Targeted RNA NextGenSeq profiling in oncology using single molecule molecular inversion probes

AbstractHundreds of biology-based precision drugs are available that neutralize aberrant molecular pathways in cancer. Molecular heterogeneity and the lack of reliable companion diagnostic biomarkers for many drugs makes targeted treatment of cancer inaccurate for many individuals, leading to futile overtreatment. To acquire a comprehensive insight in aberrant actionable biological pathways in individual cancers we applied a cost-effective targeted RNA next generation sequencing (NGS) technique. The test allows NGS-based measurement of transcript levels and splice variants of hundreds of genes with established roles in the biological behavior in many cancer types. We here present proof of concept that the technique generates a correct molecular diagnosis and a prognosis for glioma patients. The test not only confirmed known brain cancer-associated molecular aberrations but also identified aberrant expression levels of actionable genes and mutations that are associated with other cancer types. Targeted RNA-NGS is therefore a highly attractive method to guide precision therapy for the individual patient based on pathway analysis.

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Mapping actionable pathways and mutations in brain tumours using targeted RNA next generation sequencing

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0826-z ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 1

Author(s):

Krissie Lenting ◽

Corina N. A. M. van den Heuvel ◽

Anne van Ewijk ◽

Duaa ElMelik ◽

Remco de Boer ◽

...

Keyword(s):

Next Generation Sequencing ◽

Splice Variants ◽

Drug Repurposing ◽

Molecular Heterogeneity ◽

Next Generation ◽

Aberrant Expression ◽

Therapy Decision ◽

Patient Prognosis ◽

Molecular Aberrations ◽

Generation Sequencing

AbstractMany biology-based precision drugs are available that neutralize aberrant molecular pathways in cancer. Molecular heterogeneity and the lack of reliable companion diagnostic biomarkers for many drugs makes targeted treatment of cancer inaccurate for many individuals. Identifying actionable hyperactive biological pathways in individual cancers may improve this situation.To achieve this we applied a novel targeted RNA next generation sequencing (t/RNA-NGS) technique to surgically obtained glioma tissues. The test combines mutation detection with analysis of biological pathway activities that are involved in tumour behavior in many cancer types (e.g. tyrosine kinase signaling, angiogenesis signaling, immune response, metabolism), via quantitative measurement of transcript levels and splice variants of hundreds of genes. We here present proof of concept that the technique, which uses molecular inversion probes, generates a histology-independent molecular diagnosis and identifies classifiers that are strongly associated with conventional histopathology diagnoses and even with patient prognosis. The test not only confirmed known glioma-associated molecular aberrations but also identified aberrant expression levels of actionable genes and mutations that have so far been considered not to be associated with glioma, opening up the possibility of drug repurposing for individual patients. Its cost-effectiveness makes t/RNA-NGS to an attractive instrument to aid oncologists in therapy decision making.

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Single molecule imaging reveals cFos is capable of binding to and diffusing on DNA tightropes independently of cJun

10.1101/2020.01.24.918300 ◽

2020 ◽

Author(s):

James T. Leech ◽

Nicola A. Don ◽

Jody M. Mason ◽

Neil M. Kad

Keyword(s):

Single Molecule ◽

Drug Targets ◽

Leucine Zipper ◽

Diffusion Constant ◽

Basic Leucine Zipper ◽

Aberrant Expression ◽

Cellular Processes ◽

Average Diffusion ◽

Cancer Types ◽

Oncogenic Transcription Factor

AbstractAP-1 proteins are members of the basic leucine zipper (bZIP) protein family of dimeric transcription factors, responsible for controlling many integral cellular processes. These proteins form dimers with each other, and their aberrant expression can lead to a number of cancer types. The oncogenic transcription factor AP-1 binds its target TRE site (5’TCA[G/C]TGA), however the physical mechanism of how this is achieved is not understood. Such an understanding is essential to know how these proteins function, and could offer the potential to uncover new drug targets. The archetypal AP-1 complex is formed by cFos and cJun, which heterodimerise via their bZIP domains. Here, we set out to investigate how these proteins interact with DNA using a real-time single molecule fluorescence imaging approach. Using DNA tightropes as a substrate, we determine that the AP-1 bZIP dimers cJun:cFos and cJun:cJun rapidly scan DNA using a 1D diffusional search with an average diffusion constant of 0.14 µm2s-1 and 0.26 µm2s-1 respectively. Remarkably, we also found that cFos was able to bind to and diffuse on DNA (0.29 µm2s-1) both as a monomer and homodimer. Periods of diffusion were punctuated by pauses, suggesting a mechanism for how AP-1 may rapidly find its target sites on DNA. Taken together the results we have obtained indicate a considerably more complex and graded interaction between cFos, cJun and DNA than has been reported previously.

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Prognostic Role of Hedgehog-GLI1 Signaling Pathway in Aggressive and Metastatic Breast Cancers

Current Drug Metabolism ◽

10.2174/1389200221666200122120625 ◽

2020 ◽

Vol 21 (1) ◽

pp. 33-43 ◽

Cited By ~ 1

Author(s):

Prasuja Rokkam ◽

Shailender Gugalavath ◽

Deepak Kakara Gift Kumar ◽

Rahul Kumar Vempati ◽

Rama Rao Malla

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Neural Development ◽

Splice Variants ◽

Metastatic Breast ◽

Basic Function ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Aberrant Expression ◽

Cellular Processes

Glioma-associated oncogene homolog 1 (GLI1) is reported as an amplified gene in human glioblastoma cells. It is a krupple like transcription factor, belonging to the zinc finger family. The basic function of GLI1 is normal neural development at various stages of human. The GLI1 gene was first mapped on the chromosome sub-bands 12q13.3-14.1. Further, single nucleotide polymorphism is mostly observed in translating a region of 5’ and 3’- UTR of GLI1 gene in addition to two post-transcriptional splice variants, GLIΔN and tGLI. Additionally, it also regulates a plethora of gene which mediates crucial cellular processes like proliferation, differentiation, oncogenesis, EMT, and metastasis. It also regulates tumor tolerance, chemoresistance, and radioresistance. Aberrant expression of GLI1 predicts the poor survival of breast cancer patients. GLI1 is an essential mediator of the SHH signaling pathway regulating self-renewal of stem cells, angiogenesis, and expression of FOXS1, CYR61. GLI1 mediated HH pathway can induce apoptosis. Hence, GLI1 can be a future diagnostic, prognostic marker, and as well as a potent target of therapeutics in breast cancer.

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Electrochemical Biosensors for Cytokine Profiling: Recent Advancements and Possibilities in the Near Future

Biosensors ◽

10.3390/bios11030094 ◽

2021 ◽

Vol 11 (3) ◽

pp. 94

Author(s):

Nirmita Dutta ◽

Peter B. Lillehoj ◽

Pedro Estrela ◽

Gorachand Dutta

Keyword(s):

Immune System ◽

Cost Effective ◽

Anomalous Behavior ◽

Quantitative Detection ◽

Electrochemical Biosensors ◽

Aberrant Expression ◽

Detection Techniques ◽

Short Period ◽

User Friendly ◽

Cytokine Profiling

Cytokines are soluble proteins secreted by immune cells that act as molecular messengers relaying instructions and mediating various functions performed by the cellular counterparts of the immune system, by means of a synchronized cascade of signaling pathways. Aberrant expression of cytokines can be indicative of anomalous behavior of the immunoregulatory system, as seen in various illnesses and conditions, such as cancer, autoimmunity, neurodegeneration and other physiological disorders. Cancer and autoimmune diseases are particularly adept at developing mechanisms to escape and modulate the immune system checkpoints, reflected by an altered cytokine profile. Cytokine profiling can provide valuable information for diagnosing such diseases and monitoring their progression, as well as assessing the efficacy of immunotherapeutic regiments. Toward this goal, there has been immense interest in the development of ultrasensitive quantitative detection techniques for cytokines, which involves technologies from various scientific disciplines, such as immunology, electrochemistry, photometry, nanotechnology and electronics. This review focusses on one aspect of this collective effort: electrochemical biosensors. Among the various types of biosensors available, electrochemical biosensors are one of the most reliable, user-friendly, easy to manufacture, cost-effective and versatile technologies that can yield results within a short period of time, making it extremely promising for routine clinical testing.

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miR-205 in Breast Cancer: State of the Art

International Journal of Molecular Sciences ◽

10.3390/ijms22010027 ◽

2020 ◽

Vol 22 (1) ◽

pp. 27

Author(s):

Ilaria Plantamura ◽

Alessandra Cataldo ◽

Giulia Cosentino ◽

Marilena V. Iorio

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Normal Breast ◽

Response To Therapy ◽

Aberrant Expression ◽

Open Questions ◽

Tumor Tissues ◽

Breast Physiology ◽

Cancer Types

Despite its controversial roles in different cancer types, miR-205 has been mainly described as an oncosuppressive microRNA (miRNA), with some contrasting results, in breast cancer. The role of miR-205 in the occurrence or progression of breast cancer has been extensively studied since the first evidence of its aberrant expression in tumor tissues versus normal counterparts. To date, it is known that the expression of miR-205 in the different subtypes of breast cancer is decreasing from the less aggressive subtype, estrogen receptor/progesterone receptor positive breast cancer, to the more aggressive, triple negative breast cancer, influencing metastasis capability, response to therapy and patient survival. In this review, we summarize the most important discoveries that have highlighted the functional role of this miRNA in breast cancer initiation and progression, in stemness maintenance, in the tumor microenvironment, its potential role as a biomarker and its relevance in normal breast physiology—the still open questions. Finally, emerging evidence reveals the role of some lncRNAs in breast cancer progression as sponges of miR-205. Here, we also reviewed the studies in this field.

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Harnessing testing strategies and public health measures to avert COVID-19 outbreaks during ocean cruises

Scientific Reports ◽

10.1038/s41598-021-95032-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Gerardo Chowell ◽

Sushma Dahal ◽

Raquel Bono ◽

Kenji Mizumoto

Keyword(s):

Public Health ◽

Cost Effective ◽

Contact Network ◽

Social Distancing ◽

Individual Level ◽

Health Measures ◽

Testing Strategies ◽

Novel Coronavirus ◽

The Individual ◽

The Impact

AbstractTo ensure the safe operation of schools, workplaces, nursing homes, and other businesses during COVID-19 pandemic there is an urgent need to develop cost-effective public health strategies. Here we focus on the cruise industry which was hit early by the COVID-19 pandemic, with more than 40 cruise ships reporting COVID-19 infections. We apply mathematical modeling to assess the impact of testing strategies together with social distancing protocols on the spread of the novel coronavirus during ocean cruises using an individual-level stochastic model of the transmission dynamics of COVID-19. We model the contact network, the potential importation of cases arising during shore excursions, the temporal course of infectivity at the individual level, the effects of social distancing strategies, different testing scenarios characterized by the test’s sensitivity profile, and testing frequency. Our findings indicate that PCR testing at embarkation and daily testing of all individuals aboard, together with increased social distancing and other public health measures, should allow for rapid detection and isolation of COVID-19 infections and dramatically reducing the probability of onboard COVID-19 community spread. In contrast, relying only on PCR testing at embarkation would not be sufficient to avert outbreaks, even when implementing substantial levels of social distancing measures.

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Cultivating Resilience During the COVID-19 Pandemic: A Socioecological Perspective

Annual Review of Psychology ◽

10.1146/annurev-psych-030221-031857 ◽

2021 ◽

Vol 73 (1) ◽

Author(s):

Ning Zhang ◽

Shujuan Yang ◽

Peng Jia

Keyword(s):

Cost Effective ◽

Future Research ◽

Annual Review ◽

Publication Date ◽

Physical And Mental Health ◽

Pandemic Preparedness ◽

Predicting Factors ◽

Effective Interventions ◽

Interdisciplinary Framework ◽

The Individual

The coronavirus disease 2019 (COVID-19) pandemic poses wide-ranging impacts on the physical and mental health of people around the world, increasing attention from both researchers and practitioners on the topic of resilience. In this article, we review previous research on resilience from the past several decades, focusing on how to cultivate resilience during emerging situations such as the COVID-19 pandemic at the individual, organizational, community, and national levels from a socioecological perspective. Although previous research has greatly enriched our understanding of the conceptualization, predicting factors, processes, and consequences of resilience from a variety of disciplines and levels, future research is needed to gain a deeper and comprehensive understanding of resilience, including developing an integrative and interdisciplinary framework for cultivating resilience, developing an understanding of resilience from a life span perspective, and developing scalable and cost-effective interventions for enhancing resilience and improving pandemic preparedness. Expected final online publication date for the Annual Review of Psychology, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Prognostic Effects of Neutrophil-Lymphocyte Rates in Serum and Pleural Fluids in Malignant Pleural Fluids

Journal of İzmir Chest Hospital ◽

10.5222/igh.2021.91300 ◽

2021 ◽

Author(s):

Filiz Güldaval ◽

Ceyda Anar ◽

Mine Gayaf ◽

Gulru Polat ◽

Merve Ayık Türk ◽

...

Keyword(s):

Pleural Effusion ◽

Prognostic Factor ◽

Eastern Cooperative Oncology Group ◽

Cost Effective ◽

Clinical Impact ◽

Neutrophil To Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Appropriate Therapy ◽

Cancer Types ◽

The Relationship

Objective: Various studies have reported that the neutrophil-to-lymphocyte ratio in the serum (sNLR) may serve as a cost-effective and useful prognostic factor in patients with various cancer types. We investigated the clinical impact of NLR as a prognostic factor in malign pleural effusion (MPE) and sNLR on prognosis in MPE. Method: We retrospectively reviewed all of the patients who were diagnosed MPE. The relationship between sNLR and neutrophil-to-lymphocyte ratio in the malign pleural effusion (mNLR) value, age, Eastern Cooperative Oncology Group (ECOG), histopathologic type, serum albumin and lactate dehydrogenase (LDH) with survival were investigated. Results: A total of 222 patients with a mean age of 65.7±11.5 were included in the study. Patients with a mNLR value ≥0.42 and a serum NLR value ≥4.75 had a shorter survival (p: 0.000). Multivariate analysis, which showed that survival was significantly related mNLR value > 0.42 and/or sNLR value > 4.75 (Odds Ratio (OR): 2.66, %95 CI, 1,65-4,3 p: 0.001), serum LDH > 210 (OR = 1.8, %95 CI, 1,33-2,46 p: 0.001) and age > 65 (OR = 1.9, %95 CI, 1,41-2,55 p = 0.001). Conclusion: sNLR and mNLR may act as a simple, useful, and cost-effective prognostic factor in patients with MPE. Furthermore, these results may serve as the cornerstone of further research into the mNLR in the future. Although further studies are required to generalize our results, this information will benefit clinicians and patients in determining the most appropriate therapy for patients with MPE.

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Preparation and Characterization of Chitosan/Alginate Polyelectrolyte Complex Prepared by Using Calcium Tripolyphosphate Ionic Gelator

Materials Science Forum ◽

10.4028/www.scientific.net/msf.857.447 ◽

2016 ◽

Vol 857 ◽

pp. 447-451

Author(s):

Nur Syairah Muhamad Rahim ◽

Norlaily Ahmad ◽

Dzaraini Kamarun

Keyword(s):

Single Molecule ◽

Polyelectrolyte Complex ◽

Sodium Tripolyphosphate ◽

Hybrid Compound ◽

Polyelectrolyte Complexes ◽

Sem Image ◽

Degradation Temperature ◽

Prepared Material ◽

True Hybrid ◽

The Individual

The formation of polyelectrolyte complexes (PECs) between chitosan and alginate has been widely investigated for many pharmaceutical and biomedical uses. Ionotropic gelation resulted from the crosslinking of polyelectrolytes (PEs) in the presence of ionic crosslinkers to form hydrogels. The most widely used ionic crosslinker for chitosan is sodium tripolyphosphate (NaTPP); and Ca2+ ions for alginates. The use of these cross-linkers to prepare PECs of chitosan and alginates resulted in hydrogels of similar moieties: chitosan-chitosan and alginate-alginate rather than the sought for hybrid chitosan-alginate PECs. Calcium tripolyphosphate (CaTPP) is a single molecule ionic gelator of chitosan and alginate that have the capability of producing the true hybrid compound of chitosan/alginate polyelectrolyte complex. This paper reported the synthesis of calcium tripolyphosphate and the preparation of a hybrid chitosan/alginate PECs using this newly identified ionic gelator. The newly-synthesized ionic gelator was characterized using ICP-OES; the PECs thereof prepared were characterized using TGA and SEM. The degradation temperature of the prepared PECs is higher than the degradation temperatures of the individual chitosan and alginates. SEM image of the prepared PECs showed rougher surfaces compared to the images of the individual chitosan and alginate compound. Both TGA and SEM revealed the possibility of the newly prepared material to be of the PECs sought for.

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Gene Expression Imputation with Generative Adversarial Imputation Nets

10.1101/2020.06.09.141689 ◽

2020 ◽

Author(s):

Ramon Viñas ◽

Tiago Azevedo ◽

Eric R. Gamazon ◽

Pietro Liò

Keyword(s):

Gene Expression ◽

Large Scale ◽

Biological Significance ◽

Predictive Performance ◽

Cost Effective ◽

Rna Seq ◽

Comprehensive Collection ◽

Genomic Studies ◽

Biological Discovery ◽

Cancer Types

AbstractA question of fundamental biological significance is to what extent the expression of a subset of genes can be used to recover the full transcriptome, with important implications for biological discovery and clinical application. To address this challenge, we present GAIN-GTEx, a method for gene expression imputation based on Generative Adversarial Imputation Networks. In order to increase the applicability of our approach, we leverage data from GTEx v8, a reference resource that has generated a comprehensive collection of transcriptomes from a diverse set of human tissues. We compare our model to several standard and state-of-the-art imputation methods and show that GAIN-GTEx is significantly superior in terms of predictive performance and runtime. Furthermore, our results indicate strong generalisation on RNA-Seq data from 3 cancer types across varying levels of missingness. Our work can facilitate a cost-effective integration of large-scale RNA biorepositories into genomic studies of disease, with high applicability across diverse tissue types.

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