scholarly journals A Human Organoid Model of Aggressive Hepatoblastoma for Disease Modeling and Drug Testing

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2668
Author(s):  
James A. Saltsman ◽  
William J. Hammond ◽  
Nicole J. C. Narayan ◽  
David Requena ◽  
Helmuth Gehart ◽  
...  
Keyword(s):  
Drug Testing ◽  
Disease Modeling ◽  
Treatment Options ◽  
Expression Patterns ◽  
Current Treatment ◽  
Treatment Regimens ◽  
Resected Patient ◽  
Liver Organoids ◽  
New Treatments ◽  
Tumor Organoids

Hepatoblastoma is the most common childhood liver cancer. Although survival has improved significantly over the past few decades, there remains a group of children with aggressive disease who do not respond to current treatment regimens. There is a critical need for novel models to study aggressive hepatoblastoma as research to find new treatments is hampered by the small number of laboratory models of the disease. Organoids have emerged as robust models for many diseases, including cancer. We have generated and characterized a novel organoid model of aggressive hepatoblastoma directly from freshly resected patient tumors as a proof of concept for this approach. Hepatoblastoma tumor organoids recapitulate the key elements of patient tumors, including tumor architecture, mutational profile, gene expression patterns, and features of Wnt/β-catenin signaling that are hallmarks of hepatoblastoma pathophysiology. Tumor organoids were successfully used alongside non-tumor liver organoids from the same patient to perform a drug screen using twelve candidate compounds. One drug, JQ1, demonstrated increased destruction of liver organoids from hepatoblastoma tumor tissue relative to organoids from the adjacent non-tumor liver. Our findings suggest that hepatoblastoma organoids could be used for a variety of applications and have the potential to improve treatment options for the subset of hepatoblastoma patients who do not respond to existing treatments.

scholarly journals Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

2020 ◽  
Vol 8 (2) ◽  
pp. 191 ◽  
Author(s):  
Despoina Koulenti ◽  
Elena Xu ◽  
Andrew Song ◽  
Isaac Yin Sum Mok ◽  
Drosos E. Karageorgopoulos ◽  
...  
Keyword(s):  
Safety Profile ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Current Treatment ◽  
Multi Drug Resistance ◽  
Gram Positive ◽  
Treatment Regimens ◽  
Gram Positive Bacteria

Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

scholarly journals Pancreatic cancer-derived organoids – a disease modeling tool to predict drug response

2020 ◽  
Vol 8 (5) ◽  
pp. 594-606 ◽  
Author(s):  
Pierre-Olivier Frappart ◽  
Karolin Walter ◽  
Johann Gout ◽  
Alica K Beutel ◽  
Mareen Morawe ◽  
...  
Keyword(s):  
Drug Testing ◽  
Disease Modeling ◽  
Individualized Medicine ◽  
Expression Patterns ◽  
Culture Conditions ◽  
Ductal Adenocarcinoma ◽  
Small Scale ◽  
Comparative Genomic

Background Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient-derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date. Methods We conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform was set up and validated in vivo. Patient-derived organoids were investigated as well. Results First, PDOs faithfully recapitulated the morphology and marker protein expression patterns of the PDXs. Second, quantitative proteomes from the PDX as well as from corresponding organoid cultures showed high concordance. Third, genomic alterations, as assessed by array-based comparative genomic hybridization, revealed similar results in both groups. Fourth, we established a small-scale pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing, and interpretation of the results. In vitro predictions were successfully validated in an in vivo xenograft trial. Translational proof-of-concept is exemplified in a patient with PDAC receiving palliative chemotherapy. Conclusion Small-scale drug screening in organoids appears to be a feasible, robust and easy-to-handle disease modeling method to allow response predictions in parallel to daily clinical routine. Therefore, our fast and cost-efficient assay is a reasonable approach in a predictive clinical setting.

scholarly journals Differential in vitro activity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starved Mycobacterium abscessus

2020 ◽  
Author(s):  
Jin Lee ◽  
Nicole Ammerman ◽  
Anusha Agarwal ◽  
Maram Naji ◽  
Si-Yang Li ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Current Treatment ◽  
Mycobacterium Abscessus ◽  
Bacterial Populations ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Limited Effectiveness ◽  
Dependent Activity

AbstractCurrent treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time-and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.

scholarly journals Treatment of Refractory Postural Tachycardia Syndrome with Subcutaneous Octreotide Delivered Using an Insulin Pump

2015 ◽  
Vol 2015 ◽  
pp. 1-4 ◽  
Author(s):  
Muhammad Khan ◽  
Jing Ouyang ◽  
Karen Perkins ◽  
John Somauroo ◽  
Franklin Joseph
Keyword(s):  
Insulin Pump ◽  
Orthostatic Intolerance ◽  
Symptomatic Relief ◽  
Treatment Options ◽  
Current Treatment ◽  
Postural Tachycardia Syndrome ◽  
Treatment Regimens ◽  
Postural Tachycardia ◽  
Novel Treatment

Postural Tachycardia Syndrome (PoTS) represents a disorder of the autonomic nervous system that results in symptoms of orthostatic intolerance. Despite having a severe impact on the patient’s quality of life, the current treatment options for PoTS are based on limited evidence. Subsequently, this results in clinicians having to utilise a variety of treatment regimens in the hope of successfully providing symptomatic relief. However, the options available for PoTS are not without significant side effects that can worsen an already debilitating condition. Our cases provide a further novel treatment option for clinicians to consider in PoTS refractory to established treatments.

scholarly journals Strategizing the Treatment Approach to Acute Myeloid Leukemia

2021 ◽  
pp. 1-6
Author(s):  
Laura Finn ◽  
Michael Lunski ◽  
Saikrishna Gadde ◽  
Matthew Alberti ◽  
Danny Markabawi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Molecular Classification ◽  
Ongoing Research ◽  
Molecular Alterations ◽  
Treatment Regimens ◽  
New Treatments ◽  
Acute Myeloid

For decades acute myeloid leukemia, the primary acute leukemia affecting adults, had limited treatment options. Since 2017, we have seen discovery and development in cytogenetic and molecular classification of acute myeloid leukemia, improved understanding of cell signaling pathways, and development of new treatment for acute myeloid leukemia. These new treatments include novel combinations of agents and therapy targeting molecular alterations improving rates of remission and overall survival. Treatment discovery provides therapeutic opportunity to older patients and populations previously excluded from intense induction chemotherapy. In this review, we discuss the timing of first therapy, non-intense treatment regimens achieving remission, and new targets for directed therapy. We reference key clinical trials to expand our discussion of newly approved agents for acute myeloid leukemia. In this review, we highlight the discovery of treatment strategies to improve patient outcomes and ongoing research in leukemia.

scholarly journals Differential in vitro activity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starved Mycobacterium abscessus

2020 ◽  
Author(s):  
Jin Lee ◽  
Nicole Ammerman ◽  
Anusha Agarwal ◽  
Maram Naji ◽  
Si-Yang Li ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Current Treatment ◽  
Mycobacterium Abscessus ◽  
Bacterial Populations ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Limited Effectiveness ◽  
Dependent Activity

Current treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time- and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.

New Insights in Design and Development of Antitubercular Drugs

2020 ◽  
Vol 16 (1) ◽  
pp. 13-23
Author(s):  
Snehlata Yadav ◽  
Balasubramanian Narasimhan
Keyword(s):  
Treatment Options ◽  
Latent Tuberculosis ◽  
Multidrug Resistant ◽  
Current Treatment ◽  
Extensive Literature ◽  
Antitubercular Drugs ◽  
Treatment Regimens ◽  
Resistant Tuberculosis ◽  
Recent Developments ◽  
Long Course

Background: Tuberculosis, an infectious disease caused mainly by the Mycobacterium tuberculosis accounts for the highest number of deaths worldwide. Despite curing millions, the currently used drug regimens are bounded by various limitations such as long course of therapy, emergence of resistance and permanent tissue damage. The treatment of multidrug-resistant and extremely drugresistant tuberculosis is a challenging task due to its reliance on second-line drugs which are less potent and more toxic than those used in the clinical management of drug-susceptible tuberculosis. Therefore, the major challenges in the upcoming years are to overcome the emergence of increased number of multidrug-resistant as well as extensively drug-resistant strains and the ineptness of the current treatment regimens against latent tuberculosis. Bedaquiline and Delamanid are the only new anti-TB drugs that have been currently approved since more than 40 years after discovery of isoniazid. Bedaquiline is the first diarylquinoline derivative that has showed resilient culture conversion at 24 weeks in phase IIb trials. Methods: Extensive literature search on the topic was undergone using a focused question. Results: Fifty-eight research articles from journals of repute are included in the review. The vaccine and peptide-based conjugates are recent developments against Mycobacterium for selective and specific targeting to the desired tissues. Conclusion: In this review, we have focused on the different classes of chemical as well as plant based compounds as potent antitubercular agents against multidrug-resistant tuberculosis strains. This review falls light on the importance of research been undergoing in different parts of the world to combat the ever increasing problem of mycobacterial resistance and the various treatment options available for the treatment of tuberculosis.

scholarly journals The Impact of Selected Bacterial Sexually Transmitted Diseases on Pregnancy and Female Fertility

2021 ◽  
Vol 22 (4) ◽  
pp. 2170
Author(s):  
Katarzyna Smolarczyk ◽  
Beata Mlynarczyk-Bonikowska ◽  
Ewa Rudnicka ◽  
Dariusz Szukiewicz ◽  
Blazej Meczekalski ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Treatment Options ◽  
Mycoplasma Genitalium ◽  
Current Treatment ◽  
Female Fertility ◽  
Sexually Transmitted ◽  
Tubal Factor ◽  
Adverse Pregnancy ◽  
New Treatments ◽  
The Impact

Sexually transmitted infections (STIs) caused by Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium are a common cause of pelvic inflammatory disease (PID) which can lead to tubal factor infertility (TFI). TFI is one of the most common causes of infertility, accounting for 30% of female fertility problems. STIs can also have an impact on pregnancy, leading to adverse pregnancy outcomes. Escalating antibiotic resistance in Neisseria gonorrhoeae and Mycoplasma genitalium represents a significant problem and can be therapeutically challenging. We present a comprehensive review of the current treatment options, as well as the molecular approach to this subject. We have given special attention to molecular epidemiology, molecular diagnostics, current and new treatments, and drug resistance.

Drug susceptibility profiling of Australian Burkholderia species as models for developing melioidosis therapeutics

2020 ◽  
Author(s):  
Anna S. Amiss ◽  
Jessica R. Webb ◽  
Mark Mayo ◽  
Bart J. Currie ◽  
David J. Craik ◽  
...  
Keyword(s):  
Drug Susceptibility ◽  
Current Treatment ◽  
Model Organisms ◽  
Near Neighbour ◽  
Treatment Regimens ◽  
New Treatments ◽  
Susceptibility Profiles ◽  
High Degree ◽  
Microbroth Dilution ◽  
Degree Of Similarity

SynopsisBackgroundMelioidosis is a neglected tropical disease caused by the Gram-negative soil bacterium Burkholderia pseudomallei. Current treatment regimens are prolonged and costly, and acquired antimicrobial resistance has been reported for all currently used antibiotics.ObjectivesEfforts to develop new treatments for melioidosis are hampered by the risks associated with handling pathogenic B. pseudomallei, which restricts research to facilities with Biosafety Level (BSL) 3 containment. Closely related Burkholderia species that are less pathogenic can be investigated under less stringent BSL 2 containment. We hypothesized that near-neighbour Burkholderia species could be used as model organisms for developing therapies that would also be effective against B. pseudomallei.MethodsWe used microbroth dilution assays to compare the susceptibility of three Australian B. pseudomallei isolates and five near-neighbour Burkholderia species – B. humptydooensis, B. thailandensis, B. oklahomensis, B territorii and B. stagnalis – to antibiotics currently used to treat melioidosis, and general-use antibacterial agents. We also established the susceptibility profiles of B. humptydooensis and B. territorii to 400 compounds from the Medicines for Malaria Venture Pathogen Box.ResultsFrom these comparisons, we observed a high degree of similarity in the susceptibility profiles of B. pseudomallei and near-neighbour species B. humptydooensis, B. thailandensis, B. oklahomensis and B. territorii.ConclusionsLess pathogenic Australian Burkholderia species B. humptydooensis, B. thailandensis, B. oklahomensis and B. territorii are excellent model organisms for developing potential new therapies for melioidosis.

scholarly journals Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium

2021 ◽  
Vol 15 (5) ◽  
pp. e0009432
Author(s):  
Nermina Vejzagić ◽  
Ulrich Fabien Prodjinotho ◽  
Nagwa El-Khafif ◽  
Ruili Huang ◽  
Anton Simeonov ◽  
...  
Keyword(s):  
Drug Testing ◽  
Developmental Stages ◽  
Treatment Options ◽  
Extended Period ◽  
Culture Method ◽  
Current Treatment ◽  
Antianginal Agent ◽  
Optimal Drug ◽  
Antihistaminic Drug

Background Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the in vitro drug screening on Schistosoma mansoni (S. mansoni) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the NCATS Pharmaceutical Collection (340 compounds) to identify new hits with an in vitro worm culture assay. Methodology/Principal findings Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3–6 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug. Conclusion With this standardized and reliable in vitro assay, important S. mansoni developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult S. mansoni worms was achieved only for perhexiline (a prophylactic antianginal agent) and astemizole (an antihistaminic drug).

Sign in / Sign up

Export Citation Format

Share Document