scholarly journals mAb Das-1 recognizes 3’-Sulfated Lewis A/C, which is aberrantly expressed during metaplastic and oncogenic transformation of several gastrointestinal Epithelia

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261082
Author(s):  
Jeffrey W. Brown ◽  
Koushik K. Das ◽  
Vasilios Kalas ◽  
Kiron M. Das ◽  
Jason C. Mills
Keyword(s):  
Monoclonal Antibody ◽  
Risk Stratification ◽  
Complete Loss ◽  
Ductal Adenocarcinoma ◽  
High Grade ◽  
Glycan Array ◽  
Multiple Organs ◽  
Gastrointestinal Lesions ◽  
Direct Elisa ◽  
Lewis A

Introduction Multiple previous studies have shown the monoclonal antibody Das-1 (formerly called 7E12H12) is specifically reactive towards metaplastic and carcinomatous lesions in multiple organs of the gastrointestinal system (e.g. Barrett’s esophagus, intestinal-type metaplasia of the stomach, gastric adenocarcinoma, high-grade pancreatic intraepithelial neoplasm, and pancreatic ductal adenocarcinoma) as well as in other organs (bladder and lung carcinomas). Beyond being a useful biomarker in tissue, mAb Das-1 has recently proven to be more accurate than current paradigms for identifying cysts harboring advanced neoplasia. Though this antibody has been used extensively for clinical, basic science, and translational applications for decades, its epitope has remained elusive. Methods In this study, we chemically deglycosylated a standard source of antigen, which resulted in near complete loss of the signal as measured by western blot analysis. The epitope recognized by mAb Das-1 was determined by affinity to a comprehensive glycan array and validated by inhibition of a direct ELISA. Results The epitope recognized by mAb Das-1 is 3’-Sulfo-Lewis A/C (3’-Sulfo-LeA/C). 3’-Sulfo-LeA/C is broadly reexpressed across numerous GI epithelia and elsewhere during metaplastic and carcinomatous transformation. Discussion 3’-Sulfo-LeA/C is a clinically important antigen that can be detected both intracellularly in tissue using immunohistochemistry and extracellularly in cyst fluid and serum by ELISA. The results open new avenues for tumorigenic risk stratification of various gastrointestinal lesions.

scholarly journals 3'-Sulfated Lewis A is a Biomarker for Metaplastic and Oncogenic Transformation of Several Gastrointestinal Epithelia

2021 ◽  
Author(s):  
Jeffrey Wade Brown ◽  
Koushik Kumar Das ◽  
Vasilios Kalas ◽  
Kiron Das ◽  
Jason C Mills
Keyword(s):  
Monoclonal Antibody ◽  
Risk Stratification ◽  
Complete Loss ◽  
Ductal Adenocarcinoma ◽  
High Grade ◽  
Glycan Array ◽  
Multiple Organs ◽  
Gastrointestinal Lesions ◽  
Direct Elisa ◽  
Lewis A

Introduction: Multiple previous studies have shown the monoclonal antibody Das-1 (formerly called 7E12H12) specifically recognizes metaplastic and carcinomatous lesions in multiple organs of the gastrointestinal system (e.g. Barrett's esophagus, intestinal-type metaplasia of the stomach, gastric adenocarcinoma, high-grade pancreatic intraepithelial neoplasm, and pancreatic ductal adenocarcinoma) as well as in other organs (bladder and lung carcinomas). Beyond being a useful biomarker in tissue, mAb Das-1 has recently proven to be more accurate than current paradigms for identifying cysts harboring advanced neoplasia. Though this antibody has been used extensively for clinical, basic science, and translational applications for decades, its epitope has remained elusive. Methods: In this study, we chemically deglycosylated a standard source of antigen, which resulted in near complete loss of the signal as measured by western blot analysis. The epitope recognized by mAb Das-1 was determined by affinity to a comprehensive glycan array and validated by inhibition of a direct ELISA. Results: The epitope recognized by mAb Das-1 is 3'-Sulfo-Lewis A (3'-Sulfo-LeA). 3'-Sulfo-LeA is broadly reexpressed across numerous GI epithelia and elsewhere only after metaplastic and carcinomatous transformation. Discussion: 3'-Sulfo-LeA is a clinically important antigen that can be detected both intracellularly in tissue using immunohistochemistry and extracellularly in cyst fluid and serum by ELISA. The results open new avenues for tumorigenic risk stratification of various gastrointestinal lesions.

scholarly journals Intraductal Pancreatic Mucinous Neoplasms: A Tumor-Biology Based Approach for Risk Stratification

2020 ◽  
Vol 21 (17) ◽  
pp. 6386 ◽  
Author(s):  
Vincenzo Nasca ◽  
Marta Chiaravalli ◽  
Geny Piro ◽  
Annachiara Esposito ◽  
Lisa Salvatore ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Malignant Transformation ◽  
Disease Risk ◽  
Incidental Finding ◽  
Tumor Biology ◽  
Mucinous Cystic Neoplasm ◽  
Genetic Alterations ◽  
Ductal Adenocarcinoma ◽  
Cystic Neoplasm ◽  
High Grade

Pancreatic ductal adenocarcinoma is one of the most lethal human cancers. Its precursor lesions include pancreatic intra-epithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm (IPMN). IPMNs usually present as an incidental finding at imaging in 2.6% of the population and, according to the degree of dysplasia, they are classified as low- or high-grade lesions. Since the risk of malignant transformation is not accurately predictable, the management of these lesions is based on morphological and clinical parameters, such as presence of mural nodule, main pancreatic duct dilation, presence of symptoms, or high-grade dysplasia. Although the main genetic alterations associated to IPMNs have been elucidated, they are still not helpful for disease risk stratification. The growing body of genomic and epigenomic studies along with the more recent development of organotypic cultures provide the opportunity to improve our understanding of the malignant transformation process, which will likely deliver biomarkers to help discriminate between low- and high-risk lesions. Recent insights on the topic are herein summarized.

scholarly journals Pre-Operative Imaging and Pathological Diagnosis of Localized High-Grade Pancreatic Intra-Epithelial Neoplasia without Invasive Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 945
Author(s):  
Ryota Sagami ◽  
Kentaro Yamao ◽  
Jun Nakahodo ◽  
Ryuki Minami ◽  
Masakatsu Tsurusaki ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Invasive Carcinoma ◽  
Current Knowledge ◽  
Precancerous Lesions ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Ducts ◽  
High Grade ◽  
Cytologic Examination ◽  
Imaging Characteristics ◽  
Retention Cysts

Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions, such as pancreatic intra-epithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). The prognosis of high-grade precancerous lesions, including high-grade PanIN and high-grade IPMN, without invasive carcinoma is good, despite the overall poor prognosis of PDAC. High-grade PanIN, as a lesion preceding invasive PDAC, is therefore a primary target for intervention. However, detection of localized high-grade PanIN is difficult when using standard radiological approaches. Therefore, most studies of high-grade PanIN have been conducted using specimens that harbor invasive PDAC. Recently, imaging characteristics of high-grade PanIN have been revealed. Obstruction of the pancreatic duct due to high-grade PanIN may induce a loss of acinar cells replaced by fibrosis and lobular parenchymal atrophy. These changes and additional inflammation around the branch pancreatic ducts (BPDs) result in main pancreatic duct (MPD) stenosis, dilation, retention cysts (BPD dilation), focal pancreatic parenchymal atrophy, and/or hypoechoic changes around the MPD. These indirect imaging findings have become important clues for localized, high-grade PanIN detection. To obtain pre-operative histopathological confirmation of suspected cases, serial pancreatic-juice aspiration cytologic examination is effective. In this review, we outline current knowledge on imaging characteristics of high-grade PanIN.

scholarly journals Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1679
Author(s):  
Vishnu Mohan ◽  
Jean P. Gaffney ◽  
Inna Solomonov ◽  
Maxim Levin ◽  
Mordehay Klepfish ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Active Site ◽  
Drug Targets ◽  
Fas Ligand ◽  
Specific Activity ◽  
Matrix Metalloproteases ◽  
Ductal Adenocarcinoma ◽  
Enzyme Active Site ◽  
Induced Apoptosis

Matrix metalloproteases (MMPs) undergo post-translational modifications including pro-domain shedding. The activated forms of these enzymes are effective drug targets, but generating potent biological inhibitors against them remains challenging. We report the generation of anti-MMP-7 inhibitory monoclonal antibody (GSM-192), using an alternating immunization strategy with an active site mimicry antigen and the activated enzyme. Our protocol yielded highly selective anti-MMP-7 monoclonal antibody, which specifically inhibits MMP-7′s enzyme activity with high affinity (IC50 = 132 ± 10 nM). The atomic model of the MMP-7-GSM-192 Fab complex exhibited antibody binding to unique epitopes at the rim of the enzyme active site, sterically preventing entry of substrates into the catalytic cleft. In human PDAC biopsies, tissue staining with GSM-192 showed characteristic spatial distribution of activated MMP-7. Treatment with GSM-192 in vitro induced apoptosis via stabilization of cell surface Fas ligand and retarded cell migration. Co-treatment with GSM-192 and chemotherapeutics, gemcitabine and oxaliplatin elicited a synergistic effect. Our data illustrate the advantage of precisely targeting catalytic MMP-7 mediated disease specific activity.

scholarly journals Clinical use of the SelectMDx urinary-biomarker test with or without mpMRI in prostate cancer diagnosis: a prospective, multicenter study in biopsy-naïve men

2021 ◽  
Author(s):  
Rianne J. Hendriks ◽  
Marloes M. G. van der Leest ◽  
Bas Israël ◽  
Gerjon Hannink ◽  
Anglita YantiSetiasti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Stratification ◽  
Specific Antigen ◽  
Low Grade ◽  
Diagnostic Study ◽  
High Grade ◽  
Net Benefit ◽  
Conditional Strategy ◽  
Detection Rates ◽  
Guided Biopsy

Abstract Background Risk stratification in men with suspicion of prostate cancer (PCa) requires reliable diagnostic tests, not only to identify high-grade PCa, also to minimize the overdetection of low-grade PCa, and reduction of “unnecessary” prostate MRIs and biopsies. This study aimed to evaluate the SelectMDx test to detect high-grade PCa in biopsy-naïve men. Subsequently, to assess combinations of SelectMDx test and multi-parametric (mp) MRI and its potential impact on patient selection for prostate biopsy. Methods This prospective multicenter diagnostic study included 599 biopsy-naïve patients with prostate-specific antigen level ≥3 ng/ml. All patients underwent a SelectMDx test and mpMRI before systematic transrectal ultrasound-guided biopsy (TRUSGB). Patients with a suspicious mpMRI also had an in-bore MR-guided biopsy (MRGB). Histopathologic outcome of TRUSGB and MRGB was used as reference standard. High-grade PCa was defined as ISUP Grade Group (GG) ≥ 2. The primary outcome was the detection rates of low- and high-grade PCa and number of biopsies avoided in four strategies, i.e., (1) SelectMDx test-only, (2) mpMRI-only, (3) SelectMDx test followed by mpMRI when SelectMDx test was positive (conditional strategy), and (4) SelectMDx test and mpMRI in all (joint strategy). A positive SelectMDx test outcome was a risk score of ≥−2.8. Decision curve analysis (DCA) was performed to assess clinical utility. Results Prevalence of high-grade PCa was 31% (183/599). Thirty-eight percent (227/599) of patients had negative SelectMDx test in whom biopsy could be avoided. Low-grade PCa was not detected in 35% (48/138) with missing 10% (18/183) high-grade PCa. Yet, mpMRI-only could avoid 49% of biopsies, not detecting 4.9% (9/183) of high-grade PCa. The conditional strategy reduces the number of mpMRIs by 38% (227/599), avoiding biopsy in 60% (357/599) and missing 13% (24/183) high-grade PCa. Low-grade PCa was not detected in 58% (80/138). DCA showed the highest net benefit for the mpMRI-only strategy, followed by the conditional strategy at-risk thresholds >10%. Conclusions SelectMDx test as a risk stratification tool for biopsy-naïve men avoids unnecessary biopsies in 38%, minimizes low-grade PCa detection, and misses only 10% high-grade PCa. Yet, using mpMRI in all patients had the highest net benefit, avoiding biopsy in 49% and missing 4.9% of high-risk PCa. However, if mpMRI availability is limited or expensive, using mpMRI-only in SelectMDx test positive patients is a good alternative strategy.

scholarly journals Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1090
Author(s):  
Hassan Sadozai ◽  
Animesh Acharjee ◽  
Thomas Gruber ◽  
Beat Gloor ◽  
Eva Karamitopoulou
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Disease Progression ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Budding ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

scholarly journals Overexpression of MiR-155-5p and increased number of macrophage population in precancerous prostatic disease

2020 ◽  
Vol 11 (2) ◽  
pp. 85-91
Author(s):  
Rachma Greta Putri ◽  
Sari Eka Pratiwi ◽  
Didik Setyo Heriyanto ◽  
Danarto Danarto ◽  
Indwiani Astuti ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Reverse Transcriptase ◽  
Benign Prostate Hyperplasia ◽  
Intraepithelial Neoplasia ◽  
Prostate Adenocarcinoma ◽  
Prostatic Intraepithelial Neoplasia ◽  
High Grade ◽  
Prostate Hyperplasia ◽  
Macrophage Population ◽  
Benign Prostate

Latar Belakang: Gangguan regulasi mikroRNA(miR) dan inflamasi kronik dapat mengubah tumor menjadi karsinoma dan kanker dengan metastasis melalui perubahan seluler dan genomik. Lesi prekanker memiliki peluang 33,3 persen menjadi kanker. Penelitian ini bertujuan untuk mengkaji peran miR-155-5p terhadap mRNA SOCS1 dan populasi makrofag terhadap progresivitas penyakit yang berhubungan dengan Benign Prostate Hyperplasia (BPH), High Grade Prostatic Intraepithelial Neoplasia (HGPIN), dan Prostate Adenocarcinoma (PRAD). Metode: Penelitian ini merupakan penelitian potong lintang dengan 3 kelompok, yaitu BPH,HGPIN, dan PRAD. Sampel jaringan didapatkan dari Tindakan TURP. Ekspresi miR-155 dianalisis menggunakan qPCR dan dikalkulasi menggunakan metode Livak. Ekspresi mRNA SOCS-1 dianalisis menggunakan reverse transcriptase PCR. Penanda pan makrofag, anti CD-68 monoclonal antibody(MoAb) digunakan untuk mendeteksi populasi makrofag pada jaringan dengan imunohistokimia. Hasil: Ekspresi miR-155 lebih tinggi pada HGPIN dibandingkan BPH dan PRAD (p=0,14). Ekspresi mRNA SOCS1 pada HGPIN paling rendah diantara ketiga sampel (p=0,96). Terdapat korelasi negative antara miR-155 dan mRNA SOCS1 (p=0,02). Terdapat peningkatan persentase populasi makrofag yang signifikan pada HGPIN (6,03 persen) dibandingkan BPH (0.89 persen) dengan p=0,00. Kesimpulan: Pada penelitian ini, terdapat perubahan persentase makrofag dan miR-155 pada HGPIN. Variasi ekspresi miR-155 dan persentase populasi makrofag dapat disebabkan karena perubahan epigenetik. Oleh sebab itu, perlu penelitian lebih lanjut untuk memvalidasi hasil tersebut dan memahami  kemungkinan menjadi biomarker pada penyakit prekanker pada prostat. Kata Kunci: Prostatic Intaepithelial Neoplasia, miR-155, Makrofag   Abstract   Background: Impaired microRNA(miR) regulation and chronic inflammation could transform tumors into carcinoma and cancer by metastasis through cellular and genomic changes. Precancerous lesions have a 33.3 percent chance of becoming cancerous. This study investigated the role of miR-155 related to SOCS1 mRNA and macrophage population in disease progression associated  with Benign Prostate Hyperplasia (BPH), High-Grade Prostatic Intraepithelial Neoplasia (HGPIN), and Prostate Adenocarcinoma (PRAD). Methods: This was a cross-sectional study using three groups of samples, namely BPH, HGPIN, and PRAD. Tissue samples were obtained from TURP Action. The expression of miR-155 was analyzed using real-time qPCR and calculated using the Livak method. The expression of SOCS1 mRNA was analyzed using reverse transcriptase PCR. The macrophage pan-marker, anti-CD68 monoclonal antibody (MoAb), was used to detect macrophage population in tissues by immunohistochemistry. Results: The expression of miR-155 was higher in HGPIN than BPH and PRAD (p=0.14). The expression of SOCS1 mRNA in HGPIN was the lowest among the three samples (p=0.96). There was a negative correlation between miR-155 and SOCS1 mRNA (p=0.02). There was a significant increase in the percentage of the macrophage population in HGPIN (6.03 percent) compared to BPH (0.89 percent) with p=0.00. Conclusion: In this study, there were changes in the percentage of macrophage and miR-155 in HGPIN. The variation in miR-155 expression and the percentage of the macrophage may be caused by epigenetic changes. Therefore, further research is needed to validate these results and understand the possibility of being a biomarker in precancerous disease of the prostate. Keywords: Prostatic Intraepithelial Neoplasia, miR-155, Macrophage  

scholarly journals Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Marta Cáceres ◽  
Rita Quesada ◽  
Mar Iglesias ◽  
Francisco X. Real ◽  
Maria Villamonte ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Premalignant Lesions ◽  
Ductal Adenocarcinoma ◽  
High Grade ◽  
Histological Changes ◽  
Pancreatic Duct Ligation ◽  
Duct Ligation ◽  
Risk Patients ◽  
Flat Lesions ◽  
Over Time

Abstract Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. However, its influence has scarcely been described on premalignant lesions. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Selective ligation of the splenic lobe of the pancreas was performed in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice (PDL-Kras mice). Three experimental groups were evaluated: PDL group, controls and shams. The presence and number of premalignant lesions (PanIN 1–3 and Atypical Flat Lesions—AFL) in proximal (PP) and distal (DP) pancreas were studied for each group over time. Microarray analysis was performed to find differentially expressed genes (DEG) between PP and PD. Clinical human specimens after pancreaticoduodenectomy with ductal occlusion were also evaluated. PDL-Kras mice showed an intense pattern of atrophy in DP which was shrunk to a minimal portion of tissue. Mice in control and sham groups had a 7 and 10-time increase respectively of risk of high-grade PanIN 2 and 3 and AFL in their DP than PDL-Kras mice. Furthermore, PDL-Kras mice had significantly less PanIN 1 and 2 and AFL lesions in DP compared to PP. We identified 38 DEGs comparing PP and PD. Among them, several mapped to protein secretion and digestion while others such as Nupr1 have been previously associated with PanIN and PDAC. PDL in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice induces a decrease in the presence of premalignant lesions in the ligated DP. This could be a potential line of research of interest in some cancerous risk patients.

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