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Building collagen IV smart scaffolds on the outside of cells.
Brown KL, Cummings CF, Vanacore RM, Hudson BG
(2017) Protein Sci 26: 2151-2161
MeSH Terms: Amino Acid Motifs, Amino Acid Oxidoreductases, Animals, Antigens, Neoplasm, Basement Membrane, Collagen Type IV, Eukaryotic Cells, Extracellular Matrix, Gene Expression Regulation, Humans, Peroxidases, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Receptors, Interleukin-1
Show Abstract · Added November 2, 2017
Collagen IV scaffolds assemble through an intricate pathway that begins intracellularly and is completed extracellularly. Multiple intracellular enzymes act in concert to assemble collagen IV protomers, the building blocks of collagen IV scaffolds. After being secreted from cells, protomers are activated to initiate oligomerization, forming insoluble networks that are structurally reinforced with covalent crosslinks. Within these networks, embedded binding sites along the length of the protomer lead to the "decoration" of collagen IV triple helix with numerous functional molecules. We refer to these networks as "smart" scaffolds, which as a component of the basement membrane enable the development and function of multicellular tissues in all animal phyla. In this review, we present key molecular mechanisms that drive the assembly of collagen IV smart scaffolds.
© 2017 The Protein Society.
1 Communities
1 Members
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16 MeSH Terms
CD318 is a ligand for CD6.
Enyindah-Asonye G, Li Y, Ruth JH, Spassov DS, Hebron KE, Zijlstra A, Moasser MM, Wang B, Singer NG, Cui H, Ohara RA, Rasmussen SM, Fox DA, Lin F
(2017) Proc Natl Acad Sci U S A 114: E6912-E6921
MeSH Terms: A549 Cells, Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Antigens, Neoplasm, Arthritis, Rheumatoid, Cell Adhesion Molecules, Cell Line, Cell Line, Tumor, Encephalomyelitis, Autoimmune, Experimental, Humans, Ligands, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Proteins, Synovial Membrane, T-Lymphocytes
Show Abstract · Added March 22, 2018
It has been proposed that CD6, an important regulator of T cells, functions by interacting with its currently identified ligand, CD166, but studies performed during the treatment of autoimmune conditions suggest that the CD6-CD166 interaction might not account for important functions of CD6 in autoimmune diseases. The antigen recognized by mAb 3A11 has been proposed as a new CD6 ligand distinct from CD166, yet the identity of it is hitherto unknown. We have identified this CD6 ligand as CD318, a cell surface protein previously found to be present on various epithelial cells and many tumor cells. We found that, like CD6 knockout (KO) mice, CD318 KO mice are also protected in experimental autoimmune encephalomyelitis. In humans, we found that CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. In addition, soluble CD318 is chemoattractive to T cells and levels of soluble CD318 are selectively and significantly elevated in the synovial fluid from patients with rheumatoid arthritis and juvenile inflammatory arthritis. These results establish CD318 as a ligand of CD6 and a potential target for the diagnosis and treatment of autoimmune diseases such as multiple sclerosis and inflammatory arthritis.
0 Communities
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18 MeSH Terms
Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.
Campbell JD, Alexandrov A, Kim J, Wala J, Berger AH, Pedamallu CS, Shukla SA, Guo G, Brooks AN, Murray BA, Imielinski M, Hu X, Ling S, Akbani R, Rosenberg M, Cibulskis C, Ramachandran A, Collisson EA, Kwiatkowski DJ, Lawrence MS, Weinstein JN, Verhaak RG, Wu CJ, Hammerman PS, Cherniack AD, Getz G, Cancer Genome Atlas Research Network, Artyomov MN, Schreiber R, Govindan R, Meyerson M
(2016) Nat Genet 48: 607-16
MeSH Terms: Adenocarcinoma, Antigens, Neoplasm, Carcinoma, Squamous Cell, DNA Copy Number Variations, Genome, Human, Humans, Lung Neoplasms, Recurrence
Show Abstract · Added August 8, 2016
To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor-normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. New amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase-Ras-Raf pathway alterations had mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least five predicted neoepitopes. Although targeted therapies for lung ADC and SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.
0 Communities
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8 MeSH Terms
Oxidative Transformation of Demethoxy- and Bisdemethoxycurcumin: Products, Mechanism of Formation, and Poisoning of Human Topoisomerase IIα.
Gordon ON, Luis PB, Ashley RE, Osheroff N, Schneider C
(2015) Chem Res Toxicol 28: 989-96
MeSH Terms: Antigens, Neoplasm, Curcuma, Curcumin, DNA Cleavage, DNA Topoisomerases, Type II, DNA-Binding Proteins, Epoxy Compounds, Humans, Oxidation-Reduction, Plant Extracts
Show Abstract · Added October 9, 2015
Extracts from the rhizome of the turmeric plant are widely consumed as anti-inflammatory dietary supplements. Turmeric extract contains the three curcuminoids, curcumin (≈80% relative abundance), demethoxycurcumin (DMC; ≈15%), and bisdemethoxycurcumin (BDMC; ≈5%). A distinct feature of pure curcumin is its instability at physiological pH, resulting in rapid autoxidation to a bicyclopentadione within 10-15 min. Here, we describe oxidative transformation of turmeric extract, DMC, and BDMC and the identification of their oxidation products using LC-MS and NMR analyses. DMC autoxidized over the course of 24 h to the expected bicyclopentadione diastereomers. BDMC was resistant to autoxidation, and oxidative transformation required catalysis by horseradish peroxidase and H2O2 or potassium ferricyanide. The product of BDMC oxidation was a stable spiroepoxide that was equivalent to a reaction intermediate in the autoxidation of curcumin. The ability of DMC and BDMC to poison recombinant human topoisomerase IIα was significantly increased in the presence of potassium ferricyanide, indicating that oxidative transformation was required to achieve full DNA cleavage activity. DMC and BDMC are less prone to autoxidation than curcumin and contribute to the enhanced stability of turmeric extract at physiological pH. Their oxidative metabolites may contribute to the biological effects of turmeric extract.
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10 MeSH Terms
Identification and diagnostic performance of a small RNA within the PCA3 and BMCC1 gene locus that potentially targets mRNA.
Drayton RM, Rehman I, Clarke R, Zhao Z, Pang K, Miah S, Stoehr R, Hartmann A, Blizard S, Lavin M, Bryant HE, Martens-Uzunova ES, Jenster G, Hamdy FC, Gardiner RA, Catto JW
(2015) Cancer Epidemiol Biomarkers Prev 24: 268-75
MeSH Terms: Aged, Antigens, Neoplasm, Cell Line, Tumor, Humans, Male, Neoplasm Proteins, RNA, Messenger
Show Abstract · Added February 13, 2015
BACKGROUND - PCA3 is a long noncoding RNA (lncRNA) with unknown function, upregulated in prostate cancer. LncRNAs may be processed into smaller active species. We hypothesized this for PCA3.
METHODS - We computed feasible RNA hairpins within the BMCC1 gene (encompassing PCA3) and searched a prostate transcriptome for these. We measured expression using qRT-PCR in three cohorts of prostate cancer tissues (n = 60), exfoliated urinary cells (n = 484 with cancer and n = 166 controls), and in cell lines (n = 22). We used in silico predictions and RNA knockup to identify potential mRNA targets of short transcribed RNAs.
RESULTS - We predicted 13 hairpins, of which PCA3-shRNA2 was most abundant within the prostate transcriptome. PCA3-shRNA2 is located within intron 1 of PCA3 and appears regulated by androgens. Expression of PCA3-shRNA2 was upregulated in malignant prostatic tissues, exfoliated urinary cells from men with prostate cancer (13-273 fold change; t test P < 0.003), and closely correlated to PCA3 expression (r = 0.84-0.93; P < 0.001). Urinary PCA3-shRNA2 (C-index, 0.75-0.81) and PCA3 (C-index, 0.78) could predict the presence of cancer in most men. PCA3-shRNA2 knockup altered the expression of predicted target mRNAs, including COPS2, SOX11, WDR48, TEAD1, and Noggin. PCA3-shRNA2 expression was negatively correlated with COPS2 in patient samples (r = -0.32; P < 0.001).
CONCLUSION - We identified a short RNA within PCA3, whose expression is correlated to PCA3, which may target mRNAs implicated in prostate biology.
IMPACT - This short RNA is stable ex vivo, suggesting a role as a robust biomarker. We identify cytoplasmic enrichment of this RNA and potential targeting of mRNAs implicated in prostate carcinogenesis.
©2014 American Association for Cancer Research.
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7 MeSH Terms
Toward rapid, high-sensitivity, volume-constrained biomarker quantification and validation using backscattering interferometry.
Olmsted IR, Hassanein M, Kussrow A, Hoeksema M, Li M, Massion PP, Bornhop DJ
(2014) Anal Chem 86: 7566-74
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Calibration, Enzyme-Linked Immunosorbent Assay, Galectins, Humans, Keratin-19, Limit of Detection, Lung Neoplasms
Show Abstract · Added February 2, 2015
Realizing personalized medicine, which promises to enable early disease detection, efficient diagnostic staging, and therapeutic efficacy monitoring, hinges on biomarker quantification in patient samples. Yet, the lack of a sensitive technology and assay methodology to rapidly validate biomarker candidates continues to be a bottleneck for clinical translation. In our first direct and quantitative comparison of backscattering interferometry (BSI) to fluorescence sensing by ELISA, we show that BSI could aid in overcoming this limitation. The analytical validation study was performed against ELISA for two biomarkers for lung cancer detection: Cyfra 21-1 and Galectin-7. Spiked serum was used for calibration and comparison of analytical figures of merit, followed by analysis of blinded patient samples. Using the ELISA antibody as the probe chemistry in a mix-and-read assay, BSI provided significantly lower detection limits for spiked serum samples with each of the biomarkers. The limit of quantification (LOQ) for Cyrfa-21-1 was measured to be 230 pg/mL for BSI versus 4000 pg/mL for ELISA, and for Galectin-7, it was 13 pg/mL versus 500 pg/mL. The coefficient of variation for 5 day, triplicate determinations was <15% for BSI and <10% for ELISA. The two techniques correlated well, ranging from 3-29% difference for Cyfra 21-1 in a blinded patient sample analysis. The label-free and free-solution operation of BSI allowed for a significant improvement in analysis speed, with greater ease, improved LOQ values, and excellent day-to-day reproducibility. In this unoptimized format, BSI required 5.5-fold less sample quantity needed for ELISA (a 10 point calibration curve measured in triplicate required 36 μL of serum for BSI vs 200 μL for ELISA). The results indicate that the BSI platform can enable rapid, sensitive analytical validation of serum biomarkers and should significantly impact the validation bottleneck of biomarkers.
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9 MeSH Terms
Differentiation of pancreatic ductal adenocarcinoma from chronic pancreatitis by PAM4 immunohistochemistry.
Shi C, Merchant N, Newsome G, Goldenberg DM, Gold DV
(2014) Arch Pathol Lab Med 138: 220-8
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Diagnosis, Differential, Humans, Immunohistochemistry, Mucin-1, Neoplasm Grading, Neoplasm Staging, Pancreas, Pancreatectomy, Pancreatic Cyst, Pancreatic Ducts, Pancreatic Neoplasms, Pancreatitis, Chronic, Precancerous Conditions, Tissue Array Analysis
Show Abstract · Added March 10, 2014
CONTEXT - PAM4 is a monoclonal antibody that shows high specificity for pancreatic ductal adenocarcinoma (PDAC) and its neoplastic precursor lesions. A PAM4-based serum immunoassay is able to detect 71% of early-stage patients and 91% with advanced disease. However, approximately 20% of patients diagnosed with chronic pancreatitis (CP) are also positive for circulating PAM4 antigen. The specificity of the PAM4 antibody is critical to the interpretation of the serum-based and immunohistochemical assays for detection of PDAC.
OBJECTIVE - To determine whether PAM4 can differentiate PDAC from nonneoplastic lesions of the pancreas.
DESIGN - Tissue microarrays of PDAC (N = 43) and surgical specimens from CP (N = 32) and benign cystic lesions (N = 19) were evaluated for expression of the PAM4 biomarker, MUC1, MUC4, CEACAM5/6, and CA19-9.
RESULTS - PAM4 and monoclonal antibodies (MAbs) to MUC1, MUC4, CEACAM5/6, and CA19-9 were each reactive with the majority of PDAC cases; however, PAM4 was the only monoclonal antibody not to react with adjacent, nonneoplastic parenchyma. Although PAM4 labeled 19% (6 of 32) of CP specimens, reactivity was restricted to pancreatic intraepithelial neoplasia associated with CP; inflamed tissues were negative in all cases. In contrast, MUC1, MUC4, CEACAM5/6, and CA19-9 were detected in 90%, 78%, 97%, and 100% of CP, respectively, with reactivity also present in nonneoplastic inflamed tissue.
CONCLUSIONS - PAM4 was the only monoclonal antibody able to differentiate PDAC (and pancreatic intraepithelial neoplasia precursor lesions) from benign, nonneoplastic tissues of the pancreas. These results suggest the use of PAM4 for evaluation of tissue specimens, and support its role as an immunoassay for detection of PDAC.
0 Communities
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17 MeSH Terms
Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions.
Aldred KJ, Schwanz HA, Li G, McPherson SA, Turnbough CL, Kerns RJ, Osheroff N
(2013) ACS Chem Biol 8: 2660-8
MeSH Terms: Anti-Bacterial Agents, Antigens, Neoplasm, Bacillus anthracis, Cations, Divalent, DNA Cleavage, DNA Topoisomerase IV, DNA Topoisomerases, Type II, DNA, Bacterial, DNA-Binding Proteins, Drug Resistance, Bacterial, Humans, Kinetics, Magnesium, Mutation, Quinazolinones, Quinolones, Recombinant Proteins, Species Specificity, Structure-Activity Relationship, Water
Show Abstract · Added March 7, 2014
Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. On the basis of our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα.
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20 MeSH Terms
Significant variation of immunohistochemical marker expression in paired primary and metastatic clear cell renal cell carcinomas.
Pan Z, Grizzle W, Hameed O
(2013) Am J Clin Pathol 140: 410-8
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Cadherins, Carbonic Anhydrase IX, Carbonic Anhydrases, Carcinoma, Renal Cell, Humans, Kidney Neoplasms, PAX2 Transcription Factor, PAX8 Transcription Factor, Paired Box Transcription Factors, Receptor for Advanced Glycation End Products
Show Abstract · Added March 7, 2014
OBJECTIVES - To compare the immunohistochemical expression of diagnostic markers in primary clear cell renal cell carcinomas (RCCs) and their matched metastases.
METHODS - Tissue microarrays were constructed from 15 pairs of primary and metastatic clear cell RCCs and then evaluated for the immunohistochemical expression of renal cell carcinoma antigen (RCCA), kidney-specific cadherin, carbonic anhydrase IX (CAIX), and paired box genes 2 (PAX2) and 8 (PAX8).
RESULTS - There was significantly higher overall marker expression in metastatic tumors compared to their matched primaries (P < .001). Individually, there was greater CAIX, PAX2, and PAX8 expression and lower RCCA expression in metastatic tumors. Most importantly, a significant proportion of originally RCCA-positive tumors lost such expression in metastases.
CONCLUSIONS - Metastatic RCCs have significantly higher expression of PAX2 and PAX8 compared to primary RCCs. RCCA is not very reliable in this diagnostic setting, both because of its lower overall sensitivity and loss of expression in metastatic RCCs.
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12 MeSH Terms
Editorial comment.
Penson DF
(2013) J Urol 190: 398
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Humans, Male, Prostatic Neoplasms
Added March 5, 2014
0 Communities
1 Members
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5 MeSH Terms