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Archives of Pathology & Laboratory... Sep 2020The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non-small cell lung carcinomas (NSCLCs) is clinically relevant for prognostication and treatment.... (Review)
Review
CONTEXT.—
The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non-small cell lung carcinomas (NSCLCs) is clinically relevant for prognostication and treatment. Diagnosis is based on morphology and immunohistochemical staining.
OBJECTIVE.—
To determine the diagnostic value of insulinoma-associated protein 1 (INSM1), in comparison with established NE markers, in pulmonary tumors.
DESIGN.—
Fifty-four pulmonary NE tumors and 632 NSCLCs were stained for INSM1, CD56, chromogranin A, and synaptophysin. In a subset, gene expression data were available for analysis. Also, 419 metastases to the lungs were stained for INSM1. A literature search identified 39 additional studies with data on NE markers in lung cancers from the last 15 years. Seven of these included data on INSM1.
RESULTS.—
A positive INSM1 staining was seen in 39 of 54 NE tumors (72%) and 6 of 623 NSCLCs (1%). The corresponding numbers were 47 of 54 (87%) and 14 of 626 (2%) for CD56, 30 of 54 (56%) and 6 of 629 (1%) for chromogranin A, and 46 of 54 (85%) and 49 of 630 (8%) for synaptophysin, respectively. Analysis of literature data revealed that CD56 and INSM1 were the best markers for identification of high-grade NE pulmonary tumors when considering both sensitivity and specificity, while synaptophysin also showed good sensitivity. INSM1 gene expression was clearly associated with NE histology.
CONCLUSIONS.—
The solid data of both our and previous studies confirm the diagnostic value of INSM1 as a NE marker in pulmonary pathology. The combination of CD56 with INSM1 and/or synaptophysin should be the first-hand choice to confirm pulmonary high-grade NE tumors. INSM1 gene expression could be used to predict NE tumor histology.
Topics: Adenocarcinoma of Lung; Biomarkers, Tumor; CD56 Antigen; Carcinoma, Squamous Cell; Chromogranin A; Humans; Immunohistochemistry; Lung Neoplasms; Repressor Proteins; Synaptophysin
PubMed: 31913660
DOI: 10.5858/arpa.2019-0250-OA -
Frontiers in Synaptic Neuroscience 2021Synaptic vesicle release is regulated by upwards of 30 proteins at the fusion complex alone, but disruptions in any one of these components can have devastating...
Synaptic vesicle release is regulated by upwards of 30 proteins at the fusion complex alone, but disruptions in any one of these components can have devastating consequences for neuronal communication. Aberrant molecular responses to calcium signaling at the pre-synaptic terminal dramatically affect vesicle trafficking, docking, fusion, and release. At the organismal level, this is reflected in disorders such as epilepsy, depression, and neurodegeneration. Among the myriad pre-synaptic proteins, perhaps the most functionally mysterious is synaptophysin (SYP). On its own, this vesicular transmembrane protein has been proposed to function as a calcium sensor, a cholesterol-binding protein, and to form ion channels across the phospholipid bilayer. The downstream effects of these functions are largely unknown. The physiological relevance of SYP is readily apparent in its interaction with synaptobrevin (VAMP2), an integral element of the neuronal SNARE complex. SNAREs, soluble NSF attachment protein receptors, comprise a family of proteins essential for vesicle fusion. The complex formed by SYP and VAMP2 is thought to be involved in both trafficking to the pre-synaptic membrane as well as regulation of SNARE complex formation. Recent structural observations specifically implicate the SYP/VAMP2 complex in anchoring the SNARE assembly at the pre-synaptic membrane prior to vesicle fusion. Thus, the SYP/VAMP2 complex appears vital to the form and function of neuronal exocytotic machinery.
PubMed: 34616284
DOI: 10.3389/fnsyn.2021.740318 -
Molecular Autism 2018Human genetic and genomic studies have supported a strong causal role of deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying...
BACKGROUND
Human genetic and genomic studies have supported a strong causal role of deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying deficiency resulting in ASD is not fully understood. Recently, the zebrafish has become an attractive organism to model ASD because of its high efficiency of genetic manipulation and robust behavioral phenotypes. The orthologous gene to human is duplicated in the zebrafish genome and has two homologs, and . Previous studies have reported morphants in zebrafish using the morpholino method. Here, we report the generation and characterization of mutant zebrafish in larval and adult stages using the CRISPR/Cas9 genome editing technique.
METHODS
CRISPR/Cas9 was applied to generate a loss-of-function mutation ( ) in zebrafish. A series of morphological measurements, behavioral tests, and molecular analyses were performed to systematically characterize the behavioral and molecular changes in mutant zebrafish.
RESULTS
zebrafish exhibited abnormal morphology in early development. They showed reduced locomotor activity both as larvae and adults, reduced social interaction and time spent near conspecifics, and significant repetitive swimming behaviors. Additionally, the levels of both postsynaptic homer1 and presynaptic synaptophysin were significantly reduced in the adult brain of deficient zebrafish.
CONCLUSIONS
We generated the first inheritable mutant zebrafish model using CRISPR/Cas9 gene editing approach. zebrafish displayed robust autism-like behaviors and altered levels of the synaptic proteins homer1 and synaptophysin. The versatility of zebrafish as a model for studying neurodevelopment and conducting drug screening will likely have a significant contribution to future studies of human function and ASD.
Topics: Animals; Autistic Disorder; CRISPR-Cas Systems; Disease Models, Animal; Homer Scaffolding Proteins; Locomotion; Mutation; Nerve Tissue Proteins; Social Behavior; Synaptophysin; Zebrafish; Zebrafish Proteins
PubMed: 29619162
DOI: 10.1186/s13229-018-0204-x -
Brain Research Mar 2022Temporal lobe epilepsy (TLE) is one of the most common focal pharmacotherapy-resistant epilepsy in adults. Previous studies have shown significantly higher numbers of...
Temporal lobe epilepsy (TLE) is one of the most common focal pharmacotherapy-resistant epilepsy in adults. Previous studies have shown significantly higher numbers of neurons in the neocortical white matter in TLE patients than in controls. The aim of this work was to investigate whether white matter neurons are part of the neuronal circuitry. Therefore, we studied the distribution and density of synapses in surgically resected neocortical tissue of pharmacotherapy-resistant TLE patients. Neocortical white matter of temporal lobe from non-epileptic patients were used as controls. Synapses and neurons were visualized with immunohistochemistry using antibodies against synaptophysin and NeuN, respectively. The presence of synaptophysin in presynaptic terminals was verified by electron microscopy. Quantification of immunostaining was performed and the data of the patients' cognitive tests as well as clinical records were compared to the density of neurons and synapses. Synaptophysin density in the white matter of TLE patients was significantly higher than in controls. In TLE, a significant correlation was found between synaptophysin immunodensity and density of white matter neurons. Neuronal as well as synaptophysin density significantly correlated with scores of verbal memory of TLE patients. Neurosurgical outcome of TLE patients did not significantly correlate with histological data, although, higher neuronal and synaptophysin densities were observed in patients with favorable post-surgical outcome. Our results suggest that white matter neurons in TLE patients receive substantial synaptic input and indicate that white matter neurons may be integrated in epileptic neuronal networks responsible for the development or maintenance of seizures.
Topics: Drug Resistant Epilepsy; Epilepsy, Temporal Lobe; Humans; Neocortex; Nerve Net; Neurons; Synapses; Synaptophysin; Verbal Learning; White Matter
PubMed: 35041843
DOI: 10.1016/j.brainres.2022.147787 -
Lung India : Official Organ of Indian... 2021Pulmonary neuroendocrine tumors (NETs) comprise a spectrum of tumors ranging from indolent to highly aggressive neoplasm. This study aims to study the...
INTRODUCTION
Pulmonary neuroendocrine tumors (NETs) comprise a spectrum of tumors ranging from indolent to highly aggressive neoplasm. This study aims to study the clinicopathological and immunohistochemical features of NETs and assess the sensitivity of various IHC markers.
MATERIALS AND METHODS
All consecutive cases of pulmonary NETs diagnosed from January 2016 to June 2019 were analyzed retrospectively. The routine hematoxylin- and eosin-stained sections along with immunohistochemistry (IHC) slides were reviewed. IHC was done using a panel of markers which included synaptophysin, chromogranin, CD56, thyroid transcription factor-1 (TTF-1), p-40, napsin-A, and ki67.
RESULTS
Of total number of 53 patients, diagnosis was made on biopsy in 40 patients and resection specimen in 13 patients. Small cell lung carcinoma was the most common (31 cases), followed by 16 cases of typical carcinoid, 5 cases of atypical carcinoid, and 1 case of combined SCLC. Both synaptophysin and chromogranin were positive in all the cases of typical carcinoid. Synaptophysin had better sensitivity than chromogranin in atypical carcinoid and small cell carcinoma. CD56 was positive in 8 out of 9 cases done. TTF-1 was negative in all the cases of typical carcinoid. The sensitivity of TTF-1 in small cell carcinoma was 85.19%. The mean Ki67 labeling index was 1.4%, 6.6%, and 65.6% in typical, atypical carcinoid, and small cell carcinomas, respectively.
CONCLUSION
Synaptophysin was more sensitive than chromogranin, especially in atypical carcinoid and small cell carcinoma. TTF-1 along with high Ki67 differentiates small cell carcinoma from carcinoid.
PubMed: 33687006
DOI: 10.4103/lungindia.lungindia_482_19 -
Scientific Reports May 2021Altered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4)...
Altered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.
Topics: Adenosine Triphosphate; Animals; Astrocytes; Cells, Cultured; Cerebral Cortex; Electron Transport Complex I; Hippocampus; Male; Mice; Mice, Knockout; Mitochondria; Nerve Tissue Proteins; Neurites; Neurons; Organ Specificity; Synaptophysin
PubMed: 34040028
DOI: 10.1038/s41598-021-90127-4 -
Basic and Clinical Neuroscience 2022The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an...
INTRODUCTION
The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug.
METHODS
Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 μm thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC).
RESULTS
Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug.
CONCLUSION
NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.
PubMed: 37323955
DOI: 10.32598/bcn.2023.2356.2 -
Diagnostic Pathology Aug 2021Melanoma is a highly malignant tumor with diverse histopathological morphology and frequent aberrant expression of immunohistochemical markers. An occasionally reported...
BACKGROUND
Melanoma is a highly malignant tumor with diverse histopathological morphology and frequent aberrant expression of immunohistochemical markers. An occasionally reported phenomenon is the abnormal expression of neuroendocrine markers. Awareness of this situation is essential because such tumors need to be differentiated from neuroendocrine tumors because of their significant therapeutic and prognostic implications.
METHODS
We retrospectively analyzed the expression of chromogranin A (CgA), synaptophysin (Syn) and CD56 as neuroendocrine markers in 308 cases with melanomas. Kaplan-Meier curves and Cox regression analyses were used for overall survival (OS) and progression-free survival (PFS) evaluation and comparison between neuroendocrine markers expression status in all melanoma cases or stage I-II cases.
RESULTS
The expression of neuroendocrine markers in melanomas is not uncommon. CgA was positive in 6/304 (2.0%) cases, Syn in 26/304 (8.6%), and CD56 in 56/189 (29.6%). None of the cases co-expressed all the three markers. Focal or weak expression of at least one neuroendocrine marker was identified in 70/188 (37.2%) cases. The expression of CgA was correlated with age (p = 0.019), while the positive expression of Syn and CD56 showed borderline significance (p = 0.078 and 0.083, respectively), but not for any neuroendocrine marker expression. The expression of any neuroendocrine marker showed borderline significance with staging (p = 0.066). The expression of CgA, Syn, CD56, or any neuroendocrine marker did not correlate with clinicopathological features including sex, specimen type, origin, location, and histology subtype. Survival analyses revealed that the expression of neuroendocrine markers was not associated with OS or PFS.
CONCLUSIONS
Our study confirms that neuroendocrine marker expression is a common phenomenon in melanomas, but it has no prognostic significance. Nevertheless, awareness can avoid misdiagnosis in cases of melanomas with unusual morphology and immunophenotypes.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; CD56 Antigen; Child; Chromogranin A; Diagnostic Errors; Female; Humans; Immunohistochemistry; Male; Melanoma; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Predictive Value of Tests; Progression-Free Survival; Retrospective Studies; Skin Neoplasms; Synaptophysin; Time Factors; Young Adult
PubMed: 34454530
DOI: 10.1186/s13000-021-01135-x -
European Review For Medical and... Mar 2021Pancreatic neuroendocrine tumors (pNETs) are neuroendocrine tumors primarily found in the pancreas and upper small intestine. There are ten different pNETs: nine of...
Pancreatic neuroendocrine tumors (pNETs) are neuroendocrine tumors primarily found in the pancreas and upper small intestine. There are ten different pNETs: nine of these are associated with a specific functional syndrome, while one is not associated with a specific hormonal syndrome, and it is called non-functional. Up to 90% of pNETs are classified as non-functional. Immunohistochemistry is essential to define the diagnosis. However, to have a correct and reliable diagnosis, the pathologist must have adequately collected and treated tissue samples, thus the surgeon himself should be aware of some fundamental notions about tissue collection and fixation. Although several common biomarkers have been described to date, Chromogranin A and synaptophysin are currently considered the most specific immunohistochemical markers for NETs. Nearly 100% of pNETs are positive for both synaptophysin and Chromogranin A. Therefore, CgA and synaptophysin are effective for well-differentiated NETs but are less helpful in the diagnosis of poorly differentiated NECs, due to dedifferentiation, and then, degranulation of tumor cells. The Neuronal Specific Enolase (NSE) results to be an adequate marker in these cases. Considering the specific markers, many studies reported that endocrine pancreatic neoplasms are able to produce many different polypeptides and amines. Through immunohistochemical techniques, it is possible to define the diagnosis of pNET, which allows the clinicians to direct the patient to an effective therapeutic procedure. But to have a correct and reliable diagnosis, the tissue samples have to be adequately collected and treated.
Topics: Biomarkers, Tumor; Chromogranin A; Humans; Immunohistochemistry; Male; Neuroendocrine Tumors; Pancreatic Neoplasms; Surgeons; Synaptophysin
PubMed: 33829441
DOI: 10.26355/eurrev_202103_25418 -
Archives of Pathology & Laboratory... Mar 2020The incidence of neuroendocrine tumors of the prostate increases after hormonal therapy. Neuroendocrine tumors possess a broad spectrum of morphologic features and pose... (Review)
Review
CONTEXT.—
The incidence of neuroendocrine tumors of the prostate increases after hormonal therapy. Neuroendocrine tumors possess a broad spectrum of morphologic features and pose challenges in the pathologic diagnosis and clinical management of patients.
OBJECTIVE.—
To present a brief updated summary of neuroendocrine tumors of the prostate with an overview of their histopathologic and immunohistochemical profiles and differential diagnoses.
DATA SOURCES.—
Literature review, personal experience in the daily practice of pathologic diagnosis, and laboratory research.
CONCLUSIONS.—
Our understanding of neuroendocrine tumors of the prostate classification and diagnosis continues to evolve. These advances benefit the risk stratification and management of prostate cancer.
Topics: Adenocarcinoma; Chromogranin A; Diagnosis, Differential; Humans; Immunohistochemistry; Male; Neuroendocrine Tumors; Prostate; Prostatic Neoplasms; Receptors, Androgen; Synaptophysin
PubMed: 31644322
DOI: 10.5858/arpa.2019-0434-RA