Optimization of bacteriophage therapy for difficult-to-treat musculoskeletal infections: a bench-to-bedside perspective.

Given the increasing threat of antimicrobial resistance, scientists are urgently seeking adjunct antimicrobial strategies, such as phage therapy (PT). However, despite promising results for the treatment of musculoskeletal infections in our center, crucial knowledge gaps remain. Therefore, a prospective observational study (PHAGEFORCE) and a multidisciplinary approach was set up to achieve and optimize standardized treatment guidelines. At our center, PT is strictly controlled and monitored by a multidisciplinary taskforce. Each phage treatment follows the same pathway to ensure standardization and data quality. Within the PHAGEFORCE framework, we established a testing platform to gain insight in the safety and efficacy of PT, biodistribution, phage kinetics and the molecular interaction between phages and bacteria. The draining fluid is collected to determine the phage titer and bacterial load. In addition, all bacterial isolates are fully characterized by genome sequencing to monitor the emergence of phage resistance. We hereby present a standardized bench-to-bedside protocol to gain more insight in the kinetics and dynamics of PT for musculoskeletal infections.

Clinical Tumor Dormancy.

This chapter summarizes clinical evidence on tumor dormancy, with a special focus on our research supporting the role of dormancy both in local and distant recurrence of breast cancer following mastectomy. Starting from these premises, we propose a model of neoplastic development that allows us to elucidate several relevant clinical phenomena, including the mammographic paradox, the significance of ipsilateral breast tumor recurrence after conservative surgery, and the effect of surgeries performed after the removal of the primary. We will discuss the biological implications of the dormancy-based model, which are at odds with Somatic Mutation Theory. We will then review new models, alternatives to the Somatic Mutation Theory, for cancer development, with special emphasis on the Dynamic System Theory and the originality of its conceptual approach. Finally, we will put particular emphasis on the view of cancer development as a tissue-level process. We believe that this will help harmonize the molecular biology research with the new conceptual approach and bridge the knowledge gap on dormancy between bench and bedside.

Predicting substantive biomedical citations without full text.

Insights from biomedical citation networks can be used to identify promising avenues for accelerating research and its downstream bench-to-bedside translation. Citation analysis generally assumes that each citation documents substantive knowledge transfer that informed the conception, design, or execution of the main experiments. Citations may exist for other reasons. In this paper, we take advantage of late-stage citations added during peer review because these are less likely to represent substantive knowledge flow. Using a large, comprehensive feature set of open access data, we train a predictive model to identify late-stage citations. The model relies only on the title, abstract, and citations to previous articles but not the full-text or future citations patterns, making it suitable for publications as soon as they are released, or those behind a paywall (the vast majority). We find that high prediction scores identify late-stage citations that were likely added during the peer review process as well as those more likely to be rhetorical, such as journal self-citations added during review. Our model conversely gives low prediction scores to early-stage citations and citation classes that are known to represent substantive knowledge transfer. Using this model, we find that US federally funded biomedical research publications represent 30% of the predicted early-stage (and more likely to be substantive) knowledge transfer from basic studies to clinical research, even though these comprise only 10% of the literature. This is a threefold overrepresentation in this important type of knowledge flow.

Combinatorial islet protective therapeutic approaches in ß-cell transplantation: Rationally designed solutions using a target product profile.

While progress has been made in the development of islet cell transplantation (ICT) as a viable alternative to the use of exogenous insulin therapy in the treatment of type 1 diabetes, it has not yet achieved its full potential in clinical studies. Ideally, ICT would enable lifelong maintenance of euglycemia without the need for exogenous insulin, blood glucose monitoring or systemic immune suppression. To achieve such an optimal result, therapeutic approaches should simultaneously promote long-term islet viability, functionality, and localized immune protection. In practice, however, these factors are typically tackled individually. Furthermore, while the requirements of optimal ICT are implicitly acknowledged across numerous publications, the literature contains few comprehensive articulations of the target product profile (TPP) for an optimal ICT product, including key characteristics of safety and efficacy. This review aims to provide a novel TPP for ICT and presents promising tried and untried combinatorial approaches that could be used to achieve the target product profile. We also highlight regulatory barriers to the development and adoption of ICT, particularly in the United States, where ICT is only approved for use in academic clinical trials and is not reimbursed by insurance carriers. Overall, this review argues that the clear definition of a TPP in addition to the use of combinatorial approaches could help to overcome the clinical barriers to the widespread adoption of ICT for the treatment of type 1 diabetes.

Mechanistic assessment and ablation of left ventricular assist device related ventricular tachycardia in patients with severe heart failure.

Aims: Left-ventricular-assist-devices (lvad) are an established treatment for patients with severe heart failure with reduced ejection fraction (HF) and reduce mortality. However, HF patients have significant substrate for ventricular tachycardia (VT) and the lvad itself might be pro-arrhythmogenic. We investigated the mechanism of VT in lvad-patients in relation to the underlying etiology and provide in silico and ex-vivo data for ablation in these HF patients. Methods and Results: We retrospectively analyzed invasive electrophysiological (EP) studies of 17 patients with VT and lvad. The mechanism of VT was determined using electroanatomical, entrainment and activation time mapping. Ischemic cardiomyopathy was present in 70% of patients. VT originated from the lvad region in >30%. 1/6 patients with VT originating from the lvad region had episodes before lvad implantation, while 7/11 patients with VT originating from other regions had episodes before implantation. Number and time of radiofrequency (RF)-ablation lesions were not different between VTs originating from the lvad or other regions. Long-term freedom from VT was 50% upon ablation in patients with VT originating from the lvad region and 64% if ablation was conducted in other regions. To potentially preemptively mitigate lvad related VT in patients undergoing lvad implantation, we obtained in silico derived data and performed ex-vivo experiments targeting ventricular myocardium. Of the tested settings, application of 25 W for 30 s was safe and associated with optimal lesion characteristics. Conclusion: A significant percentage of patients with lvad undergoing VT ablation exhibit arrhythmia originating in close vicinity to the device and recurrence rates are high. Based on in silico and ex-vivo data, we propose individualized RF-ablation in selected patients at risk for/with lvad related VT.

[The translational medicine approach to acupuncture and moxibustion].

The idea of translational medicine from "laboratory to bedside" has become more and more popular. The main purpose of translational medicine is to promote basic research to solve practical clinical problems and improve the level of clinical treatment. It is thus a whole new medical paradigm. However, the principle of "bench to bedside" still has some obvious deficiencies in the "bench" ring, whereas the subject of acupuncture and moxibustion is carried out in the "bench" ring relatively more systematic, but also does not achieve bench to bedside regression well. Nevertheless, as a bridge between basic research and clinical practice of acupuncture and moxibustion, translational medicine has constructed a data fusion channel between them. Our basic researchers should cooperate closely with clinical experts, exchange ideas, collide sparks of wisdom, and promote the leap-forward development of acupuncture and moxibustion.

Multi-omics data integration methods and their applications in psychiatric disorders.

To study mental illness and health, in the past researchers have often broken down their complexity into individual subsystems (e.g., genomics, transcriptomics, proteomics, clinical data) and explored the components independently. Technological advancements and decreasing costs of high throughput sequencing has led to an unprecedented increase in data generation. Furthermore, over the years it has become increasingly clear that these subsystems do not act in isolation but instead interact with each other to drive mental illness and health. Consequently, individual subsystems are now analysed jointly to promote a holistic understanding of the underlying biological complexity of health and disease. Complementing the increasing data availability, current research is geared towards developing novel methods that can efficiently combine the information rich multi-omics data to discover biologically meaningful biomarkers for diagnosis, treatment, and prognosis. However, clinical translation of the research is still challenging. In this review, we summarise conventional and state-of-the-art statistical and machine learning approaches for discovery of biomarker, diagnosis, as well as outcome and treatment response prediction through integrating multi-omics and clinical data. In addition, we describe the role of biological model systems and in silico multi-omics model designs in clinical translation of psychiatric research from bench to bedside. Finally, we discuss the current challenges and explore the application of multi-omics integration in future psychiatric research. The review provides a structured overview and latest updates in the field of multi-omics in psychiatry.

Physician-Scientists: Fixing the Leaking Pipeline - A Scoping Review.

Introduction: This scoping review was undertaken to assess the current status of physician-scientists, including the challenges associated with their enrollment and retention, measures of success, and determinants of their satisfaction, all of which contribute to the dwindling numbers of physician-scientists aptly referred to as a "leaking pipeline" of physician-scientists. Methods: A total of 2555 research documents from three databases, viz. Scopus, Web of Science, and PubMed, were selected. A total of 40 documents were considered for final analysis following the 5-stage framework of Arksey and O'Malle. Results: Medical institutions should promote and sustain enrollments by addressing various perceived parameters of success and satisfaction. The challenge of attrition due to individual, regulatory, and sociocultural considerations also needs to be addressed. Conclusions: Medical institutions should focus on establishing well-documented career tracks with provisions for career advancement, promotion of team science, raising mentors, giving preference to students with peer-reviewed publications for post graduate (PG) admissions, and establishing a separate office for career development and guidance for physician-scientist. It is equally important to address the factors which promote retention and prevent attrition, viz. measures of success and determinants of satisfaction. Additional measures include creating a cadre of physician-scientists in government organizations, fostering collaboration of physician-scientists with incubation centers and startups, and adding additional mandatory curriculum components focused on project-based training.

Quantitative Framework for Bench-to-Bedside Cancer Research.

Bioscience is an interdisciplinary venture. Driven by a quantum shift in the volume of high throughput data and in ready availability of data-intensive technologies, mathematical and quantitative approaches have become increasingly common in bioscience. For instance, a recent shift towards a quantitative description of cells and phenotypes, which is supplanting conventional qualitative descriptions, has generated immense promise and opportunities in the field of bench-to-bedside cancer OMICS, chemical biology and pharmacology. Nevertheless, like any burgeoning field, there remains a lack of shared and standardized framework for quantitative cancer research. Here, in the context of cancer, we present a basic framework and guidelines for bench-to-bedside quantitative research and therapy. We outline some of the basic concepts and their parallel use cases for chemical-protein interactions. Along with several recommendations for assay setup and conditions, we also catalog applications of these quantitative techniques in some of the most widespread discovery pipeline and analytical methods in the field. We believe adherence to these guidelines will improve experimental design, reduce variabilities and standardize quantitative datasets.

Topical niclosamide (ATx201) reduces Staphylococcus aureus colonization and increases Shannon diversity of the skin microbiome in atopic dermatitis patients in a randomized, double-blind, placebo-controlled Phase 2 trial.

BACKGROUND: In patients with atopic dermatitis (AD), Staphylococcus aureus frequently colonizes lesions and is hypothesized to be linked to disease severity and progression. Treatments that reduce S. aureus colonization without significantly affecting the skin commensal microbiota are needed. METHODS AND FINDINGS: In this study, we tested ATx201 (niclosamide), a small molecule, on its efficacy to reduce S. aureus and propensity to evolve resistance in vitro. Various cutaneous formulations were then tested in a superficial skin infection model. Finally, a Phase 2 randomized, double-blind and placebo-controlled trial was performed to investigate the impact of ATx201 OINTMENT 2% on S. aureus colonization and skin microbiome composition in patients with mild-to-severe AD (EudraCT:2016-003501-33). ATx201 has a narrow minimal inhibitory concentration distribution (.125-.5 µg/ml) consistent with its mode of action - targeting the proton motive force effectively stopping cell growth. In murine models, ATx201 can effectively treat superficial skin infections of methicillin-resistant S. aureus. In a Phase 2 trial in patients with mild-to-severe AD (N = 36), twice-daily treatment with ATx201 OINTMENT 2% effectively reduces S. aureus colonization in quantitative colony forming unit (CFU) analysis (primary endpoint: 94.4% active vs. 38.9% vehicle success rate, p = .0016) and increases the Shannon diversity of the skin microbiome at day 7 significantly compared to vehicle. CONCLUSION: These results suggest that ATx201 could become a new treatment modality as a decolonizing agent.

A scale-up strategy for the synthesis of chitosan derivatives used in micellar nanomedicines.

Nanomedicines have been increasingly investigated and used by pharmaceutical industry due to their potential in solving various public health problems. However, standardizing and approving nanomedicines remains a significant challenge, as the translation from the laboratory to the market is still limited. These constraints are due to a lack of reproducibility and standardization of procedures, small batch sizes due to inability to scale-up, or the associated production costs as a result of the production methods chosen. In this work, two chitosan derivatives, methoxypolyethylene glycol-chitosan (mPEG-CS) and methoxypolyethylene glycol-chitosan-oleic acid (mPEG-CS-OA), produced at the lab scale were implemented in a pharmaceutical industry to achieve the scale-up production using cross flow filtration (CFF). The two copolymers were shown to be capable of retaining their physicochemical properties when produced in larger batch sizes, with reduced production time and increased yield. Also, both chitosan derivatives presented no in vitro cytotoxicity independent of the method of production. Furthermore, after scale-up, polymeric micelles produced from mPEG-CS-OA were tested for storage stability, demonstrating that micelles remained stable at - 20 °C for at least 6 months. This study demonstrated the feasibility of producing polymers and polymeric micelles closer to the bedside due to their suitability for GMP production.

Let's get wild: A review of free-ranging rat assays as context-enriched supplements to traditional laboratory models.

More than 24,000 rodent studies are published annually, with the vast majority of these studies focused on genetically undiverse animals in highly-controlled laboratory settings. However, findings from the laboratory have become increasingly unreliable for predicting outcomes in field and clinical settings, leading to a perceived crisis in translational research. One cause of this disparity might be that most human societies, in contrast to laboratory rodents, are genetically diverse and live in super-enriched environments. Methods for importing wild rats into the laboratory, and also exporting laboratory-style chambers into natural environments are not well-known outside their respective disciplines. Therefore, we have reviewed the current status of supplements to the laboratory rodent assay. We progress logically from highly-controlled experiments with natural breeding colonies to purely naturalistic approaches with free-ranging rats. We then highlight a number of approaches that allow genetically-diverse wild rats to be utilized in context-enriched paradigms. While considering the benefits and shortcomings of each available approach, we detail protocols for random sampling, remote-sensing, and deployment of laboratory chambers in the field. As supplements to standardized laboratory trials, some of these assays could offer key insights to help unify outcomes between laboratory and field studies. However, we note several outstanding questions that must be addressed such as: the trade-off between control and context, possible reductions in sample size, ramifications for the 'standardization fallacy', and ethical dilemmas of working with wild animals. Given these challenges, further innovation will be required before supplemental assays can be made broadly-accessible and thus, transferrable across disciplines.

Direct reprogramming of somatic cells into induced hepatocytes: Cracking the Enigma code.

There is an unmet need for functional primary human hepatocytes to support the pharmaceutical and (bio)medical demand. The unique discovery, a decade ago, that somatic cells can be drawn out of their apparent biological lockdown to reacquire a pluripotent state has revealed a completely new avenue of possibilities for generating surrogate human hepatocytes. Since then, the number of papers reporting the direct conversion of somatic cells into induced hepatocytes (iHeps) has burgeoned. A hepatic cell fate can be established via the ectopic expression of native liver-enriched transcription factors in somatic cells, thereby bypassing the need for an intermediate (pluripotent) stem cell state. That said, understanding and eventually controlling the processes that give rise to functional iHeps remains challenging. In this review, we provide an overview of the state-of-the-art reprogramming cocktails and techniques, as well as their corresponding conversion efficiencies. Special attention is paid to the role of liver-enriched transcription factors as hepatogenic reprogramming tools and small molecules as facilitators of hepatic transdifferentiation. To conclude, we formulate recommendations to optimise, standardise and enrich the in vitro production of iHeps to reach clinical standards, and propose minimal criteria for their characterisation.

Lithium beyond psychiatric indications: the reincarnation of a new old drug.

Lithium has been used in the treatment of bipolar disorders for decades, but the exact mechanisms of action remain elusive to this day. Recent evidence suggests that lithium is critically involved in a variety of signaling pathways affecting apoptosis, inflammation, and neurogenesis, all of which contributing to the complex pathophysiology of various neurological diseases. As a matter of fact, preclinical work reports both acute and long-term neuroprotection in distinct neurological disease models such as Parkinson's disease, traumatic brain injury, Alzheimer's disease, and ischemic stroke. Lithium treatment reduces cell injury, decreases α synuclein aggregation and Tau protein phosphorylation, modulates inflammation and even stimulates neuroregeneration under experimental conditions of Parkinson's disease, traumatic brain injury, and Alzheimer's disease. The therapeutic impact of lithium under conditions of ischemic stroke was also studied in numerous preclinical in vitro and in vivo studies, giving rise to a randomized double-blind clinical stroke trial. The preclinic data revealed a lithium-induced upregulation of anti-apoptotic proteins such as B-cell lymphoma 2, heat shock protein 70, and activated protein 1, resulting in decreased neuronal cell loss. Lithium, however, does not only yield postischemic neuroprotection but also enhances endogenous neuroregeneration by stimulating neural stem cell proliferation and by regulating distinct signaling pathways such as the RE1-silencing transcription factor. In line with this, lithium treatment has been shown to modulate postischemic cytokine secretion patterns, diminishing microglial activation and stabilizing blood-brain barrier integrity yielding reduced levels of neuroinflammation. The aforementioned observations culminated in a first clinical trial, which revealed an improved motor recovery in patients with cortical stroke after lithium treatment. Beside its well-known psychiatric indications, lithium is thus a promising neuroprotective candidate for the aforementioned neurological diseases. A detailed understanding of the lithium-induced mechanisms, however, is important for prospective clinical trials which may pave the way for a successful bench-to-bedside translation in the future. In this review, we will give an overview of lithium-induced neuroprotective mechanisms under various pathological conditions, with special emphasis on ischemic stroke.

Translational research in Uganda: linking basic science to bedside medicine in a resource limited setting.

BACKGROUND: Translational research is a process of applying knowledge from basic biology and clinical trials to techniques and tools that address critical medical needs. Translational research is less explored in the Ugandan health system, yet, it is fundamental in enhancing human health and well-being. With the current high disease burden in Uganda, there are many opportunities for exploring, developing and utilising translational research. MAIN BODY: In this article, we described the current state, barriers and opportunities for translational research in Uganda. We noted that translational research is underutilised and hindered by limited funding, collaborations, laboratory infrastructure, trained personnel, equipment and research diversity. However, with active collaborations and funding, it is possible to set up and develop thriving translational research in Uganda. Researchers need to leverage existing international collaborations to enhance translational research capacity development. CONCLUSION: Expanding the integration of clinical and translational research in Uganda health care system will improve clinical care.

Identifying and understanding factors that affect the translation of therapies from the laboratory to patients: a study protocol.

Background: The process of translating preclinical findings into a clinical setting takes decades. Previous studies have suggested that only 5-10% of the most promising preclinical studies are successfully translated into viable clinical applications. The underlying determinants of this low success rate (e.g. poor experimental design, suboptimal animal models, poor reporting) have not been examined in an empirical manner. Our study aims to determine the contemporary success rate of preclinical-to-clinical translation, and subsequently determine if an association between preclinical study design and translational success/failure exists. Methods: Established systematic review methodology will be used with regards to the literature search, article screening and study selection process. Preclinical, basic science studies published in high impact basic science journals between 1995 and 2015 will be included. Included studies will focus on publicly available interventions with potential clinical promise. The primary outcome will be successful clinical translation of promising therapies - defined as the conduct of at least one Phase II trial (or greater) with a positive finding. A case-control study will then be performed to evaluate the association between elements of preclinical study design and reporting and the likelihood of successful translation. Discussion: This study will provide a comprehensive analysis of the therapeutic translation from the laboratory bench to the bedside. Importantly, any association between factors of study design and the success of translation will be identified. These findings may inform future research teams attempting preclinical-to-clinical translation. Results will be disseminated to identified knowledge users that fund/support preclinical research.

Phage Therapy in the Resistance Era: Where Do We Stand and Where Are We Going?

PURPOSE: Widespread antibiotic-resistant bacteria are threatening the arsenal of existing antibiotics. Not only are antibiotics less likely to be effective today, but their extensive use continues to drive the emergence of multidrug-resistant pathogens. A new-old antibacterial strategy with bacteriophages (phages) is under development, namely, phage therapy. Phages are targeted bacterial viruses with multiple antibacterial effector functions, which can reduce multidrug-resistant infections within the human body. This review summarizes recent phage therapy clinical trials and patient cases and outlines the fundamentals behind phage treatment strategies under development, mainly through bench-to-bedside approaches. We discuss the challenges that remain in phage therapy and the role of phages when combined with antibiotic therapy. METHODS: This narrative review presents the current knowledge and latest findings regarding phage therapy. Relevant case reports and research articles available through the Scopus and PubMed databases are discussed. FINDINGS: Although recent clinical data suggest the tolerability and, in some cases, efficacy of phage therapy, the clinical functionality still requires careful definition. The lack of well-controlled clinical trial data and complex regulatory frameworks have driven the most recent human data generation on a single-patient compassionate use basis. These cases often include the concomitant use of antibiotics, which makes it difficult to draw conclusions regarding the effectiveness of phages alone. However, human data support using antibiotics as phage potentiators and resistance breakers; thus, phage adjuvants are a promising avenue for near-term clinical development. Current knowledge gaps exist on the appropriate routes of administration, phage selection, frequency of administration, dosage, phage resistance, and pharmacokinetic and pharmacodynamic properties of the phages. In addition, we highlight that some phage therapies have mild adverse effects in patients. IMPLICATIONS: Although more translational research is needed before the clinical implementation is feasible, phage therapy may well be pivotal in safeguarding humans against antibiotic-resistant infections.