scholarly journals Design principles of collateral sensitivity-based dosing strategies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Linda B. S. Aulin ◽  
Apostolos Liakopoulos ◽  
Piet H. van der Graaf ◽  
Daniel E. Rozen ◽  
J. G. Coen van Hasselt
Keyword(s):  
Population Dynamics ◽  
Bacterial Population ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Design Principles ◽  
Collateral Sensitivity ◽  
Resistance Evolution ◽  
Dosing Strategies ◽  
Increased Sensitivity ◽  
Treatment Designs

AbstractCollateral sensitivity (CS)-based antibiotic treatments, where increased resistance to one antibiotic leads to increased sensitivity to a second antibiotic, may have the potential to limit the emergence of antimicrobial resistance. However, it remains unclear how to best design CS-based treatment schedules. To address this problem, we use mathematical modelling to study the effects of pathogen- and drug-specific characteristics for different treatment designs on bacterial population dynamics and resistance evolution. We confirm that simultaneous and one-day cycling treatments could supress resistance in the presence of CS. We show that the efficacy of CS-based cycling therapies depends critically on the order of drug administration. Finally, we find that reciprocal CS is not essential to suppress resistance, a result that significantly broadens treatment options given the ubiquity of one-way CS in pathogens. Overall, our analyses identify key design principles of CS-based treatment strategies and provide guidance to develop treatment schedules to suppress resistance.

scholarly journals Design principles of collateral sensitivity-based dosing strategies

2021 ◽  
Author(s):  
Linda B. S. Aulin ◽  
Apostolos Liakopoulos ◽  
Piet H. van der Graaf ◽  
Daniel E. Rozen ◽  
J. G. Coen van Hasselt
Keyword(s):  
Antibiotic Resistance ◽  
Treatment Strategies ◽  
Antibiotic Sensitivity ◽  
Design Principles ◽  
Simultaneous Treatment ◽  
Collateral Sensitivity ◽  
End Of Treatment ◽  
Dosing Strategies ◽  
Road Project ◽  
Treatment Designs

AbstractCollateral sensitivity (CS)-based antibiotic treatments, where increased antibiotic resistance to one antibiotic leads to increased antibiotic sensitivity of second antibiotic, could constitute a strategy to limit emergence of antibiotic resistance. However, it is unclear how to design CS-based dosing schedules that effectively suppress resistance. Here, we use a mathematical modelling approach incorporating pharmacokinetic and pharmacodynamic features to simulate bacterial population dynamics for different combination treatment designs. We study how differences in pathogen- and drug-specific factors influence the probability of resistance at end of treatment for different dosing strategies. We show that drug administration sequence is critical, whilst surprisingly, reciprocal CS was not essential to suppress resistance. Overall, we find that one-day cycling or simultaneous treatment schedules were most effective to supress the probability of resistance. In conclusion, our analysis provides insight into key design principles that contribute to the success of CS-based treatment strategies in suppressing resistance.FundingThis work is funded by ZonMW Off Road (Project number 451001033) and NWA Idea Generator (Project number NWA.1228.192.140). AL and DER were supported through the JPI-EC-AMR (Project 547001002).

scholarly journals Systematic Investigation of Resistance Evolution to Common Antibiotics Reveals Conserved Collateral Responses across Common Human Pathogens

2020 ◽  
Vol 65 (1) ◽  
pp. e01273-20
Author(s):  
Mari C. Rodriguez de Evgrafov ◽  
Marius Faza ◽  
Konstantinos Asimakopoulos ◽  
Morten O. A. Sommer
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Growth Conditions ◽  
Systematic Investigation ◽  
Cross Resistance ◽  
Human Pathogens ◽  
Content Type ◽  
Collateral Sensitivity ◽  
Resistance Evolution ◽  
Drug Dependent

ABSTRACTAs drug resistance continues to grow, treatment strategies that turn resistance into a disadvantage for the organism will be increasingly relied upon to treat infections and to lower the rate of multidrug resistance. The majority of work in this area has investigated how resistance evolution toward a single antibiotic effects a specific organism’s collateral response to a wide variety of antibiotics. The results of these studies have been used to identify networks of drugs which can be used to drive resistance in a particular direction. However, little is known about the extent of evolutionary conservation of these responses across species. We sought to address this knowledge gap by performing a systematic resistance evolution study of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) under uniform growth conditions using five clinically relevant antibiotics with diverse modes of action. Evolved lineages were analyzed for collateral effects and the molecular mechanisms behind the observed phenotypes. Fourteen universal cross-resistance and two global collateral sensitivity relationships were found among the lineages. Genomic analyses revealed drug-dependent divergent and conserved evolutionary trajectories among the pathogens. Our findings suggest that collateral responses may be preserved across species. These findings may help extend the contribution of previous collateral network studies in the development of treatment strategies to address the problem of antibiotic resistance.

Using Naïve Bayes Algorithm to Estimate the Response to Drug in Lung Cancer Patients

2019 ◽  
Vol 21 (10) ◽  
pp. 734-748 ◽  
Author(s):  
Baoling Guo ◽  
Qiuxiang Zheng
Keyword(s):  
Lung Cancer ◽  
Side Effects ◽  
Cancer Patients ◽  
Drug Response ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Treatment Strategies ◽  
Cancer Resistance ◽  
Lung Cancer Patients ◽  
Bayes Algorithm

Aim and Objective: Lung cancer is a highly heterogeneous cancer, due to the significant differences in molecular levels, resulting in different clinical manifestations of lung cancer patients there is a big difference. Including disease characterization, drug response, the risk of recurrence, survival, etc. Method: Clinical patients with lung cancer do not have yet particularly effective treatment options, while patients with lung cancer resistance not only delayed the treatment cycle but also caused strong side effects. Therefore, if we can sum up the abnormalities of functional level from the molecular level, we can scientifically and effectively evaluate the patients' sensitivity to treatment and make the personalized treatment strategies to avoid the side effects caused by over-treatment and improve the prognosis. Result & Conclusion: According to the different sensitivities of lung cancer patients to drug response, this study screened out genes that were significantly associated with drug resistance. The bayes model was used to assess patient resistance.

scholarly journals Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

2021 ◽  
Vol 10 (13) ◽  
pp. 2803
Author(s):  
Carolin Czauderna ◽  
Martha M. Kirstein ◽  
Hauke C. Tews ◽  
Arndt Vogel ◽  
Jens U. Marquardt
Keyword(s):  
Clinical Care ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Growth Factor Receptor ◽  
Treatment Modalities ◽  
Precision Oncology ◽  
Recurrence Rates ◽  
Isocitrate Dehydrogenase 1 ◽  
Liver Cancers

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.

scholarly journals Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1548
Author(s):  
Mustafa N. Mithaiwala ◽  
Danielle Santana-Coelho ◽  
Grace A. Porter ◽  
Jason C. O’Connor
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Kynurenine Pathway ◽  
Economic Problem ◽  
Cns Disease ◽  
Therapeutic Implications ◽  
Efficacious Treatment ◽  
The Central Nervous System ◽  
Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

scholarly journals Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3932
Author(s):  
Dannel Yeo ◽  
Laura Castelletti ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Treatment Options ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Pleural Mesothelioma ◽  
Normal Tissues ◽  
Drug Conjugates ◽  
Aggressive Cancer ◽  
Immunotherapy Target ◽  
Bull's Eye

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody–drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

scholarly journals B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders

2021 ◽  
Vol 14 (1) ◽  
pp. 37
Author(s):  
Jan Traub ◽  
Leila Husseini ◽  
Martin S. Weber
Keyword(s):  
B Cells ◽  
Neuromyelitis Optica ◽  
Plasma Cells ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Therapeutic Interventions ◽  
Complement Factor ◽  
Major Subset ◽  
Spectrum Disorders

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

scholarly journals Nonvascular Complications of Injectable Fillers—Prevention and Management

2020 ◽  
Vol 53 (03) ◽  
pp. 335-343
Author(s):  
Kuldeep Singh ◽  
Shahin Nooreyezdan
Keyword(s):  
Early Recognition ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Vascular Complications ◽  
Physical Characteristics ◽  
Clear Understanding ◽  
Type Iv ◽  
Acute Infections ◽  
Tyndall Effect ◽  
Delayed Complications

AbstractInjectable filler treatments have increased in popularity because of enhanced safety profile and improved physical characteristics. ISAPS (International Society of Plastic Surgery) put out global data showing 3.7 million hyaluronic acid (HA) filler procedures in 2018, making it the second most often performed procedure in the world, after botulinum toxin. And these are only ‘those’ performed by qualified plastic surgeons. There was a concomitant increase in both the nonvascular and vascular complications, which coincided with the number and type of filler procedures performed. Filler complications were reviewed from existing literature, and an attempt was made to understand etiology, elucidate clinical features, and clarify optimum treatment strategies for each. Complications can be early or delayed in presentation, early consisting of injection site complications like bruising, edema, and hypersensitivity, Tyndall effect, and intravascular injection. Delayed complications included hypersensitivity type IV, acute infections like cellulitis, abscesses, and herpes and delayed ones like granulomas, biofilms, and atypical mycobacterial infections. These were analyzed and treatment options, protocols, and consensus guidelines were suggested. A clear understanding of facial anatomy, physical characteristics of all fillers used, early recognition, and treatment options of complications will ensure optimum outcomes.

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