Hormone Production Research Articles

Molecular interactions of Trichoderma: from microbial competition to soil health promotion

The increasing demand for sustainable solutions to agricultural pest and disease management has positioned Trichoderma fungi as a promising biological control agent. Trichoderma is not only capable of suppressing various plant pathogens but also promotes plant growth and strengthens natural plant defenses. This mini-review explores the molecular mechanisms underlying Trichoderma's ability to function as a biocontrol agent, focusing on nutrient competition, antibiotic production, mycoparasitism, and the induction of plant resistance. Additionally, advances in genomics and transcriptomics have facilitated a deeper understanding of the signaling pathways and genes responsible for Trichoderma's biocontrol effectiveness, including G-protein and MAPK pathways. Beyond pathogen suppression, Trichoderma plays a key role in enhancing soil health and establishing symbiotic relationships with plants, contributing to improved nutrient absorption and growth hormone production. However, challenges remain in translating laboratory success to large-scale field applications. This mini review highlights the need for further research on optimizing Trichoderma formulations, understanding its interaction with other beneficial soil organisms, and exploring genetic engineering to enhance its biocontrol capabilities. The future of Trichoderma lies in its integration into holistic, agroecological systems alongside other sustainable pest management strategies.

Effect of electronic smoking (Vaping) on thyroid hormones level and lipid profile in men

In the last period, the market quickly became saturated with vaping devices available in many flavors and forms appealing to youth. Both traditional cigarette and e-cigarette smoking are known to potentially alter metabolic processes, including hormone production and to increase the risk of lung, heart and kidney diseases. The aim of the study was to estimate the level of thyroid hormones and lipids in the blood of young men who smoked traditional or e-cigarettes. A case-control study involved 200 men aged 24-25 years who smoked 5-7 h per day, divided into two groups (100 e-cigarette smokers and 100 cigarette smokers) and 50 healthy men who did not smoke. The levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were measured using COBAS E411. The levels of total cholesterol, TG, LDL and HDL were estimated spectrophotometrically. No significant changes were found in thyroid hormone levels or lipid profiles, except for an increased TG content in the group of traditional cigarette smokers compared to the control group. Whereas in the blood of e-smokers, the increase in the level of FT3 and FT4 and a significant decrease in that of TSH, as well as the elevated content of total cholesterol, TG, and LDL, were detected compared to the control group. The results obtained indicate that e-smoking affects the function of the thyroid gland and lipid metabolism. Keywords: blood samples, lipid profile, thyroid hormones, vaping

Free long-chain fatty acids trigger early postembryonic development in starved Caenorhabditis elegans by suppressing mTORC1.

Postembryonic development of animals has long been considered an internally predetermined program, while macronutrients were believed to be essential solely for providing biomatters and energy to support this process. However, in this study, by using a nematode Caenorhabditis elegans (abbreviated as C. elegans hereafter) model, we surprisingly discovered that dietary supplementation of palmitic acid alone, rather than other abundant essential nutrients such as glucose or amino acid mixture, was sufficient to initiate early postembryonic development even under complete macronutrient deprivation. Such a development was evidenced by changes in morphology, cellular markers in multiple tissues, behaviors, and the global transcription pattern and it occurred earlier than the well-known early L1 nutrient checkpoint. Mechanistically, palmitic acid did not function as a biomatter/energy provider, but rather as a ligand to activate the nuclear hormone receptor NHR-49/80, leading to the production of an unknown peroxisome-derived secretive hormone in the intestine. This hormonal signal was received by chemosensory neurons in the head, regulating the insulin-like neuropeptide secretion and its downstream nuclear receptor to orchestrate global development. Additionally, the nutrient-sensing hub mTORC1 played a negative role in this process. In conclusion, our data indicate that free fatty acids act as a primary nutrient signal to launch the early development in C. elegans, which suggests that specific nutrients, rather than the internal genetic program, serve as the first impetus for postembryonic development.

Rola mikrobioty jelit i jej metabolitów w przebiegu otyłości i cukrzycy

The gut microbiota is an indispensable component of the proper functioning of the human body, as gut microorganisms and their metabolites strongly influence the host's metabolism and immune functions. They also contribute to the biosynthesis of vitamins, production of gut hormones, maintenance of intestinal barrier integrity, protection against pathogens, as well as digestion and absorption of nutrients. Increasingly, the relationship between disturbances in the composition of gut microbiota and the onset of metabolic diseases such as obesity and type 2 diabetes is being emphasized. Understanding the significance of the microbiota in the course of these diseases, its composition, and activity may offer new approaches to their treatment. Increasing attention is being paid to individual species of gut bacteria, among which Akkermansia muciniphila holds a special position, as a decrease in the abundance of this commensal bacterium in the gut is associated with many diseases, including obesity and diabetes.

A Novel Low-Impact Resistance Exercise Program Increases Strength and Balance in Females Irrespective of Menopause Status.

The reduction in sex hormone production across the menopause transition is thought to accelerate age-related decline in muscle mass, strength, and stability, increasing the risk of falls and fractures. We aimed to investigate whether a novel low-impact resistance exercise program could improve strength, balance, and body composition and whether any improvement was affected by menopause status. Seventy healthy, moderately active pre- (PRE; 46.7 ± (SD) 3.2 years), peri- (PERI; 52.3 ± 2.2 years) or post- (POST; 57.0 ± 2.5 years) menopausal females, not taking hormone replacement therapy (HRT), were randomised to continue habitual physical activity (CON; n = 25) or complete a supervised resistance exercise program 4 days/week for 12 weeks (EXC; n = 45). Strength at the hip and shoulder (isokinetic dynamometer), dynamic balance (Y-balance), flexibility (sit-and-reach & back-scratch), muscle thickness (rectus femoris, vastus intermedius (VI) and medial deltoid), and lean and %body fat (dual-energy X-ray absorptiometry) were measured before and after training. Results: Hip abduction and flexion peak torque (19 ± 48 and 20 ± 17%, respectively, P < 0.05), posterolateral and posteromedial balance (12 ± 15 and 13 ± 15%, respectively, P < 0.001), flexibility (21 ± 36%, P < 0.001), VI thickness (12 ± 19%, P = 0.032), lean mass (2 ± 2%, P = 0.007), all increased over 12 weeks in EXC, but not CON, with no difference in response between PRE, PERI or POST. The changes in shoulder strength and body mass over 12 weeks were not different between CON and EXC. This is the first study to demonstrate that the decline in sex hormones, and increase in age, across the menopause transition does not affect the ability of lower limb (hip) strength and balance to adapt to a low-impact resistance exercise training program in females not taking HRT.

The impact of adrenocortical carcinoma hormone secreting status as a predictor of poor survival: a systematic review and meta-analysis.

Adrenocortical carcinoma (ACC) poses a significant challenge in healthcare due to its aggressive nature and rarity. Prior reports suggest a poorer prognosis associated with hormone-secreting neoplasms. This study aims to assess the impact of ACC hormonal status on patients' oncologic survival. A comprehensive literature search of the Medline, Embase, Web of Science, CINAHL, CENTRAL and clinicaltrials.gov databases was undertaken. Utilized data involved Hazard Ratios derived from multivariable analysis in order to minimize exposure to confounding bias. Included studies were subsequently meta-analyzed using a Random effects model. Twelve studies incorporating 4483 patients were included in the quantitative analysis. Hormonally active ACCs comprised 48% of the entire pooled patient cohort and were found to be associated with significantly worse Overall Survival (HR 1.57, 95% Confidence Interval 1.39-1.78, p < 0.001). Disease-Free Survival was comparably impacted (HR 1.32, 95% CI 1.11-1.57, p < 0.001). Furthermore, cortisol secreting ACCs specifically, were also found to be associated with a 48% increase in the hazard of death or disease recurrence. Interstudy statistical heterogeneity was minimal among evaluated outcomes. Hormone-producing ACCs exhibit a poorer prognosis compared to non-secreting counterparts, with a 57% increased risk of death and a 32% increased risk of recurrence. These findings support the hypothesis that hormone production signifies an adverse tumor-specific feature, particularly when leading to hypercortisolemia, indicating an aggressive disease phenotype.

Triad of female athletes

The female sports triad is a spectrum of dysfunctions related to energy availability, menstrual function, and bone mineral density. Energy availability is considered the trigger for the triad. Scientists have proven that women who do sports consume approximately 30% less energy and carbohydrates in relation to their body weight. Sufficient energy availability ensures the presence of a menstrual cycle, directly affects the stimulation of the production of female sex hormones (estrogen in particular). Thus, it prevents resorption of bone tissue. When energy availability is too low, a physiological mechanism reduces the amount of energy used for cell maintenance, thermoregulation, growth, and reproductive function. This compensation tends to restore energy balance and promotes survival, but impairs health. Low body weight in women of reproductive age, particularly in adolescence and the first reproductive age, is a biological marker of somatic and reproductive dysfunction. Osteoporosis in young female athletes is manifested by fractures unusual for young women or by frequent and multiple bone fractures during an athletic career. In this review article, an analytical review of literary and informational sources regarding the history of research on the problem of the triad of female athletes is carried out. The specifics of the negative impact of the athlete triad on the female body, the components of the athlete triad (amenorrhea, eating disorders, and osteoporosis) are examined in detail. The article focuses on its main cause - energy imbalance. The impact of the triad of female athletes on the psyche and behavior is considered. The question of its consequences for health both in the short-term and in the long-term perspective is considered. The prevention of RED-S syndrome was also investigated. The purpose of the study: Systematization of current knowledge about the triad of female athletes (relative energy deficiency syndrome (RED-S)). Research methods. Theoretical analysis of literary sources, systematization, generalization of scientific-methodical and special literature.

Widespread production of plant growth-promoting hormones among marine bacteria and their impacts on the growth of a marine diatom

BackgroundReciprocal exchanges of metabolites between phytoplankton and bacteria influence the fitness of these microorganisms which ultimately shapes the productivity of marine ecosystems. Recent evidence suggests that plant growth-promoting hormones may be key metabolites within mutualistic phytoplankton-bacteria partnerships, but very little is known about the diversity of plant growth-promoting hormones produced by marine bacteria and their specific effects on phytoplankton growth. Here, we aimed to investigate the capacity of marine bacteria to produce 7 plant growth-promoting hormones and the effects of these hormones on Actinocyclus sp. growth.ResultsWe examined the plant growth-promoting hormone synthesis capabilities of 14 bacterial strains that enhance the growth of the common diatom Actinocyclus. Plant growth-promoting hormone biosynthesis was ubiquitous among the bacteria tested. Indeed all 14 strains displayed the genomic potential to synthesise multiple hormones, and mass-spectrometry confirmed that each strain produced at least 6 out of the 7 tested plant growth-promoting hormones. Some of the plant growth-promoting hormones identified here, such as brassinolide and trans-zeatin, have never been reported in marine microorganisms. Importantly, all strains produced the hormone indole-3 acetic acid (IAA) in high concentrations and released it into their surroundings. Furthermore, indole-3 acetic acid extracellular concentrations were positively correlated with the ability of each strain to promote Actinocyclus growth. When inoculated with axenic Actinocyclus cultures, only indole-3 acetic acid and gibberellic acid enhanced the growth of the diatom, with cultures exposed to indole-3 acetic acid exhibiting a two-fold increase in cell numbers.ConclusionOur results reveal that marine bacteria produce a much broader range of plant growth-promoting hormones than previously suspected and that some of these compounds enhance the growth of a marine diatom. These findings suggest plant growth-promoting hormones play a large role in microbial communication and broaden our knowledge of their fuctions in the marine environment.4YJWCKdNErspcm2bUDNM6tVideo

Unveiling the critical role of androgen receptor signaling in avian sexual development

Gonadal hormone activities mediated by androgen and estrogen receptors, along with cell-autonomous mechanisms arising from the absence of sex-chromosome dosage compensation, are key factors in avian sexual development. In this study, we generate androgen receptor (AR) knockout chickens (AR−/−) to explore the role of androgen signaling in avian sexual development. Despite developing sex-typical gonads and gonadal hormone production, AR−/− males and females are infertile. While few somatic sex-specific traits persist (body size, spurs, and tail feathers), crucial sexual attributes such as comb, wattles and sexual behaviors remain underdeveloped in both sexes. Testosterone treatment of young AR−/− males fails to induce crow behavior, comb development, or regression of the bursa of Fabricius, which are testosterone-dependent phenotypes. These findings highlight the significance of androgen receptor mechanisms in fertility and sex-specific traits in chickens, challenging the concept of a default sex in birds and emphasizing the dominance of androgen signaling in avian sexual development.

Epidemiological Aspects of Renal Disorders in Dogs at South-Saurastra Region of Gujarat- A Prospective Study

Background: Kidney plays a major role in eliminating metabolic wastes from body, in maintaining acid-base balance and production of hormones. Due to their anatomic and physiologic features, kidneys are most susceptible to toxicity and ischemia. No study has been carried out to assess the renal disorders in dog in this region. Hence, the epidemiological study was carried out to record renal disorders in dogs at Junagadh. Methods: The assessment of the incidence of renal disorders in dogs was performed in the hospital cases presented at Veterinary Clinical Complex, COVSAH, KU from September 2022 to August 2023. A total of 2850 caseloads of dogs with different ailments were screened, out of which 170 dogs were diagnosed as renal disorders based on clinical presentation, hematology, serum biochemistry, urine analysis and nephrosonography. Result: The overall incidence of renal disorders in dogs was 5.96%. The higher occurrence of renal disorders was noted in age group of 6-8 years (9.62%) and males (6.61%). The dog breeds that were found higher incidence were Labrador retriever (9.68%) followed by German shepherd (7.24%). Month and Season wise higher incidence was recorded in the month of October (10%) of monsoon (7.61%) season. The highest recorded incidence of renal disorder was nephritis and renal failure (AKI/CKD) (each 35.88%).

PATTERNS OF RADIOTHERAPY PRACTICE FOR FUNCTIONING PITUITARY TUMOURS - A SURVEY OF UK CENTRES

Abstract AIMS Pituitary adenomas are benign tumours that are classified as functioning or non-functioning based on the production of excess pituitary hormones. Functioning adenomas (FA) typically present as hypersecretory syndromes including acromegaly and Cushing’s disease. In FA, radiotherapy is used when surgery fails to achieve hormone normalisation and/or when medical treatment does not control hormone excess. In the absence of prospective studies that clearly define the optimal radiotherapy technique in FA, it is expected that there will be variability in practice. A survey of UK neuro-oncology centres was undertaken, aiming to establish the extent of this variability in FA. METHOD A survey was distributed electronically to 20 neuro-oncology departments across the UK. Data were collected on patient numbers, radiotherapy indications, techniques, dosing, and target volume delineation. RESULTS Responses were received from eight centres (40% response rate), treating a total of approximately 32 FA per annum. There was variability in techniques employed to treat FA. While four centres treated most FA with IMRT, two treat most with stereotactic radiosurgery (SRS), and two with fractionated stereotactic radiotherapy (fSRT). The most common dose used for IMRT treatment was 45Gy in 25 fractions (n=7), with 50.4Gy in 28 fractions, 50Gy in 30 fractions and 54Gy in 30 fractions also reported. Use of margins around residual disease (n=5) and inclusion of involved cavernous sinuses and surgical tract (n=3) within clinical target volumes also varied. Most centres (n=7) would agree to a change in target volume delineation practices for the purpose of a clinical trial in FA. CONCLUSION This survey found that there is variability in radiotherapy dosing, technique, and target volume delineation practices for radiotherapy to FA across the UK. All centres but one would accept changes in their practice within the context of a prospective clinical trial of radiotherapy for FA.

ATRAZINE AS AN ENDOCRINE DISRUPTOR AND ITS EFFECTS ON MALE REPRODUCTIVE HEALTH

Atrazine has been widely used in Brazilian agriculture, especially in corn and soybean crops. Due to its widespread use, this literature review is relevant to systematize the main studies that evaluate the impact of atrazine as an endocrine disruptor leading to changes in fertility quality, especially in males. In several tests and studies carried out with the exposure of animals to atrazine, negative effects related to changes in factors that are essential for male fertility were observed. Therefore, inhibition of the hypothalamic-pituitary-testicular axis, decreased reproductive cells’s metabolic activity, reduced testosterone levels, reduced lactate dehydrogenase (LDH) enzyme, negative effects on spermatogenesis and morphological changes in the gonads and sperm are results of atrazine toxicity on the male reproductive system that contribute to infertility. In general, it is concluded that atrazine has a potential endocrine disruptor effect, leading to changes in the form of hormone production, especially in hormones related to male sexual reproduction. For this reason, assessing the risks of exposure to this toxin at different stages of life and over several generations, combined with knowledge of its pathophysiological mechanism on the male reproductive system, is essential to preserve the reproductive health of future generations.

Public Awareness of the Symptoms and Risk Factors of Thyroid Disease in Saudi Arabia.

Thyroid disorders are a common manifestation of hormonal disorders that result from either excessive or insufficient production of thyroid hormones and the swelling of the thyroid gland. A lack of information and awareness of the signs and risk factors of thyroid problems can lead to untreated patients, thereby harming public health. Observational cross-sectional research was conducted in the Al-Baha region of Saudi Arabia, with 531 residents selected from the general population. The data were analyzed using SPSS to derive significant insights, and questionnaires were used to collect the data. The results revealed that 79 (14.9%) of the participants had been diagnosed with thyroid disease. The risk factors for thyroid diseases reported were as follows: female gender (386, 72.7%); exposure to radiation (329, 62.0%); smoking (312, 58.8%); family history (300, 56.5%); and insufficient or excess intake of iodine (277, 52.2%).Only 110 (20.7%) of the participants knew that the use of amiodarone medication is a risk factor for thyroid diseases. The symptoms reported included fatigue (430, 81.0%), feeling cold, and weight gain (409, 77.0%); neck lump (379, 71.4%); depression (367, 69.1%); and hair loss (336, 63.3%). Early diagnosis (426, 80.2%), a well-exercised program (394, 74.2%), and a well-balanced diet (392, 73.8%) were the prevention methods reported by a majority of the participants. The study results revealed an average score of 13.57±2.11, with a minimum knowledge score of 0 and a maximum of 25. A statistically significant difference was observed in knowledge scores based on the participant's gender, age, education level, previous diagnosis with thyroid diseases, family history of thyroid diseases, and having performed thyroid gland investigation with p-values <0.05 (<0.001, 0.019, 0.027, <0.001, 0.023, and 0.031), respectively. Nearly half of the participants had low knowledge scores regarding the risk factors and clinical manifestations of thyroid diseases. Although a sizable proportion of participants demonstrated awareness of some clinical presentations and prevention methods, there are serious knowledge gaps regarding the risk factors and symptoms of thyroid disease among the general population in the Al-Baha region. There is a need for targeted health education programs to improve public awareness of risk factors and early detection and prevention measures of thyroid diseases to improve the quality of life among community members.

Pregnancy-related hormonal changes and thyroid growth: do they have an impact on the higher incidence of differentiated thyroid cancer in women?

To analyze whether pregnancy could play a role in the higher prevalence of differentiated thyroid carcinoma (DTC) in women. Estrogens strongly modify thyroid economy by increasing iodine clearance, thyroid hormone requirement and production. Human chorionic gonadotropin (hCG) contributes to the increased thyroid hormone synthesis. Both estrogens and hCG can interfere with the regulation of thyroid volume and with thyroid nodule development and progression. The potential effect of hCG is exclusively related to its weak agonistic activity on TSH receptor. Estrogen implication on normal and nodule-derived thyrocyte growth has been demonstrated in vitro and in animal models. Furthermore, there is solid clinical evidence showing a promoting effect of pregnancy on thyroid volume and nodule development. Two metanalysis, one including retrospective and another prospective observational studies, failed to show an association between pregnancy and DTC. A large pooled prospective analysis using multivariable-adjusted Cox proportional hazard models did not demonstrate an association between DTC and parity. Similarly, no association between PTC occurrence and parity was observed in a prospective cohort analysis by linkage to the statewide Surveillance, Epidemiology, and End Results (SEER). The presently available evidence does not support an involvement of pregnancy in DTC etiology.

Integration analysis of transcriptome and metabolome revealed the potential mechanism of spermatogenesis in Tibetan sheep (Ovis aries) at extreme high altitude

Testis has an indispensable function in male reproduction of domestic animals. Numerous genes and metabolites were related to testicular development and spermatogenesis. However, little is known about the biological regulation pathways associated with fecundity in male Tibetan sheep. In this study, Testes were collected from Huoba Tibetan sheep (HB, 4614 m) and Gangba Tibetan sheep (GB, 4401 m) at extreme high altitude, and Alpine Merino sheep (AM, 2500 m, control group) at medium-high altitude, investigating the genes and metabolites levels of them. The histological analysis of testicular tissue using hematoxylin-eosin (HE) staining was performed for Tibetan sheep and Alpine Merino sheep, and the testes of them were analyzed by transcriptomics and metabolomics to explore the potential mechanism of testicular development and spermatogenesis. The statistical results showed that the cross-sectional area of testicular seminiferous tubules, diameter of seminiferous tubules, and spermatogenic epithelium thickness were significantly smaller in HB and GB than in AM (P < 0.05). Overall, 5648 differentially expressed genes (DEGs) and 336 differential metabolites (DMs) were identified in three sheep breeds, which were significantly enriched in spermatogenesis and other related pathways. According to integrated metabolomic and transcriptomic analysis, glycolysis/gluconeogenesis, AMPK signaling pathway, and TCA cycle, were predicted to have dramatic effects on the spermatogenesis of Tibetan sheep. Several genes (including Wnt2, Rab3a, Sox9, Hspa8, and Slc38a2) and metabolites (including L-histidinol, Glucose, Fumaric acid, Malic acid, and Galactose) were significantly enriched in pathways related to testicular development and spermatogenesis, and might affect the reproduction of Tibetan sheep by regulating the acrosome reaction, meiotic gene expression, and the production of sex hormones. Our results provide further understanding of the key genes and metabolites involved in testicular development and spermatogenesis in Tibetan sheep.

Towards the non-invasive determination of estradiol levels: Development and validation of an LC-MS/MS assay for quantification of salivary estradiol at sub-pg/mL level

BackgroundEstradiol (E2) is a female sex hormone involved in several biological processes. Although E2 levels are commonly measured in blood samples, the use of non-invasive techniques (e.g. determination of salivary E2) would allow for the collection of repeated samples and the inclusion of a greater number of participants. Immunoassay-based techniques to measure salivary E2 failed to accurately mirror the variations observed in the plasmatic concentrations of E2 during the menstrual cycle probably due to the high sensitivity required (in the sub-pg/mL range). Therefore, sensitive and rugged analytical methods for the determination of salivary E2 are required. For this, we developed and validated an analytical methodology for the accurate determination of salivary E2. ResultsThe method is based on chemical derivatization with 1,2-dimethyl-1H-imidazole-5-sulphonyl chloride and liquid chromatography-tandem mass spectrometry analysis by summing highly-specific SRM transitions. This strategy allowed for increasing the sensitivity of the method. The validation of the method showed an accurate and precise quantification of E2 in 1 mL of saliva even at 250 fg/mL (97 % accuracy and 15 % RSD intra-day, and 104 % accuracy and 18 % RSD inter-day). In order to evaluate its efficacy, we analysed saliva samples from 5 healthy female volunteers collected during a whole menstrual cycle. Our analyses showed that the variations in the concentration of E2 in the measured samples mirrored those expected during a complete menstrual cycle. Additionally, we validated the suitability of our method for determining salivary E2 levels during pregnancy. SignificanceTo the best of our knowledge, this is the first method that allows to precisely and accurately measuring E2 in saliva samples along the whole menstrual cycle of healthy females. It is also suitable for the determination of estradiol during pregnancy. Its high sensitivity makes this strategy ideal for the evaluation of the role of hormone production in women's health.

Subtyping of pancreatic neuroendocrine tumors by transcription factors, hormones, histology, and patient outcome.

Pancreatic neuroendocrine tumors (PanNETs) show pronounced heterogeneity in terms of hormone and transcription factor (TF) expression. TFs such as ARX and PDX1 are related to alpha- and beta-cell-type features, respectively, and partly associate with patient outcome. However, detailed studies correlating hormone expression, histology, and clinical data are lacking. The aim of this study was to identify subtypes of PanNETs that associate with histological, hormonal, and prognostic findings. Atotal of 185resected PanNETs were divided into five subtypes (types A1, A2, B, C, and D) by cluster analysis based on expression of four TFs (ARX, PDX1, ISL1, and CDX2) and correlated to the expression of hormones and DAXX/ATRX as well as ALT activation status, histology, and progression-free survival. Subgroup A1 (ISL1+/ARX+/PDX-/CDX2-) was most frequent (46%), followed by typeB (18%; ISL1+/ARX-/PDX+/CDX2-), A2 (15%; ISL1+/ARX+/PDX+/CDX2-), C(15%; ISL1-/ARX-/PDX-/CDX2-), and D(5%; ISL1-/ARX-/PDX+/CDX2+). Subgroups A1 and A2 showed astrong association with atrabecular growth pattern and glucagon and pancreatic polypeptide (PP) expression (p < 0.001), while A2 was in addition associated with gastrin expression. SubgroupB was associated with insulin production (p < 0.001) and included all 17insulinomas. SubgroupC was associated with solid morphology and expression of serotonin, calcitonin, and adrenocorticotropic hormone (ACTH). SubgroupD showed solid morphology, expression of ACTH, somatostatin, or serotonin and had the shortest disease-free survival (p < 0.01). ALT positivity was associated with poorer outcome in types A1 and A2 but not in other types. PanNETs can be categorized into five subgroups based on different TF signatures, which associate strongly with histology, hormone production, functionality, and patient outcome.

Acromegalia em felinos

Acromegaly in felines occurs mainly due to a pituitary adenoma of somatotropic cells, and presents slow and progressive evolution, responsible for increasing the production and secretion of growth hormones (GH). This condition is common in senile or adult male domestic cats, neutered and with short hair. The pathophysiology is due to the excessive release of GH in the adenohypophysis region, whose synthesis is regulated by growth hormone-releasing hormone (GHRH) and somatostatin, responsible for stimulating or inhibiting the secretory axis, respectively. The anabolic action of GH is responsible for increasing the secretion of IGF-1, which is mainly responsible for the clinical signs of acromegaly, such as body growth and organomegaly. The catabolic effect refers to insulin resistance. Clinical signs may be associated with secondary diabetes mellitus (DM), weight gain, exacerbated growth of various tissues and neurological signs as the tumor mass grows. The diagnosis of the disease can be performed through laboratory, imaging and endocrine tests such as the specific immunoassay for GH and/or insulin-like growth factor 1 (IGF-1). Treatment is based on controlling the DM that develops secondary to it, as well as on attempts to reduce or even inhibit the excess release of GH. Treatment can be performed with somatostatin analogues and dopamine agonists. The use of stereotactic radiotherapy can also be recommended, with favorable results for tumor reduction, as well as the surgical technique of transsphenoidal hypophysectomy, which presents better results than other techniques but is a complex surgical procedure. This project aims to inform veterinarians of this endocrine disease and its main currently recognized diagnoses and treatments, emphasizing the need to establish a differential diagnosis for difficult-to-control DM.

Nodule-specific NRF2-targeted upregulation in patients with KEAP1 mutations and familial nontoxic multinodular goiter.

Kelch-like ECH-associated protein 1 (KEAP1) is associated with nuclear factor erythroid-2 related factor 2 (NRF2) and promotes NRF2 degradation in normal conditions. Genetic abnormality in KEAP1 is a rare disease and presents with familial multinodular goiter. This study assessed the clinical and molecular findings concerning nodular formation in the thyroid gland of patients harboring KEAP1 germline mutations. Next-generation sequencing analysis targeting goiter-associated genes was performed on 39 patients with familial multinodular goiter. The expression of NRF2-targeted genes from surgical thyroid specimens of patients with KEAP1 mutations were analyzed using a whole transcript expression array and immunohistochemistry. We found five probands with pathogenic heterozygous mutations in KEAP1 (p.Q86*, p.L136P, p.V411fs, p.R415C, and p.R483H), which had no meaningful concomitance with mutations of other goiter-associated genes in germline and somatic levels. Their common histopathological features showed multinodular goiters in the entire thyroid gland with few degenerative lesions or complications of malignancy and slow proliferation indicating < 1% at the Ki-67 labeling index. Among 42 NRF2-targeted genes, antioxidant genes were most frequently upregulated (11/12) in the nodule, followed by detoxification genes (6/11). Immunohistochemical analysis showed relatively high expression of glutathione peroxidase 2 and NAD(P)H quinone oxidoreductase 1 (representative NRF2-targeted genes) in the nodules of various patients harboring KEAP1 mutations. KEAP1 germline heterozygous mutations exert excessive NRF2 activity in the thyroid gland and may confer cytoprotective effects even under abundant reactive oxygen species associated with thyroid hormone production, resulting in thyroid hyperplasia with scarce degradation.

8053 A Ligand-Based Differentiation Protocol for Human Induced Pluripotent Stem Cells Recapitulates Granulosa Cell Development and Induces Steroidogenic Pathway Genes

Abstract Disclosure: H. Kubo: None. M.M. Laronda: None. Sex determination is a developmental process that defines the gonad as a testis or ovary, and influences sex hormone production. While key signaling events are well conserved across mammals, there can be differences between species. Therefore, there is a need to develop a human model to fully understand this critical process in humans. We have developed a ligand-based differentiation protocol for human induced pluripotent stem cells (hiPSCs) to generate granulosa-like cells (GLCs). Additionally, hiPSC-derived GLCs could become the foundation for a cell-based hormone replacement therapy that recapitulates cyclicity, physiologic levels of hormones, and production of peptide hormones that are not included in currently available hormone replacement therapies. We aim to gain further understanding of the key factors and culture conditions necessary for functional GLCs that produce ovarian hormones, which includes maintained expression of FOXL2. We used our monolayer differentiation protocol that includes WNT-agonist CHIR99021 treatment for 2 days, followed by a combination treatment of BMP4, FST, and DKK1-inhibitor Gallocyanine for 3 days. We have tested our protocol on three different hiPSC lines: IISH2i-BM9s, STiPS-A3, and STiPS-A6. Expression of pluripotency marker POU5F1 is reduced during differentiation, while expression of the intermediate mesoderm markers PAX2, LHX1, and WT1 and bipotential gonad marker GATA4 peak at day 2. Peak expression of the bipotential gonad marker NR5A1 occurred at day 2 in the STiPS-A6 cells, but at day 5 in IISH2i-BM9 and STiPS-A3 cells. Interestingly, FOXL2 expression peaks at day 2 in all three lines and drops by day 5. In the IISH2i-BM9s, FOXL2 protein peaks at day 2 by Jess Western while there is the highest percentage of FOXL2-positive cells at day 5 by immunofluorescence. In murine granulosa cells, FOXL2 maintenance depends on NR5A2. NR5A2 expression drops in the GLCs, which suggests that NR5A2 loss may be preventing FOXL2 maintenance. Additionally, as FOXL2 is required for expression of aromatase and HSD17B1, we are using this model to interrogate NR5A2 upstream of FOXL2 and control hormone production. CYP19A1 and HSD17B1 along with AMH are induced during this differentiation protocol, suggesting these GLCs can be steroidogenic and produce peptide hormones. Additionally, scRNA-seq analysis of the GLCs is underway to identify types of granulosa cells produced by this protocol. Future directions include optimizing GLC culture conditions to generate hormones and to test if NR5A2 inhibitors alter FOXL2 expression. Put together, the data suggests that cells differentiated with our protocol show promise as a human model of ovarian development and a foundation for a personalized cell-based hormone replacement therapy. This work is supported by the NIH/NICHD R01HD104683 (MML), HuBMAP U01HD110336 (MML), and Gesualdo Family Research Scholar (MML). Presentation: 6/2/2024