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Endokrynologia Polska Jun 2024Not required for Clinical Vignette.
Not required for Clinical Vignette.
PubMed: 38887119
DOI: 10.5603/ep.99763 -
Proceedings of the National Academy of... Jun 2024Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two...
Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two high-resolution cryogenicelectron microscope structures of the SSTR5-G complexes bound to the cyclic neuropeptide agonists, cortistatin-17 (CST17) and octreotide, with resolutions of 2.7 Å and 2.9 Å, respectively. The structures reveal that binding of these peptides causes rearrangement of a "hydrophobic lock", consisting of residues from transmembrane helices TM3 and TM6. This rearrangement triggers outward movement of TM6, enabling Gα protein engagement and receptor activation. In addition to hydrophobic interactions, CST17 forms conserved polar contacts similar to somatostatin-14 binding to SSTR2, while further structural and functional analysis shows that extracellular loops differently recognize CST17 and octreotide. These insights elucidate agonist selectivity and activation mechanisms of SSTR5, providing valuable guidance for structure-based drug development targeting this therapeutically relevant receptor.
Topics: Receptors, Somatostatin; Humans; Octreotide; Neuropeptides; Cryoelectron Microscopy; Protein Binding; Peptides, Cyclic; Somatostatin; Models, Molecular; HEK293 Cells
PubMed: 38885377
DOI: 10.1073/pnas.2321710121 -
Zhurnal Voprosy Neirokhirurgii Imeni N.... 2024Despite slow growth of most pituitary tumors and high rates of total resection and/or effective therapy, pituitary neoplasms are characterized by aggressive behavior... (Review)
Review
Despite slow growth of most pituitary tumors and high rates of total resection and/or effective therapy, pituitary neoplasms are characterized by aggressive behavior with high growth rate, frequent relapses and resistance to standard treatments in 10% of cases. In modern WHO classifications of tumors of the central nervous system, endocrine and neuroendocrine tumors, the authors propose the definition «pituitary neuroendocrine tumor» instead of previous «pituitary adenoma» and «metastasizing pituitary neuroendocrine tumor» instead of «pituitary carcinoma». Currently, there are no effective prognostic markers of aggressive tumors. This complicates early diagnosis. It is proposed to apply a five-stage prognostic classification based on proliferation rate (including mitotic count, Ki-67 index and p53 immunoexpression) and morphometric markers of invasiveness for all resected pituitary neoplasms. This approach would be valuable for earlier detection of aggressive tumors and pituitary carcinomas. Compression of visual pathways, third ventricle and brain stem due to rapid growth of aggressive tumors usually requires redo surgeries with subsequent radiotherapy. Hormonally active tumors require therapy with somatostatin analogues and dopamine agonists in maximum possible doses. Chemotherapy with temozolomide as first-line option is recommended if standard treatment is ineffective. Alternative treatment includes peptide receptor radionuclide therapy (PRRT), molecular targeted therapy (bevacizumab, tyrosine kinase inhibitors, everolimus and cyclin-dependent kinase inhibitors) and immunotherapy (checkpoint inhibitors). Considering the need for combined treatment, these cases should always be discussed by a multidisciplinary team (neurosurgeon, endocrinologist, radiotherapist, oncologist, pathologist) with necessary qualifications and experience in treating these patients. Treatment of aggressive tumors and pituitary carcinomas is becoming an active and rapidly developing direction in neurosurgery, endocrinology and oncology.
Topics: Humans; Pituitary Neoplasms
PubMed: 38881023
DOI: 10.17116/neiro202488031103 -
European Journal of Nuclear Medicine... Jun 2024F-labelled somatostatin receptor (SSTR) analogs offer several advantages over Ga in terms of yield, cost, spatial resolution and detection rate. This study presents an...
Evaluation of the safety, biodistribution, dosimetry of [F]AlF-NOTA-LM3 and head-to-head comparison with [Ga]Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors: an interim analysis of a prospective trial.
PURPOSE
F-labelled somatostatin receptor (SSTR) analogs offer several advantages over Ga in terms of yield, cost, spatial resolution and detection rate. This study presents an interim analysis of a prospective trial designed to assess the safety, biodistribution and dosimetry of [F]AlF-NOTA-LM3, and compare its diagnostic efficacy and clinical management outcomes with [Ga]Ga-DOTATATE or [Ga]Ga-NODAGA-LM3 in patients with well-differentiated NETs.
METHODS
Twenty-one patients with histologically confirmed well-differentiated neuroendocrine tumors (G1 and G2) were prospectively recruited. The first eight patients underwent serial PET scans at 5, 15, 30, 45, 60, and 120 min after [F]AlF-NOTA-LM3 injection to assess biodistribution and dosimetry. The remaining patients underwent whole-body PET/CT scans. [F]AlF-NOTA-LM3 and [68Ga]Ga-DOTATATE PET/CT were done within a week, with a minimum 24-hour interval between the two scans. Focal uptake above the surrounding background activity and could not be explained by physiologic uptake was considered lesions of NETs. Lesion number, tumor uptake, and tumor-to-background ratio (TBR) were compared. In patients with discrepant findings, the size of the smallest lesions (measured on coregistered CT) detected on [Ga]Ga-DOTATATE and [F]AlF-NOTA-LM3 was compared.
RESULTS
[F]AlF-NOTA-LM3 was safe and well-tolerated. Physiological uptake of [F]AlF-NOTA-LM3 was significantly lower than that of [Ga]Ga-DOTATATE in abdominal organs and bone marrow, but higher in blood pool and lung. The mean effective dose was 0.024 ± 0.014 mSv/MBq. [F]AlF-NOTA-LM3 detected significantly more liver lesions (457 vs. 291, P = 0.006) and lymph node lesions (30 vs. 22, P = 0.011) compared to [Ga]Ga-DOTATATE. The tumor uptake was comparable, but TBR was significantly higher with [F]AlF-NOTA-LM3 for lesions from all sites except for the duodenum. The size of the minimum liver lesions (0.54 ± 0.15 vs. 1.01 ± 0.49, P<0.001) and lymph node lesions (0.50 ± 0.19 vs. 1.26 ± 0.86, P = 0.024) detected on [F]ALF-NOTA-LM3 were significantly smaller than those detected on [Ga]Ga-DOTATATE.
CONCLUSION
[F]AlF-NOTA-LM3 shows favorable biodistribution, higher spatial resolution and superior performance than [Ga]Ga-DOTATATE in detecting liver and lymph node metastases, with higher TBR. Notably, it is the first SSTR analog to show superiority in detecting lymph node lesions when compared to [Ga]Ga-DOTATATE.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT06056362.
PubMed: 38878175
DOI: 10.1007/s00259-024-06790-y -
Advances in Neurobiology 2024Understanding the relationship between stress and breast cancer development is essential to preventing and alleviating the cancer. Recent research has shed light on the...
Understanding the relationship between stress and breast cancer development is essential to preventing and alleviating the cancer. Recent research has shed light on the cognitive, physiological, cellular, and molecular underpinnings of how the endorphin pathway and stress pathway affect breast cancer. This chapter consists of two parts. Part 1 will discuss the role of endorphins in breast cancer development. This includes a discussion of three topics: (1) the neurophysiological effect of endorphins on breast tumor growth in vivo, along with further experiments that will deepen our knowledge of how β-endorphin affects breast cancer; (2) how both the opioid receptor and somatostatin receptor classes alter intracellular signaling in breast cancer cells; and (3) genetic alleles in the opioid signaling pathway that are correlated with increased breast cancer risk. Part 2 will discuss the role of endorphins in recovery from breast cancer. This includes a discussion of three topics: (1) the relationship between breast cancer diagnosis and depression; (2) the effectiveness of cognitive behavioral therapy in reducing stress in breast cancer patients; and (3) the effect of psychotherapy and exercise on preserving telomere length in breast cancer patients.
Topics: Animals; Female; Humans; beta-Endorphin; Breast Neoplasms; Cognitive Behavioral Therapy; Depression; Endorphins; Receptors, Opioid; Signal Transduction; Stress, Psychological
PubMed: 38874719
DOI: 10.1007/978-3-031-45493-6_5 -
Schizophrenia Bulletin Jun 2024The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given...
BACKGROUND
The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given the evidence for GABAergic, cholinergic, and neurodevelopmental disturbances in schizophrenia, we tested the potential involvement of GE neuron development in mediating genetic risk for the condition.
STUDY DESIGN
We combined data from a recent large-scale genome-wide association study of schizophrenia with single-cell RNA sequencing data from the human GE to test the enrichment of schizophrenia risk variation in genes with high expression specificity for developing GE cell populations. We additionally performed the single nuclei Assay for Transposase-Accessible Chromatin with Sequencing (snATAC-Seq) to map potential regulatory genomic regions operating in individual cell populations of the human GE, using these to test for enrichment of schizophrenia common genetic variant liability and to functionally annotate non-coding variants-associated with the disorder.
STUDY RESULTS
Schizophrenia common variant liability was enriched in genes with high expression specificity for developing neuron populations that are predicted to form dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons of the striatum, cortical somatostatin-positive GABAergic interneurons, calretinin-positive GABAergic neurons, and cholinergic neurons. Consistent with these findings, schizophrenia genetic risk was concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the GE.
CONCLUSIONS
Our study implicates prenatal development of specific populations of GABAergic and cholinergic neurons in later susceptibility to schizophrenia, and provides a map of predicted regulatory genomic elements operating in cells of the GE.
PubMed: 38869145
DOI: 10.1093/schbul/sbae083 -
Mucosal Immunology Jun 2024Corneal wound healing in diabetic patients is usually delayed and accompanied by excessive inflammation. However, the underlying cellular and molecular mechanisms remain...
Corneal wound healing in diabetic patients is usually delayed and accompanied by excessive inflammation. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we found that somatostatin (SST), an immunosuppressive peptide produced by corneal nerve fibers, was significantly reduced in streptozotocin-induced diabetic mice. In addition, we discovered that topical administration of exogenous SST significantly improved re-epithelialization and nerve regeneration following diabetic corneal epithelial abrasion. Further analysis showed that topical SST significantly reduced the expression of injury inflammation-related genes, inhibited neutrophil infiltration and shifted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 in diabetic corneas' healing. Moreover, the application of L-817,818, an agonist of the SST receptor type 5 subtype, significantly reduced the inflammatory response following epithelial injury and markedly improved the process of re-epithelialization and nerve regeneration in mice. Taken together, these data suggest that activation of the SST-SSTR5 pathway significantly ameliorates diabetes-induced abnormalities in corneal wound repair in mice. Targeting this pathway may provide a novel strategy to restore impaired corneal wound closure and nerve regeneration in diabetic patients.
PubMed: 38866206
DOI: 10.1016/j.mucimm.2024.06.002 -
Clinical Endocrinology Jun 2024Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several...
OBJECTIVE
Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.
METHODS
A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale.
RESULTS
Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.
CONCLUSION
This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
PubMed: 38865284
DOI: 10.1111/cen.15095 -
The Quarterly Journal of Nuclear... Jun 2024Theragnostics represents one of the most innovative fields of precision medicine with a huge potential in the field of oncology in the next years. The use of a pair of... (Review)
Review
Theragnostics represents one of the most innovative fields of precision medicine with a huge potential in the field of oncology in the next years. The use of a pair of selective radiopharmaceuticals for cellular receptors, used for diagnostic and therapeutic purposes (PRRT), finds applications in the Neuroendocrine tumors and metastatic Castration-Resistant prostate cancer (mCRPC) thanks, respectively, to somatostatin receptor agonists and PSMA-based peptides. Further evolutions of theragnostics will be possible to the radioimmunoconjugates used both in the diagnostic (Immuno-PET) and in the therapeutic fields (radioimmunotherapy). It is evident that in the "omics-era," theragnostics could become a necessary method, not only in order to improve our knowledge of tumor biology, but also, to find more and more targeted therapies in a multidisciplinary context and in a tailor-based approach.
Topics: Humans; Neuroendocrine Tumors; Precision Medicine; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Male
PubMed: 38860276
DOI: 10.23736/S1824-4785.24.03519-2