characteristics. Post hoc means of JCI were compared between PGY levels after accounting for multiple comparisons using Tukey's method. RESULTS: In total, 958 structures from 314 patients collected during the 2020-2021 academic year were studied. The mean JCI was 0.77, 0.75, and 0.61 for the PGY-4, PGY-3, and PGY-2 levels, respectively. The JCI score for PGY-2 was found to be lower than those for PGY-3 and PGY-4, respectively (all P < .001). No statistically significant difference of JCI score was found between the PGY-3 and PGY-4 levels. The average JCI score was lowest (0.51) for primary head and/or neck cancers, and it was highest (0.80) for gynecologic cancers. CONCLUSIONS: Tracking and comparing the concordance of resident contours with faculty physician contours is an intriguing method of assessing resident performance in contouring and target delineation and could potentially serve as a quantitative metric, which is lacking currently, in radiation oncology resident evaluation. However, additional study is necessary before this technique can be incorporated into residency assessments.

Opioid Use in Patients With Cervical Cancer at a Tertiary Academic Medical Center.

BACKGROUND/AIM: Opioids are a common treatment for cancer-related pain and information is limited on the rates of opioid use for cervical cancer patients. This study aimed to analyze outpatient opioid use and various predictors among patients with cervical cancer at a tertiary academic medical center. PATIENTS AND METHODS: Data from patients with cervical cancer receiving treatment at a single institution, from August 2019 to July 2022, were retrospectively collected. Women with unrelated chronic opioid use or opioid use associated with acute inpatient stays were excluded. Charts were reviewed for patient demographics, disease characteristics, treatment characteristics, disease outcomes, and opioid prescriptions. The primary endpoint was duration of opioid use ≥6 months. Pearson's chi-squared testing, Welch's two-sample t-testing and Fisher's exact testing were used to determine predictors of opioid use ≥6 months. RESULTS: In total, 108 patients with cervical cancer (76.1%) of the 142 that received treatment were prescribed opioids. In women who were prescribed outpatient opioids, the median duration of opioid use was 69 days (interquartile range=5-359 days). In total, 40 (37.0%) had prescriptions for ≥180 days and 27 (25.0%) had prescriptions ≥365 days. On bivariate analysis, lower stage and receipt of surgery were associated with opioid use duration <6 months. Age, race, histology, substance/tobacco/alcohol use, depression/anxiety, and the receipt of brachytherapy/radiation were not associated with length of opioid prescriptions. CONCLUSION: This study demonstrated that 37% of patients with cervical cancer were using opioids for cancer-related pain longer than 6 months. Higher stage was associated with opioid use duration ≥6 months.

Unanticipated Enhancement of Intestinal TG Output by Apoc3 ASO Inhibition.

BACKGROUND: The objective of this study was to investigate whether apoC3 (apolipoprotein C3) inhibition with an antisense oligonucleotide (ASO) modulates intestinal triglyceride secretion. METHODS: Sprague-Dawley rats were treated with subcutaneous injections of apoC3 ASO 25 mg/kg twice weekly or inactive ASO for 4 weeks before the assessment of lymph flow, triglyceride and apoB48 (apolipoprotein B48) appearance in the lymph. Rats were surgically implanted with catheters in the mesenteric lymph duct and duodenum. Following an overnight fast, an intraduodenal lipid bolus (1.5-mL intralipid) was administered. Lymph fluid was collected for the following 4 hours to compare effects on lymph flow, lymph triglyceride and apoB48 concentration, and secretion. To assess suppression of apoC3 expression and protein abundance by apoC3 ASO compared with inactive ASO (placebo), intestinal and hepatic tissues were collected from a subset of animals before (fasting) and after an enteral lipid bolus (post-lipid). RESULTS: ApoC3 ASO significantly reduced apoC3 mRNA expression in the liver compared with inactive ASO (fasting: 42%, P=0.0048; post-lipid: 66%, P<0.001) and in the duodenum (fasting: 29%, P=0.0424; post-lipid: 53%, P=0.0120). As expected, plasma triglyceride also decreased significantly (fasting: 74%, P<0.001; post-lipid: 33%, P=0.0276). Lymph flow and cumulative lymph volume remained unchanged following apoC3 ASO therapy; however, lymph triglyceride, but not apoB48 output, increased by 38% (ANOVA, P<0.001). Last, no changes were observed in stool triglyceride, intestinal fat (quantified via oil red O staining), and expression of mRNAs involved in triglyceride synthesis, lipid droplet formation, and chylomicron transport and secretion. CONCLUSIONS: Despite the marked reduction in plasma triglyceride concentration that occurs with apoC3 ASO inhibition, intestinal triglyceride output surprisingly increased rather than decreased. These data demonstrate that the reduction of intestinal triglyceride output does not contribute to the potent plasma triglyceride-lowering observed with this novel therapy for hypertriglyceridemia. Further studies are required to explore the mechanism of this intestinal effect.

The Effects of the COVID-19 Pandemic on Cancer Staging in Patients Diagnosed With Head and Neck Cancer.

Purpose The healthcare system across the world was forced to implement new policies, guidelines, and procedures due to the coronavirus disease 2019 (COVID-19) pandemic, which led many patients to make an impossible choice about their health. For various reasons, many patients chose to remain at home and delay any interaction at medical facilities to protect themselves or others from the virus. Patients managing chronic diseases faced unprecedented challenges during this period, and the long-term effects on these patient populations remain unclear. Oncology patients, specifically those diagnosed with head and neck cancers, require prompt diagnosis and initiation of treatment for better outcomes. While the overall impact of how the pandemic has affected oncology patients is unknown, this retrospective study examined how the staging of head and neck tumors at our institution has been impacted since the beginning of the pandemic. Methods Available patient data (from August 1, 2019, through June 28, 2021) were collected from medical records and compared to determine statistical significance. Patients were categorized into a Pre-pandemic group, Pandemic group, and Vaccine-approved group, and patient and treatment characteristics were analyzed to look for patterns. The pre-pandemic period was defined as the period from August 1, 2019, to March 16, 2020, the pandemic period was defined as the period from March 17, 2020, to December 31, 2020, and the vaccine-approved period was defined as the period from January 1, 2021, to June 28, 2021.  Results Fisher's exact tests were used to compare tumor, node, metastasis (TNM) staging distributions between the three groups. In the Pre-pandemic group, out of 67 patients, 33 patients (55.0%) were diagnosed with a T stage of 0-2 and 27 patients (45.0%) were diagnosed with a T stage of 3-4. In the Pandemic and Vaccine-approved groups, out of 139 patients, 50 patients (39.1%) were diagnosed with a T stage of 0-2 and 78 patients (60.9%) were diagnosed with a T stage of 3-4; these differences were statistically significant (P-value = 0.0426). The Pre-pandemic group had 25 patients (41.7%) diagnosed with a group stage of 0-2 and 35 patients (58.3%) diagnosed with a group stage of 3-4. The Pandemic and Vaccine-approved groups had 36 patients (28.1%) diagnosed with a group stage of 0-2 and 92 patients (71.9%) diagnosed with a group stage of 3-4; these results trended to statistically significant (P-value = 0.0688). Conclusions Our findings suggest that there have been a higher number of patients with head and neck cancer diagnosed with a T stage of 3 or 4 since the start of the COVID-19 pandemic. The effects of the COVID-19 pandemic are ongoing and will need further evaluation to determine the overall effects on oncology patients. Increased morbidity and mortality rates may be a potential result in the years to come.

Glucagon-like Peptide-2 Acutely Enhances Chylomicron Secretion in Humans Without Mobilizing Cytoplasmic Lipid Droplets.

CONTEXT: A portion of ingested fats are retained in the intestine for many hours before they are mobilized and secreted in chylomicron (CM) particles. Factors such as glucagon-like peptide-2 (GLP-2) and glucose can mobilize these stored intestinal lipids and enhance CM secretion. We have recently demonstrated in rodents that GLP-2 acutely enhances CM secretion by mechanisms that do not involve the canonical CM synthetic assembly and secretory pathways. OBJECTIVE: To further investigate the mechanism of GLP-2's potent intestinal lipid mobilizing effect, we examined intracellular cytoplasmic lipid droplets (CLDs) in intestinal biopsies of humans administered GLP-2 or placebo. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: A single dose of placebo or GLP-2 was administered subcutaneously 5 hours after ingesting a high-fat bolus. In 1 subset of participants, plasma samples were collected to quantify lipid and lipoprotein concentrations for 3 hours after placebo or GLP-2. In another subset, a duodenal biopsy was obtained 1-hour after placebo or GLP-2 administration for transmission electron microscopy and proteomic analysis. RESULTS: GLP-2 significantly increased plasma triglycerides by 46% (P = 0.009), mainly in CM-sized particles by 133% (P = 0.003), without reducing duodenal CLD size or number. Several proteins of interest were identified that require further investigation to elucidate their potential role in GLP-2-mediated CM secretion. CONCLUSIONS: Unlike glucose that mobilizes enterocyte CLDs and enhances CM secretion, GLP-2 acutely increased plasma CMs without significant mobilization of CLDs, supporting our previous findings that GLP-2 does not act directly on enterocytes to enhance CM secretion and most likely mobilizes secreted CMs in the lamina propria and lymphatics.

Heterogeneous attitudinal profiles towards gene editing: Evidence from latent class analysis.

Advances in gene-editing technology have important implications for the treatment and prevention of disease. Accordingly, it is important to understand public perceptions towards gene editing, as the public's willingness to endorse gene editing may be as important as technological breakthroughs themselves. Previous research has almost exclusively examined attitudes towards gene editing on specific issues, but has not addressed how attitudes towards gene editing across a range of issues coalesce in individuals: that is, the degree to which discrete, heterogeneous attitudinal profiles exist versus a simple support/oppose continuum. Here, we addressed this issue using latent class analysis on data from The Pew Research Center (N = 4726; US residents) across a wide range of gene-editing topics. We found that attitudes towards gene editing cohere into 10 distinct latent classes that showed some evidence of a support/oppose continuum, but also for clear qualitative differences between each class, even with support or oppose classes, on a number of issues. The most opposed classes significantly differed from the supporter classes in age, sex, political ideology and self-rated knowledge. These findings provide evidence that attitudes towards gene editing are heterogeneous and public discourse, as well as policy making need to consider a range of arguments when evaluating this technology.

Impact of COVID-19 on public's interest in radiotherapy and other cancer treatments: a cross-sectional Google Trends analysis.

Background: COVID-19 has significantly impacted cancer care. While previous studies have emphasized treatment modification and prioritized the delivery of cancer care, few have examined this issue from the public perspective. Materials and methods: In the following study, we examine how public interest in various forms of cancer treatment has evolved during the pandemic using Google Trends. One-way ANOVA and linear regression tests were used to compare the mean search volume indices of three periods: pre-lockdown, lockdown, and reopening. Results/Conclusions: Our findings suggest that public interest in cancer treatments decreased during lockdown and returned after reopening but, in general, is still lower than pre-lockdown levels. Despite that, healthcare professionals should strive to provide timely cancer care, assuage patients' fears of healthcare settings, and encourage patients to continue proper cancer screenings.

An Analysis of Risk Factors for Radiation Necrosis Following Cranial Radiation.

Introduction Radiation necrosis in the brain is a frequent complication of brain radiation therapy (RT) and is characterized by various neurological symptoms including cognitive dysfunction, headaches, weakness, apraxia, aphasia, and numbness. These symptoms may be progressive and treatment-resistant. Currently, risk factors for radiation necrosis are not well characterized. The goal of this study is to identify risk factors for cerebral radiation necrosis in order to improve clinicians' ability to appropriately weigh the risks and benefits of brain RT. Methods A retrospective chart review was performed on patients who were diagnosed with brain tumors and received RT (3D conformal therapy, volumetric modulated arc therapy, stereotactic radiosurgery, or stereotactic radiotherapy) at the University of Arkansas for Medical Sciences from July 1, 2017, to July 1, 2019. Data regarding demographics, characteristics of cancer, chemotherapy status and class, comorbidities, and additional medications of patients were collected via EPIC. Total RT dose, fraction size, volume of brain receiving 12 Gy (V12), and retreatment of locally recurrent tumors were recorded from Eclipse. The diagnosis of radiation necrosis was based on MRI reports that were examined for a time period of 24 months following the completion of radiation treatment and confirmed, when possible, by biopsy. Cases that did not have an MRI available at least two months after the completion of RT were excluded. Statistical association analyses were used to identify candidate risk factors to radiation necrosis. These candidate risk factors were further used to assess their associations to demographics and other characteristics of cancer and treatments. Finally, adjusted and unadjusted logistic regression models were used to predict radiation necrosis using a single risk factor or multiple risk factors. ROC curves were used to evaluate the performance of prediction or discrimination of the logistic regression models. Results A total of 139 patients were studied. The mean ± standard deviation (SD) for age was 60.4 ± 13.6 years, female:male ratio was 71:68, and White:African American:other race ratio was 112:24:3. A total of 43 (30.9%) patients were diagnosed with radiation necrosis. Radiation adjuvant to surgery, concurrent systemic therapy status, total dose, and V12 were found to be significantly associated with radiation necrosis and considered candidate risk factors of radiation necrosis in the study. Predictive models showed adjusted odds ratios ([aORs] 95% confidence intervals or CIs) of 3.70 (1.01-13.56) and 8.19 (1.78-37.78) with radiation adjuvant to surgery and concurrent systemic therapy, respectively. For every one unit (log-transformed) increase of total dose and V12, the aORs (95% CI's) were 27.35 (3.74-200.16) and 1.63 (1.15-2.32), respectively. Conclusion Our study suggested a positive correlation of concurrent systemic therapy status and post-surgical adjuvant RT with the incidence of radiation necrosis. It further demonstrated that greater total RT dose and V12 were related to the risk of developing radiation necrosis following brain RT. Given the findings of this study, the aforementioned factors should be considered when weighing the risk of radiation necrosis with the benefits of treatment.

Enteral glucose, absorbed and metabolized, potently enhances mesenteric lymph flow in chow- and high-fat-fed rats.

A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This pool of TG can be mobilized in response to several stimuli, including oral glucose. The objective of this study was to determine whether oral glucose must be absorbed and metabolized to mobilize TG in rats and whether high-fat feeding, a model of insulin resistance, alters the lipid mobilization response to glucose. Lymph flow, TG concentration, TG output, and apolipoprotein B48 (apoB48) concentration and output were assessed after an intraduodenal lipid bolus in rats exposed to the following intraduodenal administrations 5 h later: saline (placebo), glucose, 2-deoxyglucose (2-DG, absorbed but not metabolized), or glucose + phlorizin (intestinal glucose absorption inhibitor). Glucose alone, but not 2-DG or glucose + phlorizin treatments, stimulated lymph flow, TG output, and apoB48 output compared with placebo. The effects of glucose in high-fat-fed rats were similar to those in chow-fed rats. In conclusion, glucose must be both absorbed and metabolized to enhance lymph flow and intestinal lipid mobilization. This effect is qualitatively and quantitatively similar in high-fat- and chow-fed rats. The precise signaling mechanism whereby enteral glucose enhances lymph flow and mobilizes enteral lipid remains to be determined.NEW & NOTEWORTHY Glucose potently enhances mesenteric lymph flow in chow- and high-fat-fed rats. The magnitude of glucose effect on lymph flow is no different in chow- and high-fat-fed rats. Glucose must be absorbed and metabolized to enhance lymph flow and mobilize intestinal lipid.

Insights and Strategies to Revive Brachytherapy Using Social Media: A Google Trends Analysis.

INTRODUCTION: The utilization and public awareness of brachytherapy are both declining. Social media has an increasing presence in health promotions. As regards cancer care, social media has been successfully used as a platform for information dissemination, psychosocial support, and patient engagement and empowerment. METHODS AND MATERIALS: Using Google Trends (Google LLC, Mountain View, CA, USA), we analyzed the impacts on the public interest of three brachytherapy-related social media campaigns/publicity events and compared and contrasted them with three other campaigns/publicity events. We used descriptive statistics (mean ± standard deviation (SD)) to describe the search results, independent t-tests to compare means before and after campaigns/announcements for short-term effects, and one-way ANOVA (or Kruskal-Wallis test when appropriate) to compare mean values across distinct time periods for long-term effects. RESULTS: We identified three major types of social media campaigns/events: those that have a short-term impact but little long-term impact, those that have both short-term and long-term impacts, and those with little short-term or long-term impact. We examined campaigns with significant and lasting impacts and noticed that they tend to be celebrity-related/celebrity-endorsed, focused on sharing personal experiences, and occur with regular frequency. CONCLUSIONS: To increase public awareness of brachytherapy, the American Brachytherapy Society (ABS) can consider tie-ins with events and people with high search traffic (such as Breast Cancer Awareness Month), having celebrities/influencers who were treated with brachytherapy to provide testimonials, encouraging patient engagement and sharing of their experiences with brachytherapy on social media, and setting up recurring brachytherapy publicity events.

Recent advances in cytoplasmic lipid droplet metabolism in intestinal enterocyte.

Processing of dietary fats in the intestine is a highly regulated process that influences whole-body energy homeostasis and multiple physiological functions. Dysregulated lipid handling in the intestine leads to dyslipidemia and atherosclerotic cardiovascular disease. In intestinal enterocytes, lipids are incorporated into lipoproteins and cytoplasmic lipid droplets (CLDs). Lipoprotein synthesis and CLD metabolism are inter-connected pathways with multiple points of regulation. This review aims to highlight recent advances in the regulatory mechanisms of lipid processing in the enterocyte, with particular focus on CLDs. In-depth understanding of the regulation of lipid metabolism in the enterocyte may help identify therapeutic targets for the treatment and prevention of metabolic disorders.

COVID-19 and seasonal flu vaccination hesitancy: Links to personality and general intelligence in a large, UK cohort.

Vaccines are a powerful and relatively safe tool to protect against a range of serious diseases. Nonetheless, a sizeable minority of people express 'vaccination hesitancy'. Accordingly, understanding the bases of this hesitancy represents a significant public health opportunity. In the present study we sought to examine the role of Big Five personality traits and general intelligence as predictors of vaccination hesitancy across two vaccination types in a large (N = 9667) sample of UK adults drawn from the Understanding Society longitudinal household study. We found that lower levels of general intelligence were associated with COVID-19 and seasonal flu vaccination hesitancy, and lower levels of neuroticism was associated with COVID-19 vaccination hesitancy. Although the self-reported reasons for being vaccine hesitant indicated a range of factors were important to people, lower general intelligence was associated with virtually all of these reasons. In contrast, Big Five personality traits showed more nuanced patterns of association.

Glucagon-like peptide-2 mobilization of intestinal lipid does not require canonical enterocyte chylomicron synthetic machinery.

BACKGROUND & AIMS: Dietary triglycerides (TG) retained in the intestine after a meal can be mobilized many hours later by glucagon-like peptide-2 (GLP-2) in humans and animal models, despite the well-documented absence of expression of the GLP-2 receptor on enterocytes. In this study, we examined the site of GLP-2 action to mobilize intestinal lipids and enhance chylomicron production. METHODS: In mesenteric lymph duct-cannulated rats, we assessed GLP-2-stimulated lymph flow rate, TG concentration, TG output, and apoB48 abundance 5 h after an intraduodenal lipid bolus, in the presence of a validated GLP-2 antagonist or vehicle. Additionally, the same GLP-2-stimulated parameters were examined in the presence or absence of cis-Golgi disruption by Brefeldin A (BFA). RESULTS: Compared to placebo, GLP-2 administration increased lymph flow by 2.8-fold (P < 0.001), cumulative lymph volume by 2.69-fold (P < 0.001) and total TG output 2-fold (P = 0.015). GLP-2 receptor antagonism markedly diminished GLP-2's ability to stimulate lymph flow, cumulative lymph volume and total TG output, demonstrating the dependence of GLP-2 stimulation of lymph flow and TG output on its receptor activation. In contrast, disruption of the cis-Golgi apparatus with Brefeldin A did not diminish the GLP-2-response of lymph flow i.e., increased lymph flow by 2.7-fold (P = 0.001), lymph volume by 2.9-fold (P = 0.001), and total TG output i.e., increased by 2.5-fold (P = 0.003). CONCLUSIONS: GLP-2 mobilizes enteral lipid at a site distal to the Golgi, acting via its receptor. Since GLP-2 receptors are not expressed on enterocytes, GLP-2 likely mobilizes intestinal lipid residing extracellularly, either in the lamina propria or in the lymphatics.

Lymphatics - not just a chylomicron conduit.

PURPOSE OF REVIEW: Lymphatics are known to have active, regulated pumping by smooth muscle cells that enhance lymph flow, but whether active regulation of lymphatic pumping contributes significantly to the rate of appearance of chylomicrons (CMs) in the blood circulation (i.e., CM production rate) is not currently known. In this review, we highlight some of the potential mechanisms by which lymphatics may regulate CM production. RECENT FINDINGS: Recent data from our lab and others are beginning to provide clues that suggest a more active role of lymphatics in regulating CM appearance in the circulation through various mechanisms. Potential contributors include apolipoproteins, glucose, glucagon-like peptide-2, and vascular endothelial growth factor-C, but there are likely to be many more. SUMMARY: The digested products of dietary fats absorbed by the small intestine are re-esterified and packaged by enterocytes into large, triglyceride-rich CM particles or stored temporarily in intracellular cytoplasmic lipid droplets. Secreted CMs traverse the lamina propria and are transported via lymphatics and then the blood circulation to liver and extrahepatic tissues, where they are stored or metabolized as a rich energy source. Although indirect data suggest a relationship between lymphatic pumping and CM production, this concept requires more experimental evidence before we can be sure that lymphatic pumping contributes significantly to the rate of CM appearance in the blood circulation.

Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

Effective, disease-modifying, clinical approaches to patients with mild-to-moderate hypertriglyceridaemia.

Plasma triglyceride concentration is easily, inexpensively, and accurately measured, and when elevated is a highly informative disease marker that identifies individuals who frequently have a host of underlying metabolic, inflammatory, and atherogenic risk factors. Although this concept aligns with much that has been discussed regarding the metabolic syndrome, individuals identified with mild-to-moderate hypertriglyceridaemia on a screening lipid profile are not necessarily recognised as having features of the metabolic syndrome and frequently do not receive definitive, meaningful, disease-modifying therapy. This treatment would include (1) lifestyle modification; (2) LDL-lowering therapies to aggressively treat elevated apolipoprotein B-containing particles; (3) antihypertensive therapies that have optimal therapeutic profiles for those individuals with metabolic syndrome; (4) icosapent ethyl for those individuals at high risk, particularly patients with established atherosclerotic cardiovascular disease who have residual hypertriglyceridaemia despite treatment with appropriate LDL-lowering therapies; (5) preferential use of cardiovascular protective diabetes therapies, in individuals with diabetes; and (6) antithrombotic therapies for secondary prevention of atherosclerotic cardiovascular disease in the context of high vascular disease risk and diabetes. Several emerging therapies, such as novel weight reducing, anti-inflammatory, lipid-modifying therapies, and therapies targeting the progression of non-alcoholic fatty liver disease, could also soon enter the clinical arena for patients with mild-to-moderate hypertriglyceridaemia and associated metabolic syndrome.