United States

The identification of thyroid tumors with the potential for poor evolution is a major concern, as current management can range from simple active surveillance to aggressive therapeutic measures. MicroRNAs are small non-coding RNAs that play a key role in the regulation of gene expression and therefore in the pathogenesis and progression of different types of cancers. Here we employed several bioinformatics tools to investigate deregulated miRNAs in the lymph node metastasis (LNM) of two different types of thyroid tumors. Using thyroid cancer RNA-seq data available on Gene Expression Omnibus (GEO), we identified 14 common deregulated miRNAs in LNM of both medullary and papillary thyroid carcinomas, three of them still negatively deregulated when compared to their respective primary tumor: miR-199a-3p, miR-199a-5p, and miR-148a-5p. Public data available on TCGA confirmed the downregulation of miR-148a-5p in LNM and tumors with advanced AJCC stage. Looking at their predicted target genes, ITGA3, PVRL1 (also called NECTIN1), SNN, and FBXO28 genes were confirmed as positively deregulated in LNM papillary thyroid carcinomas when compared to normal tissues. Public data available on TCGA once again confirmed higher expression of the ITGA3 gene in LNM, larger and invasive tumors (T4a), and stage III and IV. Similar results were observed for PVRL1 (NECTIN1) and FBXO28, but not for SNN. These bioinformatic analysis findings suggest that miR-199a-3p, miR-199a-5p, and miR-148a-5p dysregulation, leading to epithelial-mesenchymal transition and cell adhesion failure, are associated with thyroid tumors&#39; LNM.

ENDO 2022

Identification of MicroRNAs Critical to the Lymph Node Metastatic Process of Thyroid Cancer

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

The identification of thyroid tumors with the potential for poor evolution is a major concern, as current management can range from simple active surveillance to aggressive therapeutic measures. MicroRNAs are small non-coding RNAs that play a key role in the regulation of gene expression and therefore in the pathogenesis and progression of different types of cancers. Here we employed several bioinformatics tools to investigate deregulated miRNAs in the lymph node metastasis (LNM) of two different types of thyroid tumors. Using thyroid cancer RNA-seq data available on Gene Expression Omnibus (GEO), we identified 14 common deregulated miRNAs in LNM of both medullary and papillary thyroid carcinomas, three of them still negatively deregulated when compared to their respective primary tumor: miR-199a-3p, miR-199a-5p, and miR-148a-5p. Public data available on TCGA confirmed the downregulation of miR-148a-5p in LNM and tumors with advanced AJCC stage. Looking at their predicted target genes, ITGA3, PVRL1 (also called NECTIN1), SNN, and FBXO28 genes were confirmed as positively deregulated in LNM papillary thyroid carcinomas when compared to normal tissues. Public data available on TCGA once again confirmed higher expression of the ITGA3 gene in LNM, larger and invasive tumors (T4a), and stage III and IV. Similar results were observed for PVRL1 (NECTIN1) and FBXO28, but not for SNN. These bioinformatic analysis findings suggest that miR-199a-3p, miR-199a-5p, and miR-148a-5p dysregulation, leading to epithelial-mesenchymal transition and cell adhesion failure, are associated with thyroid tumors' LNM.

technical paper

Background: The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Heterozygous variants of the genes for proopiomelanocortin (POMC), leptin receptor (LEPR), and proprotein convertase subtilisin/kexin type 1 (PCSK1) upstream of MC4R can result in impaired signaling in the MC4R pathway. This impaired signaling can lead to hyperphagia and early-onset, severe obesity. Setmelanotide (SET), an MC4R agonist, reduced weight and hunger after 3 months in patients with obesity due to these heterozygous variants in an earlier Phase 2 study. The current analysis is the first to assess continued efficacy of an additional year of SET treatment in patients with obesity due to heterozygous affectation of POMC, PCSK1, and LEPR.
Methods: Patients aged ≥6 years with obesity due to heterozygous variants in POMC, PCSK1, and LEPR were eligible for this long-term extension (LTE) trial (NCT03651765) after completing an index trial in which they received SET and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of SET treatment in the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred every 3 months and evaluated changes in body weight measures and assessed safety and tolerability. The current analysis reports outcomes after 1 year total of SET treatment across the index and LTE trials, relative to index trial baseline.
Results: As of October 29, 2021, 35 patients with obesity heterozygous for POMC, PCSK1, and LEPR had enrolled in the index trial, with 16, 17, and 17 patients continuing into the LTE trial and receiving at least 6, 9, and 12 months of treatment with SET, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all index trial patients was 50.26 (9.41) kg/m², body weight in patients ≥18 years old was 142.97 (28.70) kg, and BMI Z score in patients <18 years old was 4.04 (0.65). Mean (SD) percent change in BMI was −6.93% (9.13%; n=16), −8.14% (10.13%; n=17), and −7.83% (9.69%; n=17) after 6, 9, and 12 months of treatment, respectively. Of 15 patients ≥18 years old, the mean (SD) percent change in body weight was −10.24% (7.90%; n=15) after 12 months. For the 1 patient <18 years old, mean change in BMI Z score was 0.64 after 12 months. No new safety concerns emerged during the LTE and 1 patient discontinued due to an adverse event, likely unrelated to treatment.
Conclusions: Treatment with SET had continued efficacy in patients with obesity due to heterozygous variants in POMC, PCSK1, and LEPR after 1 year of treatment. These data support the continued investigation of SET in these patients, which is underway in the Phase 3 EMANATE trial (NCT05093634).

Body Mass Index and Weight Reductions in Patients With Obesity Due to Heterozygous Variants in POMC, PCSK1, and LEPR After 1 Year of Setmelanotide

Background: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental condition, characterized by hyperphagia, obesity, hormone deficiencies and behavioral/psychological manifestations. DCCR is under investigation as a treatment for hyperphagia in PWS through its actions on hypothalamic circuits involved in appetite regulation including NPY neurons and central inhibition of DMV neurons to improve insulin sensitivity. In addition to these effects, DCCR acts on pancreatic beta cells, to reduce glucose stimulated insulin secretion, which might have additional effects to reduce fat deposition in adipocytes, serum leptin concentrations and insulin resistance.
Objectives and methods: This analysis characterized changes in hormonal and cardiometabolic parameters in patients with PWS receiving oral daily DCCR.  125 participants with genetically-confirmed PWS ≥4 years old with hyperphagia were treated with DCCR in multi-center studies conducted at 29 sites in the US and the UK: a 13-week, Phase 3, double-blind, placebo-controlled study (DESTINY PWS) and its long-term, open-label extension study (analysis at 52 weeks). The target DCCR dose for these studies was ≥3.3 mg/kg with an optimal dose of 4.2 - 5.8 mg/kg. Overall, 103 patients received DCCR (100-525 mg/day) for 52 weeks. For all parameters, the baseline measurement was defined as (immediately prior to) start of DCCR treatment.
Results: Serum leptin, insulin, and HOMA-IR were significantly reduced following 52 weeks of DCCR administration.  Results are expressed as Least square (LS) mean change from baseline [Standard Error (SE)]. There were significant decreases in: Leptin (ng/mL) = ‑11.08[1.26], p<0.001; Insulin (μIU/mL) = ‑2.5[0.69], p<0.001; and HOMA-IR = -0.5 [0.17], p=0.003.  Serum adiponectin (µg/mL) was significantly increased: 1.82[0.41], p < 0.001.  Fat mass measured by DXA was stable at 52 weeks.
Conclusions: The reductions in fasting leptin, insulin and HOMA-IR, and the increase in adiponectin with prolonged DCCR treatment in the absence of reductions in total body fat are consistent with improved insulin sensitivity that may also reflect improvement in leptin sensitivity and healthier body fat distribution, such as reduced visceral adiposity. This could result from both direct pancreatic and hypothalamus-to-periphery actions of DCCR. It remains to be determined if such beneficial metabolic changes also result in reduced systemic inflammation and cardiovascular health.
DCCR administration was associated with significant reductions in leptin, insulin, and HOMA-IR, increases in adiponectin and stabilization of body fat. These and other changes in cardiometabolic parameters suggest that DCCR may have long term health benefit in patients with PWS.

Hormonal and Cardiometabolic Changes Associated with Diazoxide Choline Extended-Release (DCCR) Tablets in Patients with Prader-Willi Syndrome

Objective: To determine the association of anti-obesity medications (FDA-approved and off-label) with weight loss maintenance over 3-5 years.
Methods: We performed a retrospective observational study of adults 18-75 years treated for overweight/obesity at a tertiary academic weight management center with an initial visit between April 1st, 2014 and April 1st, 2016. We excluded patients who had a period of follow-up less than 2.5 years or a gap in follow-up of greater than 2 years. Patients who had bariatric surgery, pregnancy, or a medical condition predisposing them to weight loss during the study were also excluded. We extracted key demographic data, medical history, and weight at each visit. Anti-obesity medication (AOM) start date and end date was determined through chart review with attention to patient self-reporting of medication adherence to calculate total exposure to each AOM. We used the weight loss maintenance definition of weight regain ≤ 3% of the nadir weight.
Results: A total of 428 patients met inclusion criteria for the analysis and were followed for a mean of 4.4 years. The mean age was 50.9 years, 73% were female, and median initial BMI was 34.3 kg/m². Weight categories were as follows: 19% overweight, 35% class 1, 25% class 2, and 20% class 3 obesity. In addition, 16% had diabetes and 36% had prediabetes.
The median nadir BMI was 25.6 with a median maximum weight loss of 14.7%. The median time to achieving nadir weight was 1.9 years. Average weight change from the initial to final visit was -10.6% (-10.9 kg), with a final visit median BMI of 27.4. The proportion of patients who achieved ≥5%, ≥10%, ≥15%, and ≥20% total weight loss was 70.8%, 48.1%, 30.1%, and 16.8%, respectively. During the 4.4 years the patients were followed, weight regain following the nadir weight was 6.3%. At the last observation, 40.2% of all patients had maintained their maximum weight loss.
The mean number of AOMs trialed throughout the duration of the study was 4.2. At the final visit, a mean of 2.5 AOMs were being taken. The most common medications observed at the final visit alone or in combination were metformin (76.2% of patients), phentermine (31.1%), topiramate (30.8%), bupropion (29.9%), and semaglutide (24.5%).
Conclusion: Long-term weight loss of 10.6% was observed over 3-5 years in adults with overweight/obesity who were managed with pharmacotherapy. This study demonstrates clinically significant long-term weight loss maintenance can be achieved with pharmacotherapy and lifestyle interventions.

Long-term Weight Loss Maintenance with Obesity Pharmacotherapy: a 5-Year Retrospective Study

Background: Satiety is the result of postprandial physiologic events that determine the timing for the next meal by inhibiting the sensation of hunger. It is orchestrated by the brain-gut-axis, with gastric emptying and accommodation being key components of satiety and appetite sensations. Several indices have been used to quantify satiety. Longer time to empty 50% of the stomach content (GEt1/2) during a gastric emptying for solid study (GES), and lower SQ for fullness, lower SQ for satisfaction, and higher SQ for hunger after a meal challenge measured by visual analog scales (VAS) are all associated with prolonged satiety and are therefore protective against caloric overconsumption and to the development of obesity. Although obesity prevalence is higher in female compared to male subjects, there is little data on how sex affects biological indices of satiety.
Methods: This retrospective cohort study included patients with overweight and obesity who underwent anthropometric measurements, body composition evaluation, and satiety tests. After an 8-hour overnight fast, patients were provided a radiolabel breakfast (320kcal, 30% fat) to measure GES by scintigraphy over 4 hours and appetite sensations. We measured appetite sensations (hunger, fullness, and satisfaction) with 100-mm VAS every 30 minutes for 4 hours at baseline (before eating breakfast, i.e. VAS0') and after breakfast (VAS30' to VAS240'). The SQ for each appetite sensation was calculated with the following formula: (VAS0' – VAS30')/320. We performed univariate and multiple regression analyses to estimate the contribution of biological and anthropometric variables to GEt1/2.
Results: We included 743 subjects: 557 females (75%), mean age 40±11 years, mean BMI 33±8kg/m². Compared to males, female participants had significantly higher BMI and lower height, weight, waist-to-hip ratio (W/H), and percentage lean mass (%LM). Compared to males, female participants had a slower GEt1/2 (123 vs. 98 minutes, p<0.0001), lower SQ for fullness (-15 vs. -12 mm, p=0.008), and lower SQ for satisfaction (-14 vs. -11 mm, p=0.01). Females had higher but not significant SQ for hunger. On univariate analysis, height, BMI, and %LM had a negative but significant correlation with GEt1/2 (R=-0.3, p<0.0001; R=-0.1, p=0.02; and R=-0.2, p=0.0003; respectively). On multiple regression analysis, when taking into consideration age, sex, height, W/H, and %LM, only sex (parameter estimate [PE]=6.8, p=0.02), height (PE=-82, p=0.0005), and W/H (PE=49, p=0.004) were independent predictors of GEt1/2.
Conclusion: This study highlights the sex differences in indices of satiety measured by GEt1/2 with a GES, and by SQ for hunger, fullness, and satisfaction with VAS. Sex is a strong independent predictor of GEt1/2. These observations highlight the importance of considering sex as a variable to understand the pathophysiologic mechanisms involved in obesity's heterogeneity.

Sex as an Independent Variable in Satiety

Non-alcoholic fatty liver disease (NAFLD) is a serious condition whose prevalence differs by race/ethnicity. Studies have suggested that consumption of high-fructose corn syrup is likely a risk factor for NAFLD. We investigated the associations between fructose consumption and NAFLD, and its distribution by race/ethnicity in the adult US population using NHANES 2017-2018 data (n=3292). NAFLD was diagnosed by FibroScan® using controlled attenuation parameter (CAP) values of =>260 and no exclusion criteria. Fructose consumption was calculated from 24-hour dietary recall data in combination with USDA food nutritional content data files. Fructose consumption was categorized into tertiles (low= <=0.95 g, middle= >0.95-<=2.1 g, and high=  >2.1 g). We analyzed data in SAS 9.4 using Chi squared tests and multinomial logistic regression, adjusting for demographics, behavioral, and laboratory data, and including sample weights and design. Of the 3292 participants, 31.3% were in the middle tertile of the fructose consumption and 35.5% were in the high tertile. There was no significant difference in the prevalence of NAFLD by fructose consumption group [low=44%; middle=48%, and high=51%] (p=0.094).
The highest percentage of participants in the high tertile of fructose consumption were in Mexican Americans (48%) and non-Hispanic Blacks (44%), with a much lower percentage of non-Hispanic Whites (33%) (p<0.0001).  The highest prevalence of NAFLD was in Mexican Americans in the high tertile of fructose consumption (70%), which was significantly different than the prevalence in Mexican Americans in the low tertile (52%) (p=0.031). In the adjusted models, those in the high tertile of fructose consumption had higher odds of NAFLD relative to those in the low tertile (AOR = 1.6, 95%CI = 1.1 - 2.3, p=0.0224). Fructose consumption in the high tertile was associated with increased odds of NAFLD in non-Hispanic Whites (AOR = 2.0, 95%CI = 1.0 - 3.7, p=0.0387) and Mexican Americans (AOR = 1.8, 95%CI = 1.2 - 2.8, p=0.0050). We conclude that there is an association between fructose consumption and the odds of NAFLD. This association does not explain the racial/ethnic disparity in NAFLD. Interventions should aim to decrease consumption of fructose overall.

Fructose Consumption and NAFLD in US Adult Population of NHANES 17-18

Background: Body composition often changes with age. While body mass index (BMI) is used to define obesity, the degree to which BMI accurately or consistently reflects fatness in older versus younger adults remains unclear. Importantly, it is uncertain whether diabetes risk is similar for older versus younger adults within BMI-defined categories.
Objectives: We evaluated the relationship of older (≥65 years) versus younger age (<65 years) to dual-energy x-ray absorptiometry (DXA)-derived body composition measures and incident diabetes, stratified by BMI-defined categories for non-overweight/non-obese (<25 kg/m2), overweight (25-29.9 kg/m2) and obesity (≥30 kg/m2).
Design: Participants without diabetes at first DXA visit in the Baltimore Longitudinal Study of Aging were included. Linear regression models were used to investigate the association of age categories to body composition at baseline, and Cox proportional hazard models were used to study the relationship of age categories to incident diabetes, within BMI categories for men and women. Diabetes was defined based on self-reported history, medication use, and/or ADA diagnostic criteria (fasting or 2-hour OGTT glucose levels).
Results: A total of 993 men (n=463 older, n=530 younger) and 1109 women (n=385 older, n=724 younger) were examined. Comparing older versus younger participants, body weight was significantly lower across all BMI categories for both men and women (all p<0.05). Percent total fat mass (%TFM) and fat mass/lean mass ratio (FM/LM) were significantly higher in older versus younger men across all BMI categories and in non-overweight/non-obese women. Among men, in multiple regression analyses adjusting for race, education, height and weight, the relationship (β±SE) of older versus younger age (reference) to %TFM remained significant (non-overweight/non-obese: 1.84±0.59, overweight: 2.60±0.47, obese: 1.81± 0.87; all p<0.05), as did the relationship to FM/LM, across all BMI categories. Among women, the relationships of older versus younger age (reference) to %TFM and FM/LM remained significant for non-overweight/non-obese women. Over a median follow-up of 7.3 years (IQR=1.9-16.6), there were 165 incident cases of diabetes. Older obese men had an almost three-fold higher risk of developing diabetes than younger obese men (HR=2.72 [95%CI: 1.12, 6.63]), accounting for race, education, height, weight and %TFM. Among women, no differences by age group in incident diabetes were observed.
Conclusions: In our study, sex differences were observed in the relationship of older versus younger age to several measures of body composition, suggesting greater relative fat mass with aging, particularly in men. Further, our results suggest that BMI-defined categories for overweight and obesity do not fully account for changes in fat mass with aging and that the risk for diabetes is significantly greater for older compared to younger obese men. Further studies are needed to investigate the optimal BMI thresholds that predict diabetes risk in older adults.

Sex Differences in Body Composition and Incident Diabetes Across BMI Categories in Older Versus Younger Adults

Background: Thyroid eye disease (TED) can result in eye-bulging (proptosis) and double-vision (diplopia) and inflammation, which frequently impacts quality of life (QoL). Teprotumumab, an insulin like growth factor-1 receptor inhibitory antibody, improves TED outcomes and QoL¹ as measured by the Graves Ophthalmopathy-Quality of Life (GO-QoL) questionnaire and its appearance (AP) and visual function (VF) subscales. The primary factors driving QoL improvement in TED are unknown; therefore, we examined outcomes associated with improvement as observed in 2 placebo-controlled trials.
Methods: Data from Phase 2/3 placebo-controlled trials of teprotumumab were examined with a mixed-effect model with change in overall GO-QoL, AP, and VF scores as dependent variables to explain within-patient variability. Independent variables included demographics, visits, treatment, symptoms (Gorman diplopia scores [0-3], proptosis change (mm), spontaneous orbital pain, gaze-evoked orbital pain). Variability between subjects was tested over the 24-week study.
Results: Teprotumumab treatment significantly correlated with improved overall GO-QoL, VF and AP scores. Improvements in diplopia, proptosis, gaze-evoked and spontaneous orbital pain were associated with those in overall GO-QoL score (coefficient -4.01, -1.00, -31.21 and -4.37, respectively, all p<0.001). Improvements in diplopia scores and spontaneous orbital pain were significantly correlated with higher VF scores (coefficients -5.51 and -6.66, respectively, both p<0.001). Improvements in diplopia and proptosis correlated significantly with higher AP scores (coefficients -2.98, -1.62, both p<0.001). Patients with pain had lower AP scores (coefficient -38.21, p<0.001). Increasing age was positively correlated with higher GO-QoL AP scores (coefficient 0.41, p<0.001), but negatively correlated with GO-QoL VF scores (coefficient -0.29, p<0.001). Variability between subjects was considerable, accounting for >60% of random variance.
Conclusions: Improvements in diplopia, proptosis, and pain drove improvements in QoL. In older patients, changes in AP impacted QoL to a lesser degree, while reduced VF had a greater negative impact on QoL.

Teprotumumab Markedly Improves Disease-related Quality of Life: Lessons From Two Randomized, Placebo-controlled Trials

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, however, are associated with immune-related adverse events (irAEs). Thyroid dysfunction is among the most common irAEs, yet its mechanism has not been fully elucidated. To further explore the molecular mechanism of ICI-induced thyroid dysfunction, we profiled changes in transcription induced by PD-1/PD-L1 antibody treatment in a non-small cell lung cancer murine model using RNA-seq. We used bioinformatic tools to compare transcriptional changes in our model to previously published transcription data sets of drug-induced thyroiditis. C57BL6/129SvJ mice harboring LKR-M (Lung cancer K-ras metastatic tumor) flank tumors were treated with PD-1 antibody, PD-L1 antibody, or vehicle every 3 days over a period of 7 days when mice were sacrificed, and thyroid glands were removed. The tumor volume increased in the control mice (1.38 ± 0.19) and decreased in the anti PD-1 treated (0.64 ± 0.15; P=0.0001) and PD-L1 treated mice (0.74 ± 0.11; P=0.004). RNA-seq was performed in the LKR-M tumor-bearing control mice and in the anti PD-1/PD-L1 treated mice (n=4 per group). A total of 952 differentially expressed genes (DEGs), including 265 upregulated and 688 downregulated, were identified with anti PD-1 treatment (fold-change ≥1.8, FDR ≤0.05). Only 35 genes were differentially expressed with anti PD-L1 treatment, and we therefore chose to focus on the anti PD-1 treated group alone. Using Ingenuity Pathway Analysis (IPA), we determined that of the DEGs in the PD-1 treatment group, 362 were associated with functions of cell death and survival, with a predicated activation of pathways for apoptosis and necrosis (Z=2.89 and 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z=-6.22 and -6.45, respectively). When compared to previously published datasets of interleukin-1β and interferon gamma-treated human thyroid cells, the apoptosis pathways were similarly activated. To our knowledge this is the first study to evaluate transcriptomic changes in thyroid tissue following ICI therapy. Our data suggest that there are unique changes in gene expression in the thyroid associated with anti PD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.

RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies

Background. Destructive thyroiditis is the most common endocrine immune related adverse event (iRAEs) in patients treated with anti-PD1/PD-L1 agents. Given its self-limited course, current guidelines recommend no treatment for this iRAE. Nevertheless in patients with enlarged thyroid volume and a poor performance status, thyrotoxicosis may be particularly severe and harmful. Aim of the study is to evaluate if steroid treatment might be useful in improving thyrotoxicosis in subjects with a poor performance status.
Methods. We conducted a case-control study, comparing the course of thyrotoxicosis of 4 patients treated with oral prednisone at the dosage of 25 mg/d (tapered to discontinuation in three weeks) and an enlarged thyroid volume to that of 8 patients with similar thyroid volume who were left untreated.
Results. No difference was found between the two groups at the onset of thyrotoxicosis (time 0) in demographic characteristics and in the levels of thyroid hormones. The levels of thyroid hormones were lower in subjects treated with prednisone compared to those untreated at time 7, 14, 21, 28, 35, 42, 60 and 90 days (P<0.05 at each time). The median time to remission of thyrotoxicosis was 24 days in patients treated with steroids and 92 days in untreated patients (P<0.001). At 6 months, the rate of evolution to hypothyroidism was similar in the 2 groups (4/4 in steroid group vs 7/8 in untreated group, P=0.74) and no difference was found in tumor progression (Progression free survival in treated group 5.1 months vs 5.0 months in untreated patients, P=0.89).
Conclusion. A short period of prednisone therapy is useful to restore more quickly euthyroidism in patients with a poor performance status and a severe destructive thyrotoxicosis induced by PD-1 blockade. This treatment does not impair the efficacy of immunotherapy.

Steroid treatment in the management of destructive thyrotoxicosis induced by PD1 blockade

In vertebrates, thyroglobulin (Tg) is secreted into the lumen of thyroid follicles to enable its iodination for the synthesis of thyroid hormone — defective Tg secretion causes hypothyroidism. A defining step in Tg secretion is export from the endoplasmic reticulum (ER), but Tg structural features needed to meet ER quality control requirements remain poorly defined. Tg primary structure is composed of Regions I, II, III, and ChEL, each engaged in intradomain disuflide bonding. Two major surprises that have recently emerged from the visualization of bovine Tg 3D-structure by cryoEM include the first identified long-range disulfide bond (C408-C608), which appears to tether a boundary separating two halves of region I, as well as the apparent absence of an evolutionarily conserved disulfide bond between C2444 and C2455 in the ChEL domain, which is known to support folding stability of region I. To understand the cell biological importance of these findings, we employed site-directed mutagenesis to determine the impact of these structural features in protein export of recombinant Tg expressed in cultured cells.

To our surprise, we found that mutation of either a single Cys residue or both cysteines that contribute to the C408-C608 disulfide bridge had no discernible impact on the efficiency of Tg export. These data strongly suggest that the proximity of the two-halves of region I in the final Tg structure may be achieved by protein folding of individual repeating units of region I that must take place independently of (and thus presumably prior to) the formation of this interesting long-range disulfide bond.

As ChEL supports Tg region I folding stability, we turned attention to the apparent absence of the C-2444-C2455 disulfide, which is one of the three disulfide bonds that had been thought to exist in every member of the large Cholinesterase-Like gene superfamily. Reported detection of this disulfide within human Tg, but lack of detection in bovine Tg, means either that this bond is 'structurally optional', or that this surface disulfide bond might have been broken by radiolysis under the X-ray beam used for cryoEM. Unequivocally, we found that mutagenesis of either C2444, C2455, or both, blocks Tg secretion and causes a pattern of intracellular misfolding consistent with incomplete Tg compaction indicative of lack of maturation of region I. Moreover, we found that disruption of these same residues causes misfolding and blocks secretion of an expressed isolated secretory ChEL domain, or acetylcholinesterase itself.

Loss of the C2444-C2455 disulfide bridge behaves similarly to the defective folding observed in the mutant Tg encoded within cog/cog mice and rdw/rdw rats, whereas no pathogenic mutations have been reported affecting the long-range disulfide in Tg region I. Together, these results highlight the importance of ChEL domain structure in the maturation and secretion of Tg.

Identification of MicroRNAs Critical to the Lymph Node Metastatic Process of Thyroid Cancer

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Body Mass Index and Weight Reductions in Patients With Obesity Due to Heterozygous Variants in POMC, PCSK1, and LEPR After 1 Year of Setmelanotide

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