Project description:The induced pluripotent stem cell (iPSC) technology is instrumental in advancing the fields of disease modeling and cell transplantation. We herein discuss the various issues regarding disease modeling and cell transplantation presented in previous reports, and also describe new iPSC-based medicine including iPSC clinical trials. In such trials, iPSCs from patients can be used to predict drug responders/non-responders by analyzing the efficacy of the drug on iPSC-derived cells. They could also be used to stratify patients after actual clinical trials, including those with sporadic diseases, based on the drug responsiveness of each patient in the clinical trials. iPSC-derived cells can be used for the identification of response markers, leading to increased success rates in such trials. Since iPSCs can be used in micromedicine for drug discovery, and in macromedicine for actual clinical trials, their use would tightly connect both micro- and macromedicine. The use of iPSCs in disease modeling, cell transplantation, and clinical trials could therefore lead to significant changes in the future of medicine.
Project description:The novel coronavirus SARS-CoV-2, causing the disease COVID-19, first emerged in Wuhan, China in December 2019 and has now spread to 203 countries or territories, infected over 2 million people and caused over 133,000 deaths. There is an urgent need for specific treatments. One potential treatment is chloroquine and its derivatives, including hydroxychloroquine, which have both antiviral and anti-inflammatory effects. These compounds are effective against SARS-CoV-2 in vitro, but in vivo data are lacking. Although some encouraging outcomes have been reported, and these results have been received enthusiastically, we recommend careful and critical evaluation of current evidence only when all methods and data are available for peer review. Chloroquine is safe and cheap. However, further evidence from coordinated multicentre trials is required before it can be confidently said whether it is effective against the current pandemic.
Project description:Recent substantial evidence implicating commensal bacteria in human diseases has given rise to a new domain in biomedical research: microbiome medicine. This emerging field aims to understand and leverage the human microbiota and derivative molecules for disease prevention and treatment. Despite the complex and hierarchical organization of this ecosystem, most research over the years has relied on 16S amplicon sequencing, a legacy of bacterial phylogeny and taxonomy. Although advanced sequencing technologies have enabled cost-effective analysis of entire microbiota, translating the relatively short nucleotide information into the functional and taxonomic organization of the microbiome has posed challenges until recently. In the last decade, genome-resolved metagenomics, which aims to reconstruct microbial genomes directly from whole-metagenome sequencing data, has made significant strides and continues to unveil the mysteries of various human-associated microbial communities. There has been a rapid increase in the volume of whole metagenome sequencing data and in the compilation of novel metagenome-assembled genomes and protein sequences in public depositories. This review provides an overview of the capabilities and methods of genome-resolved metagenomics for studying the human microbiome, with a focus on investigating the prokaryotic microbiota of the human gut. Just as decoding the human genome and its variations marked the beginning of the genomic medicine era, unraveling the genomes of commensal microbes and their sequence variations is ushering us into the era of microbiome medicine. Genome-resolved metagenomics stands as a pivotal tool in this transition and can accelerate our journey toward achieving these scientific and medical milestones.
Project description:PB28, a cyclohexylpiperazine derivative, could be a potential strategy for Covid 19 because in a recent study it has been found more active than hydroxychloroquine without interaction with cardiac proteins. PB28 has been designed, developed, and biologically evaluated in the past decade in our research group. A possible mechanism to explain its surprising anti-COVID-19 activity is suggested..
Project description:The steady progress in genome editing, especially genome editing based on the use of clustered regularly interspaced short palindromic repeats (CRISPR) and programmable nucleases to make precise modifications to genetic material, has provided enormous opportunities to advance biomedical research and promote human health. However, limited transfection efficiency of CRISPR-Cas9 poses a substantial challenge, hindering its wide adoption for genetic modification. Recent advancements in nanoparticle technology, specifically lipid nanoparticles (LNPs), offer promising opportunities for targeted drug delivery. LNPs are becoming popular as a means of delivering therapeutics, including those based on nucleic acids and mRNA. Notably, certain LNPs, such as Polyethylene glycol-phospholipid-modified cationic lipid nanoparticles and solid lipid nanoparticles, exhibit remarkable potential for efficient CRISPR-Cas9 delivery as a gene editing instrument. This review will introduce the molecular mechanisms and diverse applications of the CRISPR/Cas9 gene editing system, current strategies for delivering CRISPR/Cas9-based tools, the advantage of LNPs for CRISPR-Cas9 delivery, an overview of strategies for overcoming off-target genome editing, and approaches for improving genome targeting and tissue targeting. We will also highlight current developments and recent clinical trials for the delivery of CRISPR/Cas9. Finally, future directions for overcoming the limitations and adaptation of this technology for clinical trials will be discussed.
Project description:Children with acquired hypothalamic obesity, e.g. following treatment for pediatric craniopharyngioma are at great risk for metabolic syndrome, cardiovascular health problems and premature mortality. Treatment for acquired hypothalamic obesity has thus far been disappointing. Several interventions were reported to be partially successful, including dextro-amphetamine and GLP-1R agonists, although results in acquired hypothalamic obesity are conflicting. Disruption of signaling through the melanocortin-4 receptor (MC4R) pathway results in hyperphagia and severe early-onset hypothalamic obesity. Recently, the MC4R agonist setmelanotide has shown promising results in children with genetic forms of hypothalamic obesity; POMC, PCSK1 and LEPR. Patient quotes such as "we have our family life back" illustrate the magnitude of the effect. Targeted hormone replacement therapy with a MC4R agonist for acquired hypothalamic obesity could be a game-changer. Preliminary results of setmelanotide treatment in 14, mostly pediatric, patients with acquired hypothalamic obesity are promising. The FDA has recommended that a prospective, randomized, blinded trial be conducted over a 12 months treatment period, comparable to pivotal trials for other obesity drugs. It may be discussed whether setmelanotide should be regarded as an obesity drug or whether it may be envisioned as an agent for hypothalamic substitution therapy. In this commentary we discuss the trial that is currently recruiting patients with acquired hypothalamic obesity.
Project description:The combination approach based on venetoclax (VEN) with azacytidine (AZA) has significantly improved outcomes for elderly patients with acute myeloid leukemia (AML). This innovative approach has led to higher rates of overall response, measurable residual disease (MRD)-negative remissions, and overall survival compared with AZA monotherapy. As a result, this combination has emerged as the gold-standard treatment for elderly or unfit patients with AML who are not eligible for intensive therapy. In younger, fit patients with AML, intensive induction and consolidation chemotherapy is commonly used as a first-line approach; however, relapse continues to be the main reason for treatment failure in approximately 30-40% of patients. Efforts to improve MRD-negative response rates and to facilitate the transition to allogeneic hematopoietic stem cell transplantation, particularly in high-risk AML, have inspired trials exploring the combination of intensive chemotherapy with targeted agents. VEN, a first-in-class anti-BCL2 agent, combined with intensive chemotherapy regimens has shown deep MRD-negative remissions, producing prolonged event-free survival and enhancing the transition to allogeneic transplant in first-complete-remission patients. These benefits support the incremental advantages of adding VEN to intensive chemotherapy approaches across ELN risk subcategories, and provides a robust benchmark to design future trials. In this review, we will discuss current studies assessing the efficacy of frontline regimens integrating VEN into intensive chemotherapy in younger patients with AML and specific molecularly defined subgroups.
Project description:Following the invasion by the pine wood nematode (PWN) into north-east China, a notable disparity in susceptibility was observed among Pinaceae species. Larix olgensis exhibited marked resilience and suffered minimal fatalities, while Pinus koraiensis experienced significant mortality due to PWN infection. Our research demonstrated that the PWNs in L. olgensis showed a 13.43% reduction in lipid content compared to P. koraiensis (p < 0.05), which was attributable to the accumulation of caffeic acid in L. olgensis. This reduction in lipid content was correlated with a decreased overwintering survival of PWNs. The diminished lipid reserves were associated with substantial stunting in PWNs, including reduced body length and maximum body width. The result suggests that lower lipid content is a major factor contributing to the lower overwintering survival rate of PWNs in L. olgensis induced by caffeic acid. Through verification tests, we concluded that the minimal fatalities observed in L. olgensis could be attributed to the reduced overwintering survival of PWNs, a consequence of caffeic acid-induced stunting. This study provides valuable insights into PWN-host interactions and suggests that targeting caffeic acid biosynthesis pathways could be a potential strategy for managing PWN in forest ecosystems.