Surfactant-like photosensitizer for endoscopic duodenal ablation: Modulating meal-stimulated incretin hormones in obese and type 2 diabetes.

Duodenal ablation improves glycaemic control and weight loss, so it has been applied using hydrothermal catheters in obese and type 2 diabetes patients, indicating similar mechanisms and therapeutic effects as bariatric surgeries. Endoscopic photodynamic therapy is an innovative procedure that easily accessible to endocrine or gastrointestinal organs, so it is critical for the sprayed photosensitizer (PS) to long-term interact with target tissues for enhancing its effects. Surfactant-like PS was more stable in a wide range of pH and 2.8-fold more retained in the duodenum at 1 h than hydrophilic PS due to its amphiphilic property. Endoscopic duodenal ablation using surfactant-like PS was performed in high fat diet induced rat models, demonstrating body weight loss, enhanced insulin sensitivity, and modulation of incretin hormones. Locoregional ablation of duodenum could affect the profiles of overall intestinal cells secreting meal-stimulated hormones and further the systemic glucose and lipid metabolism, regarding gut-brain axis. Our strategy suggests a potential for a treatment of minimally invasive bariatric and metabolic therapy if accompanied by detailed clinical trials.

Multiomics Approach to Acromegaly: Unveiling Translational Insights for Precision Medicine.

The clinical characteristics and prognoses of acromegaly vary among patients. Assessment of current and novel predictors can lead to multilevel categorization of patients, allowing integration into new clinical guidelines and a reduction in the increased morbidity and mortality associated with acromegaly. Despite advances in the diagnosis and treatment of acromegaly, its pathophysiology remains unclear. Recent advancements in multiomics technologies, including genomics, transcriptomics, proteomics, metabolomics, and radiomics, have offered new opportunities to unravel the complex pathophysiology of acromegaly. This review comprehensively explores the emerging role of multiomics approaches in elucidating the molecular landscape of acromegaly. We discuss the potential implications of multiomics data integration in the development of novel diagnostic tools, identification of therapeutic targets, and the prospects of precision medicine in acromegaly management. By integrating diverse omics datasets, these approaches can provide valuable insights into disease mechanisms, facilitate the identification of diagnostic biomarkers, and identify potential therapeutic targets for precision medicine in the management of acromegaly.

Increased Risk of Hip Fracture in Patients with Acromegaly: A Nationwide Cohort Study in Korea.

BACKGRUOUND: Acromegaly leads to various skeletal complications, and fragility fractures are emerging as a new concern in patients with acromegaly. Therefore, this study investigated the risk of fractures in Korean patients with acromegaly. METHODS: We used the Korean nationwide claims database from 2009 to 2019. A total of 931 patients with acromegaly who had never used an osteoporosis drug before and were treated with surgery alone were selected as study participants, and a 1:29 ratio of 26,999 age- and sex-matched osteoporosis drug-naïve controls without acromegaly were randomly selected from the database. RESULTS: The mean age was 46.2 years, and 50.0% were male. During a median follow-up of 54.1 months, there was no difference in the risks of all, vertebral, and non-vertebral fractures between the acromegaly and control groups. However, hip fracture risk was significantly higher (hazard ratio [HR], 2.73; 95% confidence interval [CI], 1.32 to 5.65), and non-hip and non-vertebral fractures risk was significantly lower (HR, 0.40; 95% CI, 0.17 to 0.98) in patients with acromegaly than in controls; these results remained robust even after adjustment for socioeconomic status and baseline comorbidities. Age, type 2 diabetes mellitus, cardio-cerebrovascular disease, fracture history, recent use of acid-suppressant medication, psychotropic medication, and opioids were risk factors for all fractures in patients with acromegaly (all P<0.05). CONCLUSION: Compared with controls, patients surgically treated for acromegaly had a higher risk of hip fractures. The risk factors for fracture in patients with acromegaly were consistent with widely accepted risk factors in the general population.

Dexamethasone suppression for 18F-FDG PET/CT to localize ACTH-secreting pituitary tumors.

BACKGROUND: 18Fluorine-Fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) is widely used for diagnosing various malignant tumors and evaluating metabolic activities. Although the usefulness of 18F-FDG PET has been reported in several endocrine diseases, studies on pituitary disease are extremely limited. To evaluate whether dexamethasone (DEX) suppression can improve 18F-FDG PET for the localization of adrenocorticotropic hormone-secreting adenomas in the pituitary gland in Cushing's disease (CD). METHODS: We included 22 patients with CD who underwent PET imaging before and after DEX administration. We compared the success rates of PET before and after DEX suppression, magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus sampling (BIPSS). We determined the final locations of adenomas based on intraoperative multiple-staged resection and tumor tissue identification using frozen sections. Standardized uptake value (SUV) were analyzed to confirm the change of intensity of adenomas on PET. RESULTS: Twenty-two patients were included (age at diagnosis: 37 [13-56] years), and most were women (90.91%). Pituitary adenomas compared to normal pituitaries showed increased maximum SUV after DEX suppression but without statistical significance (1.13 versus. 1.21, z=-0.765, P = 0.444). After DEX suppression, the mean and maximum SUV of adenomas showed a positive correlation with nadir cortisol levels in high-dose DEX suppression test (Rho = 0.554, P = 0.007 and Rho = 0.503, P = 0.017, respectively). In reference sites, mean SUV of cerebellum was significantly decreased (7.65 vs. 6.40, P = 0.006*), but those of the thalamus and gray matter was increased after DEX suppression (thalamus, 8.70 vs. 11.20, P = 0.010*; gray matter, 6.25 vs. 7.95, P = 0.010*). CONCLUSION: DEX suppression did not improve 18F-FDG PET/CT localization in patients with CD.

Cre-loxP System-Based Mouse Model for Investigating Graves' Disease and Associated Orbitopathy.

Background: Graves' disease (GD), one of the most common forms of autoimmune thyroid disorders, is characterized by hyperthyroidism caused by antibodies (Abs) against the extracellular A-subunit of the thyrotropin receptor (TSHR). Various approaches have been used to create mouse models of GD, including transfected fibroblasts and immunization with plasmids or adenoviruses expressing human TSHR A-subunit (hTSHR A-subunit). These models, however, require repeated immunization and produce inconsistent results. In this study, we established a novel Cre-loxP system-based mouse model that is able to generate the hTSHR A-subunit, mimicking human GD, and characterized the histological changes in Graves' orbitopathy (GO) progression after a single injection. Materials and Methods: A Cre-loxP system-based mouse model was constructed by inserting the CAG-loxP-STOP-loxP-hTSHR A-subunit cassette into the Rosa26 locus of the mouse genome. Conditional expression of the hTSHR A-subunit was successfully achieved by intramuscular injection of the transactivator of transcription-Cre recombinase (GD mice). Blood tests for anti-TSHR Abs and the total thyroxine (T4) level were performed. Magnetic resonance imaging (MRI) was used to monitor morphological changes in the eyes. A histological examination of the thyroid gland and retrobulbar tissues was performed to observe pathological changes. Results: Twenty-four (8 control and 16 GD) mice were investigated. All GD mice exhibited higher levels of TSHR Abs compared with the control group. Moreover, more than 80% of the mouse models showed elevated T4 levels accompanied by thyroid goiter. MRI analysis revealed an increased volume of retrobulbar tissue, while immunohistochemical staining of orbital tissues exhibited macrophage infiltration and muscle fibrosis in the GD mice, contrasting with the control group. Conclusions: Our novel mouse model for GD, which showed the histological features of GO, was successfully established using the Cre-loxP system. This animal model offers improved insights and contributes to advancing methodological developments for GD and GO.

Sex differences in mortality in patients with acromegaly: a nationwide cohort study in Korea.

OBJECTIVE: The results of previous studies on sex differences in mortality and comorbidities among patients with acromegaly are diverse. We assessed sex differences in mortality and the risk of complications in patients with acromegaly. METHODS: We included 1884 patients with acromegaly with 1:50 age- and sex-matched 94 200 controls using the Korean nationwide claims database from 2009 to 2019. RESULTS: During the median 5.51 years of follow-up, the acromegaly group had higher all-cause mortality than the control group (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.38-2.19), with higher risk in women than men (HR 2.17 vs 1.36). The most common cause of death was malignancy. Women with acromegaly aged ≥50 years exhibited significantly higher mortality than men with acromegaly aged ≥50 years (HR 1.74 vs 0.96). In a treatment subgroup other than surgery alone, women had a higher risk of mortality than men (HR 2.82 vs 1.58). Sex differences in mortality among patients with acromegaly remained equal after adjustment for the Charlson Comorbidity Index (CCI), socioeconomic status (SES), body mass index (BMI), alcohol consumption, smoking, fasting plasma glucose, creatinine, and total cholesterol. Patients with acromegaly had elevated risks of developing major adverse cardiovascular events (MACE), atrial fibrillation, obstructive sleep apnea (OSA), diabetes mellitus (DM), end-stage renal disease (ESRD), Parkinson's disease (PD), depression, and malignancy than age- and sex-matched controls, with a higher risk of OSA and DM in women than men. CONCLUSIONS: The risk of mortality and complications in patients with acromegaly compared to age- and sex-matched controls was higher in women than in men.

Surgical Treatment of Prolactinomas: Potential Role as a First-Line Treatment Modality.

PURPOSE: Treatment with dopamine agonists (DAs) has been the first-line standard treatment for prolactinoma, and surgery has been reserved for drug intolerance and resistance for several decades. We evaluated whether surgery plays a primary role in prolactinoma management. MATERIALS AND METHODS: We conducted a retrospective study of 210 prolactinoma patients who had received surgical treatment at our institution. We analyzed the treatment outcomes according to tumor extent, sex, and preoperative DA medication. RESULTS: Overall hormonal remission was achieved in 164 patients (78.1%), and complete removal was achieved in 194 patients (92.4%). When the tumors were completely removed, the remission rate increased to 84.5%. Anterior pituitary function was normalized or improved in 94.6% of patients, whereas only 4.1% of patients showed worsening of hormone control. Hormonal remission was higher in patients who had not received DA preoperatively than in those who had received preoperative DA treatment. Smaller tumor size (<1 cm), no invasion into the cavernous sinus, and female sex were predictors of good surgical outcomes. CONCLUSION: Although DAs remain the first-line standard treatment for prolactinomas, surgery can be an excellent option and should be considered as an alternative primary treatment modality when patients are predicted to achieve a good surgical outcome.

Olfactory marker protein regulates adipogenesis via the cAMP-IκBα pathway.

Olfactory marker protein (OMP) regulates olfactory transduction and is also expressed in adipose tissue. Since it serves as a regulatory buffer for cyclic AMP (cAMP) levels, we hypothesized that it plays a role in modulating adipocyte differentiation. To determine the role of OMP in adipogenesis, we examined the differences in body weight, adipose tissue mass, and adipogenic or thermogenic gene expression between high-fat diet-fed control and Omp-knockout (KO) mice. cAMP production, adipogenic gene expression, and cAMP response element binding protein (CREB) phosphorylation were measured during the differentiation of 3T3-L1 preadipocytes and mouse embryonic fibroblasts (MEFs). RNA sequencing was performed to determine the gene expression patterns responsible for the reduction in adipogenesis when Omp was deleted. Body weight, adipose tissue mass, and adipocyte size decreased in Omp-KO mice. Furthermore, cAMP production and CREB phosphorylation reduced during adipogenesis induced in Omp-/- MEFs, and the Nuclear factor kappa B was activated due to significantly reduced expression of its inhibitor. Collectively, our results suggest that loss of OMP function inhibits adipogenesis by affecting adipocyte differentiation.

Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer.

Medullary thyroid cancer originates from parafollicular C-cells in the thyroid. Despite successful thyroidectomy, localizing remnant cancer cells in patients with elevated calcitonin and carcinoembryonic antigen levels remains a challenge. Extranasal odorant receptors are expressed in cells from non-olfactory tissues, including C-cells. This study evaluates the odorant receptor signals from parafollicular C-cells, specifically, the presence of olfactory marker protein, and further assesses the ability of the protein in localizing and treating medullary thyroid cancer. We used immunohistochemistry, immunofluorescent staining, Western blot, RNA sequencing, and real time-PCR to analyze the expression of odorant receptors in mice thyroids, thyroid cancer cell lines, and patient specimens. We used in vivo assays to analyze acetate binding, calcitonin secretion, and cAMP pathway. We also used positron emission tomography (PET) to assess C11-acetate uptake in medullary thyroid cancer patients. We investigated olfactory marker protein expression in C-cells in patients and found that it co-localizes with calcitonin in C-cells from both normal and cancer cell lines. Specifically, we found that OR51E2 and OR51E1 were expressed in thyroid cancer cell lines and human medullary thyroid cancer cells. Furthermore, we found that in the C-cells, the binding of acetate to OR51E2 activates its migration into the nucleus, subsequently resulting in calcitonin secretion via the cAMP pathway. Finally, we found that C11-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C11-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C11-acetate PET, we identified recurrence sites in post-operative medullary thyroid cancer patients. Therefore, OR51E2 may be a novel diagnostic and therapeutic target for medullary thyroid cancer.

Long-acting recombinant human follicle-stimulating hormone (SAFA-FSH) enhances spermatogenesis.

Introduction: Administration of follicle-stimulating hormone (FSH) has been recommended to stimulate spermatogenesis in infertile men with hypogonadotropic hypogonadism, whose sperm counts do not respond to human chorionic gonadotropin alone. However, FSH has a short serum half-life requiring frequent administration to maintain its therapeutic efficacy. To improve its pharmacokinetic properties, we developed a unique albumin-binder technology, termed "anti-serum albumin Fab-associated" (SAFA) technology. We tested the feasibility of applying SAFA technology to create long-acting FSH as a therapeutic candidate for patients with hypogonadotropic hypogonadism. Methods: SAFA-FSH was produced using a Chinese hamster ovary expression system. To confirm the biological function, the production of cyclic AMP and phosphorylation of ERK and CREB were measured in TM4-FSHR cells. The effect of gonadotropin-releasing hormone agonists on spermatogenesis in a hypogonadal rat model was investigated. Results: In in vitro experiments, SAFA-FSH treatment increased the production of cyclic AMP and increased the phosphorylation of ERK and CREB in a dose-dependent manner. In animal experiments, sperm production was not restored by human chorionic gonadotropin treatment alone, but was restored after additional recombinant FSH treatment thrice per week or once every 5 days. Sperm production was restored even after additional SAFA-FSH treatment at intervals of once every 5 or 10 days. Discussion: Long-acting FSH with bioactivity was successfully created using SAFA technology. These data support further development of SAFA-FSH in a clinical setting, potentially representing an important advancement in the treatment of patients with hypogonadotropic hypogonadism.

Use of long non-coding RNAs for the molecular diagnosis of papillary thyroid cancer.

Objective: Improved molecular testing for common somatic mutations and the identification of mRNA and microRNA expression classifiers are promising approaches for the diagnosis of thyroid nodules. However, there is a need to improve the diagnostic accuracy of such tests for identifying thyroid cancer. Recent findings have revealed a crucial role of long non-coding RNAs (lncRNAs) in gene modulation. Thus, we aimed to evaluate the diagnostic value of selected lncRNAs from The Atlas of Noncoding RNAs in Cancer (TANRIC) thyroid cancer dataset. Methods: LncRNAs in TANRIC thyroid cancer dataset that have significantly increased or decreased expression in papillary thyroid cancer (PTC) tissues were selected as candidates for PTC diagnosis. Surgical specimens from patients who underwent thyroidectomy were used to determine the separation capability of candidate lncRNAs between malignant and benign nodules. Fine needle aspiration samples were obtained and screened for candidate lncRNAs to verify their diagnostic value. Results: LRRC52-AS1, LINC02471, LINC02082, UNC5B-AS1, LINC02408, MPPED2-AS1, LNCNEF, LOC642484, ATP6V0E2-AS1, and LOC100129129 were selected as the candidate lncRNAs. LRRC52-AS1, LINC02082, UNC5B-AS1, MPPED2-AS1, LNCNEF, and LOC100129129 expression levels were significantly increased or decreased in malignant nodules compared to those in benign nodules and paired normal thyroid tissues. The combination of LRRC52-AS1, LINC02082, and UNC5B-AS1 showed favorable results for the diagnosis of PTC from fine needle aspirates, with 88.9% sensitivity and 100.0% specificity. Conclusions: LncRNA expression analysis is a promising approach for advancing the molecular diagnosis of PTC. Further studies are needed to identify lncRNAs of additional diagnostic value.

Olfactory marker protein regulation of glucagon secretion in hyperglycemia.

The olfactory marker protein (OMP), which is also expressed in nonolfactory tissues, plays a role in regulating the kinetics and termination of olfactory transduction. Thus, we hypothesized that OMP may play a similar role in modulating the secretion of hormones involved in Ca2+ and cAMP signaling, such as glucagon. In the present study, we confirmed nonolfactory α-cell-specific OMP expression in human and mouse pancreatic islets as well as in the murine α-cell line αTC1.9. Glucagon and OMP expression increased under hyperglycemic conditions. Omp knockdown in hyperglycemic αTC1.9 cells using small-interfering RNA (siRNA) reduced the responses to glucagon release and the related signaling pathways compared with the si-negative control. The OMPlox/lox;GCGcre/w mice expressed basal glucagon levels similar to those in the wild-type OMPlox/lox mice but showed resistance against streptozotocin-induced hyperglycemia. The ectopic olfactory signaling events in pancreatic α-cells suggest that olfactory receptor pathways could be therapeutic targets for reducing excessive glucagon levels.

Altered Glucose Metabolism and Glucose Transporters in Systemic Organs After Bariatric Surgery.

The Roux-en-Y gastric bypass (RYGB) is highly effective in the remission of obesity and associated diabetes. The mechanisms underlying obesity and type 2 diabetes mellitus remission after RYGB remain unclear. This study aimed to evaluate the changes in continuous dynamic FDG uptake patterns after RYGB and examine the correlation between glucose metabolism and its transporters in variable endocrine organs using 18F-fluoro-2-deoxyglucose positron emission tomography images. Increased glucose metabolism in specific organs, such as the small intestine and various fat tissues, is closely associated with improved glycemic control after RYGB. In Otsuka Long-Evans Tokushima Fatty rats fed with high-fat diets, RYGB operation increases intestine glucose transporter expression and various fat tissues' glucose transporters, which are not affected by insulin. The fasting glucose decrement was significantly associated with RYGB, sustained weight loss, post-RYGB oral glucose tolerance test (OGTT) area under the curve (AUC), glucose transporter, or glycolytic enzymes in the small bowel and various fat tissues. High intestinal glucose metabolism and white adipose tissue-dependent glucose metabolism correlated with metabolic benefit after RYGB. These findings suggest that the newly developed glucose biodistribution accompanied by increased glucose transporters is a mechanism associated with the systemic effect of RYGB.

Quality reporting of radiomics analysis in pituitary adenomas: promoting clinical translation.

OBJECTIVE: To evaluate the quality of radiomics studies on pituitary adenoma according to the radiomics quality score (RQS) and Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD). METHODS: PubMed MEDLINE and EMBASE were searched to identify radiomics studies on pituitary adenomas. From 138 articles, 20 relevant original research articles were included. Studies were scored based on RQS and TRIPOD guidelines. RESULTS: Most included studies did not perform pre-processing; isovoxel resampling, signal intensity normalization, and N4 bias field correction were performed in only five (25%), eight (40%), and four (20%) studies, respectively. Only two (10%) studies performed external validation. The mean RQS and basic adherence rate were 2.8 (7.6%) and 26.6%, respectively. There was a low adherence rate for conducting comparison to "gold-standard" (20%), multiple segmentation (25%), and stating potential clinical utility (25%). No study stated the biological correlation, conducted a test-retest or phantom study, was a prospective study, conducted cost-effectiveness analysis, or provided open-source code and data, which resulted in low-level evidence. The overall adherence rate for TRIPOD was 54.6%, and it was low for reporting the title (5%), abstract (0%), explaining the sample size (10%), and suggesting a full prediction model (5%). CONCLUSION: The radiomics reporting quality for pituitary adenoma is insufficient. Pre-processing is required for feature reproducibility and external validation is necessary. Feature reproducibility, clinical utility demonstration, higher evidence levels, and open science are required. Titles, abstracts, and full prediction model suggestions should be improved for transparent reporting. ADVANCES IN KNOWLEDGE: Despite the rapidly increasing number of radiomics researches on pituitary adenoma, the quality of science in these researches is unknown. Our study indicates that the overall quality needs to be significantly improved in radiomics studies on pituitary adenoma, and since the concept of RQS and IBSI is still unfamiliar to clinicians and radiologist researchers, our study may help to reach higher technical and clinical impact in the future study.

Prevalence and clinical characteristics of primary aldosteronism in a tertiary-care center in Korea.

Approximately 29% of Korean adults have hypertension; however, the prevalence of primary aldosteronism among the hypertensive population is largely unknown. The aim of our study was to evaluate the prevalence and clinical characteristics of primary aldosteronism in a tertiary-care center in Korea. We retrospectively analyzed 1173 patients with newly diagnosed or preexisting hypertension who were referred to our tertiary-care hospital between January 2013 and December 2018. Patients were screened for primary aldosteronism with the aldosterone-renin ratio and underwent a saline infusion test for diagnostic confirmation. Adrenal computed tomography and adrenal venous sampling were performed for subtype classification for primary aldosteronism. Among the 1173 patients (mean age, 51.8 years; women, 53.2%), 360 (30.7%) had positive screening-test results, of whom 71 (6.1%) were finally diagnosed with primary aldosteronism. Conclusive subtype differentiation was made in 55 patients, of whom 15 (27%) had an aldosterone-producing adenoma, 4 (7%) had unilateral adrenal hyperplasia, and 36 (66%) had bilateral adrenal hyperplasia. Patients with primary aldosteronism had a higher ambulatory blood pressure, left ventricular mass index, and urinary albumin-to-creatinine ratio than those without. Moreover, the primary aldosteronism group had a higher prevalence of left ventricular hypertrophy and albuminuria than the non-primary aldosteronism group. Primary aldosteronism may be more common (6.1%) among Korean patients with hypertension than generally recognized. Primary aldosteronism was associated with a higher degree and prevalence of target organ damage and a higher blood pressure level. Wide application of screening tests for primary aldosteronism may be beneficial in detecting this potentially curable cause of hypertension.

Revisiting growth hormone nadir cut-offs for remission in patients with acromegaly.

Objective: Over the past decade, the growth hormone (GH) nadir cut-off during the oral glucose tolerance test for remission in patients with acromegaly was changed from 0.4 to 1.0 µg/L due to the limited use of ultrasensitive detection kits to measure GH levels. However, the optimal cut-off level for GH nadir remains unclear. This retrospective study aimed to investigate the association between different GH nadir cut-offs and prognosis in patients with acromegaly. Design and methods: A total of 285 patients with acromegaly with a glucose-suppressed GH nadir <1 µg/L at 3-6 months after trans-sphenoidal adenomectomy were divided into two groups according to the glucose-suppressed GH nadir levels at 3-6 months post-operatively (group A: <0.4 µg/L; group B: 0.4-1.0 µg/L). GH levels were measured using an ultrasensitive IRMA. The clinical, hormonal, metabolic, and neuroradiological data of the two groups were compared. Results: Female sex, as well as confirmed macroadenomas, was significantly overrepresented in group B. The 5-year rate of patients who achieved nadir GH < 1.0 µg/L and age- and sex-matched normal IGF-1 was significantly higher in group A than that in group B. However, there was no significant difference between the two groups in metabolic parameters at 12 months post-operatively. Conclusion: Different GH nadir cut-offs were associated with different 5-year rates of patients who achieved nadir GH <1.0 µg/L and age- and sex-matched normal IGF-1, suggesting that a strict GH nadir threshold of 0.4 µg/L correlates better with remission.

Sprayable nanomicelle hydrogels and inflammatory bowel disease patient cell chips for development of intestinal lesion-specific therapy.

All-in-one treatments represent a paradigm shift in future medicine. For example, inflammatory bowel disease (IBD) is mainly diagnosed by endoscopy, which could be applied for not only on-site monitoring but also the intestinal lesion-targeted spray of injectable hydrogels. Furthermore, molecular conjugation to the hydrogels would program both lesion-specific adhesion and drug-free therapy. This study validated this concept of all-in-one treatment by first utilizing a well-known injectable hydrogel that underwent efficient solution-to-gel transition and nanomicelle formation as a translatable component. These properties enabled spraying of the hydrogel onto the intestinal walls during endoscopy. Next, peptide conjugation to the hydrogel guided endoscopic monitoring of IBD progress upon adhesive gelation with subsequent moisturization of inflammatory lesions, specifically by nanomicelles. The peptide was designed to mimic the major component that mediates intestinal interaction with Bacillus subtilis flagellin during IBD initiation. Hence, the peptide-guided efficient adhesion of the hydrogel nanomicelles onto Toll-like receptor 5 (TLR5) as the main target of flagellin binding and Notch-1. The peptide binding potently suppressed inflammatory signaling without drug loading, where TLR5 and Notch-1 operated collaboratively through downstream actions of tumor necrosis factor-alpha. The results were produced using a human colorectal cell line, clinical IBD patient cells, gut-on-a-chip, a mouse IBD model, and pig experiments to validate the translational utility.

Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society.

Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.

Positive association between nonalcoholic fatty liver disease and growth hormone deficiency in patients with nonfunctioning pituitary adenoma.

Objective: Non-alcoholic fatty liver disease (NAFLD) is characterized by growth hormone deficiency (GHd). We investigated the association between NAFLD and GHd in patients with nonfunctioning pituitary adenomas (NFPA). Design and methods: We recruited patients with NFPA who underwent transsphenoidal adenectomy between January 2005 and December 2018. Pituitary function was determined by the insulin tolerance test, thyroid hormone assay, and gonadal hormone levels. NAFLD was defined as a hepatic steatosis index greater than 36. Results: Among 278 patients (mean age, 44.2 years; 58.6% [n=163] female), 103 (37.0%) had GHd, 139 (50.0%) had hypogonadism, and 75 (27.0%) had NAFLD. The prevalence of NAFLD was significantly higher in patients with GHd than in those without (36.9% vs. 21.1%, p=0.01). Even after adjusting for age, total cholesterol level, gonadal function, and prolactin level, patients with GHd had approximately two-fold higher prevalence of NALFD than those without GHd (adjusted odds ratio [OR]=1.85, 95% confidence interval [CI]=1.05-3.28, p=0.03). Among female patients, the prevalence of NALFD was significantly higher in those with GHd than in those without (adjusted OR=2.39, 95% CI=1.03-5.55, p=0.04); whereas, among male patients, the prevalence of NAFLD was statistically similar between those with and without GHd (p>0.05). In addition, gonadal function did not affect the prevalence of NAFLD in patients with NFPA (29.3% with eugonadism vs. 47.8% with hypogonadism, p=0.14). Conclusion: Among patients with NFPA, the prevalence of NAFLD was two-fold higher in patients with GHd than that in those without GHd. Thus, screening for NAFLD might be required in NFPA patients with GHd.

Efficacy and Cerebrospinal Fluid Rhinorrhea after Cabergoline Treatment in Patients with Bioactive Macroprolactinoma.

Predicting dopamine agonist resistance in patients with macroprolactinoma is essential for clinicians to prevent treatment failure and subsequent complications such as medication-induced cerebrospinal fluid (CSF) rhinorrhea. We evaluated the features of patients with cabergoline resistance and CSF rhinorrhea in patients with prolactinomas with prolactin levels ≥1000 ng/mL. A total of 140 patients who were newly diagnosed with prolactinoma secreting only prolactin ≥1000 ng/mL and treated with cabergoline for the first time were included in this study. Based on the hormonal and radiologic response of the prolactinoma, the patients were divided into responders and non-responders. Non-responders (36/140, 25.8%) included a higher number of patients receiving hormone replacement than responders (responders, n (%) = 12(11.5) vs. non-responders = 13(36.1), p = 0.001). In propensity score matching analysis, patients who developed CSF rhinorrhea presented more frequent hormone deficiency than responders regardless of initial cabergoline dose. Hormone deficiency was associated with a greater odds ratio for the risk of non-responders (adjusted odds ratio = 5.13, 95% CI 1.96-13.46, p = 0.001). Cabergoline was effective in bioactive macroprolactinoma. Furthermore, initial cabergoline dose was not significantly associated with long-term responsiveness and development of CSF rhinorrhea but the hypopituitarism was independently associated with an increased risk of cabergoline resistance and CSF rhinorrhea.