bluuebunny/crossref_metadata_2025_split huggingface dataset:
8600 Acute Peripheral Pro-inflammatory Cytokine Injection Results in a Rapid Increase in Microglia Density in the Nucleus of the Solitary Tract
Authors: Castellanos E A , Tobet S A 
Published: October 2024

Abstract
Disclosure: E.A. Castellanos: None. S.A. Tobet: None.
The autonomic nervous system (ANS) is a major integrator of stress responses throughout the body. Physical or psychological stressors lead to neuroendocrine outputs from the hypothalamus and neurotransmitter mediated alterations in circuitry that control peripheral body systems including cardiovascular, pulmonary, and gastrointestinal, among others. Chronic stress can activate immune components, including microglia, leading to increased levels of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-a) in the blood. Increased levels of these cytokines have been associated with several psychiatric disorders including major depressive disorder. In the current study, the impact of pro-inflammatory cytokines was examined in the dorsal vagal complex (DVC), a key brainstem region responsible for integrating autonomic inputs and outputs. The DVC includes the area postrema (AP), a sensory circumventricular organ, the nucleus of the solitary tract (NTS), and the vagal dorsal motor complex. The AP is in the middle of the DVC region, adjacent to cerebrospinal fluid and lacking a blood brain barrier (i.e., fenestrated capillaries). These traits make the AP uniquely located to integrate peripheral and central interactions between circulating cytokines and select immune cells in the DVC. This study concentrated on the effects of a single peripheral injection on microglia quantities in the DVC. TNF-a (50µg/Kg) and IL-6 (50µg/Kg) were administered by intraperitoneal injection and 2h later animals were perfused with 4% paraformaldehyde. Immunoreactive ionized calcium-binding adapter molecule 1 (IBA1) was used to identify microglia in the brainstem. In the area postrema there was a trend towards more immunoreactive IBA1 total area (µm^2; p = 0.08, ns) in mice that were injected with TNF-a and IL-6 compared to controls. By contrast, in the adjacent NTS there was 1.5x’s more immunoreactive IBA1 in mice that were injected with IL-6 and TNF-a (µm^2; p &lt; 0.001) compared to control vehicle injections. Comparing brain regions in the DVC, there is 1.7x more microglia cells in the area postrema per section (50µm) compared to the NTS (p &lt; 0.001), but in the NTS cells are 1.3x larger in size in comparison to the microglia cells in the AP overall (µm^2/ number of cells; p &lt; 0.05). Finally, in the NTS there was a 1.5x larger total area of the IBA1 immunoreactivity following TNF-a injections compared to IL-6 injected mice (µm^2; p &lt; 0.05). These data reveal a rapid effect of peripherally injected pro-inflammatory cytokines on microglial quantities and size in the brainstem. Future investigations will elucidate the role of neural-immune pathways in influencing the ANS during a chronic immune stress response. Supported by ORWH U54-MH118919.
Presentation: 6/3/2024
6686 Age-Associated Local GH Adversely Impacts the Microenvironmental Epithelial Landscape
Authors: Chesnokova V M , Zonis S , Apaydin T , Wang Valencia C , Ainsworth R , Barrett R , Kettenbach A , Melmed S 
Published: October 2024

Abstract
Disclosure: V.M. Chesnokova: None. S. Zonis: None. T. Apaydin: None. C. Wang Valencia: None. R. Ainsworth: None. R. Barrett: None. A. Kettenbach: None. S. Melmed: None.
The tissue microenvironmental homeostasis is disrupted with age-related changes. Knowledge of mechanisms enabling the age-associated tissue landscape is limited. Senescent cells increase with age, and the secretome released from senescence cells (SASP) affects neighboring cells, often creating a milieu favoring neoplasia. We previously showed that local non-pituitary epithelial growth hormone (GH) is induced and secreted from senescent cells, accumulates with age, and suppresses DNA repair, leading to abundant DNA damage. To examine SASP-derived autocrine GH actions, we analyzed normal human colon cells (hNCC) infected with lentivirus expressing hGH (lentiGH) or vector (lentiV). Mass spectrometry revealed significant changes in the Rho signaling pathway reflecting cell cytoskeletal rearrangements. To examine paracrine GH action, we co-cultured intact human 3D intestinal organoids with organoids infected with lentiGH for 5 weeks. Using whole-exome sequencing we found that local paracrine GH emanating from lentiGH organoids increases neighboring intact organoid cell chromosomal instability, inducing somatic mutations, including deletions, breakends, duplications, and insertions. Mechanisms for observed chromosomal instability include sequelae of GH-mediated suppressed DNA damage repair proteins including pATM, pATR, and pBRCA2, leading to DNA damage accumulation and favoring cell transformation over the long term. Furthermore, enriched gene ontology and KEGG pathway analysis of intact organoids exposed to paracrine GH identified distorted extracellular matrix (ECM) gene expression and focal adhesion pathways. We confirmed these genomic changes with Western blotting showing altered proteins associated with ECM and those responsible for cell structural rearrangements. Moreover, phospho-omics of GH-exposed cells revealed significant phosphorylation changes in proteins associated with cell skeletal rearrangement and cell migration pathways. We found that GH triggers these changes by EMT activation as shown by suppressing E-cadherin and inducing Twist2 and Snai1 transcription factors. Together, all these changes are consistent with observed increased migration, invasion, and anchorage-independent growth of hNCC infected with lentiGH or co-cultured with GH-secreting hNCC or with GH-secreting normal colon fibroblasts. As paracrine GH also facilitates metastases after intra-splenic injection of senescent cells in nude mice carrying xenografts secreting GH, our results indicate that accumulated and locally secreted GH in aging tissue enables a microenvironmental landscape favoring epithelial cell transformation.
Presentation: 6/1/2024
12404 Aging-Associated Decline in the Pituitary Gland Using Single-Cell Transcriptomes
Authors: Kim Ye bin , Lee Soohyun , Kim Na-Yeong , Lee Eun Jig , Oh Ju Hun , Oh Chang-Myung , Ku Cheol Ryong 
Published: October 2024

Abstract
Disclosure: Y. Kim: None.
Introduction: Age-related decline in endocrine function has been associated with multiple physiological changes. However, aging-associated molecular shifts in the pituitary gland have not yet been systematically investigated. This study aimed to investigate the mechanism underlying these age-related molecular changes in young and old mice model using single cell transcriptomics. Method: Single-cell RNA sequencing (scRNA-seq) were conducted in young (2-month) and old (20-month) mouse. We used systems biology techniques to build a specific protein interaction network for somatotrophs, integrating validated interactions and gene expression data. By simulating drug effects on this network, we predicted changes in transcription factor activities due to aging. We identified potential therapeutic targets for preventing aging in somatotrophs by assessing the anti-aging effects of chemical perturbations, similar to methods used in the Connectivity Map project. Results: We identified 14 distinct cell types including follicular stellate cells (FSCs), somatotrophs, corticotrophs, gonadotrophs, lactotrophs, and melanotrophs. We found that the effect of aging on transcription was cell type dependent. FSC subtypes are heterogeneously regulated by aging at the transcriptomic level. However, somatotroph subtypes shared functional alterations with aging in terms of mRNA surveillance and spliceosome pathways. Our systems biology approach identified SENP1(Sentrin specific peptidase gene), as a critical node in the regulatory network affecting somatotroph aging. The senescence-associated beta-galactosidase staining (SAbgal) showed that Momordin (Mc), a SENP1 inhibitor, had anti-aging effects on somatotrophs, regardless of age-promoting doxorubicin. Western blot analysis indicated a two-fold increase in growth hormone levels in aged GH3 cells treated with Mc compared to vehicle. Conclusion: Our data and analysis provide promising resources to better understand the molecular shifts of pituitary aging at the transcriptomic level and help the community generate interesting hypotheses to develop anti-aging strategies for the pituitary gland. We suggest that SENP1 inhibitors may represent potential anti-aging targets in somatotroph.
Presentation: 6/3/2024
7741 Artri King As A Cause Of Adrenal Insufficiency
Authors: Aziz Qurrat-ul-ain , Fatima Sanna , Laurel Amber , Mrkaic Ana , Izuora Kenneth E 
Published: October 2024

Abstract
Disclosure: Q. Aziz: None. S. Fatima: None. A.L. Champion: None. K.E. Izuora: None.
IntroductionDietary supplements are highly unregulated and may have substance that can be harmful. Due to its easy availability, more patients may have access to these supplements which can cause detrimental health outcomes, such as adrenal insufficiency. Clinical Case Patient is a 46 year old female with past medical history of hypertension and obesity presents to the hospital for worsening left hip pain, which started 2 weeks ago. She heard a crack in her left hip and denied any trauma or injury prior. She was found to have subtrochanteric fracture. Nine months ago, she had right hip pain and was unable to bear weight. Physical exam was notable for alopecia in frontal and temporal region, dorsocervical fat pad, multiple bruises, round facies, and multiple purple straie. She also reported a 50 pound weight gain in the last year. She stated that she took an over the counter “pain medication”, but denied any supplements. Due to the non-traumatic fracture and physical features, AM cortisol was ordered for suspicion of Cushing’s Syndrome by primary team and was low at 2.4. Endocrinology team was consulted. Cosyntropin stimulation test showed baseline AM cortisol level 1.4 and 1 hour after cosyntropin, cortisol was 8.3. ACTH 3.4, testosterone undetectable, androstendione undetectable, Aldosterone 42.2, DHEA undetectable. It was found later that patient was taking an over the counter supplement called Artri King, up to 4 tablets a day. Artri King has been advertised as a supplement for joint and muscle pain and contains unknown amount of dexamethasone and diclofenac. She was soon placed on hydrocortisone for adrenal insufficiency and was titrated down. The hypothalamic-pituitary-adrenal (HPA) axis can be suppressed with as low as 5 mg prednisone equivalent a day. This can lead to inadequate adrenal response to stress. If a patient has prolonged exposure to exogenous steroids, insufficient ACTH secretion can lead to atrophy of the zona fasciculata and reticularis, resulting in reduced ability to secrete cortisol. Therefore, it is important to help withdraw patient from glucocorticoids. When initiating glucocorticoid withdrawal, hydrocortisone may be helpful due to short half life, allowing HPA axis more opportunity to recover. Adrenal atrophy may be slowly reversible, but 4 years after diagnosis of glucocorticoid induced adrenal insufficiency, recovery of adrenal function is unlikely to occur. ConclusionsIt is important to obtain a thorough history, especially for supplements. Many supplements are not regulated and can pose harm to our patients. Adrenal insufficiency due to glucocorticoids may not only occur from steroid injections, long course of prescription glucocorticoids, but can include supplements if it is hidden from the ingredient list.
Presentation: 6/3/2024
7013 An Inpatient Perspective: Hyperprolactinemia and Granulomatous Mastitis
Authors: Le Andy , Wade Jarrett , Martz Kevin , Girgis Daniel , Shahlapour Mahmood , Horani Mohamad Hosam 
Published: October 2024

Abstract
Disclosure: A. Le: None. J. Wade: None. K. Martz: None. D. Girgis: None. M. Shahlapour: None. M.H. Horani: None.
Introduction: Mastitis is a highly prevalent condition impacting thousands of women every year. Most commonly associated with lactation, mastitis is estimated to impact 2-20% of lactating women particularly in the first 4-6 weeks of breastfeeding (Wilson et al., 2020). The majority of cases are associated with bacterial infection with Staphylococcus aureus precipitated by nipple trauma and hyperlactation in the setting of genetic predispositions and disturbances to the human milk microbiota (Fernández et al., 2020). In rare cases, mastitis is seen outside of the context of lactation. One cause of non-lactational mastitis is idiopathic granulomatous mastitis (IGM). The pathogenesis of IGM is poorly understood, but there has been a rare association between IGM and hyperprolactinemia reported in the literature (Nikolaev et al., 2016). Case Presentation: In January 2022, A 20 year old female with past medical history of type 2 diabetes mellitus and hypertension, initially presented to the emergency department with complaints of headache. Patient’s history is notable for two years of amenorrhea and periodic nipple discharge. MRI scan of the head revealed a 1.6 cm pituitary macroadenoma which correlated with a markedly elevated prolactin level at 533.3. She was discharged with a prescription for Cabergoline 0.5 mg BID. In July 2022, the patient presented to the ED complaining of severe left breast pain with associated discharge for 4 days. She admitted to being non-adherent to Cabergoline treatment since April 2022 due to lack of endocrine follow-up. CT of the breast at that time showed a 3.8 cm subareolar abscess. Aspiration of the abscess revealed non-purulent fluid and cultures of the aspirate were negative. In February 2023, patient presented for right breast pain with a similar workup to previous hospitalization. MRI of the brain revealed a 1.6 cm sellar mass is unchanged since January 2022. Prolactin level was elevated at 652.4. Patient stated she has been off Cabergoline for the prior 5 months. She was subsequently seen for right and left mastitis 3 times over the next 12 months. Upon endocrine consultation, the patient was counseled on the importance of Cabergoline treatment in regression of future mastitis episodes, and the patient has subsequently not returned to our service. Conclusion: This case demonstrates the rare association between prolactin secreting pituitary adenomas and granulomatous mastitis that clinicians need to consider in order to avert delays in treatment and unnecessary hospitalizations. Specifically, when working up a patient with a history of IGM and prolactinemia, it is imperative to monitor prolactin levels periodically over an extended course of time with appropriate MRI imaging of the pituitary gland to assess for regression of prolactinoma and episodes of IGM.
Presentation: 6/1/2024
8264 An Interesting Case of Hypophysitis in a Young Woman
Authors: Garcia Alejandro , Sharma Rajeev , Knight Colette M 
Published: October 2024

Abstract
Disclosure: A. Garcia: None. R. Sharma: None. C.M. Knight: None.
Background Hypophysitis is an uncommon disorder and presents with clinical signs and symptoms along with biochemical abnormalities. Herein, we present a case of hypophysitis that responded well to high dose steroids. Case An 18 y.o black, adopted woman presented to hospital with complaints of headache and vision disturbances. Endocrinology was consulted for pituitary macroadenoma. Symptoms started a month prior. She had extensive work-up at an outside hospital including brain imaging, CSF analysis, and bloodwork. No definitive diagnosis was made and she was sent home on topiramate. Her symptoms continued to worsen prompting her to seek another opinion. No family history as she is adopted. She has a history of depression controlled with medication. MRI Brain showed 1.8x1.1x1.6 cm T2-enhancing mass with suprasellar extension deforming the midline optic chiasm. Initially, a diagnosis of macroadenoma was made and Endocrinology and Neurosurgery services consulted. Patient denied galactorrhea, menstrual abnormality, polyuria, polydipsia, cold intolerance, orthostasis, or weight gain. Bloodwork was significant for low TSH (0.045 uIU/ml; normal 0.35-4.94), low free T4 (0.58 ng/dl; normal 0.76-1.79). Thyroid functions were normal approximately one year prior. Cortisol was very low at 1.8 mcg/dL and ACTH inappropriately low-normal at 12 pg/ml (normal 6-50). LH and estradiol were low, while FSH was low normal. Prolactin, GH, IGF-1, sodium, glucose and creatinine were normal. Endocrine reviewed the previous MRI brain done four weeks ago that was reported as normal. Discussion with previous outside hospital radiologist suggested that pituitary was indeed not normal but was fuller with convexity towards chiasm although no definitive adenoma was found. Since it is unlikely that such adenoma would develop over 4 weeks, Endocrinology reached out to our radiologist who assessed this as pituitary enlargement due to likely hypophysitis, especially when compared to imaging 4 weeks ago. Further work up showed mildly-elevated ESR, and normal ACE, dsDNA, ANA, and Sjogren’s antibody levels. Tests for pregnancy, Lyme disease, tuberculosis, EBV and syphilis were negative. SARS-CoV-2 was negative for COVID. IgG4 levels were normal. CSF analysis was normal. She was started on levothyroxine and high-dose corticosteroids with improvement in her symptoms. Repeat imaging after 5 days of corticosteroids showed about 30% decrease in pituitary size. A diagnosis of likely lymphocytic hypophysitis was made and pituitary surgery averted for time being. Conclusion We present a case of possible lymphocytic hypophysitis in a young woman who avoided pituitary surgery due to diligent history and examination, in addition to a multidisciplinary team approach. It is very important to have prompt multidisciplinary approach if there is any doubt about a diagnosis as in this case.
Presentation: 6/3/2024
6589 Antisense Oligonucleotides for Reducing ACTH Secretion in a Model of Cushing's Disease
Authors: Varughese Maria Susan , Eltumi Hanan , Kemp Elizabeth Helen , Newell-Price John D C 
Published: October 2024

Abstract
Disclosure: M.S. Varughese: None. H. Eltumi: None. E.H. Kemp: None. J.D. Newell-Price: None.
Antisense Oligonucleotides for Reducing ACTH Secretion in a Model of Cushing’s Disease Background: Cushing’s disease (CD) is a multi-system disorder with high morbidity and mortality characterised by pathologically raised serum cortisol due excess expression of proopiomelanocortin (Pomc) and overproduction of ACTH by a pituitary corticotroph adenoma. Trans-sphenoidal adenomectomy is the treatment of choice, but there is a 30% recurrence rate over time. Advances in medical therapy are needed. Antisense oligonucleotides (ASOs) can silence mRNA translation by specific base-pairing. Locked nucleic acid (LNA) and 2’-O-methyl (OMe) ribose terminals make ASOs more effective by improving affinity and resistance to nuclease degradation. Aims: To investigate the effectiveness of LNA- and OMe-modified anti-Pomc ASOs at reducing ACTH secretion from murine adrenotropic tumour (AtT20) cells. To analyse the nuclease resistance of Pomc ASOs and their ability to drive an immune response. Methods: Two ASOs (ASO2 and ASO3) were designed against Pomc with phosphorothioate backbones modified with either LNA or OMe ribose terminals. These were used in lipofectamine-mediated cell transfections of AtT20 cells and ACTH in the culture medium measured by immunoassay. ASO stability was assessed by nuclease degradation assays and immunogenicity by cytokine ELISAs. Results: When compared with untreated AtT20 cells, LNA- and OMe-modified Pomc ASOs at 1 nM significantly suppressed ACTH secretion for up to 120 h and 96 h, respectively (n = 4; Unpaired t tests, all P values &lt; 0.05). In contrast, control treatments, including scrambled and mismatched ASOs, did not cause a significant reduction. For comparison, 1 nM of ASO2-OMe, ASO2-LNA, ASO3-OMe and ASO3-LNA lowered ACTH at 24 h by 62%, 71%, 63% and 79%, respectively. Modified Pomc ASOs showed 14-31% degradation over a 120-min incubation period with 3’- and 5’-exonucleases, whilst equivalent unmodified Pomc ASOs were completely degraded. No secretion of IFN-α, IFN-β, TNF-α, IL-6 or IL-1β was detected following transfection of AtT20 cells with Pomc ASOs. Conclusions:Pomc ASOs caused significant reduction of ACTH secretion from AtT-20 cells. LNA-modified Pomc ASOs were more effective than those with OMe modifications, with neither stimulating a detectable immune response. These ASOs hold promise as a systemic therapy for Cushing’s disease.
Presentation: 6/3/2024
12578 Assessment Of Sarcopenic Obesity in Patients with Acromegaly
Authors: Rocha Claudia Pinheiro Sanches , Hupalowski Natália Nachbar , Fidalski Solena Ziemer Kusma , Boguszewski Cesar Luiz , Borba Victoria Z C 
Published: October 2024

Abstract
Disclosure: C.P. Rocha: None. N.N. Hupalowski: None. S.Z. Fidalski: None. C.L. Boguszewski: Consulting Fee; Self; Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Novo Nordisk. V.Z. Borba: None.
Introduction: Patients with acromegaly in activity exhibit modifications in body composition with increased skeletal muscle mass and decreased body fat. The effects of growth hormone on muscle strength and performance are uncertain, suggesting possible changes in physical performance due to compromised strength and functioning of skeletal muscle not correlated with total lean body mass. Sarcopenia is a progressive disorder of skeletal muscle, associated with risk of falls, fractures, loss of autonomy, and increased mortality, sarcopenic obesity is defined as the coexistence of both comorbidities. Objective: To assess sarcopenic obesity in patients with acromegaly compared to controls. Patients and Methods: observational, case-control study, matched 1:1 by age and sex with a control group. The study was approved by the ethics committee and individuals included after formal consent. The study group patients under clinical follow-up at a reference service in southern Brazil. All individuals underwent clinical evaluation through questionnaires; muscle strength [sit-to-stand test (STST5x) and hand grip strength (HGS)]; muscle mass quantification by dual-energy X-ray absorptiometry (DXA) and physical performance [Gait Speed, the Short Physical Performance Battery (SPPB), and the Timed-Up and Go test (TUG)]. Sarcopenic obesity was calculated following the ESPEN and EASO consensus. Results: The study population included matched 48 patients with acromegaly and 48 controls matched 1:1 by age and sex. The population was predominantly female (54.1%), mean age of 56.31 ± 11.60 years, with 79.1% below 65 years of age, and 64.58% (31) were in inactive acromegaly. The mean weight was 87.88 ± 18.02 kg, and the mean BMI was 31.25 ± 4.95. Mean muscle lean mass was higher in the patient group, and the diagnosis of sarcopenic obesity was similar between groups. However, all performance tests were worst in patients than controls with altered tests: TSL5X in 24 (50%) vs 2 (4,3%) controls; gait speed test in 14 (29.2%) vs. 3 (6,4%) controls and in the SPPB in 15 (31.37%) vs 0 (0%) controls, p&lt;0.005 for all. The investigation of sarcopenia in patients with active or inactive disease did not show significant differences. Conclusion: We identified in a population of patients with acromegaly a low performance despite of a preserved lean mass and similar diagnosis of sarcopenic obesity. This study highlights the impairment of physical performance and functionality, not reflecting the adequate muscular amount in patients with acromegaly.
Presentation: 6/2/2024