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1.
Endocrine ; 85(3): 1346-1356, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38851643

RESUMO

PURPOSE: Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. METHODS: The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. RESULTS: Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). CONCLUSION: Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.


Assuntos
Acromegalia , Gigantismo , Peptídeos e Proteínas de Sinalização Intracelular , Humanos , Acromegalia/genética , Masculino , Feminino , Adulto , Gigantismo/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Adulto Jovem , Adolescente , Criança , Povo Asiático/genética , Mutação em Linhagem Germinativa , Estudos de Coortes , Pessoa de Meia-Idade , China , Pré-Escolar , População do Leste Asiático
3.
Endocr Rev ; 45(5): 737-754, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-38696651

RESUMO

Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of patients with pituitary gigantism have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH-releasing hormone is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G-protein-coupled receptor, GPR101. This leads to the formation of a neo-TAD in which GPR101 overexpression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in 3 families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1, and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Gigantismo , Humanos , Gigantismo/genética , Gigantismo/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/genética , Acromegalia/genética , Acromegalia/terapia
5.
Best Pract Res Clin Endocrinol Metab ; 38(3): 101892, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38521632

RESUMO

It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide.


Assuntos
Acromegalia , Testes Genéticos , Gigantismo , Humanos , Acromegalia/genética , Acromegalia/diagnóstico , Acromegalia/terapia , Gigantismo/genética , Gigantismo/diagnóstico , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia
6.
BMJ Case Rep ; 17(3)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38442972

RESUMO

A newborn baby born at 34 weeks and 5 days gestation was admitted for prematurity, dysmorphic features and congenital heart defects. Antenatal scan at 21 weeks showed a large-for-gestational-age foetus with a large abdominal circumference and liver, ventricular septal defect, right prominent renal pelvis and echogenic bowel. Antenatal genetic tests for overgrowth syndromes were negative. The mother had early onset pre-eclampsia. After birth, an overgrowth syndrome was still suspected despite the baby having normal birth parameters. Raw data of the trio whole exome sequencing from the amniocentesis sample were manually inspected. Hemizygous exon 7 deletion in the GPC3 gene was found, and a postnatal diagnosis of Simpson-Golabi-Behmel syndrome, a rare overgrowth syndrome, was made. This case report discusses the significance of antenatal findings, an atypical presentation of a rare syndrome and the obstacles of diagnostic genetic testing.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Gigantismo , Cardiopatias Congênitas , Deficiência Intelectual , Feminino , Humanos , Recém-Nascido , Gravidez , Arritmias Cardíacas , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/diagnóstico , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética
7.
Clin Endocrinol (Oxf) ; 100(6): 542-557, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38549284

RESUMO

OBJECTIVE: Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion of acromegaly. DESIGN/PATIENTS: PubMed/Medline search was conducted to identify reported pseudoacromegaly cases, which were systematically reviewed to ensure they met eligibility criteria: (1) presentation suggestive of acromegaly; (2) acromegaly excluded based on normal GH, IGF-1 and/or GH suppression on oral glucose tolerance test (OGTT-GH); (3) diagnosis of the pseudoacromegaly condition was established. Data were retrieved from each case and analysed collectively. RESULTS: Of 76 cases, 47 were males, mean ages at presentation and at first acromegaloid symptoms were 28 ± 16 and 17 ± 10 years, respectively. Most common conditions were pachydermoperiostosis (47%) and insulin-mediated pseudoacromegaly (IMP) (24%). Acromegaloid facies (75%) and acral enlargement (80%) were the most common features. Measurement of random GH was reported in 65%, IGF-1 in 79%, OGTT-GH in 51%. GH excess was more frequently excluded based on two tests (53%). Magnetic resonance imaging (MRI) was performed in 30 patients, with pituitary adenoma or hyperplasia being reported in eight and three patients, respectively. Investigations differed between cases managed by endocrine and non-endocrine specialists, the former requesting more often IGF-1, OGTT-GH and pituitary MRI. CONCLUSIONS: Pseudoacromegaly is a challenging entity that may be encountered by endocrinologists. Pachydermoperiostosis and IMP are the conditions most often mimicking acromegaly. Adequate assessment of GH/IGF-1 is crucial to exclude acromegaly, which may be better performed by endocrinologists. Pituitary incidentalomas are common and require careful judgement to prevent unnecessary pituitary surgery.


Assuntos
Acromegalia , Fator de Crescimento Insulin-Like I , Humanos , Acromegalia/diagnóstico , Acromegalia/sangue , Masculino , Fator de Crescimento Insulin-Like I/análise , Feminino , Adulto , Hormônio do Crescimento Humano/sangue , Gigantismo/diagnóstico , Teste de Tolerância a Glucose , Adolescente , Adulto Jovem
8.
Front Endocrinol (Lausanne) ; 15: 1345363, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481440

RESUMO

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.


Assuntos
Acromegalia , Doenças Genéticas Ligadas ao Cromossomo X , Gigantismo , Hormônio do Crescimento Humano , Neoplasias Hipofisárias , Adulto , Humanos , Criança , Feminino , Pré-Escolar , Gigantismo/genética , Gigantismo/terapia , Gigantismo/metabolismo , Acromegalia/patologia , Hormônio do Crescimento/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia
9.
Endocrinology ; 165(5)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38500360

RESUMO

Acromegaly and gigantism are disorders caused by hypersecretion of growth hormone (GH), usually from pituitary adenomas. Although somatostatin analogues (SSA), dopamine agonists, and GH receptor antagonists are important therapeutic agents, all of these have issues with their effectiveness, safety, and/or convenience of use. To overcome these, we developed a GH-specific potent neutralizing a mouse monoclonal antibody (mAb) named 13H02. 13H02 selectively bound both to human and monkey GH with high affinity, and strongly inhibited the biological activity of GH in the Nb2 rat lymphoma cell proliferation assay. In hypophysectomized/GH-supplemented rats, a single subcutaneous administration of 13H02 significantly and dose-dependently lowered the serum insulin-like growth factor-1 levels. To pursue the therapeutic potential of this antibody for acromegaly and gigantism, we humanized 13H02 to reduce its immunogenicity and applied a single amino acid mutation in the Fc region to extend its serum half-life. The resulting antibody, Hu-13H02m, also showed GH-specific neutralizing activity, similar to the parental 13H02, and showed improved binding affinity to human FcRn.


Assuntos
Acromegalia , Gigantismo , Hormônio do Crescimento Humano , Camundongos , Humanos , Feminino , Animais , Ratos , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento Humano/metabolismo , Acromegalia/tratamento farmacológico , Gigantismo/complicações , Gigantismo/tratamento farmacológico , Peptídeos Semelhantes à Insulina , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico
11.
Int J Mol Sci ; 25(4)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38396763

RESUMO

Epidemiological evidence emphasizes that excess fat mass is associated with an increased risk of severe COVID-19 disease. Nevertheless, the intricate interplay between SARS-CoV-2 and adipocytes remains poorly understood. It is crucial to decipher the progression of COVID-19 both in the acute phase and on long-term outcomes. In this study, an in vitro model using the human SGBS cell line (Simpson-Golabi-Behmel syndrome) was developed to investigate the infectivity of SARS-CoV-2 in adipocytes, and the effects of virus exposure on adipocyte function. Our results show that SGBS adipocytes expressing ACE2 are susceptible to SARS-CoV-2 infection, as evidenced by the release of the viral genome into the medium, detection of the nucleocapsid in cell lysates, and positive immunostaining for the spike protein. Infected adipocytes show remarkable changes compared to uninfected controls: increased surface area of lipid droplets, upregulated expression of genes of inflammation (Haptoglobin, MCP-1, IL-6, PAI-1), increased oxidative stress (MnSOD), and a concomitant reduction of transcripts related to adipocyte function (leptin, fatty acid synthase, perilipin). Moreover, exogenous expression of spike protein in SGBS adipocytes also led to an increase in lipid droplet size. In conclusion using the human SGBS cell line, we detected SARS-CoV-2 infectivity in adipocytes, revealing substantial morphological and functional changes in infected cells.


Assuntos
Arritmias Cardíacas , COVID-19 , Doenças Genéticas Ligadas ao Cromossomo X , Gigantismo , Cardiopatias Congênitas , Deficiência Intelectual , Glicoproteína da Espícula de Coronavírus , Humanos , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Cultivadas , COVID-19/metabolismo , SARS-CoV-2 , Adipócitos/metabolismo , Fenótipo , Expressão Gênica
12.
Eur J Endocrinol ; 190(3): 193-200, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38391173

RESUMO

OBJECTIVES: Increased height in patients with acromegaly could be a manifestation of growth hormone (GH) excess before epiphysis closure. The aim of this study was to evaluate the relationship between the height of adult patients with GH excess related to mid-parental height (MPH) and population mean and to find whether taller patients with acromegaly come from tall families. METHODS: This is a single-centre, observational study involving 135 consecutive patients with acromegaly diagnosed as adults and no family history of GH excess. We established three categories for height for patients with acromegaly: normal stature, tall stature (TS, height above the 97th percentile (1.88 standard deviations (SD)) to <3 SD for gender- and country-specific data or as a height which was greater than 1.5 SD but less than 2 SD above the MPH) and gigantism (height which was greater than 3 SD) above the gender- and country-specific mean or greater than 2 SD above MPH). RESULTS: Thirteen percent (17/135) of patients (53% females) met the criteria for gigantism, 10% (14/135) fulfilled the criteria for TS (57% females). Parents and adult siblings were not taller than the population mean. CONCLUSION: In a group of 135 consecutive adult patients with acromegaly, 23% had increased height based on country-specific and MPH data: 13% presented with gigantism while 10% had TS. The frequency of gigantism and TS in patients diagnosed with GH excess as adults is not higher in males than in females. Patients with acromegaly come from normal-stature families.


Assuntos
Acromegalia , Gigantismo , Adulto , Feminino , Masculino , Humanos , Acromegalia/complicações , Acromegalia/epidemiologia , Gigantismo/etiologia , Osteogênese , Pais
13.
Sci Rep ; 13(1): 22124, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38212342

RESUMO

Tyrannosaurid dinosaurs dominated as predators in the Late Cretaceous of Laurasia, culminating in the evolution of the giant Tyrannosaurus rex, both the last and largest tyrannosaurid. Where and when Tyrannosaurini (T. rex and kin) originated remains unclear. Competing hypotheses place tyrannosaurin origins in Asia, or western North America (Laramidia). We report a new tyrannosaurin, Tyrannosaurus mcraeensis, from the Campanian-Maastrichtian Hall Lake Formation of New Mexico, based on a fossil previously referred to T. rex. T. mcraeensis predates T. rex by ~ 6-7 million years, yet rivaled it in size. Phylogenetic analysis recovers T. mcraeensis as sister to T. rex and suggests Tyrannosaurini originated in southern Laramidia. Evolution of giant tyrannosaurs in southern North America, alongside giant ceratopsians, hadrosaurs, and titanosaurs suggests large-bodied dinosaurs evolved at low latitudes in North America.


Assuntos
Dinossauros , Gigantismo , Animais , Filogenia , Fósseis , América do Norte , New Mexico , Dinossauros/anatomia & histologia , Evolução Biológica
14.
J Endocrinol Invest ; 47(4): 777-793, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37891382

RESUMO

PURPOSE: Tall stature is defined as height greater than the threshold of more than 2 standard deviations above the average population height for age, sex, and ethnicity. Many studies have described the main aspects of this condition during puberty, but an analysis of the characteristics that the physician should consider in the differential diagnosis of gigantism-tall stature secondary to a pituitary tumour-during the transition age (15-25 years) is still lacking. METHODS: A comprehensive search of English-language original articles was conducted in the MEDLINE database (December 2021-March 2022). We selected all studies regarding epidemiology, genetic aspects, and the diagnosis of tall stature and gigantism during the transition age. RESULTS: Generally, referrals for tall stature are not as frequent as expected because most cases are familial and are usually unreported by parents and patients to endocrinologists. For this reason, lacking such experience of tall stature, familiarity with many rarer overgrowth syndromes is essential. In the transition age, it is important but challenging to distinguish adolescents with high constitutional stature from those with gigantism. Pituitary gigantism is a rare disease in the transition age, but its systemic complications are very relevant for future health. Endocrine evaluation is crucial for identifying conditions that require hormonal treatment so that they can be treated early to improve the quality of life and prevent comorbidities of individual patient in this age range. CONCLUSION: The aim of our review is to provide a practical clinical approach to recognise adolescents, potentially affected by gigantism, as early as possible.


Assuntos
Gigantismo , Adolescente , Humanos , Adulto Jovem , Adulto , Qualidade de Vida , Síndrome , Diagnóstico Diferencial , Estatura
15.
Clin Neuropathol ; 43(1): 10-22, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38085092

RESUMO

Two of the rarest radiation-induced adverse effects are focal neuronal gigantism (FNG) and SMART syndrome (stroke-like migraine attacks after radiation therapy). Both conditions develop years, and sometimes decades, after receipt of therapeutic radiation to the brain. To date, there are only 3 previously reported cases of FNG, all of which describe cortical thickening, enlarged "hypertrophic" neurons, and neuronal cytological changes. No detailed studies exist of histological features of SMART or the comparison between FNG and SMART. In this study, we contrast histological and neuroimaging features of 3 FNG vs. 4 SMART cases, the latter diagnosed by a neuroradiologist, neurooncologist, and/or neurosurgeon. We confirm the cortical thickening, dyslamination, neuronal cytomegaly, and gliosis in FNG vs. cortical architectural preservation and normal neuronal cytology in SMART, although both showed gliosis, scattered neurons with cytoplasmic accumulation of tau and neurofibrillary protein and variable co-existence of other radiation-induced lesions. Both conditions lacked significant inflammation or consistent small vessel hyalinization throughout the entire resection specimen. The absence of pathognomonic histologic alterations in SMART cases suggests underlying vascular dysregulation. Despite differing histology, some overlap may exist in neuroimaging features. Molecular assessment conducted in 2 cases of FNG was negative for significant alterations including in the MAPK pathway.


Assuntos
Gigantismo , Humanos , Gigantismo/patologia , Gliose/patologia , Encéfalo/patologia , Neuroimagem , Neurônios
16.
J Mol Graph Model ; 127: 108676, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38006624

RESUMO

GPR101 is a G protein-coupled receptor (GPCR) implicated in a rare form of genetic gigantism known as X-linked acrogigantism, or X-LAG. In particular, X-LAG patients harbor microduplications in the long arm of the X-chromosome that invariably include the GPR101 gene. Duplications of the GPR101 gene lead to the formation of a new chromatin domain that causes over-expression of the receptor in the pituitary tumors of the patients. Notably, GPR101 is a constitutively active receptor, which stimulates cells to produce the second messenger cyclic AMP (cAMP) in the absence of ligands. Moreover, GPR101 was recently reported to constitutively activate not only the cAMP pathway via Gs, but also other G protein subunits (Gq/11 and G12/13). Hence, chemicals that block the constitutive activity of GPR101, known as inverse agonists, have the potential to be useful for the development of pharmacological tools for the treatment of X-LAG. In this study, we provide structural insights into the putative structure of GPR101 based on in-house built homology models, as well as third party models based on the machine learning methods AlphaFold and AlphaFold-Multistate. Moreover, we report a molecular dynamics study, meant to further probe the constitutive activity of GPR101. Finally, we provide a structural comparison with the closest GPCRs, which suggests that GPR101 does not share their natural ligands. While this manuscript was under review, cryo-electron microscopy structures of GPR101 were reported. These structures are expected to enable computer-aided ligand discovery efforts targeting GPR101.


Assuntos
Acromegalia , Gigantismo , Humanos , Gigantismo/genética , Gigantismo/patologia , Microscopia Crioeletrônica , Agonismo Inverso de Drogas , Acromegalia/genética , Acromegalia/patologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/química
17.
Biol Lett ; 19(11): 20230331, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37935371

RESUMO

The order Lamniformes contains charismatic species such as the white shark Carcharodon carcharias and extinct megatooth shark Otodus megalodon, and is of particular interest given their influence on marine ecosystems, and because some members exhibit regional endothermy. However, there remains significant debate surrounding the prevalence and evolutionary origin of regional endothermy in the order, and therefore the development of phenomena such as gigantism and filter-feeding in sharks generally. Here we show a basal lamniform shark, the smalltooth sand tiger shark Odontaspis ferox, has centralized skeletal red muscle and a thick compact-walled ventricle; anatomical features generally consistent with regionally endothermy. This result, together with the recent discovery of probable red muscle endothermy in filter feeding basking sharks Cetorhinus maximus, suggests that this thermophysiology is more prevalent in the Lamniformes than previously thought, which in turn has implications for understanding the evolution of regional endothermy, gigantism, and extinction risk of warm-bodied shark species both past and present.


Assuntos
Gigantismo , Tubarões , Animais , Tubarões/fisiologia , Ecossistema , Prevalência , Músculo Esquelético
18.
Ann Bot ; 132(7): 1233-1248, 2023 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-37818893

RESUMO

BACKGROUND AND AIMS: Gigantism is a key component of the domestication syndrome, a suite of traits that differentiates crops from their wild relatives. Allometric gigantism is strongly marked in horticultural crops, causing disproportionate increases in the size of edible parts such as stems, leaves or fruits. Tomato (Solanum lycopersicum) has attracted attention as a model for fruit gigantism, and many genes have been described controlling this trait. However, the genetic basis of a corresponding increase in size of vegetative organs contributing to isometric gigantism has remained relatively unexplored. METHODS: Here, we identified a 0.4-Mb region on chromosome 7 in introgression lines (ILs) from the wild species Solanum pennellii in two different tomato genetic backgrounds (cv. 'M82' and cv. 'Micro-Tom') that controls vegetative and reproductive organ size in tomato. The locus, named ORGAN SIZE (ORG), was fine-mapped using genotype-by-sequencing. A survey of the literature revealed that ORG overlaps with previously mapped quantitative trait loci controlling tomato fruit weight during domestication. KEY RESULTS: Alleles from the wild species led to lower cell number in different organs, which was partially compensated by greater cell expansion in leaves, but not in fruits. The result was a proportional reduction in leaf, flower and fruit size in the ILs harbouring the alleles from the wild species. CONCLUSIONS: Our findings suggest that selection for large fruit during domestication also tends to select for increases in leaf size by influencing cell division. Since leaf size is relevant for both source-sink balance and crop adaptation to different environments, the discovery of ORG could allow fine-tuning of these parameters.


Assuntos
Gigantismo , Solanum lycopersicum , Solanum , Solanum lycopersicum/genética , Tamanho do Órgão/genética , Gigantismo/genética , Locos de Características Quantitativas/genética , Solanum/genética , Frutas/genética
19.
Proc Natl Acad Sci U S A ; 120(27): e2218153120, 2023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-37364100

RESUMO

The evolution of the extinct megatooth shark, Otodus megalodon, and its close phylogenetic relatives remains enigmatic. A central question persists regarding the thermophysiological origins of these large predatory sharks through geologic time, including whether O. megalodon was ectothermic or endothermic (including regional endothermy), and whether its thermophysiology could help to explain the iconic shark's gigantism and eventual demise during the Pliocene. To address these uncertainties, we present unique geochemical evidence for thermoregulation in O. megalodon from both clumped isotope paleothermometry and phosphate oxygen isotopes. Our results show that O. megalodon had an overall warmer body temperature compared with its ambient environment and other coexisting shark species, providing quantitative and experimental support for recent biophysical modeling studies that suggest endothermy was one of the key drivers for gigantism in O. megalodon and other lamniform sharks. The gigantic body size with high metabolic costs of having high body temperatures may have contributed to the vulnerability of Otodus species to extinction when compared to other sympatric sharks that survived the Pliocene epoch.


Assuntos
Gigantismo , Tubarões , Animais , Tubarões/fisiologia , Filogenia , Regulação da Temperatura Corporal/fisiologia , Tamanho Corporal
20.
Pituitary ; 26(4): 333-339, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37270760

RESUMO

PURPOSE: We present a historical overview on neuropathic ulcers in patients with acromegalic gigantism. MATERIALS AND METHODS: The case histories of 6 famous patients with acromegalic gigantism and living in the twentieth century were analyzed. The combined final height and maximum weight of these giants were: 272 cm. & 215.9 kg., 218.4 cm. & 125 kg., 242 cm. & 165 kg., 220.5 cm. & 135 kg., 235 cm. & 136 kg. and 224.8 cm. & 174 kg. CONCLUSIONS: Neuropathic foot ulcers leading to hospital admissions and surgical and medical interventions were reported in 6 patients with acromegalic gigantism. These ulcers significantly impaired the daily activities of these individuals. Neuropathies of the sural nerve in patients with acromegalic gigantism can lead to hypoesthesia and hypoalgesia of the lower legs and feet. Potential contributing factors for the development of neuropathic ulcers of the feet in patients with acromegalic gigantism and neuropathy might be leg and foot deformities, muscle weakness and poor quality footwear. Diabetes mellitus, or impaired glucose intolerance does not necessarily seem to play a role.


Assuntos
Acromegalia , Pé Diabético , Gigantismo , Humanos , Úlcera ,
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