bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of Action of Irilone as a Potentiator of Progesterone Receptor Signaling
Authors: Austin Julia R , Lee Jeongho , Murphy Brian T , Burdette Joanna Elizabeth 
Published: May 2021

Abstract
Progesterone signaling and its proper regulation is important for reproductive function. When progesterone signaling is dysregulated, gynecological diseases can occur, for example endometriosis, uterine fibroids, and endometrial cancer. While these diseases are treated with progestin therapy, progestins can bind to multiple steroid receptors, exerting side effects of weight gain, immunosuppression, cardiovascular disease, and stroke. Discovering an alternative progestin that is selective for the progesterone receptor (PR) is ideal. One potential source of such an alternative is botanical dietary supplements, which have become increasingly popular among consumers with sales reaching $9.6 billion in 2019. Although botanical supplements are popular, the chemical structures and biological action of botanical supplements would benefit from deeper scientific investigation. Studies of Trifolium pratense L. (red clover), primarily used for the treatment of menopausal symptoms, identified phytoestrogen compounds as the chemicals that mitigate those symptoms. Interestingly, irilone, identified from red clover, potentiated progesterone signaling via a progesterone response element luciferase (PRE/Luc) assay. Potentiation is when a compound has no activity by itself but when combined with another molecule, i.e. progesterone, that compound enhances PR activity. Prior to irilone, a natural compound with the ability to potentiate progesterone signaling had not been previously reported. The purpose of this study was to determine the mechanism of action of irilone. We hypothesized that irilone was potentiating PR by blocking PR degradation and by altering PR post-translational modifications. Irilone was found to potentiate 5 nM P4 using a PRE-luciferase assay in both T47D and Ishikawa PR expressing cells. Since PR is a downstream target gene of ER, we investigated if irilone also had ER activity. Irilone increased expression of an ERE-luciferase reporter gene. Next, we investigated if irilone could stabilize PR degradation and if irilone altered PR phosphorylation via western blot. Irilone was found to increase PR protein levels, but when ER was blocked, this was mitigated. In the presence of P4, irilone did not increase phosphorylation of serine 294 on PR. Future studies will determine if irilone is altering sumoylation of PR, and if irilone can potentiate PR signaling in vivo. Determining how irilone is potentiating progesterone will help us understand PR biology and could be an effective treatment for gynecological diseases by enhancing endogenous progesterone action.
Optimized Immunohistochemical Detection of Rat ESR2 Proteins Using the Specific Anti-ESR2 Monoclonal Antibody PPZ0506
Authors: Hattori Yujiro , Ishii Hirotaka , Higo Shimpei , Otsuka Mai , Kanaya Moeko , Matsumoto Keisuke , Ozawa Mina , Ozawa Hitoshi 
Published: May 2021

Abstract
Background: Research on ESR2, also known as estrogen receptor β (ERβ), is a notorious example of data distortion due to the use of inadequately validated antibodies. Although the absence of reliable specific antibodies against ESR2 has severely hindered the promotion of ESR2 research, a specific anti-human ESR2 monoclonal antibody (PPZ0506) was identified in 2017 [1]. Our previous study confirmed its cross-reactivity and specificity against rodent ESR2 proteins, enabling the elucidation of the true ESR2 distribution in rodents [2].
Objective: We aimed to determine the optimized conditions for immunohistochemical detection of rat ESR2 proteins using PPZ0506. &lt;Method&gt; Several staining conditions using paraffin-embedded and frozen ovary sections were evaluated, and the distribution of rat ESR2 proteins was analyzed under optimal conditions.
Result: Immunohistochemical staining with PPZ0506 required appropriate antigen retrieval and antibody dilution. Subsequent immunohistochemical analysis in multiple tissues under optimized conditions revealed that rat ESR2 proteins are expressed in a more localized manner than previously assumed. Our optimized immunohistochemical detection of rat ESR2 proteins, using a well-validated antibody, revealed their distribution in limited tissues and cell types.
Conclusion: Our results suggest that previous immunohistochemical studies using inadequately validated antibodies against ESR2 proteins overestimated their distribution profiles. We expect that our optimized immunohistochemistry using the PPZ0506 antibody may solve conflicting problems in ESR2 research.
References: 1. Andersson S, et al. Nat Commun 15;8:15840 (2017) 2. Ishii H, et al. Int J Mol Sci 20(24):6312 (2019)
Paxillin Is Required for Androgen Receptor Expression in Granulosa Cells
Authors: Astapova Olga , Hammes Stephen R 
Published: May 2021

Abstract
Androgens are important in female reproduction, as evident from studies of mouse ovary-specific androgen receptor knockout models characterized by sub-fertility and diminished ovarian reserve. Androgen activity specifically promotes granulosa cell proliferation and follicle progression. However, the molecular mechanisms mediating androgen activity in granulosa cells are unknown. Our lab previously showed that the cytoplasmic adaptor protein paxillin is required for full transcriptional activity by the androgen receptor (AR) in prostate cancer cells, therefore we examined how paxillin affects the androgen receptor in granulosa cells. We found that paxillin knockdown results in significantly reduced AR protein levels, independently of AR gene transcription in human granulosa-derived KGN cells. Similar to previous data from other cell types, we found that paxillin directly interacts with poly-A binding protein (PABP) in KGN cells using proximity ligation assay. Ligand binding further increases AR protein expression by reducing its degradation. Using immunofluorescence, we confirm that in both KGN and primary mouse granulosa cells, similarly to the prostate, ligand-bound AR is primarily localized in the nucleus. Based on this and previous studies, we propose that paxillin enhances AR mRNA translation through interaction with PABP, and ligand binding further increases AR protein level by nuclear retention, protecting from degradation in the cytoplasm. Our findings highlight a previously unrecognized role of paxillin in granulosa cells, where it may be an important target for modulating androgen activity in androgen-related disorders of female reproduction.
Antiepileptic Drugs and Thyroid Hormone Homeostasis: Literature Review and Practical Guideline
Authors: Rochtus Anne Maria , Herijgers Dorien , Jansen Katrien , Decallonne Brigitte 
Published: May 2021

Abstract
Thyroid hormones play an essential role in central nervous system development, normal physiological brain function and repairing mechanisms. On one hand, thyroid hormone alterations influence cortical excitability and on the other hand anti-epileptic drugs (AEDs) are associated with alterations in thyroid hormone metabolism. Although this interaction has long been described, and epilepsy is a common and chronic neurological disease, studies describing the interplay are often small and retrospective.
We performed a systematic review of the current literature on epilepsy, AED therapy and thyroid hormone metabolism. Forty-seven studies were included.
Most studies were retrospective cross-sectional studies (n=25) and investigated thyroid function alterations in patients on older AEDs such as phenobarbital, phenytoin, carbamazepine and valproic acid. Overall, almost one third of patients with epilepsy had subclinical hypothyroidism, especially patients on valproate and carbamazepine. Studies with patients receiving polytherapy are scarce, but reported a higher risk for hypothyroidism in patients with older age, female sex, longer duration of epilepsy, intractable epilepsy and polytherapy. Studies on newer AEDs are also scarce and further studies essential to improve the care for epilepsy patients.
AEDs are associated with alterations in thyroid hormone metabolism. Thyroid function monitoring is indicated in patients on AEDs, especially those with refractory chronic epilepsy and those on polytherapy. We provide a practical guideline for thyroid function monitoring for the clinician taking care of patients on AEDs.
BMI Helps to Calculate the Initial Levothyroxine Dose After Total Thyroidectomy
Authors: Correia Sara , Almeida Lucia Santos , Silva José Diogo , Tavares Patrícia , Rocha Gustavo , Oliveira Maria 
Published: May 2021

Abstract
After total thyroidectomy, an initial dose of levothyroxine is often prescribed based on the patient’s body weight (1.6 mcg / kg / day), regardless of body mass index (BMI). The current literature required that hormone maintenance therapy (THR) in obese patients differs from non-obese patients. Review of the clinical processes of patients with papillary carcinoma followed in the multidisciplinary consultation of Endocrine Pathology at CHVNG / E followed a total thyroidectomy from 2015 to 2017. Patients who achieved euthyroidism with THR were included in the analysis and divided according with BMI. Statistical analysis was performed using SPSS version 25.0. A value of p &lt;0.05 was considered statistically significant. The sample included 82 patients, 90.2% (n = 74) female and 9.8% (n = 8) male, with an average age of 53.02 ± 14.27 years. Of the female gender, 52.4% (n = 43) were in menopause. In the postoperative period, 14 patients (17.1%) had a normal BMI, 46 (50%) were overweight and 22 (32.9%) were obese. The average follow-up time was 75.3 months (32-128). A dose of LT4 required to achieve euthyroidism based on the BMI categories mentioned above was 1.70; 1.54 and 1.49 mcg / kg. Patients with a higher BMI needed a higher dose of LT4 to achieve euthyroidism (p &lt;0.05), but the dose was lower in relation to weight (mcg / kg) (p &lt;0.05). There were no differences related to age and need for L-T4 suplementation (p&gt; 0.05). Our study shows that de calculation of the initial levothyroxine dose should also take into account BMI. Overweight and obese individuals should receive a lower dose than that used in normal weight patients, which goes against what has been described in the literature. The weight-based formula, unlike BMI, does not account for the volume of distribution of L-T4 well. Other methods, which include, for example, ideal body weight instead of actual weight, are being developed to help choose the starting levothyroxine dose.
Hydrocortisone Suspension Provides Similar Growth Outcomes as Hydrocortisone Tablets in Young Children With Congenital Adrenal Hyperplasia: A Cross Sectional Study
Authors: Al-Rayess Heba , Addo O Yaw , Palzer Elise , Jaber Mu’taz , Fleissner Kristin , Hodges James , Brundage Richard , Miller Bradley Scott , Sarafoglou Kyriakie 
Published: May 2021

Abstract
Young children with CAH require small doses (0.1–1.25mg) and incremental adjustments of hydrocortisone (HC) to control excess androgen production and avoid the negative effects of overtreatment. A recent 6 hour pharmacokinetic/pharmacodynamic study reported that alcohol-free HC suspension provides similar cortisol exposure to tablets (1), but more data is needed to assess its clinical efficacy. We performed a chart review to determine the effect of the alcohol-free HC suspension compared to tablets on height, weight, BMI, bone age z-scores and corrected height z-scores to target height z-scores in children aged 2 yrs and 4 yrs in a cohort with classic CAH. Independent 2-sample t-tests examined cumulative and average HC dose at 2 and 4 yrs. Triple logistic modeling of longitudinal heights were used to calculate predicted near-adult height. Adjusted linear regression models assessed the effect of HC suspension compared to tablets on final adult height. Charts of 130 children (70 females, 100 salt wasting and 30 simple virilizing) were reviewed. At 2 yrs, 97 were treated with tablets and 33 with suspension (17 previously switched from tablets). At 4 yrs, 89 were treated with tablets and 41 with suspension (25 switched). No significant differences in height or BMI z-scores at both 2 and 4 yrs, before or after adjusting for age at diagnosis and sex were found. Bone age z-scores averaged 7.2 SDs lower for patients treated with HC suspension only compared to patients on HC tablets at age 4 (p&lt;0.001), and 5.93 SDs lower for patients switched from tablets to suspension compared to tablets (p&lt;0.001). The suspension group received 16% lower (p=0.055) and 25% lower (p=0.002) cumulative HC doses by the ages of 2 yrs and 4 yrs respectively. Average daily HC dose was lower by 3.44 and by 4.46 mg/m2/d over the first 2 and 4 yrs of life respectively. No significant differences were found between patients treated with tablets and suspension in the predicted final adult height, its z-score or its corrected z-score to target height after adjusting for age at diagnosis, sex and diagnosis. Our data indicates that treatment with alcohol-free HC suspension decreased androgen exposure as shown by lower bone age z-scores, generated no significant differences in SDS in observed height, BMI or predicted near-adult height, and allowed for lower average and cumulative daily HC dose compared to HC tablets in children with CAH. Reference: (1) Sarafoglou et al., J Clin Pharmacol.2015;55(4):452–7.
Presentation and Outcome of Severe Graves’ Disease
Authors: Babu Priya Mohan , Bahl Suhani , Capatana Florin , Hamdan Khaliq , Khan Ishrat , Adlan Mohamed , Premawardhana Lakdasa D K E 
Published: May 2021

Abstract
Introduction: Subjects with “severe” Graves’ disease (GD) are known to have adverse outcomes. They have multisystem involvement (orbitopathy, dermopathy), more severe clinical features, large goitres and a higher relapse rate. Also, their response to thionamides is slower. There is a developing consensus that early definitive treatment improves prognosis in them. Methods: We retrospectively analysed the electronic case records and biochemistry databases of all subjects seen in our University Health Board between January 2017 and October 2019 with GD. Severe GD was defined by (1) a thyrotropin receptor antibody (TRAb) value greater than 10U/l (normal range: less than 0.9), (2) with any one of the following - (a) free thyroxine (T4) above 50pmol/l (reference range 9-19.1), (b) a combination of T4 more than 40 pmol/l with triiodothyronine (T3) above the detection range of the assay (46.1 pmol/l), (c) the presence of a large goitre, (d) active Graves’ orbitopathy (GO) or (e) dermopathy. We compared subjects with severe GD to those who did not fulfil the above criteria i.e. non-severe GD. Results: 176 GD subjects were seen during this period - 52 (29.5%) with severe and 124 (70.5%) with non-severe GD. However, 19 severe and 26 non-severe GD subjects were on active thionamide treatment at the time of analysis, and complete details were unavailable in 41 subjects. There was a significant difference in the following features between the severe and non-severe GD groups respectively (1) their median age (39 vs.52 years), (2) median TRAb levels (25.5 vs.18.5 U/l) (3) higher prevalence of GO (38.5 vs.13.3%) and active GO (15.4 vs.0%), (4) the presence of moderate/large goitre (51.3 vs.3.3%), (5) higher number failing to normalize biochemically within the first 6 months after treatment initiation (53.9 vs.39%), (6) the presence of a family history, and (8) a higher number requiring definitive treatment within 12 months of starting treatment (9.6vs.0.81%)(p=0.001-0.026 for the above). There was no difference between the two groups in gender, treatment regime i.e. dose titration regime or block and replacement regime, number biochemically normalizing within 12 months, and those who had more than 18 months of treatment and their relapse rates (55 vs. 59.1%, p=0.84). Conclusions: We have shown that those with severe GD were younger, have higher TRAb concentrations with multisystem involvement, and delayed initial normalization of thyroid hormones. A greater number of them require definitive treatment within 12 months of treatment initiation. However, the majority in both groups normalize thyroid hormones within 12 months irrespective of the treatment regime used. Early definitive treatment is required in a significantly higher percentage of subjects with severe GD and needs to be considered in them.
Survey of Practice: The Current Extent of Adjunctive Use of Lithium in the UK During Radioactive Iodine Therapy for Hyperthyroidism
Authors: Younes Younes R , Field Benjamin C T 
Published: May 2021

Abstract
Background: The latest United Kingdom National Institute for Health and Care Excellence (NICE) guideline recommends 131I as first-line definitive treatment for Graves’ disease in patients who are unlikely to achieve remission with antithyroid medication. A small but significant proportion of patients have recurrence of hyperthyroidism after 131I therapy. Lithium enhances thyroidal iodine retention and thus increases radiation dose delivered to the thyroid gland during 131I therapy. While clinical trial findings with adjuvant Lithium have not been universally positive, several studies have demonstrated a favorable effect on cure rate, speed of cure and stabilization of thyroid hormone status during131I therapy. Aim: To determine the extent to which Lithium is used as an adjunct to 131I therapy for hyperthyroidism in the UK. Methods: We conducted a survey of 82 nuclear medicine departments and 236 consultant endocrinologists in National Health Service (NHS) hospitals across the UK. Results: Responses were received from 43 departments and 64 endocrinologists. Ten nuclear medicine departments reported that they do not perform therapeutic procedures. Amongst the remainder, only one department stated that Lithium is considered routinely as an adjunct to 131I for selected patients. Amongst consultant endocrinologists, only two indicated that they use Lithium as an adjunct to 131I therapy. Conclusions: Owing to mixed trial evidence and a lack of guideline support for adjunctive Lithium with 131I, its use is not widespread the UK at present. However, some researchers report that it might offer faster control of hyperthyroidism and reduce the amplitude of post-therapy thyroid function fluctuations. As these could be important determinants not only of quality of life but also of safety of treatment, our findings may be valuable to those planning randomized controlled trials of adjunctive Lithium with 131I therapy for Graves’ disease.
Thyroid Immune-Related Adverse Events Are Associated With Improved Survival in Cancer Patients
Authors: Abdallah Duaa , Johnson Jake , Goldner Whitney Sears , Ganti Apar , Kotwal Anupam 
Published: May 2021

Abstract
Introduction: Thyroid immune-related adverse events (irAEs) occur frequently after immune checkpoint inhibitor (ICI) cancer therapy, but their risk factors and potential influence on survival need further investigation. Methods: We performed a retrospective single-center cohort study of adult cancer patients who received ICIs including CTLA-4, PD-1, PD-L1 inhibitors from 12/1/2012- 12/31/2019. Patients who developed thyroid irAEs after excluding surgical or ablative hypothyroidism were included. Survival analysis was performed by Kaplan-Meier curves and Cox-proportional hazards model. Results: Thyroid irAEs occurred in 145 (17.4%) of 834 ICI-treated patients (median age 64.9 y, 43.4% females) during a median follow-up of 11.6 mo. New-onset thyroid dysfunction occurred in 118 (14.2%), of which 55 presented with thyrotoxicosis (32 progressed to hypothyroidism, 22 returned to euthyroid state, 1 had Graves’ disease). Worsening of pre-existing autoimmune hypothyroidism (≥50% increase in levothyroxine dose) occurred in 27 (3.2%). Of those with new-onset thyroid dysfunction, 79 (67%) required levothyroxine eventually. Patients with thyroid irAE had similar age, sex and cancer type as compared to those without but had higher median pre-treatment TSH [2.4 vs. 1.7 mIU/L (p&lt;0.0001); multivariable OR for TSH ≥2.4 mIU/L of 2 (95% CI 1.3, 3.2; p=0.004)] and higher frequency of autoimmune disease history [26.9% vs. 14.8% (p=0.0009); multivariable OR of 2 (95% CI 1.2, 3.5; p=0.013)]. Thyroid irAEs occurred after a median of 2.4 mo from ICI, most frequently with PD-1/PD-L1 inhibitor. Thyroid irAEs were associated with better median overall survival [38.8 mo (95% CI 26.6, not reached) vs. 18.9 (95% CI 14.2, 24.8); p&lt;0.0001] which persisted on restricting to patients with new-onset thyroid dysfunction [40.1 mo (95% CI 26.6, not reached) vs. 18.8 (95% CI 13.6, 24.8); p&lt;0.0001]. On multivariable analysis, thyroid irAEs had HR for mortality of 0.51 (95% CI 0.37, 0.71; p&lt;0.0001), which persisted on restricting to new-onset thyroid dysfunction [HR 0.48 (95% CI 0.34, 0.69; p&lt;0.0001)]. Conclusions: Thyroid irAEs frequently occur after PD-1/PD-L1 inhibitor therapy, presenting as hypothyroidism or thyrotoxicosis usually progressing to hypothyroidism. Higher TSH even within normal range and autoimmune disease history may be risk factors for thyroid irAE. Improved survival with thyroid irAEs suggests these could be a marker for anti-tumor activity.