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Acta Neuropathologica May 2024GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation-inhibition regulation, and cognitive function modulation. In tuberous...
GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation-inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.
Topics: Interneurons; Tuberous Sclerosis; Humans; GABAergic Neurons; Male; Female; Median Eminence; Somatostatin; Child; Child, Preschool; Receptors, GABA-A; Adolescent; Ganglionic Eminence
PubMed: 38714540
DOI: 10.1007/s00401-024-02737-7 -
Scientific Reports May 2024Chronic stress has been implicated in mental illnesses and depressive behaviors. Somatostatin 4 receptor (SSTR4) has been shown to mediate anxiolytic and depression-like...
Chronic stress has been implicated in mental illnesses and depressive behaviors. Somatostatin 4 receptor (SSTR4) has been shown to mediate anxiolytic and depression-like effects. Here, we aimed to explore the potential of SSTR4 as a diagnostic marker for chronic stress in mice. The mice were divided into single stress, chronic restraint stress, and control groups, and Sstr4 mRNA expression in the pituitary, lungs, and thymus, its protein expression in the thymus, were analyzed. Compared to controls, Sstr4 mRNA expression decreased significantly in the pituitary gland of the chronic and single-stress groups (P = 0.0181 and 0.0022, respectively) and lungs of the single-stress group (P = 0.0124), whereas it significantly increased in the thymus of the chronic-stress group (P = 0.0313). Thymic SSTR4 expression did not decrease significantly in stress groups compared to that in the control group (P = 0.0963). These results suggest that SSTR4 expression fluctuates in response to stress. Furthermore, Sstr4 mRNA expression dynamics in each organ differed based on single or chronic restraint stress-loading periods. In conclusion, this study suggests that investigating SSTR4 expression in each organ could allow for its use as a stress marker to estimate the stress-loading period and aid in diagnosing chronic stress.
Topics: Animals; Receptors, Somatostatin; Mice; Stress, Psychological; Male; Biomarkers; Thymus Gland; Pituitary Gland; RNA, Messenger; Lung; Chronic Disease; Stress, Physiological; Restraint, Physical
PubMed: 38698013
DOI: 10.1038/s41598-024-58621-7 -
Cancers Apr 2024Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature and lack of early detection methods. A key obstacle in PDAC treatment is the highly complex tumor environment characterized by dense stroma surrounding the tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions to these challenges, particularly in creating novel drug delivery systems for existing anticancer drugs for PDAC, such as gemcitabine and paclitaxel. By using customization methods such as incorporating conjugated targeting ligands, tumor-penetrating peptides, and therapeutic nucleic acids, these nanoparticle-based systems enhance drug solubility, extend circulation time, improve tumor targeting, and control drug release, thereby minimizing side effects and toxicity in healthy tissues. Moreover, nanoparticles have also shown potential in precise diagnostic methods for PDAC. This literature review will delve into targeted mechanisms, pathways, and approaches in treating pancreatic cancer. Additional emphasis is placed on the study of nanoparticle-based delivery systems, with a brief mention of those in clinical trials. Overall, the overview illustrates the significant advances in nanomedicine, underscoring its role in transcending the constraints of conventional PDAC therapies and diagnostics.
PubMed: 38672671
DOI: 10.3390/cancers16081589 -
Radiologie (Heidelberg, Germany) Jul 2024Well-differentiated neuroendocrine tumors (NET) are rare malignancies that are clinically very heterogeneous. Accordingly, their treatment is also complex and dependent... (Review)
Review
BACKGROUND
Well-differentiated neuroendocrine tumors (NET) are rare malignancies that are clinically very heterogeneous. Accordingly, their treatment is also complex and dependent on various factors. With currently available systemic therapies, the prognosis is often favorable.
OBJECTIVES
This article aims to provide an overview of current treatment strategies for NET, addressing the most important NET locations.
METHODS
The current European guidelines and further relevant literature on the treatment of NET were reviewed for this purpose.
RESULTS
The therapeutic spectrum for NET is extremely broad: For NET of the stomach/duodenum, appendix, and rectum, endoscopic or surgical resection is often sufficient, and metastatic tumors are rare. NET of the pancreas, small intestine and lung should also undergo potentially curative resection in the early stages. In the metastatic stage, locoregional treatments such as surgery and liver tumor embolization play a role. Major advances have been made in drug therapy, with somatostatin analogs (octreotide and lanreotide), an mTOR inhibitor (everolimus), and a tyrosine kinase inhibitor (sunitinib) being widely used. Peptide receptor radionuclide therapy (PRRT) is also an invaluable option. In some cases, classic chemotherapy is indicated.
CONCLUSIONS
Many effective therapies are now available for NET. It is important to select the right therapy at the right time for each patient through interdisciplinary management.
Topics: Humans; Neuroendocrine Tumors; Antineoplastic Agents; Practice Guidelines as Topic
PubMed: 38649498
DOI: 10.1007/s00117-024-01303-2 -
Journal of Nuclear Medicine : Official... Jun 2024[Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The...
[Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from Lu. The objective of this work was to explore how postinfusion [Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Patients with GEP-NETs treated with [Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation ( < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. In patients treated with [Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.
Topics: Humans; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Male; Organometallic Compounds; Female; Stomach Neoplasms; Middle Aged; Aged; Intestinal Neoplasms; Precision Medicine; Radiometry; Dose-Response Relationship, Radiation; Adult; Aged, 80 and over; Treatment Outcome; Retrospective Studies
PubMed: 38637144
DOI: 10.2967/jnumed.123.267023 -
Hellenic Journal of Nuclear Medicine 2024We presented a case involving a 56-year-old man who had been experiencing shoulder and back pain for over a year, with extensive bone metastases revealed by a bone scan....
We presented a case involving a 56-year-old man who had been experiencing shoulder and back pain for over a year, with extensive bone metastases revealed by a bone scan. To identify the primary source of these issues, the patients underwent a fluorine-18-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) scan, which indicated moderate uptake in the right renal soft mass and low uptake in multiple osteolytic lesions. Pathological examination and immunohistochemical staining of the renal mass supported the diagnosis of neuroendocrine tumors. Subsequently, a novel somatostatin receptor imaging agent, AlF-NOTA-octreotide (F-OC), was performed to further investigate the source of metastatic lesions and to stage the tumor. The F-OC scan revealed a high-uptake lesion in the pancreatic head, as well as additional lymph node and bone metastases lesions. Compared to F-FDG, the F-OC demonstrated superior imaging capabilities and a significantly higher tumor-to-background ratio in neuroendocrine neoplasms, which contributed to improving the staging and treatment management.
Topics: Humans; Male; Middle Aged; Fluorodeoxyglucose F18; Neuroendocrine Tumors; Pancreatic Neoplasms; Kidney Neoplasms; Positron Emission Tomography Computed Tomography; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Octreotide; Radiopharmaceuticals
PubMed: 38629821
DOI: 10.1967/s002449912708 -
World Journal of Gastroenterology Mar 2024This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors (pan-NETs), emphasizing tailored approaches... (Review)
Review
This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors (pan-NETs), emphasizing tailored approaches for specific subtypes. Cytoreductive surgery and somatostatin analogs (SSAs) play pivotal roles in managing tumors, while palliative options such as molecular targeted therapy, peptide receptor radionuclide therapy, and chemotherapy are reserved for SSA-refractory patients. Gastrinomas, insulinomas, glucagonomas, carcinoid tumors and VIPomas necessitate distinct thera-peutic strategies. Understanding the genetic basis of pan-NETs and exploring immunotherapies could lead to promising avenues for future research. This review underscores the evolving landscape of pan-NET treatment, offering renewed hope and improved outcomes for patients facing this complex disease.
Topics: Humans; Neuroendocrine Tumors; Immunotherapy; Carcinoid Tumor; Cytoreduction Surgical Procedures; Pancreatic Neoplasms
PubMed: 38617746
DOI: 10.3748/wjg.v30.i12.1670 -
Journal of Indian Association of... 2024Extragonadal germ cell tumors (GCTs) are challenging to diagnose. We present a case of suprarenal GCT, with hepatic infiltration where differential diagnosis included...
Extragonadal germ cell tumors (GCTs) are challenging to diagnose. We present a case of suprarenal GCT, with hepatic infiltration where differential diagnosis included neuroblastoma and hepatoblastoma. The positive positron emission tomography scan further obfuscated the situation. The diagnosis was clinched by fine-needle aspiration cytology and cell block immunohistochemistry.
PubMed: 38616838
DOI: 10.4103/jiaps.jiaps_167_23 -
International Journal of Molecular... Mar 2024Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels...
Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08)%, < 0.001 vs. basal, = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, < 0.001 vs. basal, = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.
Topics: Humans; Antimitotic Agents; Neuroendocrine Tumors; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin
PubMed: 38612419
DOI: 10.3390/ijms25073606 -
Animals : An Open Access Journal From... Mar 2024Somatostatin shows an anti-lipolytic effect in both chickens and ducks. However, its molecular mediator remains to be identified. Here, we report that somatostatin type...
Somatostatin shows an anti-lipolytic effect in both chickens and ducks. However, its molecular mediator remains to be identified. Here, we report that somatostatin type 2 receptor (SSTR2) is expressed at a high level in chicken adipose tissue. In cultured chicken adipose tissue, the inhibition of glucagon-stimulated lipolysis by somatostatin was blocked by an SSTR2 antagonist (CYN-154086), supporting an SSTR2-mediated anti-lipolytic effect. Furthermore, a significant pro-proliferative effect was detected in SST28-treated immortalized chicken preadipocytes (ICP-1), and this cell proliferative effect may be mediated through the MAPK/ERK signaling pathway activated by SSTR2. In summary, our results demonstrate that SSTR2 may regulate adipose tissue development by affecting the number and volume of adipocytes in chickens.
PubMed: 38612272
DOI: 10.3390/ani14071034