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Virchows Archiv : An International... Feb 2022Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological... (Review)
Review
Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.
Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Chromogranin A; Humans; Immunohistochemistry; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Repressor Proteins; Synaptophysin
PubMed: 34647171
DOI: 10.1007/s00428-021-03211-5 -
Science (New York, N.Y.) May 2016Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation,...
Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3, or the microglial complement receptor CR3 reduces the number of phagocytic microglia, as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; CA1 Region, Hippocampal; Cognition Disorders; Complement C1q; Complement Pathway, Classical; Disease Models, Animal; Disks Large Homolog 4 Protein; Guanylate Kinases; Long-Term Potentiation; Macrophage-1 Antigen; Membrane Proteins; Mice; Mice, Knockout; Microglia; Phagocytosis; Plaque, Amyloid; Synapses; Synaptophysin; Up-Regulation
PubMed: 27033548
DOI: 10.1126/science.aad8373 -
Journal of Thoracic Oncology : Official... Jan 2022A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and...
INTRODUCTION
A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and define its clinical relevance.
METHODS
We used IHC to assess four subtype markers (ASCL1, NEUROD1, POU2F3, and YAP1) in 194 cores from 146 primary SCLC tumors. The profiles of tumor-associated CD3 and CD8 T-cells, MYC paralogs, SLFN11, and SYP were compared among different subtypes. Validation was performed using publicly available RNA sequencing data of SCLC.
RESULTS
ASCL1, NEUROD1, POU2F3, and YAP1 were the dominant molecular subtypes in 78.2%, 5.6%, 7%, and 2.8% of the tumors, respectively; 6.3% of the tumors were negative for all four subtype markers. Notably, three cases were uniquely positive for YAP1. Substantial intratumoral heterogeneity was observed, with 17.6% and 2.8% of the tumors being positive for two and three subtype markers, respectively. The non-ASCL1/NEUROD1 tumors had more CD8 T-cells and manifested more frequently an "inflamed" immunophenotype. L-MYC and MYC were more often associated with ASCL1/NEUROD1 subtypes and non-ASCL1/NEUROD1 subtypes, respectively. SLFN11 expression was absent in 40% of the tumors, especially those negative for the four subtype markers. SYP was often expressed in the ASCL1 and NEUROD1 subtypes and was associated with less tumor-associated CD8 T-cells and a "desert" immunophenotype.
CONCLUSIONS
We validated the new molecular subtype classification in primary SCLC tumors by IHC and identified several intriguing associations between subtypes and therapeutic markers. The new subtype classification may potentially assist treatment decisions in SCLC.
Topics: Basic Helix-Loop-Helix Transcription Factors; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neuroendocrine Tumors; Nuclear Proteins; Octamer Transcription Factors; Small Cell Lung Carcinoma; Synaptophysin; YAP-Signaling Proteins
PubMed: 34534680
DOI: 10.1016/j.jtho.2021.08.763 -
International Journal of Molecular... Aug 2020Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining...
Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, was suggested as a promising drug in hypertriglyceridemia. However, the role of pemafibrate remains obscure in DR. Therefore, we aimed to unravel systemic and retinal changes by pemafibrate in diabetes. Adult mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After STZ injection, diet supplemented with pemafibrate was given to STZ-induced diabetic mice for 12 weeks. During the experiment period, body weight and blood glucose levels were examined. Electroretinography was performed to check the retinal neural function. After sacrifice, the retina, liver, and blood samples were subjected to molecular analyses. We found pemafibrate mildly improved blood glucose level as well as lipid metabolism, boosted liver function, increased serum fibroblast growth factor21 level, restored retinal functional deficits, and increased retinal synaptophysin protein expression in STZ-induced diabetic mice. Our present data suggest a promising pemafibrate therapy for the prevention of early DR by improving systemic metabolism and protecting retinal function.
Topics: Animals; Benzoxazoles; Blood Glucose; Body Weight; Butyrates; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Disease Models, Animal; Electroretinography; Fibroblast Growth Factors; Gene Expression Regulation; Lipid Metabolism; Liver Function Tests; Male; Mice; Retina; Streptozocin; Synaptophysin; Treatment Outcome
PubMed: 32872333
DOI: 10.3390/ijms21176243 -
The Journal of Cell Biology Feb 2022Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity...
Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity in response to specific contexts and within neural networks is obscure. Here, we devised a straightforward bioengineered neural organoid culture approach entailing transcription factor-driven direct differentiation of neurons and astrocytes from human pluripotent stem cells combined with genetically encoded tools for dual cell-selective activation. This strategy revealed that Gq-GPCR activation via chemogenetics in astrocytes promotes a rise in intracellular calcium followed by induction of immediate early genes and thrombospondin 1. However, astrocytes also undergo NF-κB nuclear translocation and secretion of inflammatory proteins, correlating with a decreased evoked firing rate of cocultured optogenetic neurons in suboptimal conditions, without overt neurotoxicity. Altogether, this study clarifies the intrinsic reactivity of human astrocytes in response to targeting GPCRs and delivers a bioengineered approach for organoid-based disease modeling and preclinical drug testing.
Topics: Adenosine Triphosphate; Astrocytes; Bioengineering; Calcium; Cell Line; GTP-Binding Protein alpha Subunits, Gq-G11; Glial Fibrillary Acidic Protein; Humans; Inflammation; Neural Stem Cells; Neurons; Organoids; Pluripotent Stem Cells; Receptors, G-Protein-Coupled; Reproducibility of Results; Spheroids, Cellular; Synaptophysin
PubMed: 35139144
DOI: 10.1083/jcb.202107135 -
Archives of Pathology & Laboratory... Nov 2017Primary neuroendocrine tumors of the breast are a rare and underrecognized subtype of mammary carcinoma. Neuroendocrine tumors of the breast occur predominately in... (Review)
Review
Primary neuroendocrine tumors of the breast are a rare and underrecognized subtype of mammary carcinoma. Neuroendocrine tumors of the breast occur predominately in postmenopausal women. The tumors are subclassified into well-differentiated and poorly differentiated neuroendocrine tumors, and invasive breast carcinoma with neuroendocrine features. Well-differentiated tumors show architectural similarity to carcinoids of other sites but lack characteristic neuroendocrine nuclei. Poorly differentiated neuroendocrine tumors are morphologically identical to small cell carcinoma of the lung. Neuroendocrine differentiation, seen in up to 30% of invasive breast carcinomas, is most commonly associated with mucinous and solid papillary carcinomas. The diagnosis of neuroendocrine differentiation requires expression of the neuroendocrine markers synaptophysin or chromogranin. The main differential diagnosis is a metastatic neuroendocrine tumor from an extramammary site. Neuroendocrine tumors of the breast are treated similarly to other invasive breast carcinomas. Although no consensus has been reached on the prognosis, most studies suggest a poor outcome.
Topics: Biomarkers, Tumor; Breast Neoplasms; Breast Neoplasms, Male; Carcinoma, Neuroendocrine; Cell Differentiation; Chromogranin A; Diagnosis, Differential; Female; Humans; Male; Neoplasm Grading; Neoplasm Staging; Prognosis; Synaptophysin
PubMed: 29072945
DOI: 10.5858/arpa.2016-0364-RS -
Translational Neurodegeneration Oct 2022Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in many other neurodegenerative disorders, the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport. Notably, sensory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2 (HSAN2) and spastic paraplegia 30 (SPG30) share several causative genes with ALS, as well as having common clinical phenotypes. KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors (SVPs) and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30.
METHODS
Here, we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS.
RESULTS
We identified rare damage variants (RDVs) in the KIF1A gene associated with ALS and delineated the clinical characteristics of ALS patients with KIF1A RDVs. Clinically, these patients tended to exhibit sensory disturbance. Interestingly, the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein. Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A, VAMP2, and synaptophysin. Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor.
CONCLUSIONS
Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS, indicating KIF1A as an important player in the oligogenic scenario of ALS.
Topics: Animals; Mice; Amyotrophic Lateral Sclerosis; Hereditary Sensory and Autonomic Neuropathies; Kinesins; Neurodegenerative Diseases; Spastic Paraplegia, Hereditary; Synaptophysin; Vesicle-Associated Membrane Protein 2; Humans; Cells, Cultured
PubMed: 36284339
DOI: 10.1186/s40035-022-00320-2 -
Diagnostic Pathology Nov 2022Synaptophysin is an immunohistochemical marker for neuroendocrine differentiation and is widely used in pathologic diagnosis. Its expression in malignant lymphoma has...
BACKGROUND
Synaptophysin is an immunohistochemical marker for neuroendocrine differentiation and is widely used in pathologic diagnosis. Its expression in malignant lymphoma has not yet been described. However, we experienced an index case of classic Hodgkin lymphoma with synaptophysin expression. This experience prompted us to investigate synaptophysin expression in classic Hodgkin lymphoma.
METHOD
Immunohistochemical staining of synaptophysin was performed in 59 diagnosed cases of classic Hodgkin lymphoma, 10 anaplastic large cell lymphomas, 16 diffuse large B-cell lymphomas, and 5 extranodal marginal zone lymphoma of the mucosa-associated tissue. Synaptophysin-positive cases were stained for both chromogranin and CD56a.
RESULT
Of 59 classic Hodgkin lymphoma cases, 11 (19%) were positive for synaptophysin. None of the anaplastic large cell lymphomas expressed synaptophysin. Synaptophysin showed weak but specific expression in the cytoplasm of the Hodgkin lymphoma tumor cells. Other background inflammatory cells (such as macrophages, B-, and T-lymphocytes) were all negative for synaptophysin expression. Chromogranin and CD56a were not expressed in the synaptophysin-positive classic Hodgkin lymphomas.
CONCLUSIONS
Synaptophysin is an integral glycoprotein present in presynaptic vesicles of neurons and neuroendocrine cells. It is a diagnostic marker for neuroendocrine tumors. Aberrant synaptophysin expression has been reported in non-neuroendocrine tumors but not in lymphoma or leukemia. To the best of our knowledge, synaptophysin positivity has only been reported in a single case of precursor T-lymphoblastic leukemia/lymphoma to date. Our study showed that aberrant synaptophysin expression in classic Hodgkin lymphoma is an unexpectedly frequent finding. The mechanism underlying, and prognostic significance of, such aberrant expression is unclear. Thus, in a small biopsy, aberrant synaptophysin expression could be a diagnostic pitfall and should be carefully avoided.
Topics: Humans; Hodgkin Disease; Synaptophysin; Immunohistochemistry; Chromogranins; Lymphoma, Large-Cell, Anaplastic; Lymphoma, Large B-Cell, Diffuse; Neuroendocrine Tumors
PubMed: 36401284
DOI: 10.1186/s13000-022-01272-x -
Nature Communications Jan 2023Ectopic expression in fibroblasts of synapsin 1 and synaptophysin is sufficient to generate condensates of vesicles highly reminiscent of synaptic vesicle (SV) clusters...
Ectopic expression in fibroblasts of synapsin 1 and synaptophysin is sufficient to generate condensates of vesicles highly reminiscent of synaptic vesicle (SV) clusters and with liquid-like properties. Here we show that unlike synaptophysin, other major integral SV membrane proteins fail to form condensates with synapsin, but co-assemble into the clusters formed by synaptophysin and synapsin in this ectopic expression system. Another vesicle membrane protein, ATG9A, undergoes activity-dependent exo-endocytosis at synapses, raising questions about the relation of ATG9A traffic to the traffic of SVs. We find that both in fibroblasts and in nerve terminals ATG9A does not co-assemble into synaptophysin-positive vesicle condensates but localizes on a distinct class of vesicles that also assembles with synapsin but into a distinct phase. Our findings suggest that ATG9A undergoes differential sorting relative to SV proteins and also point to a dual role of synapsin in controlling clustering at synapses of SVs and ATG9A vesicles.
Topics: Synaptic Vesicles; Synapsins; Synaptophysin; Synapses; Membrane Proteins
PubMed: 36709207
DOI: 10.1038/s41467-023-36081-3 -
Nature Communications Jan 2020Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in...
Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.
Topics: Animals; Aurora Kinase A; Basic Helix-Loop-Helix Transcription Factors; Carcinogenesis; Carcinoma, Neuroendocrine; Cell Line, Tumor; Disease Progression; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Male; Mice; Mice, Nude; Mucin-1; N-Myc Proto-Oncogene Protein; Neoplastic Stem Cells; Neuronal Plasticity; Octamer Transcription Factor-3; POU Domain Factors; Prostate; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-myc; SOXB1 Transcription Factors; Signal Transduction; Synaptophysin; Tumor Suppressor Protein p53
PubMed: 31953400
DOI: 10.1038/s41467-019-14219-6