New Markers Of Progression Research Articles

Are We Benign? What Can Wnt Signaling Pathway and Epithelial to Mesenchymal Transition Tell Us about Intracranial Meningioma Progression.

Simple SummaryIntracranial meningiomas are one of the most common primary brain tumors. Although mostly benign, a small portion may exhibit aggressive and malignant characteristics leading to higher recurrence and mortality rate. Detecting the molecular profiles and genes that are involved in meningioma progression can lead to better stratification of patients and more efficient and targeted treatments. The results of this study reveal the role of main actors of the Wnt signaling pathway (β-catenin) and epithelial to mesenchymal transition (E-cadherin, N-cadherin, TWIST1, SNAIL and SLUG) in progression of these tumors, potentially bringing novel biomarkers in diagnostics and molecular targets for therapeutic interventions.Epithelial to mesenchymal transition (EMT), which is characterized by the reduced expression of E-cadherin and increased expression of N-cadherin, plays an important role in the tumor invasion and metastasis. Classical Wnt signaling pathway has a tight link with EMT and it has been shown that nuclear translocation of β-catenin can induce EMT. This research has showed that genes that are involved in cadherin switch, CDH1 and CDH2, play a role in meningioma progression. Increased N-cadherin expression in relation to E-cadherin was recorded. In meningioma, transcription factors SNAIL, SLUG, and TWIST1 demonstrated strong expression in relation to E- and N-cadherin. The expression of SNAIL and SLUG was significantly associated with higher grades (p = 0.001), indicating their role in meningioma progression. Higher grades also recorded an increased expression of total β-catenin followed by an increased expression of its active form (p = 0.000). This research brings the results of genetic and protein analyzes of important molecules that are involved in Wnt and EMT signaling pathways and reveals their role in intracranial meningioma. The results of this study offer guidelines and new markers of progression for future research and reveal new molecular targets of therapeutic interventions.

Unmasking the immune microecology of ductal carcinoma in situ with deep learning

Despite increasing evidence supporting the clinical relevance of tumour infiltrating lymphocytes (TILs) in invasive breast cancer, TIL spatial variability within ductal carcinoma in situ (DCIS) samples and its association with progression are not well understood. To characterise tissue spatial architecture and the microenvironment of DCIS, we designed and validated a new deep learning pipeline, UNMaSk. Following automated detection of individual DCIS ducts using a new method IM-Net, we applied spatial tessellation to create virtual boundaries for each duct. To study local TIL infiltration for each duct, DRDIN was developed for mapping the distribution of TILs. In a dataset comprising grade 2–3 pure DCIS and DCIS adjacent to invasive cancer (adjacent DCIS), we found that pure DCIS cases had more TILs compared to adjacent DCIS. However, the colocalisation of TILs with DCIS ducts was significantly lower in pure DCIS compared to adjacent DCIS, which may suggest a more inflamed tissue ecology local to DCIS ducts in adjacent DCIS cases. Our study demonstrates that technological developments in deep convolutional neural networks and digital pathology can enable an automated morphological and microenvironmental analysis of DCIS, providing a new way to study differential immune ecology for individual ducts and identify new markers of progression.

Changes of the pro-hormone levels of vitamin D 25(OH)D in patients with newly diagnosed pulmonary tuberculosis treatment failure

In Ukraine the number of patients with newly diagnosed tuberculosis (NDTB) who successfully complete the course of treatment reaches 60–65 % today. This is while the World Health Organization (WHO) criteria for successful treatment of this category of patients is 85 %. Scientists around the world are studying the possible pathogenetic factors of treatment failure of antimycobacterial therapy in patients with tuberculosis. Nowadays, the impact of vitamin D has been widely studied in this area. Studying of the dynamics of this indicator in patients with NDTB with widespread destructive tuberculosis in the lungs and bacterial excretion with the purpose of finding new markers of progression of a specific process and failure of treatment, as well as finding possible ways of additional pathogenetic therapy to accompany patients is actual. This approach will prevent treatment failure and, as a consequence, improve treatment efficiency.Purpose. To determine changes in the pro-hormone levels of vitamin D 25(OH)D in patients with NDTB treatment failure during the intensive phase of antimycobacterial therapy.Materials and methods. A prospective study involving 58 patients with NDTB lungs was performed. The patients were divided into 2 groups: 28 patients with pulmonary NDTB treatment failure were included in the 1st group (the main group), 30 patients, who subsequently successfully completed the course of treatment were included in the 2nd group (comparison group). The control group consisted of 29 healthy volunteer-donors. All the patients had been in inpatient treatment in Communal Institution “Zaporizhzhia Regional TB Clinical dispensary” during 2017–2019 years. Scientific medical-laboratory center of Zaporizhzhia State Medical University researched changes of the level of 25(OH)D in the blood serum by method of enzyme linked immunosorbent assay using immunoassay analyser Sirio S with “DIAsource ImmunoAssays S.A.” kit (Belgium) (ng/ml). Blood sampling was made after an overnight fast. Blood was collected uniformly throughout the year in all patients and volunteers to avoid the effect of seasonal variability in vitamin D in the blood.Results. While healthy volunteers have a reduction in the level of pro-hormone 25(OH)D only in 51.7 % of cases (deficiency in 13.8 % and insufficiency in 37.9 %), patients with NDTB with generalized specific process in the lungs, the presence of destruction of over 3 cm in diameter and bacterial excretion at the beginning of intensive phase of antimycobacterial therapy (0 doses), have its decrease in 96.5 % (81 % deficiency and 15.5 % insufficiency). 1/3 of patients (35.7 % at the 0th dose and 32.1 % at the 90th dose) with tuberculosis treatment failure have pro-hormone levels 25(OH)D less than 7 ng/ml, whereas in patients who successfully completed the course of treatment, this concentration of pro-hormone 25(OH)D was not even diagnosed. In the dynamics, after 3 months of intensive phase of antimycobacterial therapy (90 doses) in patients with NDTB treatment failure the levels of pro-hormone 25(OH)D continue to decrease significantly by 1.3 times relative to the initial values, which is 1.4 times lower than in patients who successfully completed the course of treatment.Conclusions. In the vast majority of patients with NDTB of lungs with a risk of ineffective treatment, a pronounced deficiency of vitamin D (1/3 patients with pro-hormone levels 25(OH)D less than 7 ng/ml) is determined at the beginning of treatment, and after 3 months of the intensive phase of antimycobacterial chemotherapy exacerbates vitamin D deficiency. Therefore, this indicator can be used as a prognostic for the tuberculosis treatment failure and reducing the level of pro-hormone 25(OH)D in the dynamics require consideration of the problem of methods of its correction by the addition of vitamin D.

Clinical implications of serum Mac-2-binding protein (M2BPGi) during regular follow-up of patients with biliary atresia.

The Mac-2-binding protein glycosylation-modified isomer (M2BPGi) is a new marker for progression of hepatic fibrosis. We examined the relationship between serum M2BPGi levels and liver histological findings in patients with biliary atresia (BA) who were not transplant candidates. Patients with BA who were not transplant candidates with good liver function were included. We examined M2BPGi levels and histological findings in relation to other laboratory markers of liver fibrosis, including aspartate aminotransferase (AST) to platelet ratio index, fibrosis-4 index, and type IV collagen 7s domain. Liver fibrosis was evaluated based on the METVIR score. 37 patients were included. The median age was 18years (range 3-38years). M2BPGi values ranged from 0.3 to 6.9 cutoff index (COI) (median 1.6). The degree of liver fibrosis varied with M2BPGi level. For predicting cirrhosis (F4) and advanced liver fibrosis (≥ F3), M2BPGi had higher areas under the curve (AUCs; 0.93, respectively) with cutoff COIs of 1.84 and 1.67, respectively, than for the four conventional markers for fibrosis. M2BPGi is a novel marker for liver fibrosis in patients with BA. It is especially useful for following patients with BA with a native liver and supporting liver biopsy interpretation findings.

The 16p13.3 (PDPK1) Genomic Gain in Prostate Cancer: A Potential Role in Disease Progression

BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer death, and distinguishing aggressive from indolent tumors is a major challenge. Identification and characterization of genomic alterations associated with advanced disease can provide new markers of progression and better therapeutic approaches. METHODS: We performed fluorescence in situ hybridization to detect the copy number gain of chromosome 16p13.3 in 75 PCa samples including 10 lymph node (LN) metastases and their matched primary tumors, 9 samples of castration-resistant prostate cancer (CRPC), and 46 additional primary PCa specimens with clinicopathologic parameters. RESULTS: We detected the gain in 5 of 10 LN metastases and 3 of 5 matched primary tumors, 3 of 9 CRPC samples, and 9 of 46 (20%) primary tumors where the 16p13.3 alteration was associated with high Gleason score and elevated preoperative prostate-specific antigen levels. The level of 16p13.3 gain was higher in LN metastasis and CRPC specimens compared to primary PCa. Chromosome mapping revealed the gain spans PDPK1 encoding the 3-phosphoinositide-dependent protein kinase-1 (PDK1). Knockdown of PDK1 in three PCa cell lines reduced migration without affecting growth and re-expressing PDK1 rescued motility. CONCLUSION: Our findings support a prognostic value of the 16p13.3 gain and a role of PDK1 in PCa progression through migration.

Abstract C25: The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression

Abstract Prostate cancer (PCa) is a leading cause of cancer death and distinguishing life threatening tumors from indolent ones is a major challenge. The identification and characterization of genomic alterations associated with advanced disease may lead to the development of new markers of progression and more efficient therapeutic approaches. Array-CGH data have shown that gain of chromosome 16p13.3 to be associated with lymph node (LN) metastases of PCa, but this region remained uncharacterized. Our goal was to establish the prognostic value of 16p13.3 gain, and identify the cancer relevant genes residing within this region. In this study, we performed Fluorescence In Situ Hybridization (FISH) to detect the copy number gain of chromosome 16p13.3 in 75 PCa samples including 10 lymph node (LN) metastases and their matched primary tumors, 9 transurethral resections of prostate (TURP) tissue samples of castration-resistant prostate cancer (CRPC), and 46 additional primary PCa specimens with clinicopathological parameters. We detected the gain in 5/10 LN metastases and 3/5 matched primary tumors, 3/9 CRPC samples, and 9/46 (20 %) primary tumors. In the latter set of samples, the 16p13.3 alteration was associated with high Gleason score (P=0.002) and elevated pre operative prostate specific antigen (PSA) levels (P=0.047). The levels of 16p13.3 gain were higher in LN metastasis and CRPC specimens compared to primary PCa (P>0.05). Chromosome mapping revealed a focal gain that spans PDPK1 encoding the 3-Phosphoinositide-dependent protein kinase-1 (PDK1). RNA interference-mediated knock down of PDK1 in three different PCa cell lines reduced cell motility without affecting growth and re-expressing PDK1 rescued motility (P>0.05). Our results support that the 16p13.3 gain is relevant to PCa progression and may represent an early marker of metastasis, since retrieved in primary PCa which is sampled by biopsies at time of diagnosis. PDK1 is implicated in PCa cell motility, a critical step for progression to metastasis. These findings provide further rationale for considering PDK1 as a target for cancer therapies and the development of new specific inhibitors of PDK1. Citation Format: Khalil Choucair, Fadi Brimo, Isabela W Cunha, Armen Aprikian, Martin Gleave, Jacques Lapointe, Karl-Philippe Guérard, Joshua Ejdelman, Simone Chevalier, Maisa Yoshimoto, Eleonora Scarlata, Ladan Fazli, Kanishka Sircar, Jeremy A. Squire. The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C25.

Pro-A-type natriuretic peptide and pro-adrenomedullin predict progression of chronic kidney disease: the MMKD Study

A-type natriuretic peptide (ANP) and adrenomedullin (ADM) are potent hypotensive, diuretic, and natriuretic peptides involved in maintaining cardiovascular and renal homeostasis. We conducted a prospective 7-year study of 177 nondiabetic patients with primary chronic kidney disease to see if ANP and ADM plasma concentrations predict the progression of their disease, using novel sandwich immunoassays covering the midregional epitopes of the stable prohormones (MRproANP and MR-proADM). Progression of chronic kidney disease was defined as doubling of baseline serum creatinine and/or terminal renal failure, which occurred in 65 patients. Analysis of the receiver operating characteristic curve for the prediction of renal endpoints showed similar areas under the curve for the glomerular filtration rate (GFR) (0.838), MR-proANP (0.810), and MRproADM (0.876), respectively, as did the Kaplan-Meier curve analyses of the patients stratified according to the median of the respective markers. In separate multiple Cox-proportional hazard regression analyses, increased plasma concentrations of both peptides were each strongly predictive of the progression of chronic kidney disease after adjustments for age, gender, GFR, proteinuria and amino-terminal pro-B-type natriuretic peptide. Our study suggests that MR-proANP and MR-proADM are useful new markers of progression of primary nondiabetic chronic kidney disease.

The Problem of Cancer Dormancy: Understanding the Basic Mechanisms and Identifying Therapeutic Opportunities

The hiatus observed in the progression of cancer after diagnosis and treatment in a large proportion of patients has led to the notion that a state of cancer dormancy must exist during tumor progression. However, research on this stage of cancer has been limited due to the lack of appropriate models and clinical correlates. Fortunately, the last decade has seen the development of new cancer dormancy models, whole animal and intravital imaging techniques and the molecular characterization of minimal residual disease. These studies enabled researchers to reveal intriguing mechanisms and molecular determinants that define tumor dormancy. It is imperative to understand the basic mechanisms of dormancy, as this will accelerate the development of new markers of progression and novel therapeutic opportunities to induce dormancy and/or eradicate dormant disease. This issue of Cell Cycle includes a “Spotlight on Cancer Dormancy” highlighting major contributions to the field of cancer dormancy from basic and clinical studies. We anticipate that this will initiate a forum of discussion on the problem of cancer dormancy and stimulate investigators to study this rather unexplored but undeniably relevant clinical stage of cancer progression.