Endocrine Research Articles

Small Cell Neuroendocrine Carcinoma of Cervix: A Rare Case Report

Neuroendocrine neoplasms (NEN) are derived from endocrine cells and are very rarely seen in gynecological practice. Here we report a case of small cell neuroendocrine carcinoma (SCNEC) of cervix in a 45 year old married female who presented with history of menorrhagia. On gynecological examination, she had bulky uterus with a palpable non tender, hard nodule on posterior wall of cervix. Ultrasonogram of pelvis was reported as bulky ? adenomyotic uterus with 2.7x2.4x1.0cm well defined collection in fundal region of endometrium. She underwent total abdominal hysterectomy for abnormal uterine bleeding. Histopathology with immunohistochemical markers was reported as small cell neuroendocrine carcinoma (SCNEC) of cervix. This case is reported here for its rarity.

Heterogenous expression of endocrine and progenitor cells within the neonatal porcine pancreatic lobes-Implications for neonatal porcine islet xenotransplantation.

Neonatal porcine islets (NPIs) are a source of islets for xenotransplantation. In the pig, the pancreatic lobes remain separate, thus, when optimizing NPI isolation, the pancreatic lobes included in the pancreatic digest should be specified. These lobes are the duodenal (DL), splenic (SL) and connecting (CL) lobe that correspond to the head, body-tail, and uncinate process of the human pancreas. In this study we are the first to evaluate all three neonatal porcine pancreatic lobes and NPIs isolated from these lobes. We report, a significant difference in endocrine and progenitor cell composition between lobes, and observed pancreatic duct glands (PDG) within the mesenchyme surrounding exocrine ducts in the DL and CL. Following in vitro differentiation, NPIs isolated from each lobe differed significantly in the percent increase of endocrine cells and final cell composition. Compared to other recipients, diabetic immunodeficient mice transplanted with NPIs isolated from the SL demonstrated euglycemic control as early as 4 weeks (p < 0.05) and achieved normoglycemia by 6 weeks post-transplant (p < 0.01). For the first time we report significant differences between the neonatal porcine pancreatic lobes and demonstrate that NPIs from these lobes differ in xenograft function.

The Impact of Different Implantation Sites and Sex on the Differentiation of Human Pancreatic Endoderm Cells Into Insulin-Secreting Cells InVivo.

Few studies have directly compared the differentiation of human embryonic stem cell-derived progenitors in different implantation sites in male and female recipients. We investigated whether the site of implantation and/or the sex of the recipient influenced the differentiation of pancreatic progenitors invivo in mice. Mice implanted with cells in macroencapsulation devices contained fewer off-target structures and developed stimulated insulin release faster than other implant sites, while females implanted with cells under the kidney capsule developed stimulated insulin release before males. Macroencapsulation devices reduced the formation of off-target cells from human embryonic stem cell-derived progenitors, a useful characteristic for clinical applications.

Contribution of Retrotransposons to the Pathogenesis of Type 1 Diabetes and Challenges in Analysis Methods.

Type 1 diabetes (T1D) is one of the most common chronic diseases of the endocrine system, associated with several life-threatening comorbidities. While the etiopathogenesis of T1D remains elusive, a combination of genetic susceptibility and environmental factors, such as microbial infections, are thought to be involved in the development of the disease. The prime model for studying the genetic component of T1D predisposition encompasses polymorphisms within the HLA (human leukocyte antigen) region responsible for the specificity of antigen presentation to lymphocytes. Apart from polymorphisms, genomic reorganization caused by repeat elements and endogenous viral elements (EVEs) might be involved in T1D predisposition. Such elements are human endogenous retroviruses (HERVs) and non-long terminal repeat (non-LTR) retrotransposons, including long and short interspersed nuclear elements (LINEs and SINEs). In line with their parasitic origin and selfish behaviour, retrotransposon-imposed gene regulation is a major source of genetic variation and instability in the human genome, and may represent the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. Autoreactive immune cell subtypes with differentially expressed retrotransposons can be identified with single-cell transcriptomics, and personalized assembled genomes can be constructed, which can then serve as a reference for predicting retrotransposon integration/restriction sites. Here we review what is known to date about retrotransposons, we discuss the involvement of viruses and retrotransposons in T1D predisposition, and finally we consider challenges in retrotransposons analysis methods.

Sequences of synaptogenesis in the human fetal and neonatal brain by synaptophysin immunocytochemistry.

Synaptogenesis is the final phase of axonal pathfinding. Its sequences of spatial and temporal development in the immature nervous system are precisely timed and consistent. Synaptophysin, a principal structural glycoprotein of synaptic vesicle membranes regardless of the chemical transmitter substance within, is a reliable means of demonstrating sequences of synaptogenesis in human fetal brain tissue at autopsy and is resistant to postmortem autolysis. Furthermore, synaptophysin molecules are demonstrated during axoplasmic flow before being assembled into membranes in immature axons and also mature axons of neurons with a high metabolic rate. In brain malformations these sequences often are altered both in distribution of synapses and in timing, often delayed but sometimes precocious, with postnatal clinical manifestations such as epilepsy and cognitive development.

β subunits of voltage-gated calcium channels in cardiovascular diseases.

Calcium signaling is required in bodily functions essential for survival, such as muscle contractions and neuronal communications. Of note, the voltage-gated calcium channels (VGCCs) expressed on muscle and neuronal cells, as well as some endocrine cells, are transmembrane protein complexes that allow for the selective entry of calcium ions into the cells. The α1 subunit constitutes the main pore-forming subunit that opens in response to membrane depolarization, and its biophysical functions are regulated by various auxiliary subunits-β, α2δ, and γ subunits. Within the cardiovascular system, the γ-subunit is not expressed and is therefore not discussed in this review. Because the α1 subunit is the pore-forming subunit, it is a prominent druggable target and the focus of many studies investigating potential therapeutic interventions for cardiovascular diseases. While this may be true, it should be noted that the direct inhibition of the α1 subunit may result in limited long-term cardiovascular benefits coupled with undesirable side effects, and that its expression and biophysical properties may depend largely on its auxiliary subunits. Indeed, the α2δ subunit has been reported to be essential for the membrane trafficking and expression of the α1 subunit. Furthermore, the β subunit not only prevents proteasomal degradation of the α1 subunit, but also directly modulates the biophysical properties of the α1 subunit, such as its voltage-dependent activities and open probabilities. More importantly, various isoforms of the β subunit have been found to differentially modulate the α1 subunit, and post-translational modifications of the β subunits further add to this complexity. These data suggest the possibility of the β subunit as a therapeutic target in cardiovascular diseases. However, emerging studies have reported the presence of cardiomyocyte membrane α1 subunit trafficking and expression in a β subunit-independent manner, which would undermine the efficacy of β subunit-targeting drugs. Nevertheless, a better understanding of the auxiliary β subunit would provide a more holistic approach when targeting the calcium channel complexes in treating cardiovascular diseases. Therefore, this review focuses on the post-translational modifications of the β subunit, as well as its role as an auxiliary subunit in modulating the calcium channel complexes.

Degradation of 2,4-diclorophenol via coupling zero valent iron and hydrodynamic cavitation for sulfite activation: A turbulence modeling

The 2,4-dichlorophenol (2,4-DCP) is an important chemical precursor that can affect human endocrine system and induce pathological symptoms. This research reports the degradation of 2,4-DCP using lab-scale hydrodynamic cavitation (HC) approach, which is considered a green and effective method. To promote the degradation efficiency, the zero-valent iron (Fe0) as the catalyst for sulfate radical (SO4•−) generation via activation of sulfite (SO32−) salts was simultaneously used. Degradation efficiency was favorable in acidic pH than the alkaline pH due to higher production of active radicals and was dependent on the dose of Fe0 and SO32−. Under optimal condition, degradation efficiency by Fe0/HC/sulfite (96.67 ± 2.90%) was considerably enhanced compared to HC alone (45.37 ± 2.26%). Quenching experiments suggested that SO4•−, •OH, 1O2, and O2•− radicals were involved in the degradation of 2,4-DCP by Fe0/HC/sulfite process, but the dominant role was related to •OH (70.09% contribution) and SO4•− (29.91% contribution) radicals. From the turbulence model, turbulent pressure at venturi throat decreased from −0.42 MPa to −2.02 MPa by increasing the inlet pressure from 1.0 to 4.0 bar and increase in pressure gradient has intensified bubble collapse due to higher turbulence tension.

Curcumin effects on Leydig cell functions and potential therapeutic uses.

Curcumin has been ascribed with countless therapeutic effects, but its impact on testicular function has been scarcely researched. Leydig cells comprise the androgen-secreting population of the testis and may give rise to Leydig cell tumours (LCTs). Due to their steroid-secreting nature, LCTs entail endocrine, reproductive, and psychological disorders. Approximately 10% are malignant and do not respond to chemotherapy and radiotherapy. The aim of this study was to assess curcumin's impact on Leydig cells' functions and its potential effect on LCT growth. In vitro assays on MA-10 Leydig cells showed that curcumin (20-80 µmol/L) stimulates acute steroidogenesis, both in the presence and absence of db-cAMP. This effect is accompanied by an increase in StAR expression. Regarding curcumin's in vitro cytostatic capacity, we show that 40-80 µmol/L curcumin reduces MA-10 Leydig cells' proliferative capacity, which could be explained by the arrest in G2/M and the reduced viability due to the activation of the apoptotic pathway. Finally, CB6F1 mice were inoculated with MA-10 cells to generate ectopic LCT in both flanks. They received i.p. injections of 20 mg/kg curcumin or vehicle every other day for 15 days. We unveiled curcumin's capacity to inhibit LCT growth as evidenced by reduced tumour volume, weight, and area under the growth curves. No detrimental effects on general health parameters or testicular integrity were observed. These results provide novel evidence of curcumin's effects on the endocrine cell population of the testis and propose this natural compound as a therapeutic agent for LCT.

Анализ заболеваемости населения старше трудоспособного возраста в Российской Федерации и ее региональные особенности

Objective assessment of the health status and medical care of the elderly in the context of progressive aging of the population is one of the leading health problems. Purpose of the study. Based on the analysis of the medical and demographic situation and the incidence of the population, as well as the results of our own research, to give recommendations on the health protection of the population older than working age. Research methods: statistical, sociological, expert assessments, direct observation. The forms of federal and sectoral statistical observation for 2018–2021 were analyzed. Results of sociological surveys of patients older than working age. Results. Over the 10 years of analysis (2012–2021), the overall incidence rate of the entire population in Russia increased by 4,5%, the adult population – by 8,2% and the working-age population – by 1.3%, in children and adolescents the indicators decreased by 8,8 and 4,7%. The overall incidence of the population older than working age in 2021 in the Russian Federation was 209164‰00, which is 1.2 times higher than the total population (167714‰00). The difference in the general morbidity rates of the population older than working age in the federal districts of the Russian Federation was 1.3 times, in the constituent entities of the Russian Federation 2.3 times. 2020, there is a significant decline in the overall incidence rate in all age groups, which is associated with the COVID‑19 pandemic. The first detected incidence of the population older than working age (in 2021) amounted to 66183,5 per 100 thousand of the corresponding population, which is lower than the total population by 22,6% (85531,6‰00). The population older than working age has significantly higher rates of newly diagnosed morbidity than the entire population in the classes: diseases of the circulatory system by 103%, the indicators were 6191,7‰00, 3048,3‰00, respectively; neoplasms (by 66%), musculoskeletal and connective tissue (by 16%) and diseases of the endocrine system, eating disorders and metabolic disorders (by 15,6%). The results of the study should be taken into account for planning the volume of preventive and dispensary work for people of older age groups. The article gives recommendations on the health protection of the population of pre-retirement and older working age using hospital-replacing technologies.

Real-world outcomes in patients with gastroenteropancreatic neuroendocrine tumors receiving somatostatin analogue: Data from a public hospital in Brazil.

650 Background: Neuroendocrine tumors are rare malignant neoplasms derived from endocrine cells and known for their heterogeneous behavior and histopathological characteristics; however, largely associated with a favorable clinical outcome. Somatostatin analogues (SSA) were initially used to control the symptoms of secretory neuroendocrine tumors, and later, they were considered effective as a first-line systemic treatment in unresectable or metastatic neuroendocrine tumors of the gastroenteropancreatic tract (NET-GEP). Randomized clinical trials are performed in controlled environments, with strict inclusion and exclusion criteria, and therefore, real-world studies can add to efficacy and safety data in the general population. Methods: To evaluate, in the real world scenario of a tertiary hospital of the public health system, the efficacy and toxicities of first-line treatment with somatostatin analogue in patients diagnosed with unresectable or metastatic NET-GEP, to find real-world progression free survival (rwPFS) and real-world overall survival (rwOS), in addition to the toxicity profile in our population and possible subgroups that benefit from first-line treatment, through the analysis of variables. Results: 29 patients met the study inclusion criteria, which were diagnosed in the period from 2009 to 2017. The median wrSLP and wrSG were 4.4 (95% CI 3.2 – 5.6) and 8.2 years (CI 95% 6.2 – 10.2), respectively. In an adjusted analysis of rwSLP, the HR for patients with hindgut tumors compared to midgut tumors was 4.41 with p 0.05, indicating that these patients had a 4x increased risk for disease progression (p 0 .05). In the adjusted analysis of wrSG, a trend towards a more favorable evolution was observed in the group of patients with well-differentiated tumors, with p 0.05. Assessment of toxicities revealed grade 2 and grade 3 adverse events in 34.48% of patients. Abdominal pain was the most incident toxicity, occurring in 17.24%, followed by headache (13.79%) and diarrhea (10.34%). Conclusions: Treatment with SSA was effective in our sample, with rwPFS and rwOS data above those found in randomized clinical trials. The toxicities were easily manageable and caused no documented harm to patients.

Viruses and Endocrine Diseases.

Viral infections have been frequently associated with physiological and pathological changes in the endocrine system for many years. The numerous early and late endocrine complications reported during the current pandemic of coronavirus disease 2019 (COVID-19) reinforce the relevance of improving our understanding of the impact of viral infections on the endocrine system. Several viruses have been shown to infect endocrine cells and induce endocrine system disturbances through the direct damage of these cells or through indirect mechanisms, especially the activation of the host antiviral immune response, which may lead to the development of local or systemic inflammation or organ-specific autoimmunity. In addition, endocrine disorders may also affect susceptibility to viral infections since endocrine hormones have immunoregulatory functions. This review provides a brief overview of the impact of viral infections on the human endocrine system in order to provide new avenues for the control of endocrine diseases.

Post-COVID Endocrine Disorders: Putative Role of Molecular Mimicry and Some Pathomorphological Correlates.

In order to identify corresponding amino acid sequences (pentapeptides) between the SPs, MPs and NPs of human coronaviruses and human autoantigens targeted in autoimmune endocrinopathies, and for a comparative analysis of the various coronaviruses proteome and the proteome of human, the original computer program was used. Quantitatively, SP, MP and NP of the human coronaviruses were found to share totally 117 minimal immune pentapeptide epitopes: 79 in SP, 14 in MP and 24 in NP, - with 18 autoantigens expressed by human endocrinocytes. The shared pentapeptides belong to the proteins of human endocrine cells. Samples of the pituitary, adrenal and thyroid from patients who died from coronavirus infection (COVID-19) were studied morphologically using histochemical methods. A high incidence of SARS-CoV-2 infection of endocrine cells was showed. The high affinity of SARS-CoV-2 the cells of the adenohypophysis was revealed, but there was no expression of viral proteins by the cells of the neurohypophysis. The foci of lesions in endocrine organs contained abundant lymphocytic infiltrates which may indicate the impact of autoimmune processes. Autoimmune disorders have a multi-faceted etiology and depend on polygenic predispose and additive action of many epigenetic and environmental factors causing hyperstimulation of imperfectly functioning immune system. It means that the phenomenon of molecular mimicry cannot be blamed as their single prerequisite, but it is just a tile in mosaic of autoimmunity. The facts revealed emphasize the need of endocrinological diagnostic alertness of a physician while observing patients with post-vaccination and post-COVID-19 health disorders.

Gastric endocrine cell hyperplasia after neoadjuvant therapy for poorly cohesive carcinoma: a diagnostic pitfall

Mucosal endocrine cell hyperplasia is a poorly described phenomenon that may occur following neoadjuvant therapy in a variety of gastrointestinal cancers. We describe two cases of poorly cohesive gastric carcinoma which underwent neoadjuvant chemotherapy. Subsequent biopsy and resection showed the presence of endocrine cells occurring singly and in micronests within the deep lamina propria, showing typical reactivity with synaptophysin and chromogranin. The distribution of these cells and cytokeratin positivity may mimic residual poorly cohesive carcinoma, particularly in small post-therapy biopsies. This phenomenon is thought to be related to normal mucosal elements being rendered relatively conspicuous by the depletion of malignant cells in cases with good neoadjuvant response. This treacherous finding may be misdiagnosed on small biopsies as residual malignancy, leading to potentially avoidable differences in subsequent management. This error may be avoided by awareness of this phenomenon and applying a simple panel of directed immunohistochemical markers, coupled with morphological correlation. Endocrine cell hyperplasia post neoadjuvant therapy in poorly cohesive carcinoma is a mimic of residual disease and may be result in false-positive interpretation of residual disease. Interpretation of post-treatment small biopsies should take into account this finding to avoid this potential clinically significant diagnostic pitfall.

Emerging role of UFMylation in secretory cells involved in the endocrine system by maintaining ER proteostasis.

Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like molecule (UBL) discovered almost two decades ago, but our knowledge about the cellular and molecular mechanisms of this novel protein post-translational modification is still very fragmentary. In this review, we first summarize the core enzymes and factors involved in the UFMylation cascade, which, similar to ubiquitin, is consecutively catalyzed by UFM1-activating enzyme 5 (UBA5), UFM1-conjugating enzyme 1 (UFC1) and UFM1-specific ligase 1 (UFL1). Inspired by the substantial implications of UFM1 machinery in the secretory pathway, we next concentrate on the puzzling role of UFMylation in maintaining ER protein homeostasis, intending to illustrate the underlying mechanisms and future perspectives. At last, given a robust ER network is a hallmark of healthy endocrine secretory cells, we emphasize the function of UFM1 modification in physiology and pathology in the context of endocrine glands pancreas and female ovaries, aiming to provide precise insight into other internal glands of the endocrine system.

Main parathyroid tumors

Primary hyperparathyroidism is the third most common disease of the endocrine system. It is characterized by an increase in parathyroid hormone, hypercalcemia, hypercalciuria, hypophosphatemia. Symptoms include polyuria, bone pain, weakness, and constipation. In most cases, primary hyperparathyroidism is caused by solitary parathyroid adenoma — 85%. Other causes include hyperplasia (5%), multiple adenomas (&lt;5%), and cancer (&lt;1%). However, particular attention in this article is paid to two causes of primary hyperparathyroidism: parathyroid adenoma and cancer, as they are of high interest both from a molecular point of view and from the clinical features of these tumors. In addition, these tumors overlap in their symptoms and signs and the diagnosis is often made only after histological examination. In total, we identified 2700 articles, of which 66 met the inclusion criteria. The 66 included studies were topical for tumor lesions of the parathyroid gland. They were held between 1997 and 2022. This review emphasizes the importance of further research of the molecular features of these diseases and, possibly, targeted treatment options, since, for example, in cancer, even with R0 resection, the risk of recurrence is high. The article also focuses on the issues of the new World Health Organization 2022 classification of tumor lesions of the parathyroid gland, which is also important for a unified study of these tumors.

Structural features of ghrelin-producing endocrine cells and their reactive changes after experimental stress

The work is devoted to the analysis of reactive changes in ghrelin-producing endocrine cells (HPEC) in the main areas of production of this regulatory peptide – in the stomach and hypothalamus during modeling of psycho-emotional stress and after replacement therapy. Reactive HPECs in experimental post stress disorder models have not previously been specifically studied. Meanwhile, the practice of modeling stress to establish the effectiveness of therapeutic interventions suggests the feasibility of obtaining new and informative criteria for assessing the degree of its impairment and therapeutic effect. The purpose of the study was to establish quantitative features and reactive changes in the GPEC of the stomach and hypothalamus in a model of psychogenic stress. Material and methods. We studied paraffin sections of the hypothalamus and the mucous membrane of the cardial part of the stomach in four groups of mature male rats. The first group (n=5) consisted of intact rats. The rest of the animals were subjected to a single emotional stress. In the nostrils of animals of two experimental groups (n=5 in each), 12 hours after stress, 20 μg of a solution of ghrelin (GHRL, Tocris, Gr. Brit.) and a peptide antagonist of ghrelin receptors ([D-Lys3]-GHRP-6, Tocris, Gr. Brit.). On the 4th day, animals were selected for the main control group (n=5). The number of endocrinocytes in the lateral part of the nuclei of the arcuate complex was counted over an area of 0,01 mm2, in the fundic glands of the stomach – over an area of 0,015 mm2; the area of endocrinocyte bodies was determined using the Imagescope program (Electronic analysis, Russia). The median, upper and lower quartiles, and the significance of their differences in the compared groups (using the nonparametric Mann–Whitney test) were measured using the GraphPad PRISM 6.0 program (GraphPad Software, USA). Differences were considered significant at p&lt;0,01. Results. During a short-term experience of psychogenic stress, the number of viable gastric and hypothalamic HPECs decreased by 2,5 and 3,8 times (respectively; p&lt;0.001), and their body area decreased by 1,5 and 1,6 times (p&lt;0,001). Pharmacological methods of correction did not significantly affect these parameters of HPEC (p&gt;0,05).

Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression

Aims/hypothesisGenome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk.MethodsA zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles.ResultsCRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function.Conclusions/interpretationTogether, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.Graphical abstract

Heterogeneity of Islet Cells during Embryogenesis and Differentiation.

Diabetes is caused by insufficient insulin secretion due to β-cell dysfunction and/or β-cell loss. Therefore, the restoration of functional β-cells by the induction of β-cell differentiation from embryonic stem (ES) and induced-pluripotent stem (iPS) cells, or from somatic non-β-cells, may be a promising curative therapy. To establish an efficient and feasible method for generating functional insulin-producing cells, comprehensive knowledge of pancreas development and β-cell differentiation, including the mechanisms driving cell fate decisions and endocrine cell maturation is crucial. Recent advances in single-cell RNA sequencing (scRNA-seq) technologies have opened a new era in pancreas development and diabetes research, leading to clarification of the detailed transcriptomes of individual insulin-producing cells. Such extensive high-resolution data enables the inference of developmental trajectories during cell transitions and gene regulatory networks. Additionally, advancements in stem cell research have not only enabled their immediate clinical application, but also has made it possible to observe the genetic dynamics of human cell development and maturation in a dish. In this review, we provide an overview of the heterogeneity of islet cells during embryogenesis and differentiation as demonstrated by scRNA-seq studies on the developing and adult pancreata, with implications for the future application of regenerative medicine for diabetes.

Applications of spatially resolved omics in the field of endocrine tumors.

Endocrine tumors derive from endocrine cells with high heterogeneity in function, structure and embryology, and are characteristic of a marked diversity and tissue heterogeneity. There are still challenges in analyzing the molecular alternations within the heterogeneous microenvironment for endocrine tumors. Recently, several proteomic, lipidomic and metabolomic platforms have been applied to the analysis of endocrine tumors to explore the cellular and molecular mechanisms of tumor genesis, progression and metastasis. In this review, we provide a comprehensive overview of spatially resolved proteomics, lipidomics and metabolomics guided by mass spectrometry imaging and spatially resolved microproteomics directed by microextraction and tandem mass spectrometry. In this regard, we will discuss different mass spectrometry imaging techniques, including secondary ion mass spectrometry, matrix-assisted laser desorption/ionization and desorption electrospray ionization. Additionally, we will highlight microextraction approaches such as laser capture microdissection and liquid microjunction extraction. With these methods, proteins can be extracted precisely from specific regions of the endocrine tumor. Finally, we compare applications of proteomic, lipidomic and metabolomic platforms in the field of endocrine tumors and outline their potentials in elucidating cellular and molecular processes involved in endocrine tumors.

Cause-Specific Mortality of Patients With Atrial Septal Defect and Up to 50 Years of Follow-Up.

Background This study aimed to evaluate the long-term mortality and cause-specific mortality of patients with atrial septal defect (ASD) in a nationwide cohort. Methods and Results All patients diagnosed with simple ASD in the hospital discharge registry from 1969 to 2019 were included in the study. Complex congenital defects were excluded. Each subject was matched with 5 controls according to sex, age, and municipality at the index time. Adjusted mortality risk ratios (MRRs) were calculated using Poisson regression models. The median follow-up time was 11.1 years. Patients with ASD had higher overall mortality during follow-up, with an adjusted MRR of 1.72 (95% CI, 1.61-1.83). Patients with closed ASDs also had higher total mortality (MRR, 1.29 [95% CI, 1.10-1.51]). However, no difference in mortality was detected if the defect was closed before the age of 30 (MRR, 1.58 [95% CI, 0.90-2.77]), and transcatheter closed defects had lower mortality than the control cohort (MRR, 0.65 [95% CI, 0.42-0.99]). Patients with ASD had significantly more deaths due to congenital malformations (MRR, 54.61 [95% CI, 34.03-87.64]), other diseases of the circulatory system (MRR, 2.90 [95% CI, 2.42-3.49]), stroke (MRR, 1.89 [95% CI, 1.52-2.33]), diseases of the endocrine (MRR, 1.88 [95% CI, 1.10-3.22]) and respiratory system (MRR, 1.71 [95% CI, 1.19-2.45]), ischemic heart disease (MRR, 1.62 [95% CI, 1.41-1.86]), and accidents (MRR, 1.41 [95% CI, 1.05-1.89]). Conclusions Patients with ASD had higher overall mortality compared with a matched general population cohort. Increased cause-specific mortality was seen in congenital malformations, stroke, and heart diseases.