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European Journal of Cancer (Oxford,... Mar 2021Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high...
BACKGROUND
Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting.
METHODS
We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests.
RESULTS
Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001).
CONCLUSIONS
Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
Topics: Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Mutation; Prognosis; Retrospective Studies; Survival Rate; Synaptophysin
PubMed: 33607478
DOI: 10.1016/j.ejca.2021.01.016 -
Frontiers in Physiology 2023In porcine healthy-lung and moderate acute respiratory distress syndrome (ARDS) models, groups that received phrenic nerve stimulation (PNS) with mechanical ventilation...
In porcine healthy-lung and moderate acute respiratory distress syndrome (ARDS) models, groups that received phrenic nerve stimulation (PNS) with mechanical ventilation (MV) showed lower hippocampal apoptosis, and microglia and astrocyte percentages than MV alone. Explore whether PNS in combination with MV for 12 h leads to differences in hippocampal and brainstem tissue concentrations of inflammatory and synaptic markers compared to MV-only animals. Compare tissue concentrations of inflammatory markers (IL-1α, IL-1β, IL-6, IL-8, IL-10, IFN-γ, TNFα and GM-CSF), pre-synaptic markers (synapsin and synaptophysin) and post-synaptic markers (disc-large-homolog 4, N-methyl-D-aspartate receptors 2A and 2B) in the hippocampus and brainstem in three groups of mechanically ventilated pigs with injured lungs: MV only (MV), MV plus PNS every other breath (MV + PNS50%), and MV plus PNS every breath (MV + PNS100%). MV settings in volume control were tidal volume 8 ml/kg, and positive end-expiratory pressure 5 cmHO. Moderate ARDS was achieved by infusing oleic acid into the pulmonary artery. Hippocampal concentrations of GM-CSF, N-methyl-D-aspartate receptor 2B, and synaptophysin were greater in the MV + PNS100% group compared to the MV group, = 0.0199, = 0.0175, and = 0.0479, respectively. The MV + PNS100% group had lower brainstem concentrations of IL-1β, and IL-8 than the MV group, = 0.0194, and = 0.0319, respectively; and greater brainstem concentrations of IFN-γ and N-methyl-D-aspartate receptor 2A than the MV group, = 0.0329, and = 0.0125, respectively. In a moderate-ARDS porcine model, MV is associated with hippocampal and brainstem inflammation, and phrenic nerve stimulation on every breath mitigates that inflammation.
PubMed: 37215178
DOI: 10.3389/fphys.2023.1182505 -
Molecular Vision 2021To explore synaptic changes and the response of microglia in a light-induced photoreceptor degeneration model.
PURPOSE
To explore synaptic changes and the response of microglia in a light-induced photoreceptor degeneration model.
METHODS
Sprague-Dawley rats were euthanized 1 h, 1 day, 3 days, 7 days, and 14 days after being exposed to intense blue light for 24 h. Hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining were used to evaluate changes in the outer nuclear layer (ONL). Transmission electron microscopy (TEM) was applied to observe the ultrastructural changes in the synapses between the photoreceptors and second-order neurons. Western blotting was conducted to evaluate specific proteins, including postsynaptic density-95 (PSD-95), metabotropic glutamate receptor 6 (mGluR6), synapsin I, and synaptophysin. Immunofluorescence of CD11b and PKC-α or mGluR6 was used to explore the spatial relationships between microglial processes and synaptic elements. Immunoelectron microscopy of PSD-95 was performed to further confirm its engulfment of synaptic materials.
RESULTS
H&E and TUNEL staining showed that the thickness of the ONL decreased markedly, and the number of apoptotic photoreceptors peaked at day 1. TEM revealed darkened photoreceptor terminals and that ribbons of them were floating in the cytoplasm, coinciding with the downregulation of PSD-95 and mGluR6. Downstream synaptic protein synapsin I and synaptophysin exhibited upregulation in the inner plexiform layer. Activated microglia migrated to the outer retina, and their processes were found in close proximity to synapses in the outer plexiform layer under light and electron microscopy levels. Double immunostaining of CD11b and mGluR6 showed colocalization. PSD-95-immunoreactive electron-dense materials were observed inside the microglia suggesting engulfment of synaptic components.
CONCLUSIONS
The study showed that there are early synaptic impairment and late compensatory changes in downstream synapses in this photic injury model. Activated microglia touched and directly engulfed synaptic materials. Microglia may play a role or a partial role in synaptic changes.
Topics: Animals; Blotting, Western; Disease Models, Animal; Disks Large Homolog 4 Protein; In Situ Nick-End Labeling; Light; Male; Microglia; Microscopy, Electron, Transmission; Microscopy, Immunoelectron; Photoreceptor Cells, Vertebrate; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Retinal Degeneration; Synapses; Synapsins; Synaptophysin
PubMed: 33967574
DOI: No ID Found -
Investigative Ophthalmology & Visual... May 2023To investigate changes in myofiber composition in the global layer (GL) and orbital layer (OL) of extraocular muscles (EOMs) from terminal amyotrophic lateral sclerosis...
PURPOSE
To investigate changes in myofiber composition in the global layer (GL) and orbital layer (OL) of extraocular muscles (EOMs) from terminal amyotrophic lateral sclerosis (ALS) donors.
METHODS
Medial recti muscles collected postmortem from spinal-onset ALS, bulbar-onset ALS, and healthy control donors were processed for immunofluorescence with antibodies against myosin heavy chain (MyHC) IIa, MyHCI, MyHCeom, laminin, neurofilaments, synaptophysin, acetylcholine receptor γ-subunit, and α-bungarotoxin.
RESULTS
The proportion of myofibers containing MyHCIIa was significantly smaller and MyHCeom was significantly larger in the GL of spinal-onset ALS and bulbar-onset ALS donors compared to control donors. Changes in the GL were more prominent in the bulbar-onset ALS donors, with a significantly larger proportion of myofibers containing MyHCeom being present compared to spinal-onset ALS donors. There were no significant differences in the myofiber composition in the OL. In the spinal-onset ALS donors, the proportions of myofibers containing MyHCIIa in the GL and MyHCeom in the OL were significantly correlated with the disease duration. Neurofilament and synaptophysin were present at motor endplates of myofibers containing MyHCeom in ALS donors.
CONCLUSIONS
The EOMs of terminal ALS donors displayed changes in the fast-type myofiber composition in the GL, with a more pronounced alteration in bulbar-onset ALS donors. Our results align with the worse prognosis and subclinical changes in eye movement function previously observed in bulbar-onset ALS patients and suggest that the myofibers in the OL might be more resistant to the pathological process in ALS.
Topics: Humans; Oculomotor Muscles; Amyotrophic Lateral Sclerosis; Synaptophysin; Myosin Heavy Chains; Protein Isoforms
PubMed: 37200039
DOI: 10.1167/iovs.64.5.15 -
Biological Trace Element Research Oct 2021Synaptosomes are used as an ex vivo model in the investigation of neuronal transmission and neurodegenerative processes. In this study, we aimed to determine the...
Synaptosomes are used as an ex vivo model in the investigation of neuronal transmission and neurodegenerative processes. In this study, we aimed to determine the protective effects of boric acid (BA) and curcumin, which have antioxidant and anti-inflammatory properties, on Aβ1-42 induced neurodegenerative damage. Synaptosomes obtained from the rat cerebral cortex were divided into five groups: control, 10 μM Aβ1-42, 10 μM Aβ1-42 + 25 mM BA, 10 μM Aβ1-42 + 10 μM curcumin, and 10 μM Aβ1-42 + 25 mM BA+10 μM curcumin. Synaptosomes treated with Aβ1-42 caused a significant decline in synaptophysin levels and increase in malondialdehyde (MDA) levels, acetylcholinesterase (AChE) activities, DNA fragmentation values, and nitric oxide (NO) levels compared with the control group (P < 0.01). Synaptosomes treated with BA showed a significant reduction in MDA and NO levels against Aβ1-42 exposure (P < 0.01). In addition, curcumin treatment has been found to cause a significant reduction in AChE activities and MDA levels in synaptosomes (P < 0.05). Co-administration of BA and curcumin on synaptosomes exposed to Aβ1-42 resulted in a significant decrease in DNA fragmentation values, MDA levels, and AChE activities. Curcumin and BA + curcumin combination showed an enhancement in synaptophysin levels of Aβ1-42-induced synaptosomes (P < 0.01). The results showed that BA and curcumin had protective effects on rat brain synaptosomes against Aβ1-42 exposure. BA and curcumin treatment can have abilities to prevent the alterations of the cholinergic system and inhibit oxidative stress in the cerebral cortex synapses of Aβ1-42 exposed.
Topics: Amyloid beta-Peptides; Animals; Boric Acids; Curcumin; Oxidative Stress; Rats; Synaptosomes
PubMed: 33237490
DOI: 10.1007/s12011-020-02511-2 -
International Immunopharmacology May 2023Fibromyalgia is a widespread chronic pain syndrome associated with several comorbid conditions that affect the quality of patients' life. Its pathogenesis is complex,...
The immunomodulatory effects of ethosuximide and sodium butyrate on experimentally induced fibromyalgia: The interaction between IL-4, synaptophysin, and TGF-β1/NF-κB signaling.
BACKGROUND AND AIMS
Fibromyalgia is a widespread chronic pain syndrome associated with several comorbid conditions that affect the quality of patients' life. Its pathogenesis is complex, and the treatment strategies are limited by partial efficacy and potential adverse effects. So, our aim was to investigate the possible ameliorative effects of ethosuximide and sodium butyrate on fibromyalgia and compare their effects to pregabalin.
MATERIALS AND METHODS
In a mouse model of reserpine induced fibromyalgia, the effect of ethosuximide, sodium butyrate, and pregabalin was investigated. Evaluation of mechanical allodynia, cold hypersensitivity, anxiety, cognitive impairment, and depression was performed. Also, the brain and spinal cord tissue serotonin, dopamine and glutamate in addition to the serum levels of interleukin (IL)-4 and transforming growth factor beta 1 (TGF-β1) were assayed. Moreover, the expression of nuclear factor kappa B (NF-κB) synaptophysin was immunoassayed in the hippocampal tissues.
KEY FINDINGS
Ethosuximide and sodium butyrate restored the behavioral tests to the normal values except for the antidepressant effect which was evident only with ethosuximide. Both drugs elevated the levels of the anti-inflammatory cytokines IL-4 and TGF-β1, reduced the hippocampal NF-κB, and increased synaptophysin expression with superiority of sodium butyrate. Ethosuximide reduced only spinal cord and brain glutamate while improved brain dopamine while sodium butyrate elevated spinal cord dopamine and serotonin with no effect on glutamate. Also, sodium butyrate elevated brain serotonin and reduced glutamate with no effect on brain dopamine.
SIGNIFICANCE
Each of sodium butyrate and ethosuximide would serve as a promising therapeutic modality for management of fibromyalgia and its comorbid conditions.
Topics: Mice; Animals; NF-kappa B; Transforming Growth Factor beta1; Fibromyalgia; Butyric Acid; Ethosuximide; Pregabalin; Interleukin-4; Synaptophysin; Dopamine; Serotonin; Glutamates
PubMed: 36989891
DOI: 10.1016/j.intimp.2023.110061 -
The American Journal of Surgical... Feb 2021Insulinoma-associated protein 1 (INSM1) has emerged as a promising diagnostic marker for high-grade neuroendocrine carcinomas (HGNECs); however, it is controversial... (Review)
Review
INSM1 Is Less Sensitive But More Specific Than Synaptophysin in Gynecologic High-grade Neuroendocrine Carcinomas: An Immunohistochemical Study of 75 Cases With Specificity Test and Literature Review.
Insulinoma-associated protein 1 (INSM1) has emerged as a promising diagnostic marker for high-grade neuroendocrine carcinomas (HGNECs); however, it is controversial whether INSM1 is more sensitive than conventional markers chromogranin, synaptophysin, and CD56. Here, we investigated immunohistochemical expression of INSM1 in 75 gynecologic HGNECs using full tissue sections (30 small-cell carcinomas [SmCCs], 34 large-cell neuroendocrine carcinomas [LCNECs], and 11 mixed SmCC and LCNEC), with specificity analysis in 422 gynecologic non-neuroendocrine tumors (410 in tissue microarrays and 12 full sections) and comparison with conventional neuroendocrine markers for their sensitivity and specificity. Positive INSM1 staining was seen in 69 (92%) HGNECs, whereas chromogranin, synaptophysin, and CD56 staining was seen in 61 (81%), 72 (96%), and 44 (69%) tumors, respectively (INSM1 vs. chromogranin, P=0.09; INSM1 vs. synaptophysin, P=0.4942; and INSM1 vs. CD56, P<0.001). The mean percentage of INSM1-positive tumor cells was 54% (median: 60%, range: 0% to 100%), similar to chromogranin (58%, P=0.2903) and higher than CD56 (30%, P=0.00001) but significantly lower than synaptophysin (89%, P<0.00001). INSM1 showed no staining difference among SmCCs, LCNECs, and mixed SmCC-LCNECs. Among the 422 non-neuroendocrine tumors, positive staining was seen in 5% tumors for INSM1, 18% for chromogranin, 19% for synaptophysin, and 25% for CD56. Our study indicates that INSM1 is a highly specific marker (95% specificity) for gynecologic HGNECs with high sensitivity (92%), but it is less sensitive than synaptophysin (96% sensitivity). INSM1 is more specific than chromogranin, synaptophysin, and CD56 for gynecologic HGNECs. Our literature review reveals that INSM1 has consistently (the same antibody clone A8 used for all reported studies) shown higher or similar sensitivity to chromogranin (for all 3 chromogranin antibody clones LK2H10, DAK-A3, DAKO polyclonal); however, whether INSM1 is more or less sensitive than synaptophysin or CD56 for HGNECs is highly dependent on the antibody clones used for synaptophysin (clones MRQ-40 and SNP88 showing higher sensitivity than clones 27G12 and DAK-SYNAP) or CD56 (clones CD564, MRQ-42, and MRQ-54 showing higher sensitivity than clones 123C3D5, 1B6, and Leu243).
Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Female; Genital Neoplasms, Female; Humans; Repressor Proteins; Sensitivity and Specificity; Synaptophysin
PubMed: 33264139
DOI: 10.1097/PAS.0000000000001641 -
International Journal of Surgical... Jan 2024
PubMed: 38291661
DOI: 10.1177/10668969241226710 -
The American Journal of Surgical... Apr 2022The precise contributions of histopathologic features in the determination of stage and prognosis in small intestinal neuroendocrine tumors (NETs) are still under...
The precise contributions of histopathologic features in the determination of stage and prognosis in small intestinal neuroendocrine tumors (NETs) are still under debate, particularly as they pertain to primary tumor size, mesenteric tumor deposits (TDs), and number of regional lymph nodes with metastatic disease. This single-institution series reviewed 162 patients with small bowel NETs (84 females, mean age: 60.3±12.0 y). All cases examined (100%) were immunoreactive for both chromogranin A and synaptophysin. Primary tumor size >1 cm (P=0.048; odds ratio [OR]=3.06, 95% confidence interval [CI]: 1.01-9.24) and lymphovascular invasion (P=0.007; OR=4.85, 95% CI: 1.53-15.40) were associated with the presence of lymph node metastasis. Conversely, TDs (P=0.041; OR=2.73, 95% CI: 1.04-7.17) and higher pT stage (P=0.006; OR=4.33, 95% CI: 1.53-12.28) were associated with the presence of distant metastasis (pM). A cutoff of ≥7 positive lymph nodes was associated with pM (P=0.041), and a thusly defined modified pN stage (pNmod) significantly predicted pM (P=0.024), compared with the prototypical pN (cutoff of ≥12 positive lymph nodes), which did not. Over a median follow-up of 35.7 months, higher pNmod (P=0.014; OR=2.15, 95% CI: 1.16-3.96) and pM (P<0.001; OR=11.00, 95% CI: 4.14-29.20) were associated with disease progression. Proportional hazards regression showed that higher pNmod (P=0.020; hazard ratio=1.51, 95% CI: 1.07-2.15) and pM (P<0.001; hazard ratio=5.48, 95% CI: 2.90-10.37) were associated with worse progression-free survival. Finally, Kaplan-Meier survival analysis demonstrated that higher pNmod (P=0.003), pM (P<0.001), and overall stage group (P<0.001) were associated with worse progression-free survival, while higher pM also predicted worse disease-specific survival (P=0.025). These data support requiring either chromogranin or synaptophysin, but not both, for small bowel NET diagnosis, the current inclusion of a 1 cm cutoff in primary tumor size and the presence of TDs in staging guidelines, and would further suggest lowering the cutoff number of positive lymph nodes qualifying for pN2 to 7 (from 12).
Topics: Aged; Female; Humans; Intestinal Neoplasms; Intestine, Small; Lymph Nodes; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Stomach Neoplasms; Synaptophysin
PubMed: 35192293
DOI: 10.1097/PAS.0000000000001808 -
The World Journal of Biological... Jan 2022Extracellular vesicles, including exosomes, cross the blood brain barrier with their contents intact and can be assayed peripherally. Circulating exosomes have been...
OBJECTIVES
Extracellular vesicles, including exosomes, cross the blood brain barrier with their contents intact and can be assayed peripherally. Circulating exosomes have been studied in other neurodegenerative disorders, but there is scarce data in schizophrenia. This study aimed to examine neuropathology-relevant protein biomarkers in circulating plasma-derived exosomes from patients with schizophrenia and age- and sex-matched healthy controls.
METHODS
Nanoparticle tracking analysis was used to determine the size and concentration of exosomes. Exosomal membrane marker (CD9) and specific target cargo protein (glial fibrillary acid protein[GFAP], synaptophysin, and α-II-Spectrin) immunopositivity was examined using Western blot analyses with band intensity quantified. Methods were consistent with the 'Minimal information for studies of extracellular vesicles 2018' (MISEV2018) guidelines.
RESULTS
Exosomal GFAP concentration was significantly higher and α-II-Spectrin expression significantly lower in plasma obtained from schizophrenia patients. No group differences were observed between in plasma exosomal concentration and size or in CD9, calnexin, or synaptophysin levels.
CONCLUSIONS
Our results demonstrate a differential pattern of exosomal protein expression in schizophrenia compared to matched healthy controls, consistent with the hypothesised astroglial pathology in this disorder. These results warrant further examination of circulating exosomes as vehicles of novel peripheral biomarkers of disease in schizophrenia and other neuropsychiatric disorders.
Topics: Astrocytes; Biomarkers; Exosomes; Humans; Proteomics; Schizophrenia
PubMed: 33821753
DOI: 10.1080/15622975.2021.1907720