scholarly journals Mathematical Modelling Using Predictive Biomarkers for the Outcome of Canine Leishmaniasis upon Chemotherapy

2020 ◽  
Vol 8 (5) ◽  
pp. 745
Author(s):  
Rafaela de Sousa Gonçalves ◽  
Flaviane Alves de Pinho ◽  
Ricardo Jorge Dinis-Oliveira ◽  
Rui Azevedo ◽  
Joana Gaifem ◽  
...  
Keyword(s):  
Treatment Group ◽  
Animal Health ◽  
Early Period ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Parasite Load ◽  
Response To Therapy ◽  
Canine Leishmaniasis ◽  
Th2 Response ◽  
Therapeutic Decisions

Prediction parameters of possible outcomes of canine leishmaniasis (CanL) therapy might help with therapeutic decisions and animal health care. Here, we aimed to develop a diagnostic method with predictive value by analyzing two groups of dogs with CanL, those that exhibited a decrease in parasite load upon antiparasitic treatment (group: responders) and those that maintained high parasite load despite the treatment (group: non-responders). The parameters analyzed were parasitic load determined by q-PCR, hemogram, serum biochemistry and immune system-related gene expression signature. A mathematical model was applied to the analysis of these parameters to predict how efficient their response to therapy would be. Responder dogs restored hematological and biochemical parameters to the reference values and exhibited a Th1 cell activation profile with a linear tendency to reach mild clinical alteration stages. Differently, non-responders developed a mixed Th1/Th2 response and exhibited markers of liver and kidney injury. Erythrocyte counts and serum phosphorus were identified as predictive markers of therapeutic response at an early period of assessment of CanL. The results presented in this study are highly encouraging and may represent a new paradigm for future assistance to clinicians to interfere precociously in the therapeutic approach, with a more precise definition in the patient’s prognosis.

scholarly journals FML/QuilA-Vaccinated Dogs Naturally Infected with Leishmania infantum: Serum Cytokines, Clinicopathological Profile, and Parasitological Parameters

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Gregório Guilherme Almeida ◽  
Fernanda Morcatti Coura ◽  
Jonata de Melo Barbieri ◽  
Ana Carolina Junqueira Moura ◽  
Fabiola de Oliveira Paes-Leme ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Hematological Parameters ◽  
Parasite Burden ◽  
Parasite Load ◽  
Serum Levels ◽  
Canine Leishmaniasis ◽  
Th2 Response ◽  
Mild Disease ◽  
Clinicopathological Profile ◽  
G Ratio

Dogs are the main reservoir of Leishmania infantum in endemic regions. Canine leishmaniasis, caused by L. infantum, can progress to a chronic disease resulting in death. Vaccines have been developed with a certain degree of success. The pathogenesis of this disease is not completely understood, especially in previously vaccinated dogs. We herein described clinical data, parasite load, serum levels of cytokines, and the reservoir potential in vdogs vaccinated with the fucose-mannose ligand (FML)/QuilA saponin vaccine (Leishmune™) naturally infected (Vi) and compared to vaccinated not infected dogs (Vn). Thirty-four dogs from private owners were divided into two groups: vaccinated/infected and vaccinated/uninfected. Clinical evaluation, hematological and biochemical parameters, and serum levels of cytokines were measured by conventional methods. The parasite burden in the bone marrow was measured by quantitative real-time PCR, and the transmissibility of parasites to sand flies was assessed by xenodiagnosis. Clinical, biochemical, and hematological parameters of vaccinated infected dogs were mostly normal. Vi dogs developed mild disease with low clinical scores. Serum levels of IL-10 were higher in Vi dogs, and a strong correlation was observed in IL-4 levels and the A/G ratio in Vi dogs. These results suggest a role of TH2 response in Vi dogs, although more data is needed to better understand the disease in vaccinated dogs.

Melanoma: Prognostic Factors and Factors Predictive of Response to Therapy

2020 ◽  
Vol 27 (17) ◽  
pp. 2792-2813
Author(s):  
Martina Strudel ◽  
Lucia Festino ◽  
Vito Vanella ◽  
Massimiliano Beretta ◽  
Francesco M. Marincola ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Lactate Dehydrogenase ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Elevated Serum ◽  
Predictive Biomarkers ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Prognostic Features ◽  
Programmed Death

Background: A better understanding of prognostic factors and biomarkers that predict response to treatment is required in order to further improve survival rates in patients with melanoma. Predictive Biomarkers: The most important histopathological factors prognostic of worse outcomes in melanoma are sentinel lymph node involvement, increased tumor thickness, ulceration and higher mitotic rate. Poorer survival may also be related to several clinical factors, including male gender, older age, axial location of the melanoma, elevated serum levels of lactate dehydrogenase and S100B. Predictive Biomarkers: Several biomarkers have been investigated as being predictive of response to melanoma therapies. For anti-Programmed Death-1(PD-1)/Programmed Death-Ligand 1 (PD-L1) checkpoint inhibitors, PD-L1 tumor expression was initially proposed to have a predictive role in response to anti-PD-1/PD-L1 treatment. However, patients without PD-L1 expression also have a survival benefit with anti-PD-1/PD-L1 therapy, meaning it cannot be used alone to select patients for treatment, in order to affirm that it could be considered a correlative, but not a predictive marker. A range of other factors have shown an association with treatment outcomes and offer potential as predictive biomarkers for immunotherapy, including immune infiltration, chemokine signatures, and tumor mutational load. However, none of these have been clinically validated as a factor for patient selection. For combined targeted therapy (BRAF and MEK inhibition), lactate dehydrogenase level and tumor burden seem to have a role in patient outcomes. Conclusions: With increasing knowledge, the understanding of melanoma stage-specific prognostic features should further improve. Moreover, ongoing trials should provide increasing evidence on the best use of biomarkers to help select the most appropriate patients for tailored treatment with immunotherapies and targeted therapies.

scholarly journals The combined detection of Amphiregulin, Cyclin A1 and DDX20/Gemin3 expression predicts aggressive forms of oral squamous cell carcinoma

2021 ◽  
Author(s):  
Ekaterina Bourova-Flin ◽  
Samira Derakhshan ◽  
Afsaneh Goudarzi ◽  
Tao Wang ◽  
Anne-Laure Vitte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Squamous Cell ◽  
Large Scale ◽  
Biomarker Discovery ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Specific Gene ◽  
Specific Expression ◽  
Intrinsic Nature ◽  
Independent Cohort

Abstract Background Large-scale genetic and epigenetic deregulations enable cancer cells to ectopically activate tissue-specific expression programmes. A specifically designed strategy was applied to oral squamous cell carcinomas (OSCC) in order to detect ectopic gene activations and develop a prognostic stratification test. Methods A dedicated original prognosis biomarker discovery approach was implemented using genome-wide transcriptomic data of OSCC, including training and validation cohorts. Abnormal expressions of silent genes were systematically detected, correlated with survival probabilities and evaluated as predictive biomarkers. The resulting stratification test was confirmed in an independent cohort using immunohistochemistry. Results A specific gene expression signature, including a combination of three genes, AREG, CCNA1 and DDX20, was found associated with high-risk OSCC in univariate and multivariate analyses. It was translated into an immunohistochemistry-based test, which successfully stratified patients of our own independent cohort. Discussion The exploration of the whole gene expression profile characterising aggressive OSCC tumours highlights their enhanced proliferative and poorly differentiated intrinsic nature. Experimental targeting of CCNA1 in OSCC cells is associated with a shift of transcriptomic signature towards the less aggressive form of OSCC, suggesting that CCNA1 could be a good target for therapeutic approaches.

Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 343-343
Author(s):  
Pedro C. Barata ◽  
Shuchi Gulati ◽  
Andrew Elliott ◽  
Arpit Rao ◽  
Hans J. Hammers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Hierarchical Clustering ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Primary Tumors ◽  
Metastatic Sites ◽  
Patient Subgroups

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

scholarly journals Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 688 ◽  
Author(s):  
Yu-Min Huang ◽  
Chia-Hsiung Cheng ◽  
Shiow-Lin Pan ◽  
Pei-Ming Yang ◽  
Ding-Yen Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Cycle ◽  
Therapeutic Potential ◽  
Specific Inhibitor ◽  
Gene Expression Signature ◽  
Hsp90 Inhibitor ◽  
Response To Therapy ◽  
Mesenchymal Transition ◽  
Potential Inhibitor

Human high-mobility group A2 (HMGA2) encodes for a non-histone chromatin protein which influences a variety of biological processes, including the cell cycle process, apoptosis, the DNA damage repair process, and epithelial–mesenchymal transition. The accumulated evidence suggests that high expression of HMGA2 is related to tumor progression, poor prognosis, and a poor response to therapy. Thus, HMGA2 is an important molecular target for many types of malignancies. Our recent studies revealed the positive connections between heat shock protein 90 (Hsp90) and HMGA2 and that the Hsp90 inhibitor has therapeutic potential to inhibit HMGA2-triggered tumorigenesis. However, 43% of patients suffered visual disturbances in a phase I trial of the second-generation Hsp90 inhibitor, NVP-AUY922. To identify a specific inhibitor to target HMGA2, the Gene Expression Omnibus (GEO) database and the Library of Integrated Network-based Cellular Signatures (LINCS) L1000platform were both analyzed. We identified the approved small-molecule antifungal agent ciclopirox (CPX) as a novel potential inhibitor of HMGA2. In addition, CPX induces cytotoxicity of colorectal cancer (CRC) cells by induction of cell cycle arrest and apoptosis in vitro and in vivo through direct interaction with the AT-hook motif (a small DNA-binding protein motif) of HMGA2. In conclusion, this study is the first to report that CPX is a novel potential inhibitor of HMGA2 using a drug-repurposing approach, which can provide a potential therapeutic intervention in CRC patients.

scholarly journals Proteomics in Melanoma Biomarker Discovery: Great Potential, Many Obstacles

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Michael S. Sabel ◽  
Yashu Liu ◽  
David M. Lubman
Keyword(s):  
Biomarker Discovery ◽  
Predictive Biomarkers ◽  
Clinical Staging ◽  
Fresh Tissue ◽  
Primary Tumors ◽  
Unique Challenge ◽  
Advantages And Disadvantages ◽  
Serum Proteomics ◽  
Therapeutic Decisions ◽  
Large Populations

The present clinical staging of melanoma stratifies patients into heterogeneous groups, resulting in the application of aggressive therapies to large populations, diluting impact and increasing toxicity. To move to a new era of therapeutic decisions based on highly specific tumor profiling, the discovery and validation of new prognostic and predictive biomarkers in melanoma is critical. Genomic profiling, which is showing promise in other solid tumors, requires fresh tissue from a large number of primary tumors, and thus faces a unique challenge in melanoma. For this and other reasons, proteomics appears to be an ideal choice for the discovery of new melanoma biomarkers. Several approaches to proteomics have been utilized in the search for clinically relevant biomarkers, but to date the results have been relatively limited. This article will review the present work using both tissue and serum proteomics in the search for melanoma biomarkers, highlighting both the relative advantages and disadvantages of each approach. In addition, we review several of the major obstacles that need to be overcome in order to advance the field.

scholarly journals Patient-Derived Xenograft and Organoid Models for Precision Medicine Targeting of the Tumour Microenvironment in Head and Neck Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3743
Author(s):  
Tet Woo Lee ◽  
Amy Lai ◽  
Julia K. Harms ◽  
Dean C. Singleton ◽  
Benjamin D. Dickson ◽  
...  
Keyword(s):  
Head And Neck ◽  
Precision Medicine ◽  
Patient Survival ◽  
Predictive Biomarkers ◽  
Tumour Microenvironment ◽  
Response To Therapy ◽  
Preclinical Models ◽  
Therapeutic Success ◽  
Patient Derived Xenograft ◽  
Individualise Therapy

Patient survival from head and neck squamous cell carcinoma (HNSCC), the seventh most common cause of cancer, has not markedly improved in recent years despite the approval of targeted therapies and immunotherapy agents. Precision medicine approaches that seek to individualise therapy through the use of predictive biomarkers and stratification strategies offer opportunities to improve therapeutic success in HNSCC. To enable precision medicine of HNSCC, an understanding of the microenvironment that influences tumour growth and response to therapy is required alongside research tools that recapitulate the features of human tumours. In this review, we highlight the importance of the tumour microenvironment in HNSCC, with a focus on tumour hypoxia, and discuss the fidelity of patient-derived xenograft and organoids for modelling human HNSCC and response to therapy. We describe the benefits of patient-derived models over alternative preclinical models and their limitations in clinical relevance and how these impact their utility in precision medicine in HNSCC for the discovery of new therapeutic agents, as well as predictive biomarkers to identify patients’ most likely to respond to therapy.

Biomarkers of hyperprogression and pseudoprogression with immune checkpoint inhibitor therapy

2019 ◽  
Vol 15 (22) ◽  
pp. 2645-2656 ◽  
Author(s):  
Jarrett J Failing ◽  
Olivia A Dudek ◽  
Julian A Marin Acevedo ◽  
Razvan M Chirila ◽  
Haidong Dong ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Small Sample ◽  
Inhibitor Therapy ◽  
Laboratory Findings ◽  
Therapeutic Decisions ◽  
Checkpoint Inhibitor Therapy

Hyperprogression and pseudoprogression are two atypical responses to immune checkpoint inhibitor therapy that affect therapeutic decisions and prognosis. Identification of predictive biomarkers for atypical responses either before or during treatment remains a huge unmet need in cancer immunotherapy. Many studies have looked at potential biomarkers, including clinical factors and laboratory findings (e.g., peripheral blood counts, circulating tumor DNA, cytokine levels). The results of these studies have been inconsistent, possibly due to small sample sizes, different tumor types and heterogeneity of the definition of these atypical responses.

Investigation of tumor biomarkers as response predictors in a monotherapy study with lapatinib (L) as a first line treatment in ErbB2 amplified women with breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10562-10562 ◽  
Author(s):  
H. L. Gomez ◽  
M. A. Chavez ◽  
D. C. Doval ◽  
S. Franco ◽  
M. Arbushites ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Preliminary Analysis ◽  
Response Rate ◽  
Metastatic Breast ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Tumor Biomarker ◽  
Mrna Levels ◽  
First Line ◽  
Response Predictors

10562 Background: Lapatinib is a potent inhibitor of both EGFR and HER2 tyrosine kinase activity. Results of the phase II trial EGF20009 in advanced or metastatic breast cancer (MBC) indicated an overall response rate of 24% to monotherapy L as first line (1L) treatment in 138 patients. In an effort to better define predictive biomarkers of response, we evaluated correlations between baseline tumor biomarker expression levels and clinical response to L. Methods: Response rate (RR) was defined as either complete response (CR) or partial response (PR). Tumor blocks were available on 118 patients from the time of most recent biopsy, and mRNA was extracted from 65 individual patient blocks for this preliminary analysis. Using qRT-PCR Taqman analysis, tumors were evaluated for expression of ERBB1- 4, PTEN, c-MYC, as well as two comparator genes for normalization. DecisionTree analysis using SpotFire software was performed to determine the genes most significantly associated with RR. Results: For the initial 65 patient samples analyzed, an elevation of ERBB2 expression was significantly associated with response to treatment with L (p=0.02) and a longer time to progression following treatment with L (p<0.0025). Furthermore, of the 17/65 responders in this preliminary study, SpotFire Decision Tree Analysis demonstrated that 16/17 (94%) who responded to L had a gene expression signature combining ERBB1, 2, and 3, which is currently being confirmed. No association was observed with ERBB4, PTEN and c-MYC in this preliminary analysis. Conclusion: This analysis suggests a correlation between elevated ERBB2 mRNA levels and both RR and TTP in patients treated with L as a 1L treatment. Analysis of the full set of samples (including genome-wide microarray analysis) is ongoing in an effort to determine biomarkers predictive of clinical activity beyond HER2. No significant financial relationships to disclose.

scholarly journals THE LEVEL OF SYSTEMIC INFLAMMATION AND CHANGES IN ADAPTIVE IMMUNITY IN ALCOHOLIC PSYCHOSES

2019 ◽  
Vol 19 (1S) ◽  
pp. 68-70
Author(s):  
N A Didkovsky ◽  
I K Malashenkova ◽  
D P Ogurtsov ◽  
S A Krynskiy ◽  
N A Hailov ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Adaptive Immunity ◽  
Systemic Inflammation ◽  
Early Period ◽  
Control Group ◽  
Acute Psychosis ◽  
Th2 Response ◽  
Proinflammatory Mediators ◽  
The Central Nervous System

The aim of the work is to study the level of systemic inflammation and changes in adaptive immunity in the early period after acute psychosis to assess their participation in the pathogenesis of alcoholic mental and cognitive disorders. We examined 28 patients with alcoholic psychosis (AP) and a control group of 17 healthy volunteers. Indicators of systemic inflammation and immunity, including key cytokines and lymphocyte subpopulations, were investigated. After acute psychosis of patients with alcoholism, pronounced activation of humoral immunity with impaired clearance of immune complexes, increased content and activity of Th2 with signs of insufficiency and dysfunction of Th1, reduced content and activity of cytotoxicity system cells and signs of systemic inflammation (increased CRP, cortisol, cytokines). Activation of Th2 response and an excess of proinflammatory mediators in patients with AP through various ways of interaction with the Central nervous system (n. vagus, choroidal plexus of the ventricles, and others) can participate in the disorders of metabolism of neurotransmitters in the Central nervous system involved in the pathogenesis of alcoholism, and in the maintenance of neuroinflammation. A high level of systemic inflammation can be both a trigger of psychosis and a manifestation of violations of neuroimmune interactions, as well as the development of excitotoxicity and damage to neurons in acute psychosis.

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