The gC1qR (i.e., gC1q receptor, gC1q binding protein, p32, p33) is a multifunctional cellular protein that interacts with components of the complement, kinin, and coagulation cascades and select ...microbial pathogens. Enhanced gC1qR expression has been reported in adenocarcinomas arising in a variety of organs. The present study compared gC1qR expression in normal, inflammatory, dysplastic, and malignant tissue of epithelial and mesenchymal origin. gC1qR expression was visualized in tissue sections by immunohistochemistry using the 60.11 monoclonal antibody (i.e., IgG1 mouse monoclonal antibody directed against gC1qR) and the UltraVision LP Detection System. Sections were counterstained with hematoxylin and examined by light microscopy. Strongest gC1qR expression was noted in epithelial tumors of breast, prostate, liver, lung, and colon, as well as in squamous and basal cell carcinoma of the skin. However, increased gC1qR staining was appreciated also in inflammatory and proliferative lesions of the same cell types, as well as in normal continuously dividing cells. In contrast, tumors of mesenchymal origin generally stained weakly, with the exception of osteoblasts, which stained in both benign and malignant tissues. The data suggest that increased gC1qR expression may be a marker of benign and pathologic cell proliferation, particularly in cells of epithelial origin, with potential diagnostic and therapeutic applications.
The accurate distinction of leiomyoma from leiomyosarcoma is essential for patient management. However, the distinction can be difficult to make, particularly in tissue biopsy samples. ...Immunohistochemistry has been established as a useful technique to aid in the diagnosis of malignancies. The advantages of immunohistochemical studies are their ease of use and interpretation. This study is the first to evaluate the utility of the promyelocytic leukemia zinc finger (PLZF) protein and the histone 1.5 (H1.5) protein as potential diagnostic immunohistochemical markers for distinguishing leiomyosarcoma from leiomyoma.
Tissue samples from 21 leiomyosarcomas and 26 leiomyomas were studied. The student t-test and the Fisher exact test were used to calculate the differences in staining between the 2 groups.
Statistically significant differences were found in the staining indices of anti-PLZF and anti-H1.5 when comparing benign and malignant tumors (P < .0001 and P < .0001, respectively). The mean H1.5 staining score in leiomyosarcomas was 158.3, compared to 28.3 in leiomyomas. The mean PLZF score in leiomyosarcomas was 1.5 in contrast to 71.5 in leiomyomas. For H1.5 at a score ≥60, the sensitivity and specificity were 90.5% and 84.6%, respectively. For PLZF, a score ≤15 had a test sensitivity and specificity of 100% and 80.8%, respectively. This suggests that staining for H1.5 or PLZF can serve as a good screening test. Additionally, combining the 2 immunostains results in a sensitivity and specificity of 90.5% and 97.5%, respectively, in differentiating between leiomyoma and leiomyosarcoma.
We describe immunostaining for PLZF and H1.5 in benign and malignant uterine smooth muscle tumors. Statistically significant differences in staining patterns were found, suggesting utility in distinguishing leiomyosarcomas from leiomyomas.
Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a ...novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5'-untranslated region contains Pur alpha and hnRNP-K. Pur alpha expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Pur alpha expression reduced AR at the transcription and protein levels. Pur alpha knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Pur alpha protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Pur alpha is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Pur alpha and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC.
1 Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, 700 West Olney Road, Norfolk, VA 23501, USA
2 Departments of Pathology and Neuroscience, Mount Sinai School ...of Medicine, New York, NY 10029, USA
3 Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA 19122, USA
Correspondence Edward M. Johnson johnsoem{at}EVMS.edu
JC virus (JCV) is the aetiological agent of progressive multifocal leukoencephalopathy (PML), a fatal, demyelinating disease of the brain affecting people with AIDS. Although immunosuppression is involved in infection of the brain by JCV, a direct influence of human immunodeficiency virus type 1 (HIV-1) has also been established. The Tat protein of HIV-1 has been implicated in activation of the cytokine transforming growth factor (TGF)- β in HIV-1-infected cells and in stimulating JCV gene transcription and DNA replication in oligodendroglia, the primary central nervous system cell type infected by JCV in PML. This study demonstrated that Tat can cooperate with SMAD proteins, the intracellular effectors of TGF- β , at the JCV DNA control region (CR) to stimulate JCV gene transcription. Tat stimulated JCV early gene transcription in KG-1 oligodendroglial cells when expressed via transfection or added exogenously. Using chromatin immunoprecipitation, it was shown that exogenous Tat enhanced binding of SMAD2, -3 and -4 and their binding partner Fast1 to the JCV CR in living cells. When SMAD2, -3 and -4 were expressed together, Tat, expressed from plasmid pTat, stimulated transcription from both early and late gene promoters, with the early promoter exhibiting stimulation of >100-fold. Tat, SMAD4 and JCV large T-antigen were all visualized in oligodendroglial cells at the border of an active PML lesion in the cerebral frontal lobe. These results revealed a positive reinforcement system in which the SMAD mediators of the TGF- β system act cooperatively with Tat to stimulate JCV gene transcription.
The MCM8 protein from HeLa cells, a new member of the MCM family, co‐isolates through several steps with MCM6 and MCM7, and MCM8 co‐immunoprecipitates with MCM4, MCM6 and MCM7, proteins reportedly ...forming a helicase complex involved in initiation of DNA replication. MCM8 mRNA is expressed in placenta, lung and liver, but is also significantly expressed in adult heart, a tissue with a low percentage of proliferating cells. The MCM8 gene, consisting of 19 exons, is located contrapodal to a gene, consisting of 11 exons, encoding a homolog of the yeast GCD10 gene product. The region between these two transcription units, comprising as few as 62 bp, is TATA‐less and highly GC‐rich, containing multiple CpG units. MCM8 expression is altered in certain forms of neoplasia. In a case of choriocarcinoma MCM8 mRNA is aberrant, leading to expression of a protein lacking 16 amino acids. In several cases of colon adenocarcinoma MCM8 expression is greatly reduced relative to matched non‐cancerous tissue. The potential helicase domain of MCM8 is different from those of other MCM proteins in that it is more homologous to canonical ATP‐binding domains of other known helicases. Results suggest that MCM8 may interact with other MCM proteins to alter the function of the replicative MCM protein complex.
Cushing's disease (CD) is caused by pituitary corticotroph adenomas that secrete excess adrenocorticotropic hormone (ACTH). In these tumors, somatic mutations in the gene
have been identified as ...recurrent and pathogenic and are the sole known molecular driver for CD. Although other somatic mutations were reported in these studies, their contribution to the pathogenesis of CD remains unexplored. No molecular drivers have been established for a large proportion of CD cases and tumor heterogeneity has not yet been investigated using genomics methods. Also, even in
-mutant tumors, a possibility may exist of additional contributing mutations, following a paradigm from other neoplasm types where multiple somatic alterations contribute to neoplastic transformation. The current study utilizes whole-exome discovery sequencing on the Illumina platform, followed by targeted amplicon-validation sequencing on the Pacific Biosciences platform, to interrogate the somatic mutation landscape in a corticotroph adenoma resected from a CD patient. In this
-mutated tumor, we identified an interesting somatic mutation in the gene
, which is a component of the corticotropin-releasing hormone receptor signaling system. This finding may provide insight into a novel mechanism involving loss of feedback control to the corticotropin-releasing hormone receptor and subsequent deregulation of ACTH production in corticotroph tumors.
Let A be a commutative ring and I an ideal of A with a reduction Q. In this article, we give an upper bound on the reduction number of I with respect to Q, when a suitable family of ideals in A is ...given. As a corollary it follows that if some ideal J containing I satisfies J
2
= QJ, then I
v+2
= QI
v+1
, where v denotes the number of generators of J/I as an A-module.
Diagnoses of prostatic carcinoma (PC) have increased with widespread screening. While the use of α-methylacyl coA racemase and high molecular weight cytokeratins have aided in distinguishing benign ...mimics from malignancy, their sensitivity and specificity are limited. We studied 6C4, a monoclonal antibody to glutamate receptor 2, an excitatory amino acid receptor subunit distributed throughout the central nervous system, on benign prostatic epithelium, high-grade prostatic intraepithelial neoplasia, and PC. Ten cases with post-atrophic or adenosis-like prostate glands were also stained with prostatic intraepithelial neoplasia 4, an immunostain cocktail against α-methylacyl coA racemase, p63, and high molecular weight cytokeratin, in parallel with 6C4. Immunoreactivity for 6C4 was graded as negative (0% to 10%), +1 (11%% to 50%), and +2 (>50%). Malignant epithelium was classified by Gleason patterns. Gleason patterns 4 and 5 were subdivided into cribriform or noncribriform type. Its utility in distinguishing postatrophic or adenosis-like glands from prostate cancer, both of which show absence of basal cells on prostatic intraepithelial neoplasia 4 immunostain, was also investigated. Our results revealed a statistically significant difference in staining of benign secretory prostatic epithelium, high-grade prostatic intraepithelial neoplasia, and low Gleason pattern carcinomas. The results also showed 6C4 is a sensitive marker in separating basal cell negative postatrophic or adenosis-like glands from prostate carcinoma. In addition, there was a statistically significant difference between staining of cribriform versus noncribriform Gleason pattern 4 and 5 carcinomas. A limited number of lymph node metastases from cribriform and noncribriform carcinomas were studied, and they stained the same as the primary tumor in the majority of cases. In conclusion, our preliminary data demonstrated potential utility of 6C4 in the pathologic evaluation of PC.
Objective: Meningiomas are the most common primary central nervous system tumor. Emerging data supports that higher mutational burden portends worse clinical outcomes in meningiomas. However, there ...is a lack of imaging biomarkers that are associated with tumor genomics in meningiomas. Methods: We performed next generation targeted sequencing in a cohort of 75 primary meningiomas and assessed pre-operative imaging for tumor volume and peritumoral brain edema (PTBE). An Edema Index was calculated. Results: Meningiomas that were high-grade (WHO Grade II or Grade III) had significantly larger tumor volume and were more likely to present with PTBE. Moreover, PTBE was associated with brain invasion on histopathology and reduced overall survival. There was a direct association between Edema Index and mutational burden. For every one increase in Edema Index, the number of single nucleotide variants increased by 1.09-fold (95%CI: 1.02, 1.2) (P=0.01).Conclusion: These data support that Edema Index may serve as a novel imaging biomarker that can inform underlying mutational burden in patients with meningiomas.
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