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Human Pathology Sep 2022INSM1, ASCL1, and POU2F3 are novel transcription factors involved in neuroendocrine (NE) differentiation of neoplasms in several organs, but data on their expression in...
INSM1, ASCL1, and POU2F3 are novel transcription factors involved in neuroendocrine (NE) differentiation of neoplasms in several organs, but data on their expression in breast carcinomas (BCs) are limited. We retrospectively evaluated the expression of these markers in a series of 97 BCs (58 with NE morphology and 39 with otherwise uncommon morphology) tested prospectively using immunohistochemistry (IHC). Nuclear staining in >50% of the cells was used as the positive cut-off. Thirty-two of the 97 BCs (33%) were INSM1-positive. INSM1-positivity correlated significantly with histologic type and presence of stromal mucin. INSM1 also correlated with synaptophysin and chromogranin, established markers of NE differentiation (P < .0001 and P = .0023, respectively). In BC with NE morphology, the expression of INSM1 supported NE differentiation, and INSM1 was more specific than synaptophysin and more sensitive and specific than chromogranin. INSM1 was the most expressed NE marker in 17 BCs. INSM1-positive BCs included 56% of solid papillary BCs, 88% of BCs with solid papillary features, and 75% of high-grade NE carcinomas. Of 35 BCs tested for POU2F3 and ASCL1, only 1 and 4 cases were positive, respectively. Our results show that INSM1 is a sensitive marker of NE differentiation in BC and should be included with synaptophysin and chromogranin in the IHC panel used to evaluate NE differentiation in BC with NE morphology. ASCL1 and POU2F3 are uncommon in BC and their routine assessment is not warranted.
Topics: Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Neuroendocrine; Chromogranins; Female; Humans; Mucins; Octamer Transcription Factors; Repressor Proteins; Retrospective Studies; Synaptophysin; Transcription Factors
PubMed: 35690220
DOI: 10.1016/j.humpath.2022.06.003 -
Aging Jan 2020The neuropathogenesis of postoperative delirium remains mostly unknown. The gut microbiota is implicated in the pathogenesis of neurological disorders. We, therefore,...
The neuropathogenesis of postoperative delirium remains mostly unknown. The gut microbiota is implicated in the pathogenesis of neurological disorders. We, therefore, set out to determine whether anesthesia/surgery causes age-dependent gut microbiota dysbiosis, changes in brain IL-6 level and mitochondrial function, leading to postoperative delirium-like behavior in mice. Female 9 or 18 months old mice received abdominal surgery under 1.4% isoflurane for two hours. The postoperative delirium-like behavior, gut microbiota, levels of brain IL-6, PSD-95 and synaptophysin, and mitochondrial function were determined by a battery of behavioral tests, 16s rRNA sequencing, ELISA, Western blot and Seahorse XFp Extracellular Flux Analyzer. Intragastric administration of Lactobacillus (10 days) and probiotic (20 days) were used to mitigate the anesthesia/surgery-induced changes. Anesthesia/surgery caused different alterations in gut microbiota, including change rate of reduction in the levels of gut lactobacillus, between the 18 and 9 months old mice. The anesthesia/surgery induced greater postoperative delirium-like behavior, increased brain IL-6 levels, decreased PSD-95 and synaptophysin levels, and mitochondrial dysfunction in 18 than 9 months old mice. Treatments with Lactobacillus and probiotic mitigated the anesthesia/surgery-induced changes. These data suggest that microbiota dysbiosis may contribute to neuropathogenesis of postoperative delirium and treatment with Lactobacillus or a probiotic could mitigate postoperative delirium.
Topics: Age Factors; Anesthesia; Animals; Behavior, Animal; Biomarkers; Brain; Cognition; Cytokines; Delirium; Gastrointestinal Microbiome; Maze Learning; Mice; Microbiota; Mitochondria; Probiotics; Surgical Procedures, Operative
PubMed: 31974315
DOI: 10.18632/aging.102736 -
Scientific Reports Oct 2022Slowing down age-related neurocognitive impairment has been a challenge. We evaluated the therapeutic effects of metformin in D-galactose-induced aging. Additionally, we...
Slowing down age-related neurocognitive impairment has been a challenge. We evaluated the therapeutic effects of metformin in D-galactose-induced aging. Additionally, we studied the potential molecular mechanisms that could be responsible for metformin's anti-aging effects. Thirty male rats were equally divided into: 1-control group, which received saline solution, 2-D-galactose (D-gal) group, which received D-galactose (100 mg/kg/day) by gastric lavage for eight weeks, and 3-D-galactose + Metformin (D-gal + Met) treated group, which received D-galactose + metformin (200 mg/kg/day) by gastric lavage for eight weeks. Neurocognitive assessment was done. Measurement of inflammatory, oxidative stress, and BDNF biomarkers was performed. AMPK and PI3K genes expression were assessed. Hippocampal tissues were dissected for histopathological and immunohistochemical studies. D-gal resulted in neurocognitive impairments, elevation of inflammatory biomarkers, altered oxidative stress markers, decreased BDNF, decreased expression of synaptophysin and Bcl2 with increased expression of Caspase-3, and down-regulation of AMPK and PI3K genes. Neurodegenerative changes were present in the hippocampus. Metformin restored significantly D-gal induced neurodegenerative changes. We concluded that metformin could alleviate age-induced neurocognitive deficit via amelioration of neuroinflammation, attenuation of oxidative stress, reduction of apoptosis, as well as promotion of synaptic plasticity. These mechanisms could be mediated via the activation of the AMPK/BDNF/PI3K pathway.
Topics: AMP-Activated Protein Kinases; Aging; Animals; Brain-Derived Neurotrophic Factor; Caspase 3; Galactose; Male; Metformin; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-bcl-2; Rats; Saline Solution; Synaptophysin
PubMed: 36224264
DOI: 10.1038/s41598-022-20945-7 -
Cancers Oct 2021Colorectal mixed adenoneuroendocrine carcinomas (MANECs) are clinically highly aggressive neoplasms. MANECs are composed of variable adenocarcinoma components combined...
BACKGROUND
Colorectal mixed adenoneuroendocrine carcinomas (MANECs) are clinically highly aggressive neoplasms. MANECs are composed of variable adenocarcinoma components combined with morphologically distinct neuroendocrine carcinoma components, which are confirmed by synaptophysin immunohistochemistry, the gold standard marker of a neuroendocrine differentiation. However, the biological behavior of adenocarcinomas that express synaptophysin but do not show a typical neuroendocrine morphology remains unclear.
METHODS
We investigated synaptophysin expression in 1002 conventional colorectal adenocarcinomas and correlated the results with clinicopathological characteristics and patient survival and compared the survival characteristics of synaptophysin expression groups to MANECs.
RESULTS
Synaptophysin expression in conventional colorectal adenocarcinomas was associated with a shortened disease-free survival ( = 0.037), but not with overall survival or disease-specific survival (DSS) in univariate analyses and without any survival impact in multivariate analyses. Patients with "true" MANECs, on the other hand, showed a significantly shorter survival than all conventional adenocarcinomas with or without synaptophysin expression in uni- and multivariate analyses (e.g., multivariate DSS: < 0.001, HR: 5.20).
CONCLUSIONS
Our study demonstrates that synaptophysin expression in conventional colorectal adenocarcinomas, in contrast to MANECs, is not associated with a significantly poorer clinical outcome when compared to adenocarcinomas without synaptophysin expression. Furthermore, our data suggest that conventional adenocarcinomas with a diffuse synaptophysin expression should not be classified as MANECs, also strongly arguing that synaptophysin testing should be reserved for carcinomas with an H&E morphology suggestive of a neuroendocrine differentiation.
PubMed: 34680258
DOI: 10.3390/cancers13205111 -
Journal of Cutaneous Pathology Feb 2023Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor characterized by unique histomorphologic and immunohistochemical features as well as...
Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor characterized by unique histomorphologic and immunohistochemical features as well as recurrent MEF2C::SS18 gene fusion. Since 2019, 24 cases have been reported in the literature, primarily arising in the oral cavity, with a single reported case arising in the parotid gland. Here, we present a case of MSA that arose in the external ear canal in an 89-year-old woman and was discovered during management of vertigo symptoms. Excisional biopsy of the lesion showed multiple fragments of squamous epithelium with hyperplastic changes and a distinct subepithelial infiltrating neoplasm composed of bland cells forming tubules and cords. Neoplastic cells expressed keratin, S100 protein, p63, and TLE1 and did not express p40, mammaglobin, pan-TRK, synaptophysin, or chromogranin by immunohistochemistry. SS18 gene rearrangement was shown with break-apart fluorescent in situ hybridization. Overall, the histomorphologic, immunohistochemical, and cytogenetic findings confirm a diagnosis of MSA arising in a unique extraoral location.
Topics: Female; Humans; Aged, 80 and over; In Situ Hybridization, Fluorescence; Ear Canal; Adenocarcinoma; Immunohistochemistry; S100 Proteins; Salivary Gland Neoplasms; Biomarkers, Tumor
PubMed: 35710690
DOI: 10.1111/cup.14277 -
Veterinary Sciences Apr 2024A 13-month-old, neutered, male, domestic shorthair cat was referred with a history of progressive paraparesis, proprioceptive ataxia, and lumbar spinal pain....
A 13-month-old, neutered, male, domestic shorthair cat was referred with a history of progressive paraparesis, proprioceptive ataxia, and lumbar spinal pain. Neurological examination revealed non-ambulatory paraparesis consistent with L4-S1 myelopathy. Magnetic resonance of the thoracolumbar spinal cord identified a dorsal intradural extramedullary space-occupying lesion extending from L5 to L6. It was homogeneously hyperintense in T2-weighted imaging and isointense in T1-weighted imaging and exhibited marked and homogeneous contrast enhancement in the T1-weighted post-contrast imaging. The removed tissue was composed of neoplastic cells arranged as pseudostratified or multilayered trabecular and tubular structures, supported by internal and external limiting PAS-positive membranes. The neoplastic cells were immunoreactive for vimentin and NSE and negative for GFAP, Olig2, synaptophysin, PCK, S-100, NeuN, and nestin. The Ki-67 nuclear labeling index was up to 90%. The tumor was consistent with the diagnosis of medulloepithelioma, which is most frequently reported as an intraocular tumor. The morphological and immunohistochemical features of the tumor showed remarkable concordance with most human medulloepitheliomas. This is the first spinal cord medullopethelioma report in a cat, with the clinical, neuroradiological, histological, and immunohistochemical findings being described.
PubMed: 38668444
DOI: 10.3390/vetsci11040177 -
Cancers Aug 2022A recent study found that multifocal jejunoileal neuroendocrine tumors (SI-NETs) are genetically unrelated synchronous neoplasms. So far, it is unclear if this finding...
BACKGROUND
A recent study found that multifocal jejunoileal neuroendocrine tumors (SI-NETs) are genetically unrelated synchronous neoplasms. So far, it is unclear if this finding of synchronous independent neoplasms is mirrored by heterogeneity of key morphological parameters of SI-NETs and how it affects patient survival.
METHODS
We separately assessed WHO grade (based on the Ki-67 index), expression of basal diagnostic markers (synaptophysin/chromogranin A/CDX2/serotonin), SSTR2a, and the contexture of the immunogenic microenvironment in 146 separate tumors from 28 patients with multifocal SI-NETs and correlated the results with clinicopathological factors and survival.
RESULTS
Synaptophysin and chromogranin A were strongly expressed in all tumors. WHO grade was concordant within all multifocal lesions in more than 80% of cases and the highest grade was usually found in the most advanced primary. Intertumoral expression of serotonin, SSTR2, and CDX2 was discrepant in 32%, 43%, and 50% of all patients, respectively. Neither heterogeneity of any of the aforementioned markers nor multifocality itself had any impact on patient survival ( = n.s.).
DISCUSSION
Multifocal SI-NET show considerable variability in some of the central diagnostic parameters. However, neither intertumoral heterogeneity of those parameters nor multifocality itself had any impact on patient survival, showing that extensive testing of all multifocal lesions is not necessarily required.
PubMed: 36010956
DOI: 10.3390/cancers14163963 -
American Journal of Translational... 2021Currently, there is no favorable treatment plan for inflammatory pain, so exploring new analgesics is still a research hotspot in this area. Cyclin-dependent protein...
PURPOSE
Currently, there is no favorable treatment plan for inflammatory pain, so exploring new analgesics is still a research hotspot in this area. Cyclin-dependent protein kinase 5 (Cdk5) is a pain-related protein kinase, but its mechanism in inflammatory pain has not been clarified. This research aimed to explore the mechanism of Cdk5-synaptophysin (Syn)-soluble N-ethylmaleimide-sensitivity factor (NSF) attachment protein receptor (SNARE) in acute and chronic inflammatory pain.
METHODS
Rat models of acute and chronic inflammatory pain were induced by formalin and complete Freund's adjuvant (CFA), separately, and some rats injected with normal saline through intraplantar injection were divided into a control group. Thirty minutes before modeling, rats were given Cdk5 inhibitor (Roscovitine, Ros), SNARE scavenger (botulinum toxin A, BTTA), glutamate receptor inhibitor (MK801), and dimethyl sulfoxide (DMSO) through spinal canals, and the paw withdrawal threshold (PWT) and thermal withdrawal latency (PWL) at difference time points were compared.
RESULTS
Compared with rats in the control group, those in the rat models of acute and chronic inflammatory pain showed lower PWT and PWL, higher Cdk5 enzyme level, tight correlation of Cdk5 with Syn, SNARE, p25 proteins, and higher levels of Cdk5, Syn and SNARE. And the above situation was dramatically reversed under intervention of Ros, BTTA and MK801.
CONCLUSION
Cdk5-Syn-SNARE pathway is a therapeutic target for inflammatory pain. Blocking the activation of this pathway is beneficial to exert analgesic effect.
PubMed: 33841641
DOI: No ID Found -
Biology Sep 2021When analyzing tumors by histopathology, endocrine pathologists have traditionally been restricted to a few key immunohistochemical markers related to secretory vesicles...
When analyzing tumors by histopathology, endocrine pathologists have traditionally been restricted to a few key immunohistochemical markers related to secretory vesicles in order to pinpoint neuroendocrine differentiation-most notably Chromogranin A (CGA) and Synaptophysin (SYP). Although proven of great clinical utility, these markers sometimes exhibit tissue-specific patterns depending on tumor origin, and non-neuroendocrine tumors might sometimes display focal expression. Moreover, CGA and SYP might be partially or totally absent in highly proliferative neuroendocrine carcinomas, making the diagnosis particularly challenging on small biopsies of metastatic lesions with unknown location of the primary tumor. The advent of second-generation neuroendocrine markers ISL LIM Homeobox 1 (ISL1), INSM Transcriptional Repressor 1 (INSM1) and Secretagogin (SECG) have expanded the pathology toolbox considerably, constituting markers that often retain expression even in poorly differentiated neuroendocrine carcinomas. As non-neuroendocrine tumors seldom express these antigens, the specificity of ISL1, INSM1 and SECG make them welcome additions to clinical practice. In this commentary, recent advances of this field as well as initial clinical experiences from a tertiary neuroendocrine center are discussed.
PubMed: 34571751
DOI: 10.3390/biology10090874 -
The Prostate May 2023Amphicrine prostate carcinoma (AMPC) is a poorly defined subset of prostate cancer in which cells co-express luminal prostate epithelial and neuroendocrine markers. The...
BACKGROUND
Amphicrine prostate carcinoma (AMPC) is a poorly defined subset of prostate cancer in which cells co-express luminal prostate epithelial and neuroendocrine markers. The optimal treatment strategy is unknown. We sought to further characterize the clinical, histomorphologic, and molecular characteristics of AMPC and to identify areas of potential future treatment investigations.
METHODS
We retrospectively identified 17 cases of AMPC at a single institution, defined as synaptophysin expression in >70% of cells and co-expression of androgen receptor (AR) signaling markers (either AR, PSA, or NKX3.1) in >50% of cells. Clinical and histologic features of AMPC cases as well as response to treatment and clinical outcomes were described.
RESULTS
Five AMPC cases arose de novo in the absence of prior systemic treatment and behaved distinctly from cases that were treatment-emergent. In these de novo cases, despite expression of neuroendocrine markers, prognosis appeared more favorable than high-grade neuroendocrine carcinoma, with two (40%) patients with de novo metastatic disease, universal response to androgen deprivation therapy, and no deaths at a median follow-up of 12.3 months. Treatment-emergent AMPC arose a median of 41.1 months after androgen deprivation therapy initiation and was associated with poor response to therapy.
CONCLUSIONS
We show that amphicrine prostate cancer is a unique entity and differs in clinical and molecular features from high-grade neuroendocrine carcinomas of the prostate. Our study highlights the need to recognize AMPC as a unique molecularly defined subgroup of prostate cancer.
Topics: Male; Humans; Prostatic Neoplasms; Retrospective Studies; Androgen Antagonists; Androgens; Prostate; Carcinoma, Neuroendocrine; Prostatic Neoplasms, Castration-Resistant
PubMed: 36779357
DOI: 10.1002/pros.24497