ResearchPad - treatment https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Retrospective observational cohort study on innovation in oncology and progress in survival: How far have we gotten in the two decades of treating patients with advanced non-small cell lung cancer as a single population?]]> https://www.researchpad.co/article/elastic_article_13816 We assessed the impact of new antineoplastic agents on the overall survival (OS) of advanced non-small cell lung cancer (aNSCLC) patients followed up until 2012. Multivariate regression models were run for OS (outcome) and four proxies for innovation (exposure): Index (InnovInd, for SEER-Research data 1973–2012) and three levels of aggregation of Mean Medication Vintage, i.e. Overall (MMVOverall), using data aggregated at the State Level (MMVState), and using patient-level data (MMVPatient) using data from the US captured in SEER-Medicare 1991–2012. We derived Hazard ratios (HR) from Royston-Parmar models and odds ratios (OR) from a logistic regression on 1-year OS. Including 164,704 patients (median age 72 years, 56.8% stage IV, 61.8% with no comorbidities, 37.8% with adenocarcinoma, 22.9% with squamous-cell, 6.1% were censored). One-year OS improved from 0.22 in 1973 to 0.39 in 2012, in correlation with InnovInd (r = 0.97). Ten new NSCLC drugs were approved and 28 more used off-label. Regression-models results indicate that therapeutic innovation only marginally reduced the risk of dying (HROverall = 0.98 [0.98–0.98], HRMMV-Patient = 0.98 [0.97–0.98], and HRMMV-State = 0.98 [0.98–0.98], and slightly improved 1-year survival (ORMMV-Overall = 1.05 95%CI [1.04–1.05]). These results were validated with data from the Swedish National Health Data registers. Until 2013, aNSCLC patients were treated undifferentiated and the introduction of innovative therapies had statistically significant, albeit modest, effects on survival. Most treatments used off-guidelines highlight the high unmet need; however new advancements in treatment may further improve survival.

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<![CDATA[Administration of lower doses of radium-224 to ankylosing spondylitis patients results in no evidence of significant overall detriment]]> https://www.researchpad.co/article/elastic_article_11232 The use of low doses of radium-224 (224Ra) chloride for the treatment of ankylosing spondylitis was stopped following the discovery that patients treated with it had a higher than control incidence of leukaemia and other cancers. This was so even though the treatment resulted in decreased pain and increased mobility–both of which are associated with decreased mortality. It was decided to re-analyze the epidemiological data looking at all causes of death. The risk of leukaemia, solid cancer, death from non-cancer causes and from all causes in a study populations of men that received either the typical dose of 5.6 to 11.1 MBq of 224Ra, any dose of 224Ra or no radium were compared using the Cox proportional hazard model. For patients that received the typical dose of 224Ra agreed with the excess cancer was similar to that reported in previous studies. In contrast, these patients were less likely to die from non-cancer diseases and from all causes of death than the control patients. No excess mortality was also found in the population of all males that received the radionuclide. It is concluded that 224Ra treatment administered at low doses to patients with ankylosing spondylitis did not impact mortality from all causes. The study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation.

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<![CDATA[A modified arginine-depleting enzyme NEI-01 inhibits growth of pancreatic cancer cells]]> https://www.researchpad.co/article/elastic_article_11227 Arginine deprivation cancer therapy targets certain types of malignancies with positive result in many studies and clinical trials. NEI-01 was designed as a novel arginine-depleting enzyme comprising an albumin binding domain capable of binding to human serum albumin to lengthen its half-life. In the present work, NEI-01 is shown to bind to serum albumin from various species, including mice, rat and human. Single intraperitoneal administration of NEI-01 to mice reduced plasma arginine to undetectable level for at least 9 days. Treatment of NEI-01 specifically inhibited cell viability of MIA PaCa-2 and PANC-1 cancer cell lines, which were ASS1 negative. Using a human pancreatic mouse xenograft model, NEI-01 treatment significantly reduced tumor volume and weight. Our data provides proof of principle for a cancer treatment strategy using NEI-01.

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<![CDATA[Practical Challenges of Mask-to-Mask Encounters with Patients with Head and Neck Cancers amid the Coronavirus Disease 2019 Pandemic]]> https://www.researchpad.co/article/elastic_article_11180 The coronavirus disease 2019 (COVID-19) pandemic has forced a re-design of care in radiation oncology. Perhaps more than any other disease site we commonly see, the evaluation and treatment of head and neck cancer has posed the greatest risk of COVID-19 transmission between patients and radiotherapy providers. In our early experience with the novel coronavirus, several staff members were exposed to a COVID-positive patient and this caused us to devise policies and procedures to mitigate further risk in a way that could practically be employed across a large health system while not compromising care delivery. Here, we formulate a concise summary of simple steps, including a novel thermoplastic mask fitting technique and procedures for intraoral immobilization devices, to guide practices and provide new layers of protection for both patients and staff.

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<![CDATA[Radiation Therapy Department Reorganization during the Coronavirus Disease 2019 (COVID-19) Outbreak: Keys to Securing Staff and Patients During the First Weeks of the Crisis and Impact on Radiation Therapy Practice from a Single Institution Experience]]> https://www.researchpad.co/article/elastic_article_11084 During the first weeks of the coronavirus disease 2019 (COVID-19) outbreak in France, it was necessary to clearly define organizational priorities in the radiation therapy (RT) departments. In this report, we focus on the urgent measures taken to reduce risk for both our staff and patients by reducing the number of patients receiving treatment.Methods and MaterialsWe reviewed the fractionation schemes for all patients in our department, including those receiving treatment and those soon to start treatment. Our goals were to (1) decrease the number of patients coming daily to the hospital for RT, (2) adapt our human resources to continue patients’ care in the department, and (3) help to cover understaffed COVID-19 sectors of the hospital.ResultsWe identified 50 patients who were receiving treatment (n = 6), were going to start radiation after CT scan simulation (n = 41), or for whom the CT scan was pending (n = 3). The majority were women (64%) treated for breast cancer (54%). RT was delayed for 22 (44%) patients. The majority were offered hormone therapy as “waiting therapy.” Hypofractionation was considered in 21 (42%) patients mainly with breast cancer (18 of 21, 86%). The number of courses initially planned and replanned as a result of the COVID-19 outbreak during the period of March 15 to May 31, 2020, were 1383 and 683, respectively, which represented a reduction of 50% (including delayed sessions) that allowed our reorganization process.ConclusionsTo conserve resources during the pandemic, we successfully reduced the number of patients receiving treatment in a proactive fashion and adapted our organization to minimize the risk of COVID-19 contamination. Departments across the world may benefit from this same approach. ]]> <![CDATA[MON-LB108 Measurement Of Carotid Intima,hepatic Steatosis And Inflammatory Markers In Obese Children]]> https://www.researchpad.co/article/elastic_article_8593 Measurement of carotid intima,hepatic steatosis and inflammatory markers in obese children. Elevated levels of inflammatory factors and increased mean intimal carotid thickness (IMT) would increase the risk of atherothrombotic events and contribute to the progression of cardiovascular disease in obese children. Objectives: Evaluate inflammatory factors, metabolic syndrome and non-alcoholic liver steatosis and carotid IMT as an early cardiovascular risk marker. Patients and methods: Descriptive cross-sectional exploratory study. Consider 41 obese children both sexes between 6- 12 years old. Evaluated: anthropometry and determinations of lipid and liver profile, blood glucose, insulin, HOMA, ultrasensitive CRP, fibrinogen. Hepatic ultrasound and measurement of carotid IMT with ESAOTE Mylab 50 Exdicion equipment. . Results: From 41 studied patients, 57% were female. 51% presented MS and 68% elevated triglycerides. CRP> 1 was found in 71% of cases. Hepatic steatosis was observed in 60%, which only 10% had altered transaminases. 12% presented high fibrinogen. Patients with MS had a significant positive difference in the IMTCC (X = 0.41 ± 0.12; p 0.024), HDL (X 37.89 ± 1.72; p 0.004) triglycerides (X 149.42 ± 10.69; p 0.002) in relation to patients without MS. Conclusion: CRP is an inflammatory risk factor associated with elevated BMI and MS. There was a higher prevalence of MS in our study. The increase in the average intimal thickness is significantly related to the presence of MS and RCP>1. The determination of marker molecules of an inflammatory state and measurement of carotid IMT would contribute to the implementation of strategies to prevent cardiovascular, hepatic and metabolic risk since childhood.

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<![CDATA[MON-590 Presence of Diabetes Diminishes the Ultimate Weight Loss After Bariatric Surgery]]> https://www.researchpad.co/article/elastic_article_8574 Background

Obesity and diabetes as well as their related complications result in both individual and global health burdens. Among patients who present with both obesity and diabetes, bariatric surgery can lead to remission of both these diseases. However, the possible impact of diabetes on the magnitude of weight loss outcomes after bariatric surgery has not been quantified.

Methods

To address this question, we extracted data from Michigan Bariatric Surgery Cohort (MI-BASiC) to see whether diabetes at baseline could be a predictor of weight loss outcomes. Consecutive patients 18 years of age or older undergoing gastric bypass (GB) or sleeve gastrectomy (SG) for obesity at the University of Michigan between January 2008 and November 2013 were included in our retrospective cohort. All patients had either body mass index (BMI) > 40 kg/m2 or BMI 35 – 39.9 kg/m2 with comorbid condition. Firstly, we performed Generalized Linear Mixed Model (GLMM) analysis to compare the probability of achieving BMI under 30kg/m2 or achieving excess body weight loss (EBWL) 50% or more for patients with or without diabetes. We then further tested the effect of presence of diabetes for the BMI outcomes across time using Linear Mixed Model (LMM) analysis. Finally, we conducted a LMM analysis to determine if diabetes is a predictor of the future weight loss, percentage of total weight loss or percentage of excess weight loss over 5 years of follow up.

Results

Based on our criteria, 380 patients were included for GB [female 305 (80.3%), mean age 43.6±0.6 years, mean BMI 47.3±0.4kg/m2, diabetes 149 (39.2%), on insulin 45 (11.8%)] and 334 for SG [female 259 (77.5%), mean age 45.3±0.6 years, mean BMI 49.9±0.5kg/m2, diabetes 108 (32.3%), on insulin 29(8.7%)]. From GLMM analysis, the presence of diabetes at baseline did not impact the probability of achieving BMI under 30kg/m2 (p=0.0848), but substantially impacted the probability of achieving 50% or more EBWL (p=0.0021) with individuals without diabetes having a 1.6 (odds ratio 1.56, 95% CL [1.18-2.08]) times higher chance to achieve this threshold. We also showed that individuals with diabetes at baseline had a significant effect to modify BMI points lost, regardless of the surgery type (p=0.0178). The presence of diabetes at baseline diminished weight loss by 1.2 BMI points (95% CL [0.21- 2.20]) which is roughly 10 to 15% of the total BMI points to be lost. LMM analysis further confirmed that after adjusting the time, surgery type, age, gender and baseline weight, there was still a significant difference of absolute weight loss (p=0.0110), percentage of total weight loss (p=0.0089) and percentage of excess weight loss (p=0.0365) between individuals with diabetes versus individuals without diabetes.

Conclusion

In conclusion, our data demonstrate that diabetes diminishes the ultimate weight loss effect of bariatric surgery. Further research is needed to understand why this is the case.

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<![CDATA[MON-596 Effects of Angiotensin Type 1 Receptor Blockers (ARBs) on the Expression and Secretion of Adiponectin and Leptin in Human White Adipocytes]]> https://www.researchpad.co/article/elastic_article_8534 [Introduction]

Adiponectin and leptin are adipokines that are mainly produced in adipocytes and exert various functions. Adiponectin decreases atherosclerosis, oxidative stress, angiogenesis, inflammation, and apoptosis, whereas leptin works oppositely. Angiotensin type-1 receptor (AT1R) blockers (ARBs) are widely used as antihypertensive drugs. Some ARBs are known to activate peroxisome proliferator-activated receptor (PPAR) γ, which is a key regulator of fatty acid metabolism. It is reported that adiponectin secretion increases by pioglitazone, a full agonist of PPARγ, and some ARBs via PPAR γ activation. However, the effects of ARBs on leptin secretion are controversial. The present study aimed to examine the effects of ARBs on the expression and secretion of adiponectin and leptin in human white adipocytes.

[Materials and Methods]

Human white preadipocytes (Promo Cell) were differentiated into mature adipocytes in the medium containing insulin, dexamethasone, thyroxin and isobutylmethylxanthine. Pioglitazone and ARBs including telmisartan, irbesartan, azilsartan, candesartan, losartan, olmesartan and valsartan (1µM) were administered in the culture medium on day 4 and 8. The medium was collected on day 12 and the concentrations of adiponectin and leptin were measured by enzyme immunoassay. Real time PCR was performed to quantitate the mRNA expression of adiponectin and leptin in adipocytes. The experiments were performed in quadruplicate.

[Results]

Pioglitazone significantly increased adiponectin secretion (386.7 ± 133.7 vs. 7.3 ± 1.9 ng/ml in control) from human adipocytes. Among ARBs, adiponectin secretion significantly increased by telmisartan (136.7 ± 16.3 ng/ml) and irbesartan (69.7 ± 23.1 ng/ml), while the other 5 ARBs did not have any influence on adiponectin secretion. Real-time PCR also showed that mRNA expression increased 5.1-fold, 3.8-fold and 1.5-fold by pioglitazone, telmisartan and irbesartan, respectively. Leptin secretion significantly decreased by pioglitazone (27.7 ± 5.0 vs. 82.5 ± 3.8 ng/ml in control). Among ARBs, only telmisartan (38.7 ± 4.2 ng/ml) decreased leptin secretion. Real-time PCR also showed that mRNA expression decreased to be 0.5-fold and 0.7-fold by pioglitazone and telmisartan, respectively. GW9662, a selective antagonist of PPARγ, potently blocked pioglitazone-induced changes of adiponectin and leptin expression and secretion. On the other hand, GW9662 did not reverse telmisartan and irbesartan induced changes.

[Conclusion]

The changes in adiponectin and leptin secretion by pioglitazone are via PPARγ activation, while those by telmisartan and irbesartan may occur in PPARγ-independent manner.

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<![CDATA[Imaging dataset of fresh hydrous plants obtained by field-emission scanning electron microscopy conducted using a protective NanoSuit]]> https://www.researchpad.co/article/elastic_article_7644 Although scanning electron microscopy (SEM) can generate high-resolution images of nanosized objects, it requires a high vacuum to do so, which precludes direct observations of living organisms and often produces unwanted structural changes. It has previously been reported that a simple surface modification gives rise to a nanoscale layer, termed the “NanoSuit”, which can keep small animals alive under the high vacuum required for field-emission scanning electron microscopy (FE-SEM). We have previously applied this technique to plants, and successfully observed healthy petals in a fully hydrated state using SEM. The flower petals protected with the NanoSuit appeared intact, although we still lack a fundamental understanding of the images of other plants observed using FE-SEM. This report presents and evaluates a rich set of images, acquired using the NanoSuit, for a taxonomically diverse set of plant species. This dataset of images allows the surface features of various plants to be analyzed and thus provides a further complementary morphological profile. Image data can be accessed and viewed through Figshare (https://doi.org/10.6084/m9.figshare.c.4446026.v1).

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<![CDATA[MON-600 Hydroethanolic Extract of Lampaya Medicinalis Phil. (Verbenaceae) Decreases Intracellular Triglycerides and Proinflammatory Marker Expression in Fatty Acid-Exposed HepG2 Hepatocytes]]> https://www.researchpad.co/article/elastic_article_7037 Background: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic chronic disease worldwide. NAFLD is characterized by an abnormal triglyceride (TG) accumulation (steatosis) in the liver, that may lead to hepatic inflammation (1). DGAT2 is a key enzyme that catalyzes the final step of TG synthesis and whose expression is elevated in NAFLD (2). FABP4 is a transporter of intracellular lipids and its levels are related with inflammation, characterized by a high expression of proinflammatory cytokines such as TNF-α, IL-6 and IL-1β. Palmitic acid (PA, C16:0) and oleic acid (OA; C18:1) are two of the most abundant fatty acids that participate in the formation of TGs in hepatic cells in vivo and in vitro (3). Lampaya medicinalis Phil. (Verbenaceae) is a small bush that grows in the “Puna atacameña” in the North of Chile. The infusion from leaves and aerial parts of the plant has been used by local ethnic groups to treat and cure inflammatory diseases (4). The aim of this study was to assess in vitro the effect of the hydroalcoholic extract of Lampaya medicinalis (HEL) against OA/PA-induced steatosis and proinflammatory marker expression in HepG2 hepatocytes.

Methods: HEL (0.01, 0.1, 1, 10 μg/mL) cytotoxicity potential (48 h) was evaluated by Trypan blue exclusion. Cells were exposed for 48 h to 1 mM OA/PA (2:1) in the presence or not of 0.01 or 10 μg/mL HEL. Intracellular TGs were assessed with Oil Red O staining and quantified with Nile Red reagent by fluorimetry. mRNA expression of DGAT2, TNF-α, IL-6 and IL-1β was evaluated by qRT-PCR. FABP4 content was assessed by Western blot. The levels of TNF-α and IL-6 in the culture media were analysed by ELISA.

Results: HEL was not cytotoxic at any concentration assessed (n=4; p>0.05). The increased content of TG induced by OA/PA was reduced in the presence of HEL (n=7; p<0.05), showing a strong consistency with Oil Red O staining. The increase in the protein content of FABP4 as well as the increment in mRNA expression of DGAT2, TNF-α, IL-6 and IL-1β induced by OA/PA were lower in cells co-exposed to HEL (n=6-9; p<0.05). The incubation with HEL+OA/PA reduced proinflammatory cytokine levels in culture media compared to cells exposed to OA/PA alone (n=6-7; p<0.05).

Conclusion: HEL reduces the OA/PA-induced increase in intracellular TG, DGAT2 and proinflammatory cytokine expression and FABP4 content, as well as the levels of secreted proinflammatory cytokines in HepG2 cells. These findings suggest a protective role for HEL against OA/PA-induced steatosis and inflammation, and therefore that Lampaya medicinalis may represent a promising therapeutic tool for pathologies such as NAFLD.

References: (1) Gluchowski L, et al. Nat Rev Gastroenterol Hepatol. 2017;14(6):343-355. (2) Perry, et al. Nature. 2014;510(7503):84-91. (3) Cunningham P, et al. J Nutr. 2009;139(4):636–639. (4) Morales G, et al. Biol Res. 2014;47:6.

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<![CDATA[OR33-07 ARNT2: A Potential Novel Candidate Gene for Monogenic Obesity in Humans]]> https://www.researchpad.co/article/elastic_article_7007 Introduction: Aryl hydrocarbon nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH)-PAS (Per/Arnt/Sim) transcription factor shown to be critical to the development of paraventricular nucleus of the hypothalamus (PVN), key region for energy homeostasis and feeding response. In vivo and in vitro studies have shown that ARNT2 is an obligate heterodimer for SIM1, known cause of monogenic obesity. Null mutations in Arnt2 in animals are not viable, but hypomorphic mutation results in hyperphagic obesity and its associated consequences (1). Due to the critical role of ARNT2 in the development of PVN, we hypothesize that hypomorphic mutations may result in early onset obesity in humans.

Methods: The Genetics of Early Childhood Obesity (GECO) study recruits children with severe obesity (BMI > 120% of 95th percentile) of early onset (< 6 years). Whole exome sequencing (WES) was performed in a subset of proband-parent trios. The functional validation of the mutation(s) in ARNT2 is ongoing with co-transfection of tagged Arnt2 and Sim1 in HEK293 cells, with the induction of a luciferase reporter gene under the control of 6 repeats of bHLH-PAS core binding element by the Arnt2-Sim1 complex.

Results: Two adolescents from unrelated families were found to have genetic variants in ARNT2. Subject 1 has a novel de novo heterozygous coding variant in ARNT2, c.388 C>G (p.P130A, CADD 25), predicted to be deleterious by 8/12 in silico algorithms. She is a 14-year old Caucasian girl with severe early onset obesity, BMI 28.1 kg/m2 (BMIz +4.72) at 2.5 years of age that has increased to 53.54 kg/m2 (BMIz + 3.25) at 14-years, and height > 95th %tile. She is non-dysmorphic, has developmental delay, absence seizures, behavior abnormalities & glucose intolerance/dyslipidemia secondary to obesity. Using genematcher, we identified another proband with the phenotype of obesity: an African American girl (BMIz +1.9) with biallelic inherited heterozygous variants in ARNT2, c.1228T>A (p.W410R, CADD 29) and c.916G>A (p.G306S, CADD 22). An only child conceived by IVF, she is non-dysmorphic and on treatment for bilateral focal epilepsy. All 3 variants are rare, with mean allele frequency < 0.005 in population-based databases such as gNOMAD. Both the patients have early onset obesity and a significant neurological phenotype. ARNT2 is a highly constrained gene of 717 amino acids with a significant depletion of missense variants in the N-terminus (1-244 aa) and overall fewer loss of function variants in ~282,644 alleles sequenced in gNOMAD.

Conclusions: We propose that hypomorphic mutations in ARNT2 could be a potential novel cause of monogenic obesity in humans. Future studies will investigate the molecular mechanisms causing weight dysregulation in patient specific disease relevant hypothalamic neurons.

Reference: (1) Turer et al., Dis Model Mech. 2018; 11(12)

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<![CDATA[MON-588 Anthropometric Parameters, Body Fat Percentage and Metabolic Profile in Sarcopenic Women with Recommendation for Bariatric Surgery]]> https://www.researchpad.co/article/elastic_article_6939 INTRODUCTION: Sarcopenia (SARC) is a musculoskeletal disorder that predisposes several complications, including metabolic ones. Obesity also provides higher risk for metabolic complications, however, there is lack of evidences regarding the association of obesity with SARC on metabolic parameters in non-elderly individuals. OBJECTIVE: To evaluate anthropometric parameters, body fat percentage (BFP) and metabolic parameters in women with and without SARC preceding Bariatric Surgery (BS). METHODS: A cross-sectional study involving 60 obese women in the outpatient care in a public Brazilian University Hospital between March to September 2018. Body composition was given by bio-impedance (inbody-370), multifrequency (5, 50, 250Hz) with 12 hours fasting, dominant Handgrip Strength (HS) was evaluated by Jamar dynamometer (3 measurements; 30 sec interval). Were also evaluated fasting blood glucose, HbA1c, homeostatic model assessment-insulin resistance (HOMA-IR), total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides and high-sensitive C-reactive protein (hs-CRP). SARC was defined by the association of a low muscle mass index (weight-adjusted appendicular skeletal muscle mass: ASMM/weight x 100%) and decreased HS, using as cutoff points the smallest quintile for each variable. Data were expressed as mean ± standard deviation and independent t-test was used for comparison between groups. Statistics were made by SPSS software, 20th version (IBM Corp., Armonk, NY). RESULTS: The mean age, weight, body mass index and BFP of sarcopenic and non-sarcopenic women were: 40.75 ± 11 x 39.23 ± 8.92 years old (p=0.665), 102.93 ± 9.58 x 109.19 ± 14.25 Kg (p=0.237), 44.88 ± 2.7 x 42.24 ± 4.79 Kg/m2 and 54.12 ± 1.11 x 51.44 ± 3.43% (p=0.052), respectively. Regarding the laboratory parameters of women with and without SARC: fasting blood glucose 89.25 ± 14.48 x 98.40 ± 27.48 mg/dL (p=0.359), HbA1c 5.83 ± 0.33 x 6.21 ± 1.18% (p=0.185), HOMA-IR 3.61 ± 1.28 x 5.31 ± 4.74 (p=0.160), TC 170.87 ± 39.36 x 180.82 ± 34.51 mg/dL, LDL 94.67 ± 26.63 x 105.60 ± 30.85 mg/dL, HDL 53.37 ± 18.50 x 50.84 ± 10.32 mg/dL, triglycerides 114.12 ± 38.84 x 127.30 ± 75.04 mg/dL and hs-CRP 8.51 ± 6.50 x 7.51 ±6.52 mg/L (p=0.792). CONCLUSION: Women with SARC and recommendation for BS when compared to women without SARC had similar anthropometric, metabolic and BFP parameters.

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<![CDATA[OR33-02 The Treatment of Partial Lipodystrophy in the Setting of Neutralizing Antibody Against Metreleptin with Leptin Receptor Agonist REGN4461]]> https://www.researchpad.co/article/elastic_article_6892 Background: An 18-year-old patient with atypical partial lipodystrophy had a transient initial metabolic response to metreleptin that deteriorated when neutralizing antibodies against metreleptin developed. A therapeutic trial with setmelanotide did not result in any metabolic benefit as desired. Because her status continued to deteriorate, we attempted to treat her with REGN4461, a fully human monoclonal antibody that is an agonist to the human leptin receptor (LEPR). Clinical Case: A compassionate use protocol (IND No. 144013) was initiated to treat the patient with REGN4461. The treatment consisted of 5 mg/kg intravenous infusion followed by 300 mg weekly subcutaneous injections of REGN4461. The primary endpoint was achievement of fasting triglycerides < 500 mg/dL without the need for ongoing plasmapheresis. Treatment-emergent adverse events were also followed. Here, we report her first 21-week response to treatment with REGN4461. The treatment resulted in a reduction of triglycerides from 1288 mg/dL to 344 mg/dl and allowed her to discontinue plasmapheresis. She lost 3.4 kilograms so far, and her liver size reduced per liver span measured by physical examination. Also, the liver MRI at week 12 showed a significant reduction in liver size and fat content (from 29.9% to 16.6%). Although her glucose control is still challenging, a slight reduction in her HbA1c was observed at week 12 along with improvements in her average glucose levels and total daily insulin requirement so far. No untoward signals were detected in her safety measurements. Conclusion: To date, treatment with REGN4461 offered substantial clinical benefit by improving the metabolic abnormalities in this unique patient. This experience represents the longest human exposure with REGN4461. The improvements noted in metabolic parameters and hepatic steatosis are similar to previous observations in lipodystrophic humanized LEPR mice. Our results suggest that REGN4461 showed clinical benefit even in the presence of neutralizing antibodies to metreleptin.

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<![CDATA[Hypoglycaemia is reduced with use of inhaled Technosphere<sup>®</sup> Insulin relative to insulin aspart in type 1 diabetes mellitus]]> https://www.researchpad.co/article/elastic_article_6704 Hypoglycaemia and fear of hypoglycaemia are barriers to effective insulin therapy and may prevent people with diabetes from achieving glycaemic targets.Administration of inhaled Technosphere® Insulin at mealtime provides comparable glycaemic control and lower rates of hypoglycaemia across a range of HbA1c levels compared with subcutaneous insulin aspart in people with type 1 diabetes mellitus.The ultra‐rapid time‐action profile of Technosphere Insulin offers the flexibility to dose at the beginning of or 20 min after starting a meal, and allows for the convenience of between‐meal dosing with a lower risk of hypoglycaemic events compared with subcutaneous rapid‐acting insulin analogues.

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<![CDATA[OR33-04 The Effect of Adiposity on the Fasting Serum Proteome in Normal Weight and Obese Men]]> https://www.researchpad.co/article/elastic_article_6678 In many individuals with obesity, adipose tissue is not only increased in mass but also exhibits altered function. Disordered adipokine secretion contributes to a pro-inflammatory milieu that may lead to obesity-related co-morbidities. Hypothesis-generating, high-throughput techniques can generate novel insights. Our objective was to identify proteome-wide alterations in serum proteins related to adiposity. We evaluated the fasting serum proteome in 25 men [13 normal weight (mean±SD body mass index (BMI 21.2±1.4 kg/m2) and 12 with obesity (BMI 31.5±4.8 kg/m2)]. Blood was drawn at 0, 15, 30, and 55 minutes for proteomic analysis after an overnight fast (SOMAScan, SomaLogic, Inc.). The number of proteins and pathways that significantly differed between the two groups was determined across all time points during the fasting period. Normalized protein levels were compared between adiposity groups using rank product testing. Overrepresentation of protein constituents of established biological pathways was evaluated by hypergeometric test. P-values were adjusted using the Benjamini-Hockberg method, and those with an associated false discovery rate (FDR) of <0.05 were considered statistically significant. A total of 4,785 protein isoforms were robustly identified in serum of normal weight and men with obesity, of which 226 protein isoforms were significantly higher in obesity (vs. normal weight), and 178 were significantly lower in obesity (vs. normal weight). Higher levels of leptin and lower levels of IGFBP1 and IGFBP2 were observed in individuals with obesity during fasting (all FDR < 0.019). Functional annotation using Gene Ontology indicated that the following pathways differed most between obese vs. normal weight men: complement and coagulation cascade activation, amine metabolism, phosphatase activity, cellular response to nutrients (lipids, alcohol, and vitamin D), organic acid catabolism, and regulation of inflammatory responses. The protein isoforms identified in serum likely reflect systemic tissue-level changes in metabolism that may yield insights into the pathogenesis of obesity-related comorbidities and rational targets for intervention.

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<![CDATA[MON-607 Very Low-Calorie Ketogenic Diet Modifies Visceral Adipose Tissue Distribution and Taxonomic Composition of Gut Microbiota in Obese Patients with Insulin Resistance Depending on Protein Source]]> https://www.researchpad.co/article/elastic_article_6631 Background. Short-term interventions based on very low-calorie ketogenic diets (VLCKDs) and meal replacements may be prescribed to selected overweight or obese patients. Few, inconsistent data are available on protein intake from various sources on body weight, composition of gut microbiota and metabolic outcomes in these patients.

Aim. To compare efficacy, safety and effect on microbiota composition of short-term isocaloric very low-calorie ketogenic diets encompassing whey, vegetable or animal proteins, in obese patients with insulin resistance.

Materials and Methods. 48 obese patients (19 males and 29 females) with HOMA-index ≥ 2.5, age mean: 55.2 years (range: 45-73), BMI mean 35.9 kg/m2 (range: 30.2 - 46.4) were randomly assigned to three isocaloric VLCKD regimens (≤800 kcal/day) containing either whey, plant or animal proteins for 45 days, with assessments of anthropometric indexes, blood and urine chemistry, body composition, muscle strength, taxonomic composition of the gut microbiome.

Results. A significant reduction of body weight, BMI, blood pressure, waist circumference, HOMA index, insulin, total and LDL cholesterol was observed in all the patients, regardless the dietary protein source. Patients fed with whey proteins and vegetable proteins had a more pronounced decrease of visceral adipose tissue (VAT) compared with the group fed with animal proteins. The markers of renal function slightly worsened in the group fed with animal proteins. A decrease in relative abundance of Firmicutes and an increase of Bacteroidetes was observed after VLCKDs. This pattern was less pronounced in patients consuming animal proteins.

Conclusions. VLCKDs lead to significant weight loss and a striking improvement of the metabolic parameters over a short period of time. VLCKDs based on whey or vegetable proteins induce a larger reduction of VAT, have a safer profile and determine a healthier microbiota composition compared to those containing animal proteins.

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<![CDATA[MON-594 The Peculiarity of the Gut Microbiota in Patients with Different Phenotypes of Obesity (Pilot Study)]]> https://www.researchpad.co/article/elastic_article_6564 Recent studies have shown that obesity is not a homogeneous condition and that there is a subgroup of people with obesity, but without metabolic disturbance. This phenotype of obesity is called “metabolically healthy obesity” (MHO) [1]. More and more data are appearing in the scientific literature, indicating that quantitative and qualitative changes in the gut microbiota (GM) can be a trigger in the development of obesity and metabolic disorders [2]. In order to study the role of GM in the development of various types of obesity, 37 patients were examined, divided into 3 groups: group 1 (n = 11) - healthy people without obesity and overweight (control), group 2 (n = 13) - patients with MHO, group 3 (n = 13) - patients with metabolically unhealthy obesity (MUHO). The basic metabolic parameters were determined for all of them and a quantitative assessment of the condition of the GM was performed using the Real-time PCR method. Results: 1. In people from the control group (group 1) in the GM, compared with formal normative indicators, the number of Lactobacillus spp., Bifidobacterium spp., B. thetaiotaomicron was reduced (p<0.05) and indicators of the total bacterial mass and Enterobacter spp./Citrobacter spp. were increased (p<0.05). 2. In subjects with MHO (group 2), GM changes similar to group 1 were observed. However, in comparison to group 1, Klebsiella spp. and Proteus spp. were recorded in feces in quantities exceeding the formal regulatory. In patients with MUHO (group 3), in addition to changes detected in group 2, C. difficile was found in feces, as well as a significant (p <0.05) decrease in F. prausnitzii and an increase (p <0.05) in the detection frequency of banal E.coli, as well as the more diverse composition of the microbiota. Thus, the data obtained as a result of a pilot study certainly indicate changes in the GM in people with different phenotypes of obesity and in healthy ones. Further study of the GM in patients with various types of obesity, but in a larger groups, is required. Reference: 1) Phillips C.M. Metabolically healthy obesity across the life course: epidemiology, determinants and implications. Ann N.Y. Acad Sci 2017 Mar;139(1):85-100.doi:10.1111/nyas.13230. 2). Giovanna Muscogiuri, Elena Cantone, Sara Cassarano, Dario Tuccinardi, Luigi Barrea, Silvia Savastano, Annamaria Colao & on behalf of the Obesity Programs of nutrition, Education, Research and Assessment (OPERA) group. Gut microbiota: a new path to treat obesity. International Journal of Obesity Supplements 2019 Apr;9(1):10-19. doi: 10.1038/s41367-019-0011-7

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<![CDATA[OR33-03 Congenital Leptin Deficiency: Clinical Insights from the First Reported US Cases]]> https://www.researchpad.co/article/elastic_article_6374 Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). Previous case series have reported dramatic weight loss and metabolic improvements with treatment, but metreleptin’s only FDA-approved indication is acquired generalized lipodystrophy (AGL). Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in AGL patients, both treated and untreated with metreleptin.

Clinical Case: Two sisters ages 18 yrs (sister A; BMI 45.2 kg/m2) and 20 yrs (sister B; 45.0 kg/m2) were referred for evaluation of obesity. They are of Pakistani origin with a family history of consanguinity. Birth weight was normal, but hyperphagia and excessive weight gain developed by age 3 months. They had been seen by endocrinologists, obesity specialists, and a geneticist during childhood but work-up for monogenic obesity was not pursued. They were treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years. Sister B had comorbidities of hydrocephalus s/p VP shunt, developmental delay, hyponatremia, autoimmune thyroid disease, growth hormone deficiency, and prediabetes. At the time of their present evaluation, serum leptin levels were obtained and were undetectable in both sisters. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, sister B had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (a B cell lymphoma), Stage II disease. She was treated with R-ABVD with adjuvant radiation and achieved clinical remission, prior to treatment with metreleptin. The patients were enrolled in an observational treatment protocol, and responses to metreleptin therapy will be reported in future.

Conclusion: To our knowledge, these are the first cases of CLD diagnosed in the U. S. In previous reports, CLD and other monogenic obesity disorders were prevalent among children with severe obesity in a consanguineous Pakistani population. Leptin deficiency should be considered in all patients with early onset obesity and hypothalamic amenorrhea. Furthermore, to our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to any treatment with metreleptin. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmune disease or immunologic abnormalities related to leptin deficiency rather than medication adverse effect.

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<![CDATA[SUN-624 Low Risk of Major Adverse Cardiovascular Events After Pancreas Transplantation Alone]]> https://www.researchpad.co/article/elastic_article_6360 INTRODUCTION: Type 1 Diabetes (T1D) patients have an increased risk for major adverse cardiovascular events (MACE). Pancreas Transplantation Alone (PTA) in patients with T1D achieves near normal glucose control for a prolonged period but limited data are available to date regarding MACE during a 10 year follow up period after the procedure.

OBJECTIVE: We studied incidence of MACE after PTA in T1D patients over a 10 year follow-up period.

METHODS: Retrospectively, we studied 113 T1D recipients of PTA at Mayo Clinic, Rochester with the procedure performed between January 1998 and August 2018 and follow up of at least 1 year. Data were collected before transplantation and up to 10 year follow up after the first PTA. MACE data were gathered until primary non function, re-transplantation, or complete loss of c-peptide (<0.01ng/ml). We report vascular risk factors including hypertension, hyperlipidemia, smoking and BMI along with MACE (defined as cardiac events as unstable angina, Myocardial Infarction (MI), need for re-vascularization, cardiac death, cerebral events as Transient ischemic attack (TIA), stroke, need for re-vascularization and peripheral arterial disease as need for re-vascularization, gangrene and amputation).

RESULTS: Eighteen subjects had pre-transplant MACE. A total of 14 subjects had graft failure within 24 to 36 hours due to thrombosis, with 3 in pre-transplant MACE cohort and 11 in no MACE cohort. Thus, we followed 99 subjects for the development of post-transplant MACE for a period of 6.3 ± 3.6 years. T1D subjects with MACE (n=15) had baseline characteristics: Age 48± 7.8 years, gender F/M 9/6,, duration of diabetes 33 ± 12 years, BMI 26± 3.1(Kg/m2), HbA1c 9.3 ± 1.5% and C-peptide 0.09 ng/ml. 84 T1D patients without MACE were age 42 ± 10.6 years, gender F/M 55/29, duration of diabetes 26.5 ± 10.7 years, BMI 26 ± 5.2(Kg/m2), HbA1c 6.7 ± 2.5 and C-peptide 0.09 ng/ml. There are a total of 584 person-years of follow up to first MACE event and 632 person-years of graft failure, death or last follow-up. Nine patients developed 11 MACE events post-PTA. Therefore, the event rate is 1.5 MACE events per 100 person-years for first MACE event and the total event rate is 1.7 MACE events per 100 person-years of follow-up. Age, smoking (yes), gender, duration of diabetes, HTN and Hyperlipidemia presence did not show any significant impact on post-transplant MACE outcome based on univariate Cox regression but the pre-transplant BMI (HR = 1.14; CI = (1.04, 1.26); p = 0.008) and pre-transplant HbA1c (HR = 1.26; CI = (1.06, 1.51); p = 0.01) showed statistically significant impact.

CONCLUSIONS: At our center, MACE is low in PTA recipients. There is no impact of presence of pre-transplant MACE on development of post-transplant MACE but pre-transplant BMI and HbA1c account for risk of MACE.

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<![CDATA[SUN-620 Gender Difference in the Outcome of Patients with Diabetes Admitted for Hyperosmolar Hyperglycemia. from the National Inpatient Sample]]> https://www.researchpad.co/article/elastic_article_6263 Objective: There is paucity of literature on the impact of gender on outcomes of hyperosmolar hyperglycemic state (HHS) among adult patients with diabetes. The aim of this study was to evaluate the effect of gender on the outcome of these patients. Methodology: The National Inpatient Sample (NIS) was queried for all patients who were admitted with a diagnosis of hyperosmolar hyperglycemic state (HHS) during the years 2005-2014. The primary outcomes of the study were all-cause mortality, acute myocardial infarction (MI), and acute stroke. The secondary outcomes were acute kidney injury (AKI), rhabdomyolysis, acute respiratory failure (ARF), need for mechanical ventilation (MV), length of stay (LOS), and total cost of stay. Results: Overall, 188,725 patients were admitted for HHS. Mean age of males was 53.7, standard error of the mean (SEM: 0.13), and of females was 58.5 (SEM: 0.15), p<0.001. Females were (43.9%), Caucasians were 37.4% while African Americans were 35.2%. Total mortality was 1.1%, MI was 1.3% and stroke was 1.1%. Most common secondary outcome was AKI seen in 31.3% followed by ARF seen in 2.9% of total. The mean cost was 7887 $ (SEM: 84.6) and mean LOS was 4.1 days (SEM: 0.03). Both males and females had equivalent rates of mortality, stroke, ARF and need for mechanical ventilation. Compared to males, females had significantly higher risk for MI 1.6% vs 1.1%, p<0.001, lower risk for AKI 29.3% vs 32.9%, p<0.001, lower risk for rhabdomyolysis 1.1% vs 2%, p<0.001 and higher LOS 4.3 vs 3.9 days, p<0..01 and higher total costs 8165.6 $ vs 7669.3 $, p < 0.001. On multivariable analysis, female gender was independently predictive for higher risk for MI with adjusted odds ratio (aOR) 1.34 [95%CI: 1.08-1.67] p=0.01 and lower risk for rhabdomyolysis with aOR 0.52 [95%CI: 0.42-0.63] p<0.001 and lower risk for AKI with aOR 0.74 [95%CI: 0.7-0.78] p<0.001. In addition, female gender correlated with higher cost and length of stay. Conclusion: Females with hyperosmolar hyperglycemic state are at higher risk for MI and lower risk for AKI and rhabdomyolysis.

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