Alterations in Thyroid Hormones in Obese Patients are Associated with Body Composition Changes after Bariatric Surgery.

BACKGROUND: This study investigates how metabolic/bariatric surgery (MBS) affects thyroid hormone (TH) levels and TH resistance in obese euthyroid individuals, focusing on their correlation with changes in body composition. METHODS: We included 470 obese individuals and 118 controls for baseline assessment, and 125 obese patients receiving MBS for longitudinal study. Data on body composition and thyroid function were collected. Correlations between baseline and changes in thyroid function and body composition were assessed. RESULTS: In the obese group, thyroid stimulating hormone (TSH), free triiodothyronine (fT3) levels, and thyroid feedback quantile-based index (TFQI) were elevated and significantly decreased post-MBS, along with visceral fat area (VFA) and body fat percentages, while skeletal muscle mass (SMM) percentage increased. Preoperative partial correlation analysis adjusted for age and sex revealed that TSH positively correlated with VFA (r=0.109, P=0.019), body fat percentage (r=0.114, P=0.013), and negatively correlated with SMM percentage (r=-0.104, P=0.024). Similar correlations were observed between central TH resistance indices and body composition, but no significant correlations were found in the control group. Post-MBS, decreased TSH positively correlated with decreased VFA (r=0.251, P=0.006) and increased SMM percentage (r=0.233, P=0.011). While reductions in VFA and body fat percentage were linked to improved central thyroid hormone resistance, a decrease in peripheral TH conversion was noted. CONCLUSIONS: MBS significantly impacts thyroid function and TH resistance, with notable correlations to changes in body composition.

Normal Values for the fT3/fT4 Ratio: Centile Charts (0-29 Years) and Their Application for the Differential Diagnosis of Children with Developmental Delay.

Primary congenital hypothyroidism is easily diagnosed on the basis of elevated plasma levels of thyroid-stimulating hormone (TSH). In contrast, in the rare disorders of thyroid hormone resistance, TSH and, in mild cases, also thyroid hormone levels are within the normal range. Thyroid hormone resistance is caused by defects in hormone metabolism, transport, or receptor activation and can have the same serious consequences for child development as congenital hypothyroidism. A total of n = 23,522 data points from a large cohort of children and young adults were used to generate normal values and sex-specific percentiles for the ratio of free triiodothyronine (T3) to free thyroxine (T4), the fT3/fT4 ratio. The aim was to determine whether individuals with developmental delay and genetically confirmed thyroid hormone resistance, carrying defects in Monocarboxylate Transporter 8 (MCT8), Thyroid Hormone Receptor alpha (THRα), and Selenocysteine Insertion Sequence-Binding Protein 2 (SECISBP2), had abnormal fT3/fT4 ratios. Indeed, we were able to demonstrate a clear separation of patient values for the fT3/fT4 ratio from normal and pathological controls (e.g., children with severe cerebral palsy). We therefore recommend using the fT3/fT4 ratio as a readily available screening parameter in children with developmental delay for the identification of thyroid hormone resistance syndromes. The fT3/fT4 ratio can be easily plotted on centile charts using our free online tool, which accepts various SI and non-SI units for fT3, fT4, and TSH.

Diet at birth is critical for healthy growth, independent of effects on the gut microbiota.

BACKGROUND: Colostrum is the first milk for a newborn. Its high content in microbiota shaping compounds and its intake at the time of gut microbiota seeding suggests colostrum may be critical in the establishment of a healthy microbiota. There is also accumulating evidence on the importance of the gut microbiota for healthy growth. Here, we aimed to investigate the contribution of colostrum, and colostrum-induced microbiota to growth promotion. Addressing this question is highly significant because (1) globally, less than half of the newborns are fully colostrum fed (2) the evidence for the importance of the microbiota for the prevention of undernutrition has only been demonstrated in juvenile or adult pre-clinical models while stunting already starts before weaning. RESULTS: To address the importance of diet at birth in growth failure, we developed a unique mouse model in which neonates are breastfed by mothers at an advanced stage of lactation who no longer provide colostrum. Feeding newborn mice with mature milk instead of colostrum resulted in significant growth retardation associated with the biological features of chronic undernutrition, such as low leptin levels, dyslipidemia, systemic inflammation, and growth hormone resistance. We next investigated the role of colostrum in microbiota shaping. At the end of the lactation period, we found a major difference in gut microbiota alpha diversity, beta diversity, and taxa distribution in control and colostrum-deprived mice. To determine the causal relationship between changes in microbiota and growth trajectories, we repeated our experiment in germ-free mice. The beneficial effect of colostrum on growth remained in the absence of microbiota. CONCLUSION: Our data suggest that colostrum may play an important role in the prevention of growth failure. They highlight that the interplay between neonatal gut microbiome assembly and diet may not be as crucial for growth control in the developing newborn as described in young adults. This opens a paradigm shift that will foster research for colostrum's bioactives that may exert a similar effect to microbiota-derived ligands in promoting growth and lead to new avenues of translational research for newborn-tailored prevention of stunting. Video Abstract.

Assessment of Cardiometabolic Risk Factors and Insulin Sensitivity by Hyperinsulinemic-Euglycemic Clamp in Resistance to Thyroid Hormone ß Syndrome.

Background: Resistance to thyroid hormone beta (RTHß) is a rare disease resulting from mutations in the THRB gene, characterized by reduced T3 action in tissues with high thyroid hormone receptor ß expression. Thyroid hormones regulate body composition and metabolism in general, and increased or decreased hormone levels are associated with insulin resistance. This study evaluated the presence of cardiometabolic risk factors and insulin sensitivity in patients with RTHß. Methods: In all, 16 patients, 8 adults (52.3 ± 16.3 years of age) and 8 children (10.9 ± 3.9 years of age), were compared to 28 control individuals matched for age, sex, and body mass index (BMI). Anthropometry evaluation and blood samples were collected for glycemia, lipids, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, adiponectin, ultrasensitive C-reactive protein (CRPus), free thyroxine, total triiodothyronine, thyrotropin, and anti-thyroid peroxidase measurements. Body composition was assessed using dual-emission X-ray absorptiometry and bioimpedance. Insulin sensitivity was evaluated in adult patients and controls using the hyperinsulinemic-euglycemic clamp (HEC), whereas homeostasis model assessment of insulin resistance (HOMA-IR) was calculated in all individuals studied. Results: Patients and controls presented similar weight, BMI, abdominal perimeter, and total fat body mass. Patients with RTHß demonstrated higher total cholesterol (TC), p = 0.04, and low-density lipoprotein cholesterol (LDL-C), p = 0.03, but no alteration was observed in other parameters associated with metabolic risk, such as leptin, TNF-α, and CRPus. Two adult patients met the criteria for metabolic syndrome. There was no evidence of insulin resistance assessed by HEC or HOMA-IR. Elevated IL-6 levels were observed in patients with RTHß. Conclusion: Using HEC as the gold standard method, no evidence of reduced insulin sensitivity in skeletal muscle was documented in RTHß adult patients; however, higher levels of TC and LDL-C were observed in these patients, which suggest the need for active monitoring of this abnormality to minimize cardiometabolic risk. In addition, we demonstrated, for the first time, that the increase in IL-6 levels in patients with RTHß is probably secondary to metabolic causes as they have normal levels of TNF-α and CRPus, which may contribute to an increase in cardiovascular risk. A larger number of patients must be studied to confirm these results.

Pseudohypoparathyroidism Type IB with Subclinical Hypothyroidism: a Pedigree Investigation and Literature Review.

Pseudohypoparathyroidism (PHP) is a rare genetic disease characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) in serum. Here, we report a case of a patient with pseudohypoparathyroidism type IB (PHPIB) and subclinical hypothyroidism, analyze the clinical and genetic data of his family members, review the relevant literature, and classify and discuss the pathogenesis and clinical characteristics of each subtype. Finally, we discuss the treatment approach to improve clinicians' understanding of the disease.

A Clinical Trial of High Dose Growth Hormone in a Patient with a Dominant Negative Growth Hormone Receptor Mutation.

CONTEXT: Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention. OBJECTIVE: To determine whether high dose GH can overcome GH resistance in this specific patient resulting in normal IGF-1 levels and improved growth rates. DESIGN: Single patient trial of ascending doses of GH followed by dose stable phase; total 12 months of treatment. PATIENT: Patient has a heterozygous variant in GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. INTERVENTIONS: Daily subcutaneous GH starting at 50 micrograms/kg/day and escalating to 250 micrograms/kg/day until goal IGF-1 achieved. Subject continued 250 micrograms/kg/day for a total treatment duration of 12 months. OUTCOME MEASURES: The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the mid-point of the normal range. Secondary endpoints included height velocity and the change in height SDS during the 1st year of treatment. RESULTS: A dose of GH of 250 micrograms/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height. CONCLUSIONS: A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels.

Concurrent THRB and DUOX2 variants in a patient detected via newborn screening for congenital hypothyroidism: a case of resistance to thyroid hormone.

Most patients with resistance to thyroid hormone (RTH) test negative in newborn screening (NBS) for congenital hypothyroidism (CH). Here, we present a case of RTH diagnosed through NBS. The patient presented to us after her NBS for CH revealed high TSH (23.4 µIU/mL) and free T4 (FT4) (5.40 ng/dL) levels. Apart from tachycardia, she exhibited no other manifestations related to excess or deficiency of thyroid hormones. A confirmatory test replicated the findings, showing elevated serum TSH levels (35.7 µIU/mL) along with high FT4 levels (5.84 ng/dL). Ultrasonography showed marked thyroid gland enlargement (> +4 SD). Targeted next-generation sequencing of genes associated with genetic thyroid disorders revealed a previously reported THRB variant, p.Gly345Cys. Unexpectedly, two biallelic DUOX2 variants (p.His678Arg and p.Arg1334Trp) were also detected. At her last visit, no significant issues were observed with neurological development, growth, bone maturation, or gastrointestinal symptoms related to thyroid function at the age of 1 year, without treatment for RTH and CH. During follow-up, the TSH and FT4 levels gradually decreased. In conclusion, we report a patient with simultaneous RTH and DUOX2 defects, demonstrating the value of conducting a comprehensive analysis of multiple genes associated with thyroid diseases to better comprehend the pathogenesis in patients with atypical thyroid-related phenotypes.

Growth hormone resistance induced by amino acid deprivation in fao cells is independent of FGF21.

Adequate dietary intake of amino acids is imperative for normal animal growth. Our previous work using rat hepatocarcinoma Fao cells demonstrated that growth hormone (GH) resistance, coupled with a concurrent reduction in insulin-like growth factor 1 (Igf1) mRNA levels, may underlie the growth retardation associated with a low-protein diet (LPD). In this study, we investigated whether FGF21 contributes to liver GH resistance in Fao rat hepatoma cells under amino acid deprivation conditions. Mice subjected to an LPD exhibited growth retardation, compromised GH signaling in the liver, and decreased blood IGF-1 levels compared with those on a control diet. To assess the potential involvement of fibroblast growth factor (FGF) 21, produced in response to amino acid deficiency, in the development of GH resistance, we examined GH signaling and Igf1 mRNA levels in Fao cells cultured in amino acid-deprived medium. Despite the inhibition of Fgf21 expression by the integrated stress response inhibitor, an inhibitor of the eukaryotic initiation factor 2-activating transcription factor 4 pathway, GH resistance persisted in response to amino acid deprivation. Additionally, the introduction of FGF21 into the control medium did not impair either GH signaling or GH-induced Igf1 transcription. These data suggest that, in Fao cells, amino acid deprivation induces GH resistance independently of FGF21 activity. By shedding light on the mechanisms behind growth retardation-associated GH resistance linked to amino acid deficiencies, our findings provide valuable insights for clinicians in formulating effective treatment strategies for individuals facing these challenges.

Thyroid hormone resistance and large goiter mimicking infiltrative carcinoma in a pediatric patient.

OBJECTIVES: Resistance to thyroid hormone (RTH) is a genetic condition, caused by mutations in the thyroid hormone receptor gene and characterized by impaired end organ responsiveness to thyroid hormone. Here we describe a novel case of THR associated with large goiter mimicking infiltrative c. CASE PRESENTATION: A 13-year-old male with a hyperthyroid phenotype of RTH diagnosed as a toddler, on methimazole and nadolol therapies presented with an increase in goiter size and possible nodule. Thyroid ultrasound was concerning for a diffuse infiltrative process or malignancy. Methimazole was discontinued and he underwent further imaging, fine needle aspiration and core biopsies. Biopsy results were reassuring and imaging findings were subsequently attributed to RTH rather than malignancy. He started every other day liothyronine therapy, which led to a decrease in goiter size, thyroglobulin level, and improvement of hyperthyroid symptoms. CONCLUSIONS: This is the first case to our knowledge describing the above thyroid imaging findings in association with RTH. It also adds important information to the pediatric literature regarding management of the hyperthyroid phenotype of RTH, including the role of liothyronine therapy.

Influencing factors and hormone resistance of 510 children with nephrotic syndrome / 公共卫生与预防医学

Objective To investigate the hormone resistance and analyze its influencing factors in 510 children with nephrotic syndrome. Methods The clinical data of 510 children with primary nephrotic syndrome admitted to our hospital from January 2019 to August 2023 were retrospectively collected and analyzed. After 8 weeks of continuous treatment with conventional full-dose prednisone, urine protein detection was performed. Urine protein (+-+++) was listed as drug-resistant group, and urine protein (-) was regarded as control group. The general data, pathological types, and laboratory indicators were compared. Univariate analysis and Logistic regression analysis were used to screen the risk factors for hormone resistance in children with nephrotic syndrome. Results (1) After the end of 8 weeks of treatment, among the 510 children, there were 19 children with urine protein (+), 22 children with urine protein (++), 12 children with urinary protein (+++) and 457 children with urine protein (-). The total number of children with hormone resistance (drug-resistant group) was 53 cases (10.39%, 53/510), and the number of children with hormone sensitivity (control group) was 457 cases (89.61%, 457/510). (2) The proportions of children with onset age>8 years old and pathological type of focal stage glomerulosclerosis in drug-resistant group were higher than those in control group (P8, serum creatinine, D-dimer and β2-microglobulin, and low 25-hydroxyvitamin and CD4 at disease onset were risk factors for hormone resistance in children with nephrotic syndrome (P8, serum creatinine, D-dimer and β2-microglobulin and low 25-hydroxyvitamin and CD4 at disease onset, it is necessary to take targeted anticoagulation, immune regulation and other treatments as soon as possible in order to achieve the best efficacy and improve the prognosis.

Genotype-phenotype correlations in pseudohypoparathyroidism type 1a patients: a systemic review.

BACKGROUND: Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding protein (Gsα) resulting from maternal GNAS gene variation. The clinical manifestations are related to PTH resistance (hypocalcemia, hyperphosphatemia, and elevated serum intact PTH) in the presence or absence of multihormone resistance, and Albright's hereditary osteodystrophy (AHO). OBJECTIVES: To summarize the molecular genetics results and clinical characteristics as well as to explore the correlations between them. METHODS: Articles pertaining to PHP1a until May, 31, 2021 were reviewed and 527 patients with genetic diagnosis were included in the data analysis. The clinical characteristics and molecular genetics results of these patients were analyzed and compared to explore the correlations between them. RESULTS: A total of 258 GNAS rare variants (RVs) were identified in 527 patients. The RVs were most commonly found in exons 1 and 7 (17.6% each), with frameshift (36.8%), and missense (31.3%) being the main types of RVs. The median age of onset was 5.0 years old. The most common clinical manifestations were elevation of PTH (86.7%) and AHO (87.5%). Thyroid stimulating hormone resistance was the most common hormone resistance (75.5%) other than PTH resistance. Patients with missense and in-frame RVs had lower incidence rates of the round face (P = .001) and subcutaneous ossifications (P < .001) than those with loss-of-function (non-sense, frameshift, splicing site variants, and large deletions) variants. CONCLUSIONS: This study revealed the correlation between loss-of-function RVs with round faces and subcutaneous ossifications in PHP 1a patients. Further exploration of genotype-phenotype correlations through more standardized and prospective studies with long-term follow-up is necessary.

Honokiol inhibits the growth of hormone-resistant breast cancer cells: its promising effect in combination with metformin.

Background and purpose: Primary and metastatic breast cancers still represent an unmet clinical need for improved chemotherapy and hormone therapy. Considerable attention has been paid to natural anticancer compounds, especially lignans. The study aimed to evaluate the activity of several lignans against breast cancer cells and assess the effect of leading lignans on signaling pathways in combination with metformin. Experimental approach: Human breast cancer cell lines MCF7 (hormone-dependent), MDA-MB-231, and SKBR3 (hormone-independent) were used. A hormone-resistant MCF7/hydroxytamoxifen (HT) subline was obtained by long-term cultivation of the MCF7 line with hydroxytamoxifen. Antiproliferative activity was assessed by the MTT test; the expression of signaling pathway proteins was evaluated by immunoblotting analysis. Findings/Results: We evaluated the antiproliferative activity of lignans in breast cancer cells with different levels of hormone dependence and determined the relevant IC50 values. Honokiol was chosen as the leading compound, and its IC50 ranged from 12 to 20 µM, whereas for other tested lignans, the IC50 exceeded 50 µM. The accumulation of cleaved PARP and a decrease in the expression of Bcl-2 and ERα in MCF7/HT were induced following the combination of honokiol with metformin. Conclusions and implications: Honokiol demonstrated significant antiproliferative activity against both hormone-dependent breast cancer cells and lines with primary and acquired hormone resistance. The combination of honokiol with metformin is considered an effective approach to induce death in hormone-resistant cells. Honokiol is of interest as a natural compound with antiproliferative activity against breast cancers, including resistant tumors.

A novel variant of THRß and its 4-year clinical course in a Korean boy with resistance to thyroid hormone.

Thyroid hormone resistance (RTH) is characterized by a decreased sensitivity of target tissues to thyroid hormones due to a defect in the THRα- and THRß-encoded thyroid hormone receptors (THRs). The clinical manifestations range from no symptoms to simple goiter and hypo- or hyperthyroidism, depending on the receptor subtype distribution in the tissues. Here, we report the case of a thyroid hormone-resistant 12-month-old boy carrying a novel THRß variant who was initially diagnosed with congenital hypothyroidism. An extensive evaluation revealed increased free T4 level and inappropriately increased thyroid-stimulating hormone (TSH) level; a normal lipid profile, sex hormone-binding globulin, and free alpha subunit of TSH; exaggerated TSH response to THR; and no radiological evidence of pituitary adenoma. A targeted next-generation sequencing panel identified a heterozygote c.993T>G (p.Asn331Lys) mutation in the THRß gene. During the first year of life, a higher dose of levothyroxine was administered to the patient due to uncompensated RTH. Levothyroxine treatment was continued after 3 years to maintain TSH level <5 mIU/mL, but the observed weight gain was poor, height increase was insufficient, and bone development was delayed. However, neither hyperactivity nor developmental delay was observed. Patients with RTH exhibit various clinical features. Due to its heterogeneous nature, genetic test for accurate diagnosis is important to provide proper management.

Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant.

Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of disorders that often severely impair vision. Some patients manifest poor central vision as the first symptom due to cone-dysfunction, which is consistent with cone dystrophy (COD), Stargardt disease (STGD), or macular dystrophy (MD) among others. Here, we aimed to identify the genetic cause of autosomal dominant COD in one family. WGS was performed in 3 affected and 1 unaffected individual using the TruSeq Nano DNA library kit and the NovaSeq 6,000 platform (Illumina). Data analysis identified a novel spliceogenic variant (c.283 + 1G>A) in the thyroid hormone receptor beta gene (THRB) as the candidate disease-associated variant. Further genetic analysis revealed the presence of the same heterozygous variant segregating in two additional unrelated dominant pedigrees including 9 affected individuals with a diagnosis of COD (1), STGD (4), MD (3) and unclear phenotype (1). THRB has been previously reported as a causal gene for autosomal dominant and recessive thyroid hormone resistance syndrome beta (RTHß); however, none of the IRD patients exhibited RTHß. Genotype-phenotype correlations showed that RTHß can be caused by both truncating and missense variants, which are mainly located at the 3' (C-terminal/ligand-binding) region, which is common to both THRB isoforms (TRß1 and TRß2). In contrast, the c.283 + 1G>A variant is predicted to disrupt a splice site in the 5'-region of the gene that encodes the N-terminal domain of the TRß1 isoform protein, leaving the TRß2 isoform intact, which would explain the phenotypic variability observed between RTHß and IRD patients. Interestingly, although monochromacy or cone response alterations have already been described in a few RTHß patients, herein we report the first genetic association between a pathogenic variant in THRB and non-syndromic IRDs. We thereby expand the phenotype of THRB pathogenic variants including COD, STGD, or MD as the main clinical manifestation, which also reflects the extraordinary complexity of retinal functions mediated by the different THRB isoforms.

Neuroendocrine adaptations to starvation.

Famine and starvation have punctuated the evolutionary past of the human species. As such, we have developed hormonal responses to undernutrition that minimize energy expenditure on processes that are not critical for the survival of the individual, such as reproduction. In this review, we discuss neuroendocrine adaptations to starvation including hypogonadotropic hypogonadism, growth hormone resistance, hypercortisolemia, and the downregulation of the hypothalamic-pituitary-thyroid axis. We review the time-course of these adaptations by describing studies involving the short-term fasting of healthy individuals as well as studies describing the hormonal changes in states of chronic undernutrition, using individuals with anorexia nervosa as a model of chronic starvation. Lastly, we review representative clinical effects of chronic undernutrition.

Influence of Leptin on the Secretion of Growth Hormone in Ewes under Different Photoperiodic Conditions.

Leptin is an adipokine with a pleiotropic impact on many physiological processes, including hypothalamic-pituitary-somatotropic (HPS) axis activity, which plays a key role in regulating mammalian metabolism. Leptin insensitivity/resistance is a pathological condition in humans, but in seasonal animals, it is a physiological adaptation. Therefore, these animals represent a promising model for studying this phenomenon. This study aimed to determine the influence of leptin on the activity of the HPS axis. Two in vivo experiments performed during short- and long-day photoperiods were conducted on 12 ewes per experiment, and the ewes were divided randomly into 2 groups. The arcuate nucleus, paraventricular nucleus, anterior pituitary (AP) tissues, and blood were collected. The concentration of growth hormone (GH) was measured in the blood, and the relative expression of GHRH, SST, GHRHR, SSTR1, SSTR2, SSTR3, SSTR5, LEPR, and GH was measured in the collected brain structures. The study showed that the photoperiod, and therefore leptin sensitivity, plays an important role in regulating HPS axis activity in the seasonal ewe. However, leptin influences the release of GH in a season-dependent manner, and its effect seems to be targeted at the posttranscriptional stages of GH secretion.

The clinical characteristics and gene mutations associated with thyroid hormone resistance syndrome coexisting with pituitary tumors.

Aims: Resistance to thyroid hormone (RTH) and pituitary tumors are both rare diseases, and the differential diagnosis of these two diseases is difficult in some cases. There are also patients who have both conditions, making diagnosis more difficult. To better understand this aspect, we analyzed the clinical characteristics and gene mutations of RTH coexisting with pituitary tumors. Methods: Database retrieval was conducted in the PubMed, Cochrane Library, and SinoMed databases, and the search contents were case reports or case series of patients with RTH coexisting with pituitary tumors. The demographic, clinical manifestations, and imaging characteristics of pituitary tumors and gene mutations were summarized. Results: Thirteen articles involving 16 patients with RTH coexistent with pituitary tumors, consisting of 13 female patients, one male patient, and two patients with unknown sex, were included. The patients were 10 to 79 years old and most patients were 41-55 years old (43.75%). The 16 patients were from seven different countries and three continents (Asia, the Americas, and Europe). All the patients showed an abnormal secretion of TSH, and five patients underwent transsphenoidal surgery. Finally, four patients were pathologically confirmed to have TSHoma. A total of 11 different mutations occurred at nine amino acid sequence sites (251, 310, 344, 347, 383, 429, 435, 438, and 453). Two different mutations occurred in both the no. 435 and no. 453 amino acid sequences. Fourteen patients provided their treatment histories, and all had undergone different treatment regimens. Conclusions: Patients with both RTH and pituitary tumors had multiple clinical manifestations and different thyroid functions, imaging characteristics of pituitary tumors, genetic mutations of THRß, and treatments. However, due to the limited number of cases, the patients were mainly women. Further studies with more cases that focus on the mechanism are still needed.

Pleomorphic giant cell carcinoma of the prostate: clinicopathologic analysis and oncological outcomes.

We report on the clinicopathologic features of 27 pleomorphic giant cell carcinoma (PGCC) cases of the prostate identified in 20 patients with an age range of 51 to 84 years (68 ± 9; median 71 years). Charlson comorbidity index ranged from 3 to 12. Serum PSA ranged from 4.30 to 662 ng/mL (median 13 ng/mL). On histologic examination, bizarre giant cells with pleomorphic nuclei characterized pleomorphic giant cell carcinoma of the prostate. PGCC component was present in 5% to 100%, with half of the patients presenting with ≥ 20%. Half of the patients initially presented with T4 and 26% with T3 disease. All patients were considered Gleason scores of 9 to 10 (ISUP grade 5). A combination of hormone therapy with chemotherapy with or without radiation therapy was applied in 68% of patients. On follow-up, 14 patients (52%) were alive with disease (1-69 months) or dead of disease (1-38 months). Patients diagnosed earlier with lower TNM stage had longer survival than those diagnosed at a later T-stage or with metastatic disease (p = 0.02). The percentage of PGCC was not related to survival in the current study. Molecular alterations in 3 samples showed a microsatellite-stable disease with low tumor mutation burden and variable PTEN, PTCH1, KDM6A, ARv7, and PIK3CA loss/alteration, TP53 mutation, TMPRSS2-ERG fusion, and MYC, PIK3CB, RICTOR, or IRS2 amplification. Our findings suggest that PGCC is a rare and aggressive subtype of prostate carcinoma whose recognition may steer clinicians to adopt more aggressive treatments and investigate new therapeutic strategies.

Morphological and Functional Colonic Defects Caused by a Mutated Thyroid Hormone Receptor α.

Background: Mutations of thyroid hormone receptor α (TRα1) result in resistance to thyroid hormone (RTHα), exhibiting symptoms of retarded growth, delayed bone maturation, anemia, and severe constipation. Using a mouse model of RTHα (Thra1PV/+ mouse), we aimed at understanding the molecular basis underlying the severe constipation observed in patients. Methods: The Thra1PV/+ mouse expresses a strong dominant negative mutant, PV, which has lost T3 binding and transcription activity. Thra1PV/+ mouse faithfully reproduces growth abnormalities and anemia as shown in RTHα patients and therefore is a valid model to examine causes of severe constipation in patients. We used histopathological analysis, confocal fluorescence imaging, transmission electron microscopy (TEM), and gene expression profiles to comprehensively analyze the colonic abnormalities of Thra1PV/+ mouse. Results: We found a significant increase in colonic transit time and decrease stool water content in Thra1PV/+ mouse, mimicking constipation as found in patients. Histopathological analysis showed expanded lamina propria filled with interstitium fluid between crypt columns, enlarged muscularis mucosa, and increased content of collagen in expanded submucosa. The TEM analysis revealed shorter muscle fibers with wider gap junctions between muscle cells, fewer caveolae, and hypoplastic interstitial cells of Cajal (ICC) in the rectal smooth muscles of Thra1PV/+ mice. These abnormal histological manifestations suggested defective intercellular transfer of small molecules, electrolytes, and signals for communication among muscles cells, validated by Lucifer Yellow transferring assays. Expression of key smooth muscle contractility regulators, such as calmodulin, myosin light-chain kinase, and phosphorylated myosin light chain, was markedly lower, and c-KIT signaling in ICC was attenuated, resulting in decreased contractility of the rectal smooth muscles of Thra1PV/+ mice. Collectively, these abnormal histopathological alterations and diminished contractility regulators led to the constipation exhibited in patients. Conclusions: This is the first demonstration that TRα1 mutants could act to cause abnormal rectum smooth muscle organization, defects in intercellular exchange of small molecules, and decreased expression of contractility regulators to weaken the contractility of rectal smooth muscles. These findings provide new insights into the molecular basis underlying constipation found in RTHα patients.

[Therapeutic strategies for the treatment of endocrine resistant hormone receptor positive advanced breast cancer]. / Stratégies pour la prise en charge des cancers du sein métastatiques récepteurs hormonaux positifs hormonorésistants.

HR+ breast cancers are defined by the prominence of signaling pathways dependent on the estrogen receptor. Endocrine therapy is the standard treatment for these advanced diseases. Resistance to these treatments, called hormone resistance, appears invariably with biological mechanisms that have led to the development of therapeutic opportunities. An exhaustive literature review was carried out concerning the biology of the hormone resistance pathways, the therapeutic options before the era of CDK4/6 inhibitors, the rise of CDK4/6 inhibitors and the therapeutic prospects in a situation of hormone resistance. Various biological abnormalities have been identified in the mechanisms of hormone resistance such as changes in the estrogen receptor, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle deregulations. Historical strategies for circumventing this hormone resistance have been based on hormonal manipulation, on the development of new endocrine therapy such as fulvestrant (selective estrogen receptor inhibitor, SERD), on combinations of treatments such as everolimus, a mTOR inhibitor. This strategy combining endocrine therapy and targeted therapy has led to the development of combinations with CDK4/6 inhibitors which have now become a standard treatment in the hormone resistance phase. The future of this therapeutic era remains to be written with new combinations of hormone therapy and targeted therapy such as PI3K inhibitors or even with the positioning of new SERDs in clinical development.