Weight loss outcomes with semaglutide based on diabetes severity using the individualized metabolic surgery score.

Background: Semaglutide demonstrated inferior weight loss responses in patients with type 2 diabetes (T2D) compared to patients with obesity without T2D. The individualized metabolic surgery (IMS) score was validated to predict T2D remission after bariatric surgery. The parameters of the IMS are HbA1c (<7%), insulin use, T2D medications and T2D duration. We aim to assess weight loss outcomes of semaglutide based on IMS score in patients with obesity and T2D. Methods: This is a retrospective multicentered cohort study of patients with T2D and BMI≥ 27 kg/m2 taking ≥1 mg of semaglutide recruited from January 2020 to December 2022. We excluded patients with a history of bariatric surgery or taking other anti-obesity medications. IMS was calculated at baseline and patients weight change was recorded at baseline, 3, 6, 9 and 12 months. IMS was classified as mild (0-24.9 points), moderate (25-94.9 points), and severe (95-180 points). Analysis was performed based on IMS score quartiles and combination of Mild-Moderate vs Severe categories. We performed mixed linear regression models including age, sex, and baseline weight to assess associations between IMS categories with total body weight loss percentage (TBWL%). Findings: We included 297 patients (42% female, mean age 62 ± 12 years) in the analysis. At 12 months, there was a stepwise decrease in weight loss outcomes when comparing patients by IMS quartiles (LS mean TBWL%± SE): 8.8 ± 0.8% vs 6.9 ± 0.8% vs 5.7 ± 0.9% vs 5.0 ± 0.8%. In the mixed linear model, patients in the mild-moderate category achieved significantly superior weight loss outcomes (LS mean TBWL± SE: -8.3 ± 0.7%) than patients in the severe category (-5.5 ± 0.6%; difference: -2.9, 95% CI: -5.2 to -0.5, p = 0.006) at 12 months. There was no significant difference in glycemic improvement regardless of IMS severity at baseline. Interpretation: In our cohort, lower IMS severity was associated with more weight loss in patients with obesity and T2D. Further studies are needed to understand T2D severity and its effect on semaglutide outcomes. Funding: Beyond payment to the research staff by Mayo Clinic, this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Weight loss response to semaglutide in postmenopausal women with and without hormone therapy use.

OBJECTIVE: To compare weight loss response and changes in cardiometabolic risk markers in postmenopausal women using semaglutide with and without menopause hormone therapy (HT) use. METHODS: Retrospective cohort study of postmenopausal women treated with semaglutide for overweight or obesity for ≥3 months. Endpoints: total body weight loss percentage (TBWL%) at 3, 6, 9, and 12 months after semaglutide initiation; and percentage of women achieving ≥5% and ≥10% TBWL and changes in cardiometabolic risk markers (glucose, blood pressure, and lipids) at 12 months. RESULTS: There were 16 women on HT and 90 on no-HT; mean age 56 ± 8 vs 59 ± 8 yr, P = 0.2 and mean BMI 36 ± 5 vs 39 ± 8 kg/m 2 , P = 0.1; respectively. Among women on no-HT, White race, dyslipidemia, and depression were more prevalent. Women on HT had a higher TBWL% at 3, 6, 9, and 12 months: 7 ± 3% vs 5 ± 4%, P = 0.01; 13 ± 6% vs 9 ± 5%, P = 0.01; 15 ± 6% vs 10 ± 6%, P = 0.02; and 16 ± 6% vs 12 ± 8%, P = 0.04; respectively. After adjusting for potential confounders, this association remained significant across time. At 12 months, a greater percentage of women on HT achieved ≥5% and ≥10% TBWL. Both groups experienced an improvement in cardiometabolic risk markers. CONCLUSION: In postmenopausal women with overweight or obesity treated with semaglutide, HT use was associated with an improved weight loss response. This association was maintained when adjusted for confounders. Larger studies should be conducted to confirm these results.

Weight-centric prevention of cancer.

Background: The link between excess adiposity and carcinogenesis has been well established for multiple malignancies, and cancer is one of the main contributors to obesity-related mortality. The potential role of different weight-loss interventions on cancer risk modification has been assessed, however, its clinical implications remain to be determined. In this clinical review, we present the data assessing the effect of weight loss interventions on cancer risk. Methods: In this clinical review, we conducted a comprehensive search of relevant literature using MEDLINE, Embase, Web of Science, and Google Scholar databases for relevant studies from inception to January 20, 2024. In this clinical review, we present systematic reviews and meta-analysis, randomized clinical trials, and prospective and retrospective observational studies that address the effect of different treatment modalities for obesity in cancer risk. In addition, we incorporate the opinions from experts in the field of obesity medicine and oncology regarding the potential of weight loss as a preventative intervention for cancer. Results: Intentional weight loss achieved through different modalities has been associated with a reduced cancer incidence. To date, the effect of weight loss on the postmenopausal women population has been more widely studied, with multiple reports indicating a protective effect of weight loss on hormone-dependent malignancies. The effect of bariatric interventions as a protective intervention for cancer has been studied extensively, showing a significant reduction in cancer incidence and mortality, however, data for the effect of bariatric surgery on certain specific types of cancer is conflicting or limited. Conclusion: Medical nutrition therapy, exercise, antiobesity medication, and bariatric interventions, might lead to a reduction in cancer risk through weight loss-dependent and independent factors. Further evidence is needed to better determine which population might benefit the most, and the amount of weight loss required to provide a clinically significant preventative effect.

Menopause transition and cardiovascular disease risk.

The risk of cardiovascular disease (CVD) notably increases in the fifth decade of a woman's life, coinciding with the onset of menopause and occurring 10 years later than the similar age-related increase in men. Menopause marks a significant transition in a woman's life and is accompanied by cardiometabolic changes, including a shift in body composition, increased blood pressure, disruptions in lipoproteins, and insulin resistance. There is increasing evidence that the menopause transition is a risk factor for CVD, independent of age-related changes, especially considering that the earlier the onset of menopause, the greater is the CVD risk. Further, menopause-related symptoms such as vasomotor symptoms, sleep disturbances, and mood changes may all have a direct impact on CVD risk. In this review, we summarize the current literature regarding CVD in midlife women, focusing on the cardiometabolic changes related to ovarian aging versus chronological aging, as well as those related to specific menopause characteristics, including age, type of menopause and the use of menopause hormone therapy.

Weight Gain in Midlife Women.

PURPOSE OF REVIEW: To summarize the evidence and clinical implications of weight and body composition changes during midlife in women and provide an overview of weight gain prevention and management in this population. RECENT FINDINGS: Aging-related changes such as decreased energy expenditure and physical activity are important culprits for weight gain in midlife women. The hormonal changes of menopause also influence body adiposity distribution and increase central adiposity. These body changes can have health consequences including the development of cardiometabolic diseases, osteoarthritis, cancer, worsening in cognition, mental health, and menopause symptoms. Midlife women experience changes related to aging, menopause, and lifestyle which favor weight gain. Clinical practice should focus on early counseling and anticipatory guidance on the importance of dietary changes and physical activity to attenuate this phenomenon. Future research should focus on the longitudinal relationship between weight trends in midlife and health consequences and mortality.

The relation between excess adiposity and breast cancer in women: Clinical implications and management.

BACKGROUND: Breast cancer (BC) is the most common cancer in women. While the combination of improved screening, earlier detection, and advances in therapeutics has resulted in lower BC mortality, BC survivors are now increasingly dying of cardiovascular disease. Cardiovascular disease in the leading cause of non-cancer related mortality among BC survivors. This situation underscores the critical need to research the role of modifiable cardiometabolic risk factors, such as excess adiposity, that will affect BC remission, long-term survivorship, and overall health and quality of life. PURPOSE: First, this review summarizes the evidence on the connection between adipose tissue and BC. Then we review the data on weight trends after BC diagnosis with a focus on the effect of weight gain on BC recurrence and BC- and non-BC-related death. Finally, we provide a guide for weight management in BC survivors, considering the available data on the effect of weight loss interventions on BC.

Severe Insulin Resistance in a Patient Treated With Nivolumab and Brentuximab-Vedotin for Hodgkin Lymphoma.

This is a case of a 26-year-old male patient, with relapsing Hodgkin lymphoma, treated with nivolumab and brentuximab-vedotin, who was admitted with hyperglycemia and severe insulin resistance requiring approximately 2000 units of intravenous insulin per day. He had no prior diagnosis of diabetes. He was eventually diagnosed with massive cytokine release and hemophagocytic lymphohistiocytosis that led to multi-organ failure and death. The mechanisms behind the hyperglycemia with severe insulin resistance remain unclear but are possibly related to hyperinflammation and immune dysregulation resulting from massive cytokine release. Nivolumab among other immunotherapeutic agents, brentuximab-vedotin, and lymphoid malignancies are rare but known risk factors for massive cytokine release and hemophagocytic lymphohistiocytosis.

Efficacy of Antiobesity Medications in Patients With Celiac Disease on a Gluten-free Diet: A Retrospective Matched Cohort Study.

GOALS: We aim to describe the weight loss outcomes of patients with celiac disease (CeD) taking antiobesity medications (AOMs) and compare it with the weight loss outcomes of patients without CeD taking AOMs. BACKGROUND: Increasing rates of obesity and obesity-associated comorbidities have been previously reported in patients with CeD on a gluten-free diet. The effectiveness of AOMs in this population has not been previously described. METHODS: In our retrospective cohort study, we matched 39 patients with treated CeD to 78 patients without CeD based on sex and AOM. We assessed the weight loss outcomes at 3, 6, and 12 months after starting the AOM in both cohorts and analyzed if there was a differential response when comparing by type of AOM [injectable glucagon-like peptide 1 (GLP-1) receptor agonists vs. oral non-GLP-1 AOMs]. RESULTS: Both cohorts had similar baseline demographic and anthropometric characteristics. At 12 months, the CeD cohort had a nonsignificantly inferior total body weight loss percentage compared with the cohort without CeD (6.5% vs. 9.5%, P=0.13). The CeD cohort had a similar proportion of patients achieving a total body weight loss percentage of ≥5% than the cohort without CeD (72.7% vs. 72.1%, P=1.00). No significant difference was observed when comparing the weight loss outcomes of injectables (GLP-1 receptor agonists) to oral AOMs. The proportion of patients reporting side effects was similar for both groups, regardless of the type of AOM. CONCLUSION: Patients with CeD taking AOMs had similar weight loss outcomes to patients without CeD. Hence, AOMs can be a safe and effective therapy for weight management in patients with CeD.

Type 2 Diabetes Remission in Patients with Heterozygous Variants in the Leptin-Melanocortin Pathway after Roux-en-Y Gastric Bypass: A Matched Case-Control Study.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is associated with a high rate of type 2 diabetes (T2D) remission. Carriers of heterozygous variants in the leptin-melanocortin pathway (LMP) are more likely to experience weight recurrence after RYGB. Our aim was to investigate if carrier status and associated weight regain affects the rate of T2D remission after RYGB. METHODS: Carriers of LMP variants with a diagnosis of T2D prior to RYGB (N = 16) were matched to non-carriers (N = 32) based on sex, age, and BMI. We assessed for post-operative T2D remission status post-surgery on a yearly basis, for up to 15 years. Our primary endpoint was the proportion of patients achieving T2D remission at 1 year. We conducted a survival analysis for all patients that achieved remission at least at one time-point to evaluate for maintenance of T2D remission by using a log-rank test. RESULTS: Both carriers and non-carriers had similar baseline and procedural characteristics. The proopiomelanocortin gene in the LMP pathway had the most variants (n = 5, 31%). Carriers had a lower total body weight loss percentage at nadir (28.7% ± 6.9) than non-carriers (33.7% ± 8.8, p = 0.04). The proportion of patients achieving T2D remission at 1 year was 68.8% for carriers and 71.9% for non-carriers (p = 1.0). Survival curves for maintenance of first remission were similar for both groups (p = 0.73), with a median survival of 8 years for both carriers and non-carriers. CONCLUSIONS: Despite inferior weight loss outcomes at nadir, carriers had similar T2D remission rates when compared to non-carriers. Weight-independent metabolic benefits of RYGB might contribute to this observation.

Phenotype tailored lifestyle intervention on weight loss and cardiometabolic risk factors in adults with obesity: a single-centre, non-randomised, proof-of-concept study.

Background: Lifestyle interventions for weight loss are currently not individualised to underlying pathophysiology and behavioral traits in obesity. We aim to compare the outcome of a standard lifestyle intervention (SLI) to phenotype-tailored lifestyle interventions (PLI) on weight loss, cardiometabolic risk factors and physiologic variables contributing to obesity. Methods: This 12-week, single-centre non-randomised proof-of-concept clinical trial including men and women aged 18-65 years with a body mass index (BMI) greater than 30 without history of any bariatric procedure, and current use of any medication known to affect weight. Participants lived anywhere in the United States, and underwent in-person testing in Rochester, MN at a teaching hospital. All participants completed in-person phenotype testing at baseline and after 12 weeks. Participants were assigned to their intervention based on their period of enrollment. In the first phase, participants were assigned to SLI with a low-calorie diet (LCD), moderate physical activity, and weekly behavioral therapy sessions. In the second phase, other participants were assigned to PLI according to phenotype: abnormal satiation (time-restricted volumetric LCD); abnormal postprandial satiety (LCD with pre-meal protein supplementation); emotional eating (LCD with intensive behavioral therapy); and abnormal resting energy expenditure (LCD with post-workout protein supplementation and high-intensity interval training). The primary outcome was total body weight loss in kg at 12 weeks using multiple imputation for missing data. Linear models estimated the association of study group allocation and study endpoints adjusting for age, sex, and baseline weight. This study was registered with ClinicalTrials.gov, NCT04073394. Findings: Between July 2020 and August 2021, 211 participants were screened, and 165 were assigned to one of the two treatments in the two phases: 81 SLI (mean [SD] age 42.9 [12] years; 79% women; BMI 38.0 [6.0]) and 84 PLI (age 44.8 [12.2] years; 83% women; BMI 38.7 [6.9]); 146 completed the 12-week programs. The weight loss was -7.4 kg (95%CI, -8.8, -6.0) with PLI vs. -4.3 kg (95%CI, -5.8, -2.7) with SLI (difference, -3.1 kg [95%CI, -5.1 to -1.1]; P = 0.004). No adverse events were reported in any group. Interpretation: Phenotype-tailored lifestyle interventions may result in significant weight loss, but a randomised controlled trial is required to confirm causality. Funding: Mayo Clinic; NIH (K23-DK114460).

Cardiovascular Risk and Diseases in Patients With and Without Leptin-Melanocortin Pathway Variants.

OBJECTIVE: To study differences in cardiovascular risk factors and diseases between patients with and without genetic variants in the leptin-melanocortin pathway. METHODS: A cross-sectional study of patients with a history of severe obesity genotyped in June 2019 as participants of the Mayo Clinic Biobank was conducted in March 2022 to assess differences in cardiovascular risk and diseases between carriers of a heterozygous variant in the leptin-melanocortin pathway and noncarriers. Cardiovascular risk factors included hypertension, diabetes, dyslipidemia, and smoking. Cardiovascular disease includes coronary artery disease, peripheral artery disease, and cerebrovascular accidents. Patients with a history of bariatric surgery were excluded. We used logistic regression models to estimate the odds ratio and 95% CI, adjusting for age, body mass index (BMI), and sex. RESULTS: Among a total of 168 carriers (8%; 121 [72%] female; mean [SD] age, 65.1 [14.9] years; BMI, 44.0 [7.4] kg/m2) and 2039 noncarriers (92%; 1446 [71%] female; mean [SD] age, 64.9 [14.4] years; BMI, 42.9 [6.6] kg/m2), carriers had higher prevalence odds of hypertension (odds ratio, 3.26; 95% CI, 2.31 to 4.61; P<.001) and reported higher number of cardiovascular risk factors compared with noncarriers (2.4 [1.1] vs 2.0 [1.1]; P<.001). There were no significant differences in the adjusted odds associated with diabetes, dyslipidemia, smoking, or cardiovascular disease. CONCLUSION: Despite having similar body weight and BMI, carriers of heterozygous variants in the leptin-melanocortin pathway had higher rates of hypertension than noncarriers. These findings point to an association between hypertension and leptin-melanocortin pathway variants.

Sex as an independent variable in the measurement of satiation: a retrospective cohort study.

BACKGROUND: Satiation is a key component of food intake regulation as it brings an eating episode to an end. The effect of sex on satiation measurement has not been characterized. OBJECTIVE: To assess the effects of biological variables on satiation. DESIGN: Retrospective cohort study. We included 959 participants (mean age 39 [SD 12] years; 70.7% female, and BMI 33 kg/m2 [8]) who had measurements of satiation with a nutrient-drink test to assess volume to fullness (VTF) and maximum tolerated volume (MTV), and/or an ad libitum meal test to assess calories consumed to fullness (CTF). We performed univariate and multiple regression analyses to estimate the contribution of sex to VTF, MTV, and CTF, compared to other biological variables, such as age, weight, height, BMI, waist-to-hip circumference (W/H), and lean mass percentage (LM%), that are known to affect these parameters. RESULTS: Females had higher BMI, W/H, and LM%. VTF, MTV, and CTF were lower in females: 704 [323] vs. 783 [328] mL, p = 0.001; 1226 [384] vs. 1419 [410] mL, p < 0.001; and 871 [291] vs. 1086 [326] kcal, p < 0.001; respectively. Sex was a strong and independent predictor of VTF, MTF and CTF: parameter estimate [PE] = -80.8, p = 0.006; PE = -124.2, p = 0.0007; and PE = -110, p = 0.001; respectively. CONCLUSIONS: Sex has a strong effect on satiation measured by VTF, MTV, and CTF, even after adjusting for other biological factors known to affect these parameters. Females seem to integrate intra-meal inhibition signals to consume fewer calories unrelated to body size or composition. CLINICAL TRIAL REGISTRATION: None.

Association between CYP metabolizer phenotypes and selective serotonin reuptake inhibitors induced weight gain: a retrospective cohort study.

BACKGROUND: Prescription medications such as selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with weight gain. The role of pharmacogenomics in predicting SSRI-induced weight gain is unclear. METHODS: In this retrospective cohort study from participants in the Mayo Clinic RIGHT study who were prescribed citalopram, paroxetine, sertraline, or fluoxetine, our aim was to evaluate the association of metabolizer phenotype and total body weight after 6 months of SSRIs initiation. We evaluated the metabolizer phenotypes (poor/intermediate, normal, and rapid/ultra-rapid) of the cytochromes P450 enzymes genes: CYP2C9, CYP2C19, and CYP2D6 known to influence the metabolism of SSRI medications: CYP2C19 for citalopram, CYP2D6 for paroxetine, CYP2D6 and CYP2C19 for sertraline, and CYP2D6 and CYP2C9 fluoxetine. In addition, we assessed the association of metabolizer phenotype and total body weight change at six months following SSRI prescription using parametric analysis of covariance adjusted for baseline body weight and multivariate regression models. RESULTS: CYP2C19 poor/intermediate metabolizers prescribed citalopram gained significantly more weight than normal or rapid/ultra-rapid metabolizers at 6 months (TBWG %: 2.6 [95% CI 1.3-4.1] vs. 0.4 [95% CI -0.5 - 1.3] vs. -0.1 [-95% CI -1.5-1.1]; p = 0.001). No significant differences in weight outcomes at six months of treatment with paroxetine, sertraline, or fluoxetine were observed by metabolizer status. CONCLUSIONS: Weight gain observed with citalopram may be mediated by CYP2C19 metabolizer status.

Evaluation and Management of Patients Referred for Post-Bariatric Surgery Hypoglycemia at a Tertiary Care Center.

PURPOSE: Following bariatric surgery, patients can develop non-specific symptoms self-described as hypoglycemia. However, confirming hypoglycemia can be technically challenging, and therefore, these individuals are frequently treated empirically. This study aimed to describe what diagnostic evaluation and therapeutic interventions patients referred for post-bariatric surgery hypoglycemia undergo. METHODS: Retrospective observational cohort study of patients with a history of bariatric surgery was evaluated for post-bariatric surgery hypoglycemia in a tertiary referral center from 2008 to 2017. We collected demographic and bariatric surgery information, clinical presentation of symptoms referred to as hypoglycemia, laboratory and imaging studies performed to evaluate these symptoms, and symptom management and outcomes. RESULTS: A total of 60/2450 (2.4%) patients who underwent bariatric surgery were evaluated in the Department of Endocrinology for hypoglycemia-related symptoms. The majority were middle-aged women without type 2 diabetes who had undergone Roux-en-Y gastric bypass. Thirty-nine patients (65%) completed a biochemical assessment for hypoglycemia episodes. Six (10%) had confirmed hypoglycemia by Whipple's triad, and four (6.7%) met the criteria for post-bariatric surgery hypoglycemia based on clinical and biochemical criteria. All patients were recommended dietary modification as the initial line of treatment, and this intervention resulted in most patients reporting at least some improvement in their symptoms. Eight patients (13%) were prescribed pharmacotherapy, and two patients required additional interventions for symptom control. CONCLUSIONS: In our experience, evaluation for hypoglycemia-related symptoms after bariatric surgery was rare. Hypoglycemia was confirmed in the minority of patients. Even without establishing a diagnosis of hypoglycemia, dietary changes were a helpful strategy for symptom management for most patients.

A comparison between weight loss outcomes with anti-obesity medications before and during Covid-19 pandemic at a tertiary weight management center.

Background: /Objectives: Obesity is a risk factor for COVID-19 infection severity and mortality. Anti-obesity medications (AOM) are effective for weight loss. However, weight loss outcomes with AOM during the COVID-19 pandemic are yet to be described. Subjects: /Methods: Between January 1, 2016, and June 30, 2021, a total of 966 patients were prescribed long-term FDA-approved AOMs at the Mayo Clinic. From these patients, 711 patients did not meet inclusion criteria. A total of 255 patients were included. Interventions/methods: We performed a retrospective systematic review of electronic medical records and included patients who started a long-term FDA-approved AOM. We excluded patients with history of bariatric procedure, AOM prescription with lorcaserin, orlistat, semaglutide (approved for weight loss after the pandemic), or phentermine (short-term AOM), those taking ≥2 AOMs, <3 months of prescribed AOM, and/or pregnancy. Analysis was divided by 1)preCOVID-19: those who started an AOM before COVID-19 restrictions, 2)COVID-19: those who started an AOM during first quarter of 2020 after the establishment of COVID-19 restrictions. Our primary endpoint was the total body weight loss percentage (%TBWL) at 3, 6, and 12 months after AOM initiation. Results: There was a statistical difference in TBWL% between the preCOVID-19 and COVID-19 group: 5.3 ± 3.5% vs 4 ± 3.0% (95% CI -2.4 to -0.2; p = 0.02) and 9.7 ± 7.2% vs 6.2 ± 4.7% (95% CI -5.7 to -1.3; p = 0.002) at 3 and 12 months, respectively. At 6 months, the TBWL% was 7.1 for the preCOVID-19 group compared to 6.2% for the COVID-19 (95% CI -2.5 to 0.7; p = 0.25). Conclusion: With the possible exception of liraglutide, this study shows that weight loss outcomes to AOMs were inferior when prescribed during the routine clinical practice throughout COVID-19 pandemic, compared to the outcomes observed prior to the COVID-19 pandemic.

The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma.

No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2-induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion-activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC.

The Mayo Clinic Histiocytosis Working Group Consensus Statement for the Diagnosis and Evaluation of Adult Patients With Histiocytic Neoplasms: Erdheim-Chester Disease, Langerhans Cell Histiocytosis, and Rosai-Dorfman Disease.

Histiocytic neoplasms, a rare and heterogeneous group of disorders, primarily include Erdheim-Chester disease, Langerhans cell histiocytosis, and Rosai-Dorfman disease. Due to their diverse clinical manifestations, the greatest challenge posed by these neoplasms is the establishment of a diagnosis, which often leads to a delay in institution of appropriate therapy. Recent insights into their genomic architecture demonstrating mitogen-activated protein kinase/extracellular signal-regulated kinase pathway mutations have now enabled potential treatment with targeted therapies in most patients. This consensus statement represents a joint document from a multidisciplinary group of physicians at Mayo Clinic who specialize in the management of adult histiocytic neoplasms. It consists of evidence- and consensus-based recommendations on when to suspect these neoplasms and what tests to order for the diagnosis and initial evaluation. In addition, it also describes the histopathologic and individual organ manifestations of these neoplasms to help the clinicians in identifying their key features. With uniform guidelines that aid in identifying these neoplasms, we hope to improve the awareness that may lead to their timely and correct diagnosis.

Salivary peptide tyrosine-tyrosine 3-36 modulates ingestive behavior without inducing taste aversion.

Hormone peptide tyrosine-tyrosine (PYY) is secreted into circulation from the gut L-endocrine cells in response to food intake, thus inducing satiation during interaction with its preferred receptor, Y2R. Clinical applications of systemically administered PYY for the purpose of reducing body weight were compromised as a result of the common side effect of visceral sickness. We describe here a novel approach of elevating PYY in saliva in mice, which, although reliably inducing strong anorexic responses, does not cause aversive reactions. The augmentation of salivary PYY activated forebrain areas known to mediate feeding, hunger, and satiation while minimally affecting brainstem chemoreceptor zones triggering nausea. By comparing neuronal pathways activated by systemic versus salivary PYY, we identified a metabolic circuit associated with Y2R-positive cells in the oral cavity and extending through brainstem nuclei into hypothalamic satiety centers. The discovery of this alternative circuit that regulates ingestive behavior without inducing taste aversion may open the possibility of a therapeutic application of PYY for the treatment of obesity via direct oral application.

Modulation of taste responsiveness by the satiation hormone peptide YY.

It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immunohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, via viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically.

Distribution of Y-receptors in murine lingual epithelia.

Peptide hormones and their cognate receptors belonging to neuropeptide Y (NPY) family mediate diverse biological functions in a number of tissues. Recently, we discovered the presence of the gut satiation peptide YY (PYY) in saliva of mice and humans and defined its role in the regulation of food intake and body weight maintenance. Here we report the systematic analysis of expression patterns of all NPY receptors (Rs), Y1R, Y2R, Y4R, and Y5R in lingual epithelia in mice. Using four independent assays, immunohistochemistry, in situ hybridization, immunocytochemistry and RT PCR, we show that the morphologically different layers of the keratinized stratified epithelium of the dorsal layer of the tongue express Y receptors in a very distinctive yet overlapping pattern. In particular, the monolayer of basal progenitor cells expresses both Y1 and Y2 receptors. Y1Rs are present in the parabasal prickle cell layer and the granular layer, while differentiated keratinocytes display abundant Y5Rs. Y4Rs are expressed substantially in the neuronal fibers innervating the lamina propria and mechanoreceptors. Basal epithelial cells positive for Y2Rs respond robustly to PYY(3-36) by increasing intracellular Ca(2+) suggesting their possible functional interaction with salivary PYY. In taste buds of the circumvallate papillae, some taste receptor cells (TRCs) express YRs localized primarily at the apical domain, indicative of their potential role in taste perception. Some of the YR-positive TRCs are co-localized with neuronal cell adhesion molecule (NCAM), suggesting that these TRCs may have synaptic contacts with nerve terminals. In summary, we show that all YRs are abundantly expressed in multiple lingual cell types, including epithelial progenitors, keratinocytes, neuronal dendrites and TRCs. These results suggest that these receptors may be involved in the mediation of a wide variety of functions, including proliferation, differentiation, motility, taste perception and satiation.