scholarly journals A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery

2020 ◽  
Author(s):  
Jeroen H.A. Creemers ◽  
Willem J. Lesterhuis ◽  
Niven Mehra ◽  
Winald R. Gerritsen ◽  
Carl G. Figdor ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Patient Survival ◽  
Predictive Biomarkers ◽  
Tipping Point ◽  
Success Rates ◽  
Molecular Approaches ◽  
Patient Status ◽  
New Biomarkers ◽  
The Right ◽  
Selection Of

ABSTRACTBackgroundIn the field of immuno-oncology, predicting treatment response or survival of cancer patients remains a challenge. Efforts to overcome these challenges focus mainly on the discovery of new biomarkers. Owing to the complexity of cancers and their tumor microenvironment, only a limited number of candidate biomarkers eventually enters clinical practice, despite advances in cellular and molecular approaches.MethodsA computational modeling approach based on ordinary differential equations was used to simulate the fundamental mechanisms that dictate tumor-immune dynamics and show its implications on responses to immune checkpoint inhibition (ICI) and patient survival. Using in silico biomarker discovery trials, we extracted fundamental principles underlying the success rates of biomarker discovery programs.ResultsOur main finding is the prediction of a tipping point – a sharp state transition between immune control and immune evasion – that follows a strongly non-linear relationship between patient survival and both immunological and tumor-related parameters. In patients close to the tipping point, ICI therapy may lead to long-lasting survival benefits, whereas patients far from the tipping point may fail to benefit from these potent treatments.ConclusionThese findings have two important implications for clinical oncology. First, the apparent conundrum that ICI induces substantial benefits in some patients yet completely fails in others could be, to a large extent, explained by the presence of a tipping point. Second, predictive biomarkers for immunotherapy should ideally combine both immunological and tumor-related markers, as the distance of a patient’ status from the tipping point cannot, in general, be reliably determined from solely one of these. The notion of a tipping point in cancer-immune dynamics could help to optimize strategies in biomarker discovery to ensure accurate selection of the right patient for the right treatment.

scholarly journals A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery

2021 ◽  
Vol 9 (5) ◽  
pp. e002032
Author(s):  
Jeroen H A Creemers ◽  
W Joost Lesterhuis ◽  
Niven Mehra ◽  
Winald R Gerritsen ◽  
Carl G Figdor ◽  
...  
Keyword(s):  
State Transition ◽  
Biomarker Discovery ◽  
Patient Survival ◽  
Predictive Biomarkers ◽  
Tipping Point ◽  
Checkpoint Inhibition ◽  
Success Rates ◽  
Patients With Cancer ◽  
Molecular Approaches ◽  
New Biomarkers

BackgroundPredicting treatment response or survival of cancer patients remains challenging in immuno-oncology. Efforts to overcome these challenges focus, among others, on the discovery of new biomarkers. Despite advances in cellular and molecular approaches, only a limited number of candidate biomarkers eventually enter clinical practice.MethodsA computational modeling approach based on ordinary differential equations was used to simulate the fundamental mechanisms that dictate tumor-immune dynamics and to investigate its implications on responses to immune checkpoint inhibition (ICI) and patient survival. Using in silico biomarker discovery trials, we revealed fundamental principles that explain the diverging success rates of biomarker discovery programs.ResultsOur model shows that a tipping point—a sharp state transition between immune control and immune evasion—induces a strongly non-linear relationship between patient survival and both immunological and tumor-related parameters. In patients close to the tipping point, ICI therapy may lead to long-lasting survival benefits, whereas patients far from the tipping point may fail to benefit from these potent treatments.ConclusionThese findings have two important implications for clinical oncology. First, the apparent conundrum that ICI induces substantial benefits in some patients yet completely fails in others could be, to a large extent, explained by the presence of a tipping point. Second, predictive biomarkers for immunotherapy should ideally combine both immunological and tumor-related markers, as a patient’s distance from the tipping point can typically not be reliably determined from solely one of these. The notion of a tipping point in cancer-immune dynamics helps to devise more accurate strategies to select appropriate treatments for patients with cancer.

scholarly journals Current Approaches for Predicting a Lack of Response to Anti-EGFR Therapy inKRASWild-Type Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Tze-Kiong Er ◽  
Chih-Chieh Chen ◽  
Luis Bujanda ◽  
Marta Herreros-Villanueva
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Genetic Determinants ◽  
Secondary Resistance ◽  
Epidermal Growth ◽  
The Right ◽  
Colorectal Cancer Patients ◽  
Selection Of Patients ◽  
Selection Of

Targeting epidermal growth factor receptor (EGFR) has been one of the most effective colorectal cancer strategies. Anti-EGFR antibodies function by binding to the extracellular domain of EGFR, preventing its activation, and ultimately providing clinical benefit.KRASmutations in codons 12 and 13 are recognized prognostic and predictive biomarkers that should be analyzed at the clinic prior to the administration of anti-EGFR therapy. However, still an important fraction ofKRASwild-type patients do not respond to the treatment. The identification of additional genetic determinants of primary or secondary resistance to EGFR targeted therapy for further improving the selection of patients is urgent. Herein, we review the latest published literature highlighting the most important genes that may predict resistance to anti-EGFR monoclonal antibodies in colorectal cancer patients. According to the available findings, the evaluation ofBRAF,NRAS,PIK3CA, andPTENstatus could be the right strategy to select patients who are likely to respond to anti-EGFR therapies. In the future, the combination of those biomarkers will help establish consensus that can be introduced into clinical practice.

scholarly journals Glycans as Biomarkers: Status and Perspectives

2011 ◽  
Vol 30 (3) ◽  
pp. 213-223 ◽  
Author(s):  
Miroslava Janković
Keyword(s):  
Large Scale ◽  
Biomarker Discovery ◽  
High Sensitivity ◽  
Disease Diagnosis ◽  
Protein Glycosylation ◽  
Post Translational Modification ◽  
Different Types ◽  
Progression Of Disease ◽  
New Biomarkers ◽  
Selection Of

Glycans as Biomarkers: Status and PerspectivesProtein glycosylation is a ubiquitous and complex co- and post-translational modification leading to glycan formation, i.e. oligosaccharide chains covalently attached to peptide backbones. The significance of changes in glycosylation for the beginning, progress and outcome of different human diseases is widely recognized. Thus, glycans are considered as unique structures to diagnose, predict susceptibility to and monitor the progression of disease. In the »omics« era, the glycome, a glycan analogue of the proteome and genome, holds considerable promise as a source of new biomarkers. In the design of a strategy for biomarker discovery, new principles and platforms for the analysis of relatively small amounts of numerous glycoproteins are needed. Emerging glycomics technologies comprising different types of mass spectrometry and affinity-based arrays are next in line to deliver new analytical procedures in the field of biomarkers. Screening different types of glycomolecules, selection of differentially expressed components, their enrichment and purification or identification are the most challenging parts of experimental and clinical glycoproteomics. This requires large-scale technologies enabling high sensitivity, proper standardization and validation of the methods to be used. Further progress in the field of applied glycoscience requires an integrated systematic approach in order to explore properly all opportunities for disease diagnosis.

PROBLEM ASPECTS OF THE IMPLEMENTATION OF CRIMINAL PROCEDURAL NORMS OF PROTECTION OF THE VICTIMS FROM CRIME

2020 ◽  
pp. 72-76
Author(s):  
Яна Валерьевна Самиулина
Keyword(s):  
Preventive Measure ◽  
Criminal Procedure ◽  
Legal Rights ◽  
Criminal Proceedings ◽  
Effective Mechanism ◽  
The Russian Federation ◽  
The Individual ◽  
The Right ◽  
To Receive ◽  
Selection Of

В настоящей статье предпринята попытка исследовать отдельные проблемные аспекты института потерпевшего в российском уголовном процессе. В этих целях подвергнуты анализу правовые нормы, регламентирующие его процессуальный статус. Раскрываются отдельные пробелы уголовно-процессуального законодательства в сфере защиты законных прав и интересов потерпевшего. Автор акцентирует внимание на том, что совершенствование уголовно-процессуального законодательства в части расширения правомочий потерпевшего по отстаиванию своих нарушенных преступлением прав следует продолжить. На основании проведенного исследования действующего законодательства в части регламентации прав потерпевшего от преступления предлагается расширить перечень получаемых им копий постановлений, указанных в п. 13 ч. 2 ст. 42 УПК РФ. Автор предлагает включить в перечень указанной законодательной нормы право получения потерпевшим копии постановления об избрании конкретного вида меры пресечения, избранного в отношении подозреваемого (обвиняемого). Для создания действенного механизма защиты интересов потерпевших от преступления юридических лиц предлагаем ч. 9 ст. 42 УПК РФ изложить в следующей редакции: «в случае признания потерпевшим юридического лица его процессуальное право в уголовном процессе осуществляет представляющий его профессиональный адвокат». This article attempts to investigate certain problematic aspects of the institution of the victim in the Russian criminal process. For this purpose, analyzed the individual norms governing his procedural status. Separate gaps of the criminal procedure legislation in the sphere of protection of the legal rights and interests of the victim are disclosed. The author emphasizes that the improvement of the criminal procedure legislation in terms of the extension of the victim’s authority to defend his rights violated by the crime should be continued. On the basis of the study of the current legislation regarding the regulation of the rights of the victim of a crime, it is proposed to expand the list of decisions received by him, referred to in paragraph 13, part 2 of article 42 Code of Criminal Procedure. The author proposes to include in the list of the indicated legislative norm the right to receive the victim a copy of the decision on the selection of a specific type of preventive measure, selected in relation to the suspect (accused). To create an effective mechanism for protecting the interests of legal entities victims of a crime, we offer part 9 of art. 42 of the Code of Criminal Procedure of the Russian Federation shall be reworded as follows: «if a legal entity is recognized as a victim, his procedural right in criminal proceedings is exercised by the professional lawyer representing him».

scholarly journals The Impact of Alkaloid-Producing Epichloë Endophyte on Forage Ryegrass Breeding: A New Zealand Perspective

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 158
Author(s):  
Colin Eady
Keyword(s):  
Seed Production ◽  
Health Issues ◽  
Abiotic Stressors ◽  
Livestock Health ◽  
The Right ◽  
The Impact ◽  
The Relationship ◽  
And Storage ◽  
Selection Of ◽  
Epichloë Endophyte

For 30 years, forage ryegrass breeding has known that the germplasm may contain a maternally inherited symbiotic Epichloë endophyte. These endophytes produce a suite of secondary alkaloid compounds, dependent upon strain. Many produce ergot and other alkaloids, which are associated with both insect deterrence and livestock health issues. The levels of alkaloids and other endophyte characteristics are influenced by strain, host germplasm, and environmental conditions. Some strains in the right host germplasm can confer an advantage over biotic and abiotic stressors, thus acting as a maternally inherited desirable ‘trait’. Through seed production, these mutualistic endophytes do not transmit into 100% of the crop seed and are less vigorous than the grass seed itself. This causes stability and longevity issues for seed production and storage should the ‘trait’ be desired in the germplasm. This makes understanding the precise nature of the relationship vitally important to the plant breeder. These Epichloë endophytes cannot be ‘bred’ in the conventional sense, as they are asexual. Instead, the breeder may modulate endophyte characteristics through selection of host germplasm, a sort of breeding by proxy. This article explores, from a forage seed company perspective, the issues that endophyte characteristics and breeding them by proxy have on ryegrass breeding, and outlines the methods used to assess the ‘trait’, and the application of these through the breeding, production, and deployment processes. Finally, this article investigates opportunities for enhancing the utilisation of alkaloid-producing endophytes within pastures, with a focus on balancing alkaloid levels to further enhance pest deterrence and improving livestock outcomes.

Two decades of experience on ablation in children with Ebstein’s anomaly

2021 ◽  
pp. 1-7
Author(s):  
Tevfik Karagöz ◽  
İlker Ertuğrul ◽  
Ebru Aypar ◽  
Aydın Adıgüzel ◽  
Hayrettin Hakan Aykan ◽  
...  
Keyword(s):  
Atrial Flutter ◽  
Atrial Tachycardia ◽  
Ebstein’S Anomaly ◽  
Atrioventricular Nodal Reentrant Tachycardia ◽  
Success Rates ◽  
Recurrence Rates ◽  
Ebstein's Anomaly ◽  
Accessory Pathways ◽  
Rare Occasion ◽  
The Right

Abstract Introduction: Accessory pathways are commonly seen due to delamination of tricuspid valve leaflets. In addition to accessory pathways, an enlarged right atrium due to tricuspid regurgitation and incisional scars creates substrates for atrial re-entries and ectopic tachycardia. We sought to describe our experience with catheter ablation in children with Ebstein’s anomaly. Methods and results: During the study period, of 89 patients diagnosed with Ebstein’s anomaly, 26 (30.9%) of them who underwent 33 ablation procedures were included in the study. Accessory pathways were observed in the majority of procedures (n = 27), whereas atrial flutter was observed in five, atrioventricular nodal reentrant tachycardia in five, and atrial tachycardia in two procedures. Accessory pathways were commonly localised in the right posteroseptal (n = 10 patients), right posterolateral (n = 14 patients), septal (n = two patients), and left posteroseptal (n = one patient) areas. Multiple accessory pathways and coexistent arrhythmia were observed in six procedures. All ablation attempts related to the accessory pathways were successful, but recurrence was observed in five (19%) of the ablations. Ablation for atrial flutter was performed in five patients; two of them were ablated successfully. One of the atrial tachycardia cases was ablated successfully. Conclusions: Ablation in patients with Ebstein’s anomaly is challenging, and due to nature of the disease, it is not a rare occasion in this group of patients. Ablation of accessory pathways has high success, but also relatively high recurrence rates, whereas ablation of atrial arrhythmias has lower success rates, especially in operated patients.

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.

scholarly journals Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now?

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2274
Author(s):  
Filippo Pelizzaro ◽  
Romilda Cardin ◽  
Barbara Penzo ◽  
Elisa Pinto ◽  
Alessandro Vitale ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liquid Biopsy ◽  
Predictive Biomarkers ◽  
Invasive Procedure ◽  
Therapeutic Monitoring ◽  
Comprehensive Overview ◽  
Improve Patient Survival ◽  
Prognostic Tests ◽  
Prognostic Stratification ◽  
New Biomarkers

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.

scholarly journals Next-Generation Biomarkers for Cholangiocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3222
Author(s):  
Pedro M. Rodrigues ◽  
Arndt Vogel ◽  
Marco Arrese ◽  
Domingo C. Balderramo ◽  
Juan W. Valle ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Tumor Development ◽  
Predictive Biomarkers ◽  
Disease Diagnosis ◽  
Future Research ◽  
Tumor Biopsy ◽  
Non Invasive ◽  
Tumor Stages ◽  
At Risk Populations ◽  
Early Tumor

The increasing mortality rates of cholangiocarcinoma (CCA) registered during the last decades are, at least in part, a result of the lack of accurate non-invasive biomarkers for early disease diagnosis, making the identification of patients who might benefit from potentially curative approaches (i.e., surgery) extremely challenging. The obscure CCA pathogenesis and associated etiological factors, as well as the lack of symptoms in patients with early tumor stages, highly compromises CCA identification and to predict tumor development in at-risk populations. Currently, CCA diagnosis is accomplished by the combination of clinical/biochemical features, radiological imaging and non-specific serum tumor biomarkers, although a tumor biopsy is still needed to confirm disease diagnosis. Furthermore, prognostic and predictive biomarkers are still lacking and urgently needed. During the recent years, high-throughput omics-based approaches have identified novel circulating biomarkers (diagnostic and prognostic) that might be included in large, international validation studies in the near future. In this review, we summarize and discuss the most recent advances in the field of biomarker discovery in CCA, providing new insights and future research directions.

scholarly journals Emerging Biomarkers for the Selection of Advanced NSCLC-Affected Immunotherapy Patients

2021 ◽  
Vol 2 (2) ◽  
pp. 197-206
Author(s):  
Luigi Della Gravara ◽  
Ciro Battiloro ◽  
Antonietta Letizia ◽  
Rosa Cantile ◽  
Vito D'Agnano ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Predictive Biomarkers ◽  
Treatment Algorithms ◽  
Combination Treatments ◽  
Near Future ◽  
Selection Of

Immunotherapy in the form of ICIs has revolutionized advanced NSCLC treatment algorithms, with ICI-containing combination treatments being the latest addition to approved regimens. However, PD-L1 still represents the only routinely assessed and validated biomarker apart from genetic drivers testing, impairing our capacity to personalize and guide treatment. Therefore, this paper aims to analyze the most promising emerging predictive biomarkers that could help us in the near future to select patients more effectively.

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