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The Journal of Clinical Investigation Dec 2023Tumor burden, considered a common chronic stressor, can cause widespread anxiety. Evidence suggests that cancer-induced anxiety can promote tumor progression, but the...
Tumor burden, considered a common chronic stressor, can cause widespread anxiety. Evidence suggests that cancer-induced anxiety can promote tumor progression, but the underlying neural mechanism remains unclear. Here, we used neuroscience and cancer tools to investigate how the brain contributes to tumor progression via nerve-tumor crosstalk in a mouse model of breast cancer. We show that tumor-bearing mice exhibited significant anxiety-like behaviors and that corticotropin-releasing hormone (CRH) neurons in the central medial amygdala (CeM) were activated. Moreover, we detected newly formed sympathetic nerves in tumors, which established a polysynaptic connection to the brain. Pharmacogenetic or optogenetic inhibition of CeMCRH neurons and the CeMCRH→lateral paragigantocellular nucleus (LPGi) circuit significantly alleviated anxiety-like behaviors and slowed tumor growth. Conversely, artificial activation of CeMCRH neurons and the CeMCRH→LPGi circuit increased anxiety and tumor growth. Importantly, we found alprazolam, an antianxiety drug, to be a promising agent for slowing tumor progression. Furthermore, we show that manipulation of the CeMCRH→LPGi circuit directly regulated the activity of the intratumoral sympathetic nerves and peripheral nerve-derived norepinephrine, which affected tumor progression by modulating antitumor immunity. Together, these findings reveal a brain-tumor neural circuit that contributes to breast cancer progression and provide therapeutic insights for breast cancer.
Topics: Mice; Animals; Corticotropin-Releasing Hormone; Neurons; Anxiety; Brain; Neoplasms
PubMed: 37847562
DOI: 10.1172/JCI167725 -
Signal Transduction and Targeted Therapy Oct 2023Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and... (Review)
Review
Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.
Topics: Humans; Precision Medicine; Microbiota; Gastrointestinal Microbiome; Pharmacogenetics; Drug-Related Side Effects and Adverse Reactions
PubMed: 37806986
DOI: 10.1038/s41392-023-01619-w -
Precision Clinical Medicine Dec 2023Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative... (Review)
Review
Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD, exhibit tendency to develop complications and substantial heterogeneity in terms of frequency and severity of relapse, thus posing great challenges to the clinical management for IBD. Current treatment strategies are effective in different ways in induction and maintenance therapies for IBD. Recent advances in studies of genetics, pharmacogenetics, proteomics and microbiome provide a strong driving force for identifying molecular markers of prognosis and treatment response, which should help clinicians manage IBD patients more effectively, and then, improve clinical outcomes and reduce treatment costs of patients. In this review, we summarize and discuss precision medicine in IBD, focusing on predictive markers of disease course and treatment response, and monitoring indices during therapeutic drug monitoring.
PubMed: 38638127
DOI: 10.1093/pcmedi/pbad033 -
JAMA Network Open Oct 2023Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia.
OBJECTIVE
To evaluate the clinical effectiveness of MPGT in schizophrenia in a randomized clinical trial (RCT).
DESIGN, SETTING, AND PARTICIPANTS
This RCT was conducted from March 2020 to March 2022. Male Chinese Han inpatients aged 18 to 60 years diagnosed with schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 60 or more from 2 selected study hospitals were included. Patients and raters were masked to MPGT or treatment as usual (TAU) randomization.
INTERVENTIONS
Participants were randomly assigned in a 1:1 ratio to receive either MPGT or TAU for 12 weeks.
MAIN OUTCOMES AND MEASURES
The primary efficacy outcome was the percentage change in PANSS total scores (range, 30 to 210) from baseline to week 6 analyzed by a modified intention-to-treat mixed model for repeated measures. The secondary outcome included response and symptomatic remission rates.
RESULTS
A total of 210 participants (mean [SD] age, 29.2 [8.8] years) were enrolled and analyzed, with 113 assigned to MPGT and 97 to TAU. Compared with those randomized to TAU, participants randomized to MPGT demonstrated a significantly higher percentage change in PANSS score (74.2% vs 64.9%; adjusted mean difference, 9.2 percentage points; 95% CI, 4.4-14.1 percentage points; P < .001) and a higher response rate (93 of 113 [82.3%] vs 63 of 97 [64.9%]; adjusted odds ratio, 2.48; 95% CI, 1.28-4.80; P = .01) at the end of week 6.
CONCLUSIONS AND RELEVANCE
In this RCT of MPGT, MPGT was more effective than TAU in treating patients with schizophrenia. These findings suggest that multigenetic pharmacogenomic testing could serve as an effective tool to guide the treatment of schizophrenia.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2000029671.
Topics: Male; Humans; Adult; Pharmacogenetics; Schizophrenia; Treatment Outcome
PubMed: 37801319
DOI: 10.1001/jamanetworkopen.2023.35518 -
Cancer Cell Apr 2024Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor...
Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and β-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.
Topics: Humans; Biological Specimen Banks; Pharmacogenetics; Precision Medicine; Liver Neoplasms; Organoids; Phenylurea Compounds; Quinolines
PubMed: 38593780
DOI: 10.1016/j.ccell.2024.03.004 -
Paediatrics & Child Health Jul 2023The past two decades have seen enormous advancements in medical knowledge around the role of genetic factors of variability, both in human disease and drug response.... (Review)
Review
The past two decades have seen enormous advancements in medical knowledge around the role of genetic factors of variability, both in human disease and drug response. This knowledge is increasingly being translated into guidelines that inform drug dosing, monitoring for efficacy and safety, and determining the suitability of specific agents to treat patients. Health Canada and the U.S. Food and Drug Administration have recommended using genetic information to guide dosing for more than 20 drugs. There are no current, comprehensive paediatric guidelines to assist health care professionals in the use of genetics to inform medication dosing, safety, and efficacy in children, and such guidance is urgently needed. This statement helps to guide clinician understanding of the role of pharmacogenetics and how to use this information when prescribing medications in paediatrics.
PubMed: 37287477
DOI: 10.1093/pch/pxad002 -
Biomedicine & Pharmacotherapy =... Aug 2023Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in... (Review)
Review
Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in these processes. They are being discussed as potential drug targets in an increasing number of diseases, ranging from Alzheimer's disease to malaria. Protein prenylation and the development of specific PTase inhibitors (PTIs) have been subject to intense research in recent decades. Recently, the FDA approved lonafarnib, a specific farnesyltransferase inhibitor that acts directly on protein prenylation; and bempedoic acid, an ATP citrate lyase inhibitor that might alter intracellular isoprenoid composition, the relative concentrations of which can exert a decisive influence on protein prenylation. Both drugs represent the first approved agent in their respective substance class. Furthermore, an overwhelming number of processes and proteins that regulate protein prenylation have been identified over the years, many of which have been proposed as molecular targets for pharmacotherapy in their own right. However, certain aspects of protein prenylation, such as the regulation of PTase gene expression or the modulation of PTase activity by phosphorylation, have attracted less attention, despite their reported influence on tumor cell proliferation. Here, we want to summarize the advances regarding our understanding of the regulation of protein prenylation and the potential implications for drug development. Additionally, we want to suggest new lines of investigation that encompass the search for regulatory elements for PTases, especially at the genetic and epigenetic levels.
Topics: Protein Prenylation; Proteins; Dimethylallyltranstransferase; Enzyme Inhibitors; Terpenes; Prenylation
PubMed: 37236024
DOI: 10.1016/j.biopha.2023.114915