tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial
Authors: W. Timothy Garvey, Andreas L. Birkenfeld, Dror Dicker, Geltrude Mingrone, Sue D. Pedersen, Altynai Satylganova, Dorthe Skovgaard, Danny Sugimoto, Camilla Jensen, Ofri Mosenzon
Journal: Diabetes Care (2020)

OBJECTIVE Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population. RESEARCH DESIGN AND METHODS Satiety and Clinical Adiposity—Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and ≤2 oral antidiabetic drugs. RESULTS Individuals were randomized to liraglutide 3.0 mg (n = 198) or placebo (n = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was −5.8% for liraglutide 3.0 mg versus −1.5% with placebo (estimated treatment difference −4.3% [95% CI −5.5; −3.2]; P &amp;lt; 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved ≥5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; P &amp;lt; 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA1c and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed. CONCLUSIONS In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events.
Contrast-enhanced ultrasonography (CEUS) in retroperitoneal liposarcomas
Authors: M. Brandi, G. Badalamenti, F. Sorrentino, L. Vizzini, L. Incorvaia, G. Rinaldi, M. Sanfilippo, N. Gebbia, C. Intrivici, G. Caruso
Journal: Journal of Clinical Oncology (2007)

20514 Background: CEUS with second-generation contrast agents has been proposed to monitor tumor response to imatinib in patients with metastatic GIST. There are no data in patients with other sarcomas. Our aim was to assess the value of CEUS as a marker of tumor response in retroperitoneal liposarcoma, in addition to its ability to render the baseline malignancy grade of the disease. Methods: CEUS was performed after a SonoVue injection (Bracco, Milano, Italia). SonoVue is a suspension of microbubbles of exafluoride sulphure gas (average diameter 3 μm) with a phospholipidic shell. A low mechanical index (MI&lt;0.09) was used in order to minimize microbubbles rupture. Ultrasound device systems (Philips ATL HDI 5000, Bothel, Washington) with a broandband probe (2–5 Mhz) and specific contrast agent algorithms (Pulse Inversion Harmonic Imaging) were used. The use of this algorithm allowed a real time imaging of all vascular phases (arterial, portal and late). All patients underwent CT scan, PET tomography and routine blood examinations. Ten patients with retroperitoneal liposarcomas were enrolled in this study (5 high grade, 3 intermediate grade, 2 low grade). Results: Five males and five females with metastatic or relapsed disease were enrolled. Median age was 57 years (range 40–70). All underwent chemotherapy with Ifosfamide and Doxorubicin. In all patients there was a clear correlation between contrast enhancement and grading: in low-grade patients there was no contrast enhancement, while the highest level of enhancement was seen in undifferentiated sarcomas. With regard to tumor response to chemotherapy, only 4 patients were evaluable. One patient had a PR and 3 patients had PD. In the 3 patients with PD CEUS showed contrast enhancement, PET was uptaking, but CT scan did not detect any change. In the patient with a PR, strong decrease of tumor perfusion on CEUS and uptaking on PET was seen, again with no change on CT scan. Conclusions: These preliminary observations suggest that CEUS may be more useful than CT scan on assessing tumor response in retroperitoneal sarcomas, and may predict the baseline malignancy grade. Data on a larger number of patients will be presented. No significant financial relationships to disclose.
Putting the Pieces Together: Completing the Mechanism of Action Jigsaw for Sipuleucel-T
Authors: Ravi A Madan, Emmanuel S Antonarakis, Charles G Drake, Lawrence Fong, Evan Y Yu, Douglas G McNeel, Daniel W Lin, Nancy N Chang, Nadeem A Sheikh, James L Gulley
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.
Abstract 35: Estimated Impact of Achieving Optimal Cardiovascular Health in the US Adult Population on Cardiovascular Disease Events
Authors: Joshua D Bundy, Zhengbao Zhu, Hongyan Ning, Victor W Zhong, Amanda E Paluch, Paul K Whelton, Donald M Lloyd-jones, John T Wilkins, Jiang He, Norrina B Allen
Journal: Circulation (2020)

Introduction: Quantifying the potential impact of achieving optimal cardiovascular health (CVH) in US adults could aid researchers, clinicians, and policymakers in developing and implementing strategies to reduce the burden of cardiovascular disease (CVD). Hypothesis: CVH is suboptimal in US adults. Attaining an optimal level of CVH in all US adults would prevent a substantial number of CVD events. Methods: We pooled individual-level data from 7 US cohort studies (n=30447) included in the Lifetime Risk Pooling Project to estimate annual incidence rates of major CVD (CVD deaths, myocardial infarction, stroke, heart failure) by sex, race, and age. Using data from the National Health and Nutrition Examination Survey 2013 to 2016, we estimated the proportions of US adults in different CVH groups, defined by levels of 7 health factors: smoking status, body mass index, physical activity, dietary pattern, total cholesterol, blood pressure, and fasting glucose. Each factor was scored as ideal (2 points), intermediate (1 point), or poor (0 points). We defined overall CVH as optimal (12-14 points), moderate (9-11 points), or poor (0-8 points). Using the 2 data sources and Monte Carlo simulation, we estimated hazard ratios (HRs) for CVD, population attributable fractions, and the number of CVD events that could be prevented annually if all US adults achieved optimal CVH. Results: An optimal level of CVH was identified in 6.5% (95% CI, 4.5-8.5%) of US adults (Table) and was associated with a lower risk for CVD (HR [95% CI], 0.29 [0.17-0.43]). Our analysis suggests that 70% (95% CI, 55-82%) of all CVD events can be attributed to non-optimal levels of CVH. If US adults attained an optimal level of CVH, 2.0 (95% CI, 1.6-2.3) million CVD events could be prevented annually. Conclusions: The potential impact of achieving an optimal level of CVH in all US adults is considerable, and even a partial improvement would be beneficial. Population- and individual-level strategies to maintain or restore optimal CVH to reduce CVD event rates are highly desirable.
Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target
Authors: Haibo Zhang, Josef M. Penninger, Yimin Li, Nanshan Zhong, Arthur S. Slutsky
Journal: Intensive Care Medicine (2020)

A novel infectious disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in Wuhan, China, in December 2019.The disease (COVID-19) spread rapidly, reaching epidemic proportions in China, and has been found in 27 other countries.As of February 27, 2020, over 82,000 cases of COVID-19 were reported, with > 2800 deaths.No specific therapeutics are available, and current management includes travel restrictions, patient isolation, and supportive medical care.There are a number of pharmaceuticals already being tested [1, 2], but a better understanding of the underlying pathobiology is required.In this context, this article will briefly review the rationale for angiotensin-converting enzyme 2 (ACE2) receptor as a specific target.
TIMP1 preserves the blood–brain barrier through interacting with CD63/integrin 1 complex and regulating downstream FAK/RhoA signaling
Authors: Jingshu Tang, Yuying Kang, Longjian Huang, Lei Wu, Ying Peng
Journal: Acta Pharmaceutica Sinica B (2020)

Blood–brain barrier (BBB) breakdown and the associated microvascular hyperpermeability are hallmark features of several neurological disorders, including traumatic brain injury (TBI). However, there is no viable therapeutic strategy to rescue BBB function. Tissue inhibitor of metalloproteinase-1 (TIMP1) has been considered to be beneficial for vascular integrity, but the molecular mechanisms underlying the functions of TIMP1 remain elusive. Here, we report that TIMP1 executes a protective role on neuroprotective function via ameliorating BBB disruption in mice with experimental TBI. In human brain microvessel endothelial cells (HBMECs) exposed to hypoxia and inflammation injury, the recombinant TIMP1 (rTIMP1) treatment maintained integrity of junctional proteins and trans-endothelial tightness. Mechanistically, TIMP1 interacts with CD63/integrin β1 complex and activates downstream FAK signaling, leading to attenuation of RhoA activation and F-actin depolymerization for endothelial cells structure stabilization. Notably, these effects depend on CD63/integrin β1 complex, instead of the MMP-inhibitory function. Together, our results identified a novel MMP-independent function of TIMP1 in regulating endothelial barrier integrity. Therapeutic interventions targeting TIMP1 and its downstream signaling may be beneficial to protect BBB function following brain injury and neurological disorders.
Abstract MP61: Evidence of Impaired Microvascular Function a Decade After Delivery in Women With Placental Malperfusion Lesions
Authors: Alisse Hauspurg, Judith Brands, Robin Gandley, Matthew F Muldoon, William Tony Parks, Carl A Hubel, Janet M Catov
Journal: Circulation (2020)

Introduction: Maternal vascular malperfusion (MVM) lesions in the placenta are characterized by incomplete vascular remodeling and vessel features similar to atherosclerosis. MVM lesions indicate a maladaptive maternal vascular response to pregnancy, are often detected in hypertensive disorders of pregnancy (HDP), and may provide a pathologic link to future cardiovascular disease. The endothelial glycocalyx is a glycoprotein-rich layer that is critical for microvascular health and damage may have an important role in the pathophysiology of microcardiovascular disease risk. Hypothesis: We hypothesized that women with malperfusion lesions of the placenta are more likely to evidence microvascular glycocalyx derangement a decade after delivery compared to women without these lesions and that this effect would be most pronounced among women with a history of HDP. Methods: A total of 412 women with placental pathology (N=129 with MVM lesions, N=283 without MVM lesions) were evaluated at 8-10 years postpartum. Placental specimens were reviewed by a blinded perinatal pathologist . HDP (including preeclampsia and gestational hypertension) were abstracted from the medical record. Glycocalyx barrier function was assessed using sublingual sidestream dark field imaging, with reduction defined as deeper penetration of red blood cells (RBCs) into the glycocalyx of the sublingual microcirculation (5-25μm diameter). We compared the median diameter (size) of microvessels, penetration of RBCs into the glycocalyx (perfused boundary region, PBR) and microvascular density (total length of perfused microvessels/mm 2 surface area) in women with and without MVM lesions. Results: Women with placental MVM lesions had smaller-sized sublingual vessels (median 8.59 μM [IQR 8.12, 9.19] vs. 9.01 μM [IQR 8.37, 9.64]; p&lt;0.001), and a lower density of vessels compared to women without lesions. Glycocalyx perfused boundary region was unexpectedly lower in women with MVM lesions (median 2.20 μM [IQR 2.06, 2.43] vs. 2.32 μM [IQR 2.15, 2.50]; p=0.003) in 10-19 μM vessels. Women with HDP and MVM lesions appear to be the most impacted, with the smallest size vessels (median 8.47 [IQR 8.09-9.13]) and the lowest glycocalyx PBR across all vessel sizes. Women with MVM lesions without a HDP similarly had evidence of microvascular glycocalyx derangement whereas women with HDP without placental lesions had a glycocalyx profile similar to women without MVM or a history of HDP. Conclusions: A decade after delivery, women with a history of placental malperfusion lesions had alterations in microvascular perfusion. Women with MVM lesions and a history of HDP appear to be the most severely impacted, which may reflect an underlying maladaptive vascular phenotype detected in the placenta at the time of pregnancy that might provide pathologic insight into future maternal microvascular health.
GI highlights from the literature
Authors: Philip J Smith
Journal: Gut (2020)

### Atlas of colonic CD8+ T cells in UC

Corridoni D, Antanaviciute A, Gupta T, et al . Single-cell atlas of colonic CD8+ T cells in ulcerative colitis. Nat Med 2020;26:1480–90.

The aetiology of UC remains unclear but the immune system undoubtedly has a central role in the pathogenesis. The colonic mucosa lamina propria contains an abundance of tissue resident CD8+ T cells. Their transcriptional regulation, effector function and how they dynamically remodel to influence inflammation in IBD remain poorly characterised.

This study profiled CD8+ T cells from three healthy volunteers and compared these with patients with UC using single drop, single cell RNA sequencing. They then linked this with T cell receptor analysis to help define functional relationships and crosstalk with epithelial cell subtypes. They used various techniques to study CD8+ T cells to include gene expression data and gene ontology enrichment analysis followed by area under the receiver operating characteristic curve analysis.

The key findings of this paper highlighted extensive heterogeneity in CD8+ T cell composition, including expanded effector and posteffector terminally differentiated CD8+ T cells. Furthermore, they found that UC-associated CD8+ effector T cells can trigger tissue destruction and produce tumour necrosis factor (TNF)-α. Furthermore, the posteffector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Other key findings included observations that interleukin-26+ ( IL-26+ ) CD8+ cells demonstrated features of chronic stimulation displaying a colitis-specific ETS variant transcription factor 7 transcriptional network that limits inflammation through inhibition of ETS proto-oncogene 1 ( ETS1 )-controlled genes. The authors summarised that an imbalance between granzyme K+ TNF+ effectors and immunoregulatory IL-26+ + may facilitate tissue destruction that manifests as UC. They demonstrated that IL-26 attenuates the severity of colitis when tested in a rodent model but this would require more exploration in IBD human populations.

### IFN signalling preserves the stemness of intestinal stem cells

Sato T, Ishikawa S, Asano J et al . Regulated IFN signalling preserves …
Abstract MP36: Changes in High-density Lipoprotein (hdl) Subclasses and Particle Size Over the Menopause Transition are Associated With Higher Levels of Complement Proteins C3 and C4. The Study of Women's Health Across the Nation Hdl Ancillary Study
Authors: Samar R El Khoudary, Xirun Chen, Dan McConnell, Maria M Brooks, Trevor Orchard, Jeff Billheimer, Karen A Matthews
Journal: Circulation (2020)

Objective: High density lipoprotein (HDL) is emerging as a key player in modulating inflammation-related response impacting atherosclerosis development. HDL carries multiple proteins with direct roles in complement system activation including C3 and C4. Postmenopausal women have higher levels of C3 than premenopausal women suggesting a role of the menopause transition (MT) in modulating complement proteins. Preliminary work showed significant declines in large HDL particles (HDL-P) and overall HDL particle size, but increases in small HDL-P during the MT. Whether these changes contribute to higher levels of C3 reported after menopause is not known. Our objectives were to test whether C3 and C4 increase around the final menstrual period (FMP) and whether changes in HDL subclasses over the MT associate with C3 and C4 levels in midlife women. Design: We evaluated 558 women (at baseline: age 49.9(2.8) years; 86.6% perimenopausal) who had nuclear magnetic resonance spectroscopy HDL subclasses, C3 and C4 measured up to 5 times over the MT. Piecewise linear mixed-effects models were used to estimate and compare yearly changes in C3 and C4 at 3 time segments relative to the FMP. Linear mixed effect models were used to test associations between changes in each HDL subclass and overall HDL particle size with C3 and C4 separately. Results: Adjusted annual changes in C3 and C4 varied by time segments relative to FMP with significant increases only observed within 1 year before to 2 years after the FMP ( Figure ). These changes were significantly greater than changes in the other 2 time segments. Greater decreases in large and increases in small HDL-P concentrations and decreases in the overall size of HDL-P were independently associated with higher levels of C3 and C4 over time ( Table ). Conclusions: Complement proteins C3 and C4 significantly rise around menopause with C3 showing the steepest rise. Changes in HDL subclasses and overall size over the MT may play role in modulating inflammation responses known to be related to atherosclerosis.
Abstract 15845: Exploring the Causal Pathway From Omega-6 Levels to Coronary Heart Disease: A Network Mendelian Randomization Study
Authors: Xiaodong Zhuang, Lizhen Liao, Xinxue Liao
Journal: Circulation (2019)

Introduction: Omega-6 fats are essential fatty acids that play vital roles in many physiological functions. However, evidence on the effect of omega-6 fats on coronary heart disease (CHD) risk rema...
Severe Lung Injury Associated With Use of e-Cigarette, or Vaping, Products—California, 2019
Authors: Amy Heinzerling, Christina Armatas, Ellora Karmarkar, Kathleen Attfield, Weihong Guo, Yun Wang, Gordon Vrdoljak, Bahman Moezzi, Dadong Xu, Jeff Wagner, Jefferson Fowles, Charity Dean, Kristin J. Cummings, Jason A. Wilken
Journal: JAMA Internal Medicine (2020)

<h3>Importance</h3> Since August 2019, more than 2700 patients have been hospitalized with e-cigarette, or vaping, product use–associated lung injury (EVALI) across the United States. This report describes the outbreak in California, a state with one of the highest case counts and with a legal adult-use (recreational) cannabis market. <h3>Objective</h3> To present clinical characteristics and vaping product exposures of patients with EVALI in California. <h3>Design, Setting, and Participants</h3> Case series describing epidemiologic and laboratory data from 160 hospitalized patients with EVALI reported to the California Department of Public Health by local health departments, who received reports from treating clinicians, from August 7 through November 8, 2019. <h3>Exposures</h3> Standardized patient interviews were conducted to assess vaping products used, frequency of use, and method of product acquisition. Vaping products provided by a subset of patients were tested for active ingredients and other substances. <h3>Main Outcomes and Measures</h3> Demographic and clinical characteristics, level of care, and outcomes of hospitalization were obtained from medical record review. <h3>Results</h3> Among 160 patients with EVALI, 99 (62%) were male, and the median age was 27 years (range, 14-70 years). Of 156 patients with data available, 71 (46%) were admitted to an intensive care unit, and 46 (29%) required mechanical ventilation. Four in-hospital deaths occurred. Of 86 patients interviewed, 71 (83%) reported vaping tetrahydrocannabinol (THC)-containing products, 36 (43%) cannabidiol (CBD)-containing products, and 39 (47%) nicotine-containing products. Sixty-five of 87 (75%) THC-containing products were reported as obtained from informal sources, such as friends, acquaintances, or unlicensed retailers. Of 87 vaping products tested from 24 patients, 49 (56%) contained THC. Vitamin E or vitamin E acetate was found in 41 (84%) of the THC-containing products and no nicotine products. <h3>Conclusions and Relevance</h3> Patients' clinical outcomes and vaping behaviors, including predominant use of THC-containing products from informal sources, are similar to those reported by other states, despite California's legal recreational cannabis market. While most THC products tested contained vitamin E or vitamin E acetate, other underlying cause(s) of injury remain possible. The California Department of Public Health recommends that individuals refrain from using any vaping or e-cigarette products, particularly THC-containing products from informal sources, while this investigation is ongoing.
Abstract 14622: Nexilin Mutation Impairs LV Compensatory Ability to Pressure Overload in Mice
Authors: Jianping Li, Wenxin Zou, Ruirui Ji, Yutao Xi, Lianghao Lu, Daniel J Penny, Yuxin Fan
Journal: Circulation (2019)

Mutations of nexilinhave been recently identified as novel causes for dilated and hypertrophic cardiomyopathy (DCM and HCM, respectively). Knockout of nexilin led to development of DCM in different...