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Seminars in Oncology Dec 2006Advanced and metastatic hepatocellular carcinomas (HCC) are challenging to treat, and no cytotoxic agents have impacted survival. The underlying liver cirrhosis that... (Review)
Review
Advanced and metastatic hepatocellular carcinomas (HCC) are challenging to treat, and no cytotoxic agents have impacted survival. The underlying liver cirrhosis that commonly accompanies HCC provides an additional challenge; indeed, functional scoring of cirrhosis and HCC is a critical component of patient evaluation. Currently, the molecular biology and pathogenesis of HCC are being increasingly investigated, which may lead to better understanding of the evolution of the disease, especially differing etiologies and identification of survival genes that may affect outcome. Early studies of targeted therapies in HCC have shown disease stabilization, and an increased understanding of the mechanism(s) of these novel agents combined with correlative studies may lead to the identification of an active agent or combination of agents that impacts the natural history of HCC.
Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Molecular Biology
PubMed: 17178294
DOI: 10.1053/j.seminoncol.2006.10.015 -
Clinical Microbiology and Infection :... Sep 2022The diagnosis of bacterial infections continues to rely on culture, a slow process in which antibiotic susceptibility profiles of potential pathogens are made available... (Review)
Review
BACKGROUND
The diagnosis of bacterial infections continues to rely on culture, a slow process in which antibiotic susceptibility profiles of potential pathogens are made available to clinicians 48 hours after sampling, at best. Recently, clinical metagenomics, the metagenomic sequencing of samples with the purpose of identifying microorganisms and determining their susceptibility to antimicrobials, has emerged as a potential diagnostic tool that could prove faster than culture. Clinical metagenomics indeed has the potential to detect antibiotic resistance genes (ARGs) and mutations associated with resistance. Nevertheless, many challenges have yet to be overcome in order to make rapid phenotypic inference of antibiotic susceptibility from metagenomic data a reality.
OBJECTIVES
The objective of this narrative review is to discuss the challenges underlying the phenotypic inference of antibiotic susceptibility from metagenomic data.
SOURCES
We conducted a narrative review using published articles available in the National Center for Biotechnology Information PubMed database.
CONTENT
We review the current ARG databases with a specific emphasis on those which now provide associations with phenotypic data. Next, we discuss the bioinformatic tools designed to identify ARGs in metagenomes. We then report on the performance of phenotypic inference from genomic data and the issue predicting the expression of ARGs. Finally, we address the challenge of linking an ARG to this host.
IMPLICATIONS
Significant improvements have recently been made in associating ARG and phenotype, and the inference of susceptibility from genomic data has been demonstrated in pathogenic bacteria such as Staphylococci and Enterobacterales. Resistance involving gene expression is more challenging however, and inferring susceptibility from species such as Pseudomonas aeruginosa remains difficult. Future research directions include the consideration of gene expression via RNA sequencing and machine learning.
Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Genes, Bacterial; Metagenome; Metagenomics
PubMed: 35551982
DOI: 10.1016/j.cmi.2022.04.017 -
Polymers Jan 2023With economic development, environmental problems are becoming more and more prominent, and achieving green chemistry is an urgent task nowadays, which creates an... (Review)
Review
With economic development, environmental problems are becoming more and more prominent, and achieving green chemistry is an urgent task nowadays, which creates an opportunity for the development of supercritical foaming technology. The foaming agents used in supercritical foaming technology are usually supercritical carbon dioxide (ScCO) and supercritical nitrogen (ScN), both of which are used without environmental burden. This technology can reduce the environmental impact of polymer foam production. Although supercritical foaming technology is already in production in some fields, it has not been applied on a large scale. Here, we present a detailed analysis of the types of foaming agents currently used in supercritical foaming technology and their applications in various fields, summarizing the technological improvements that have been made to the technology. However, we have found that today's supercritical technologies still need to address some additional challenges to achieve large-scale production.
PubMed: 36679284
DOI: 10.3390/polym15020402 -
The Journal of Molecular Diagnostics :... May 2008More than 50 emerging and reemerging pathogens have been identified during the last 40 years. Until 1992 when the Institute of Medicine issued a report that defined... (Review)
Review
More than 50 emerging and reemerging pathogens have been identified during the last 40 years. Until 1992 when the Institute of Medicine issued a report that defined emerging infectious diseases, medicine had been complacent about such infectious diseases despite the alarm bells of infections with human immunodeficiency virus. Molecular tools have proven useful in discovering and characterizing emerging viruses and bacteria such as Sin Nombre virus (hantaviral pulmonary syndrome), hepatitis C virus, Bartonella henselae (cat scratch disease, bacillary angiomatosis), and Anaplasma phagocytophilum (human granulocytotropic anaplasmosis). The feasibility of applying molecular diagnostics to dangerous, fastidious, and uncultivated agents for which conventional tests do not yield timely diagnoses has achieved proof of concept for many agents, but widespread use of cost-effective, validated commercial assays has yet to occur. This review presents representative emerging viral respiratory infections, hemorrhagic fevers, and hepatitides, as well as bacterial and parasitic zoonotic, gastrointestinal, and pulmonary infections. Agent characteristics, epidemiology, clinical manifestations, and diagnostic methods are tabulated for another 22 emerging viruses and five emerging bacteria. The ongoing challenge to the field of molecular diagnostics is to apply contemporary knowledge to facilitate agent diagnosis as well as to further discoveries of novel pathogens.
Topics: Animals; Bacterial Infections; Communicable Diseases, Emerging; Humans; Molecular Diagnostic Techniques; Virus Diseases
PubMed: 18403608
DOI: 10.2353/jmoldx.2008.070063 -
BMC Medicine Dec 2013The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result... (Review)
Review
The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB.
Topics: Anti-Retroviral Agents; Antitubercular Agents; Chemoprevention; Developing Countries; Early Diagnosis; HIV Infections; Humans; Time Factors; Tuberculosis
PubMed: 24295487
DOI: 10.1186/1741-7015-11-253 -
Biomolecules Feb 2020Peptic ulcer disease (PUD) is a multifactorial and complex disease caused by an imbalance of protective and aggressive factors (endogenous and exogenous). Despite... (Review)
Review
Peptic ulcer disease (PUD) is a multifactorial and complex disease caused by an imbalance of protective and aggressive factors (endogenous and exogenous). Despite advances in recent years, it is still responsible for substantial mortality and triggering clinical problems. Over the last decades, the understanding of PUD has changed a lot with the discovery of Helicobacter pylori infection. However, this disease continues to be a challenge due to side-effects, incidence of relapse from use of various anti-ulcer medicines, and the rapid appearance of antimicrobial resistance with current H. pylori therapies. Consequently, there is the need to identify more effective and safe anti-ulcer agents. The search for new therapies with natural products is a viable alternative and has been encouraged. The literature reports the importance of monoterpenes based on the extensive pharmacological action of this class, including wound healing and anti-ulcerogenic agents. In the present study, 20 monoterpenes with anti-ulcerogenic properties were evaluated by assessing recent in vitro and in vivo studies. Here, we review the anti-ulcer effects of monoterpenes against ulcerogenic factors such as ethanol, nonsteroidal anti-inflammatory drugs (NSAIDs), and Helicobacter pylori, highlighting challenges in the field.
Topics: Helicobacter Infections; Helicobacter pylori; Humans; Monoterpenes; Peptic Ulcer; Risk Factors
PubMed: 32050614
DOI: 10.3390/biom10020265 -
Expert Opinion on Drug Delivery Oct 2022Poor or inconsistent adherence to daily oral pre-exposure prophylaxis (PrEP) has emerged as a key barrier to effective HIV prevention. The advent of potent long-acting... (Review)
Review
INTRODUCTION
Poor or inconsistent adherence to daily oral pre-exposure prophylaxis (PrEP) has emerged as a key barrier to effective HIV prevention. The advent of potent long-acting (LA) antiretrovirals (ARVs) in conjunction with advances in controlled release technologies has enabled LA ARV drug delivery systems (DDS) capable of providing extended dosing intervals and overcome the challenge of suboptimal drug adherence with daily oral dosing.
AREAS COVERED
This review discusses the current state of the LA PrEP field, recent advances, and emerging technologies, including ARV prodrug modifications and new DDS. Technological challenges, knowledge gaps, preclinical testing considerations, and future directions important in the context of clinical translation and implementation of LA HIV PrEP are discussed.
EXPERT OPINION
The HIV prevention field is evolving faster than ever and the bar for developing next-generation LA HIV prevention options continues to rise. The requirements for viable LA PrEP products to be implemented in resource-limited settings are challenging, necessitating proactive consideration and product modifications during the design and testing of promising new candidates. If successfully translated, next-generation LA PrEP that are safe, affordable, highly effective, and accepted by both end-users and key stakeholders will offer significant potential to curb the HIV pandemic.
Topics: Humans; Pre-Exposure Prophylaxis; Anti-HIV Agents; HIV Infections; Acquired Immunodeficiency Syndrome; Drug Delivery Systems
PubMed: 36252277
DOI: 10.1080/17425247.2022.2135699 -
Annals of Oncology : Official Journal... Feb 2016Immunostimulatory monoclonal antibodies (imAbs) targeting immune checkpoint molecules are revolutionizing oncology not only regarding cancer therapeutics and clinical... (Review)
Review
BACKGROUND
Immunostimulatory monoclonal antibodies (imAbs) targeting immune checkpoint molecules are revolutionizing oncology not only regarding cancer therapeutics and clinical care, but also from a drug development point of view. A handful of first-generation molecules have been approved so far based on their tremendous efficacy, after an expedited development phase that has challenged most paradigms established in the era of conventional cytotoxic therapy and to some extent molecularly targeted agents. A huge wave of second-generation imAbs is just entering into phase 1 trials now, in monotherapy or in combination. In order to maximize their chances of success in early phase trials, and eventually for patients' benefit, their clinical development has to benefit from lessons learnt from previous imAbs phase 1 trials.
MATERIALS AND METHODS
We reviewed the early clinical development of anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed death-1 receptor/ligand. Particularities of each agent, including safety, dose--toxicity and dose--efficacy relationships, scheduling, pharmacokinetics (PK), pharmacodynamics (PD), trial design, biomarkers, response assessment and overall drug development strategies, are described and challenged.
RESULTS
As opposed to conventional cytotoxic agents, dose of imAbs is not linearly associated with efficacy and toxicity. Therefore, the definition of a minimal immunologically active dose could be proposed. Traditional patient eligibility criteria might also be revisited as the toxicity profile and mechanism of toxicity--immune-related adverse events--are mostly known and their physiopathology somehow less unexpected than with molecularly targeted small molecules. Most challenging are the comprehensive investigation of complex PK and PD characteristics as well as the definition of patient selection biomarkers. Finally, the early focus on efficacy (and not only dose confirmation) in expansion cohorts challenges the traditional phase 1/2/3 drug development process.
CONCLUSION
Several drug development paradigms have been challenged by imAbs. Here, we discuss novel approaches for an efficient and successful drug development of these agents.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; B7-H1 Antigen; CTLA-4 Antigen; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Immunologic; Drug Discovery; Humans; Immunotherapy; Maximum Tolerated Dose; Molecular Targeted Therapy; Neoplasms; Patient Selection
PubMed: 26578728
DOI: 10.1093/annonc/mdv550 -
AIMS Microbiology 2022Concern about microbial tolerance and resistance to established antimicrobials drives research into alternatives for local antiseptic wound treatment. Precise efficacy...
Concern about microbial tolerance and resistance to established antimicrobials drives research into alternatives for local antiseptic wound treatment. Precise efficacy profiles are thereby important in the evaluation of potential alternative antimicrobials, and protein interference ("protein error") is a key factor. Here, the antimicrobial efficacy of cetylpyridinium chloride (CPC) and miramistin (MST) was compared to the established antimicrobials octenidine (OCT), povidon-iodine (PVP-I), polyhexamethylene-biguanide (PHMB) and chlorhexidine (CHX). Efficacy was evaluated after 0.5, 1, 3, 5 and 10 min against , , and using an in vitro quantitative suspension method (based on DIN EN 13727). To investigate protein interference, 0.3% or 3% bovine albumin was used as the challenge. OCT and PVP-I demonstrated a significant efficacy within 0.5 min, regardless of the microbial organism and protein challenge ( < 0.01). CPC and MST showed no inferiority in efficacy, with only MST needing up to 3 min to achieve the same microbial reduction. PHMB and CHX also achieved significant reduction rates over the tested time-course, yet demonstrated a necessity for prolonged exposure (up to 10 min) for comparable reduction. A protein interference was predominantly observed for PHMB against , but without statistically significant differences in antimicrobial efficacy between the 0.3% and 3% protein challenges. All other tested agents showed no relevant interference with the presence of protein. CPC and MST proved to be non-inferior to established wound antiseptics agents in vitro. In fact, CPC showed a more efficient reduction than PHMB and CHX despite there being an introduced protein challenge. Both agents demonstrated no significant "protein error" under challenging conditions (3% albumin), posing them as valid potential candidates for alternative antimicrobials in wound management.
PubMed: 36694590
DOI: 10.3934/microbiol.2022026 -
Epidemics Sep 2022African swine fever (ASF) is an emerging disease currently spreading at the interface between wild boar and pig farms in Europe and Asia. Current disease control...
African swine fever (ASF) is an emerging disease currently spreading at the interface between wild boar and pig farms in Europe and Asia. Current disease control regulations, which involve massive culling with significant economic and animal welfare costs, need to be improved. Modelling enables relevant control measures to be explored, but conducting the exercise during an epidemic is extremely difficult. Modelling challenges enhance modellers' ability to timely advice policy makers, improve their readiness when facing emerging threats, and promote international collaborations. The ASF-Challenge, which ran between August 2020 and January 2021, was the first modelling challenge in animal health. In this paper, we describe the objectives and rules of the challenge. We then demonstrate the mechanistic multi-host model that was used to mimic as accurately as possible an ASF-like epidemic, provide a detailed explanation of the surveillance and intervention strategies that generated the synthetic data, and describe the different management strategies that were assessed by the competing modelling teams. We then outline the different technical steps of the challenge as well as its environment. Finally, we synthesize the lessons we learnt along the way to guide future modelling challenges in animal health.
Topics: African Swine Fever; African Swine Fever Virus; Animals; Epidemics; Europe; Sus scrofa; Swine
PubMed: 35878574
DOI: 10.1016/j.epidem.2022.100616