Modelling bioactivities of combinations of whole extracts of edibles with a simplified theoretical framework reveals the statistical role of molecular diversity and system complexity in their mode of action and their nearly certain safety

Mapping Intimacies ◽

10.1101/2020.01.09.899823 ◽

2020 ◽

Author(s):

Pascal Mayer

Keyword(s):

Mode Of Action ◽

Theoretical Framework ◽

Network Pharmacology ◽

Cancer Treatments ◽

Perturbation Mode ◽

Nutritional Health ◽

Anti Cancer ◽

System Robustness ◽

The Many ◽

Novel Drug

AbstractNetwork pharmacology and polypharmacology are emerging as novel drug discovery paradigms. The many discovery, safety and regulatory issues they raise may become tractable with polypharmacological combinations of natural compounds found in whole extracts of edible and mixes thereof. The primary goal of this work is to get general insights underlying the innocuity and the emergence of beneficial and toxic activities of combinations of many compounds in general and of edibles in particular. A simplified model of compounds’ interactions with an organism and of their desired and undesired effects is constructed by considering the departure from equilibrium of interconnected biological features. This model allows to compute the scaling of the probability of significant effects relative to nutritional diversity, organism complexity and synergy resulting from mixing compounds and edibles. It allows also to characterize massive indirect perturbation mode of action drugs as a potential novel multi-compound-multi-target pharmaceutical class, coined Ediceuticals when based on edibles. Their mode of action may readily target differentially organisms’ system robustness as such based on differential complexity for discovering nearly certainly safe novel antimicrobials and anti-cancer treatments. This very general model provides also a theoretical framework to several pharmaceutical and nutritional observations. In particular, it characterizes two classes of undesirable effects of drugs, and may question the interpretation of undesirable effects in healthy subjects. It also formalizes nutritional diversity as such as a novel statistical supra-chemical parameter that may contribute to guide nutritional health intervention. Finally, it is to be noted that a similar formalism may be further applicable to model whole ecosystems in general.

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Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 5)

Case Medical Research ◽

10.31525/ct1-nct04126200 ◽

2019 ◽

Author(s):

Keyword(s):

Multiple Myeloma ◽

Cancer Treatments ◽

Refractory Multiple Myeloma ◽

Anti Cancer

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Sam Domains in Multiple Diseases

Current Medicinal Chemistry ◽

10.2174/0929867325666181009114445 ◽

2020 ◽

Vol 27 (3) ◽

pp. 450-476 ◽

Cited By ~ 1

Author(s):

Marian Vincenzi ◽

Flavia Anna Mercurio ◽

Marilisa Leone

Keyword(s):

Disease Onset ◽

Protein Domain ◽

Sam Domain ◽

Different Types ◽

Protein Functions ◽

Helical Protein ◽

The Many ◽

Novel Therapeutic Strategies ◽

Novel Drug ◽

Pathological Event

Background: The sterile alpha motif (Sam) domain is a small helical protein module, able to undergo homo- and hetero-oligomerization, as well as polymerization, thus forming different types of protein architectures. A few Sam domains are involved in pathological processes and consequently, they represent valuable targets for the development of new potential therapeutic routes. This study intends to collect state-of-the-art knowledge on the different modes by which Sam domains can favor disease onset and progression. Methods: This review was build up by searching throughout the literature, for: a) the structural properties of Sam domains, b) interactions mediated by a Sam module, c) presence of a Sam domain in proteins relevant for a specific disease. Results: Sam domains appear crucial in many diseases including cancer, renal disorders, cataracts. Often pathologies are linked to mutations directly positioned in the Sam domains that alter their stability and/or affect interactions that are crucial for proper protein functions. In only a few diseases, the Sam motif plays a kind of "side role" and cooperates to the pathological event by enhancing the action of a different protein domain. Conclusion: Considering the many roles of the Sam domain into a significant variety of diseases, more efforts and novel drug discovery campaigns need to be engaged to find out small molecules and/or peptides targeting Sam domains. Such compounds may represent the pillars on which to build novel therapeutic strategies to cure different pathologies.

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Network Pharmacology of Ayurveda Formulation Triphala with Special Reference to Anti-Cancer Property

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207318666151019093606 ◽

2015 ◽

Vol 18 (9) ◽

pp. 846-854 ◽

Cited By ~ 25

Author(s):

Uma Chandran ◽

Neelay Mehendale ◽

Girish Tillu ◽

Bhushan Patwardhan

Keyword(s):

Special Reference ◽

Network Pharmacology ◽

Anti Cancer

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Circadian rhythms, sleep, and anti-cancer treatments

10.1093/oso/9780198778240.003.0016 ◽

2018 ◽

Author(s):

Pasquale F. Innominato ◽

David Spiegel

Keyword(s):

Quality Of Life ◽

Circadian Rhythms ◽

Biological Functions ◽

Cancer Treatments ◽

Anti Cancer ◽

Timing System ◽

Physical Wellbeing ◽

Circadian Timing System ◽

Chemotherapy Agents

The circadian timing system temporally regulates biological functions relevant for psycho-physical wellbeing, spanning all the systems related to health. Hence, disruption of circadian rhythms, along with sleep cycles, is associated with the development of several diseases, including cancer. Moreover, altered circadian and sleep functions negatively impact on cancer patients’ quality of life and survival, above and beyond known determinants of outcome. This alteration can occur as a consequence of cancer, but also of anti-cancer treatments. Indeed, circadian rhythms govern also the ability of detoxifying chemotherapy agents across the 24 hours. Hence, adapting chemotherapy delivery to the molecular oscillations in relevant drug pathways can decrease toxicity to healthy cells, while increasing the number of cancer cells killing. This chronomodulated chemotherapy approach, together with the maintenance of proper circadian function throughtout the whole disease challenge, would finally result in safer and more active anticancer treatments, and in patients experiencing better quality and quantity of life.

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4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

Microorganisms ◽

10.3390/microorganisms9040826 ◽

2021 ◽

Vol 9 (4) ◽

pp. 826

Author(s):

Dorien Mabille ◽

Camila Cardoso Santos ◽

Rik Hendrickx ◽

Mathieu Claes ◽

Peter Takac ◽

...

Keyword(s):

Mode Of Action ◽

Drug Target ◽

Drug Targets ◽

De Novo ◽

Treatment Options ◽

Adenosine Kinase ◽

Nucleoside Analogues ◽

Purine Salvage ◽

Interacting Protein ◽

Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

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Autoimmune Responses in Oncology: Causes and Significance

International Journal of Molecular Sciences ◽

10.3390/ijms22158030 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8030

Author(s):

Halin Bareke ◽

Pablo Juanes-Velasco ◽

Alicia Landeira-Viñuela ◽

Angela-Patricia Hernandez ◽

Juan Jesús Cruz ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Protein Microarrays ◽

Cross Reactivity ◽

Fine Tuning ◽

Cancer Treatments ◽

Aberrant Expression ◽

Specificity And Sensitivity ◽

Anti Cancer ◽

Life Threatening ◽

Considerable Impact

Specific anti-tumor immune responses have proven to be pivotal in shaping tumorigenesis and tumor progression in solid cancers. These responses can also be of an autoimmune nature, and autoantibodies can sometimes be present even before the onset of clinically overt disease. Autoantibodies can be generated due to mutated gene products, aberrant expression and post-transcriptional modification of proteins, a pro-immunogenic milieu, anti-cancer treatments, cross-reactivity of tumor-specific lymphocytes, epitope spreading, and microbiota-related and genetic factors. Understanding these responses has implications for both basic and clinical immunology. Autoantibodies in solid cancers can be used for early detection of cancer as well as for biomarkers of prognosis and treatment response. High-throughput techniques such as protein microarrays make parallel detection of multiple autoantibodies for increased specificity and sensitivity feasible, affordable, and quick. Cancer immunotherapy has revolutionized cancer treatments and has made a considerable impact on reducing cancer-associated morbidity and mortality. However, immunotherapeutic interventions such as immune checkpoint inhibition can induce immune-related toxicities, which can even be life-threatening. Uncovering the reasons for treatment-induced autoimmunity can lead to fine-tuning of cancer immunotherapy approaches to evade toxic events while inducing an effective anti-tumor immune response.

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Understanding relevant immune mechanisms in gastrointestinal oncology

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155221992862 ◽

2021 ◽

pp. 107815522199286

Author(s):

Bulent Cetin ◽

Ozge Gumusay

Keyword(s):

Checkpoint Inhibitors ◽

Treatment Options ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Gastrointestinal Cancers ◽

Therapeutic Approaches ◽

Cancer Treatments ◽

Multiple Treatment ◽

Gi Cancers ◽

The Many

Rapid and successful drug development has resulted in multiple treatment options for gastrointestinal cancer, requiring careful decision making for individual patients. The general theme in modern immunology is that the field is moving beyond establishing the fundamental principles of immune response mechanisms to applying these propositions to understand human diseases and develop new therapies. Immunotherapy has contributed enormously to cancer treatments with a virtual explosion in novel therapeutics including checkpoint inhibitors and other recently developed immunomodulators and the development of novel therapeutic approaches. Although the majority of gastrointestinal (GI) cancers are generally considered poorly immunogenic, clinical trials have revealed that some of the patients with various gastrointestinal cancers are highly responsive to immune checkpoint inhibition-based therapies. We paid special attention to the clinical relevance of immunology and emphasized how newly developed therapies work, including what their strengths and pitfalls are. This review aims to enhance the interest of practitioners in the many specialties and subspecialties that the discipline influences and to assist them in understanding this increasing complexity.

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Polycomb genes role in cancer pathophysiology is offering targets for therapeutics including gene therapy

10.31219/osf.io/sfvej ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Catalytic Activity ◽

Detailed Understanding ◽

The Core ◽

Chromatin Regulators ◽

Genetic Modifications ◽

Anti Cancer ◽

The Many ◽

The One ◽

Context Specific ◽

Study Context

Several phenotypes can come from transcription regulation. Sequence-specific transcription factors are needed to effectively execute transcriptional programs, however they are often not operating alone. Polycomb PcG proteins are a well-known class of chromatin regulators found in Drosophila melanogaster and other species, including humans. As time passed, the concept of a PCG gene or protein shifted from the original phenotypic meaning of mutant flies to the contemporary biochemical description. PCG genes and proteins are under investigation for their critical contributions to physiology and their cancer treatment potential. Adding additional PcG members, with substantial responsibilities in PRC modulation, has opened new routes of inquiry in the issue. It is still needed to discover the many PRC variations' roles and how their catalytic activity is controlled. This review covers mutually exclusive PRC2 variants and employs a technique like the one used for PRC1 variants. Based on current biochemical findings, these classifications are valid. More auxiliary PcG subunit research is needed for now. Moreover, it is unknown how many PRC cell variations occur (hypothetically, there could be more than 100 different PRC variants).In order to fully elucidate the new PcG proteins and complexes, it is necessary to perform comprehensive research. We must study context-specific genetic modifications to better provide remedies. Current anti-cancer drugs target mainly the core subunits and catalytic activity of PRC2 and PRC1, and understanding these functions is critical. Targeting each particular activity that has been deregulated might be rather beneficial. PCG proteins are involved in oncogenesis, tumor suppression, and development/congenital illness as well. PcG involvement in cancer, once revealed, would be intriguing. Successful and effective therapeutic therapies will be helped by a detailed understanding of the pathways that contain PcG proteins.

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Precision Medicine: From “Omics” to Economics towards Data-Driven Healthcare - Time for European Transformation

Biomedicine Hub ◽

10.1159/000480117 ◽

2017 ◽

Vol 2 (Suppl. 1) ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Denis Lacombe ◽

Lifang Liu ◽

Françoise Meunier ◽

Vassilis Golfinopoulos

Keyword(s):

Drug Development ◽

Development Process ◽

Precision Oncology ◽

Drug Development Process ◽

Cancer Treatments ◽

True Value ◽

Efficient Access ◽

Funding Agencies ◽

Anti Cancer

There is room for improvement for optimally bringing the latest science to the patient while taking into account patient priorities such as quality of life. Too often, regulatory agencies, governments, and funding agencies do not stimulate the integration of research into care and vice versa. Re-engineering the drug development process is a priority, and healthcare systems are long due for transformation. On one hand, patients need efficient access to treatments, but despite precision oncology approaches, efficiently shared screening platforms for sorting patients based on the biology of their tumour for trial access are lacking and, on the other hand, the true value of cancer care is poorly addressed as central questions such as dose, scheduling, duration, and combination are not or sub-optimally addressed by registration trials. Solid evidence on those parameters could potentially lead to a rational and wiser use of anti-cancer treatments. Together, optimally targeting patient population and robust comparative effectiveness data could lead to more affordable and economically sound approaches. The drug development process and healthcare models need to be interconnected through redesigned systems taking into account the full math from drug development into affordable care.

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