There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The ‘exhaustion’ in natural killer cells and CD8+ t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microRNAs, thereby impacting on patterned gene expression. Within the tumor microenvironment, the tumor, in a quest for survival, seeks to ‘dominate’ the dynamic intercellular interactions by limiting the capacity of cells to optimally function, via the regulation of their mitochondrial melatonergic pathway. One aspect of this is the tumor’s upregulation of kynurenine and the activation of the aryl hydrocarbon receptor, which acts to metabolize melatonin and increase the N-acetylserotonin/melatonin ratio, with effluxed N-acetylserotonin acting as a brain-derived neurotrophic factor (BDNF) mimic via its activation of the BDNF receptor, TrkB, thereby increasing the survival and proliferation of tumors and cancer stem-like cells. This article highlights how many of the known regulators of cells in the tumor microenvironment can be downstream of the mitochondrial melatonergic pathway regulation. Future research and treatment implications are indicated.

/pdf/tumor-microenvironment-and-metabolism-role-of-the-1s7l6gv4.pdf

Tumor Microenvironment and Metabolism: Role of the Mitochondrial Melatonergic Pathway in Determining Intercellular Interactions in a New Dynamic Homeostasis

Cytochrome P450 and other families of drug metabolizing enzymes are commonly thought of and studied for their ability to metabolize xenobiotics and other foreign entities as they are eliminated from the body. Equally as important, however, is the homeostatic role that many of these enzymes play in maintaining the proper levels of endogenous signaling molecules such as lipids, steroids, and eicosanoids, as well as their ability to modulate protein-protein interactions involved in downstream signaling cascades. Throughout the years, many of these endogenous ligands or protein partners of drug metabolizing enzymes have been associated with a wide range of disease states from cancer to various cardiovascular, neurological or inflammatory diseases, prompting an interest in whether or not modulation of drug metabolizing enzyme activity could have a subsequent pharmacological impact or lessening of disease severity. Beyond direct regulation of endogenous pathways, drug metabolizing enzymes have also been proactively targeted for their ability to activate pro-drugs with subsequent pharmacological activity or enhance the efficacy of a co-administered drug by inhibiting the metabolism of that drug through a rationally designed drug-drug interaction (i.e., ritonavir and HIV antiretroviral therapy). The focus of this minireview will be to highlight research aimed at characterizing cytochrome P450 and other drug metabolizing enzymes as therapeutic targets. Examples of successfully marketed drugs as well as early research efforts will be discussed. Finally, emerging areas of research utilizing typical drug metabolizing enzymes to impact clinical outcomes will be discussed. Significance Statement While generally thought of for their drug metabolizing capabilities, enzymes such as the cytochromes P450, glutathione S-transferases, soluble epoxide hydrolases and others play a significant role in regulating key endogenous pathways, making them potential drug targets. This minireview will cover various efforts over the years to modulate drug metabolizing enzyme activity towards pharmacological outcomes.

/pdf/cytochrome-p450-and-other-drug-metabolizing-enzymes-as-m28ez2l5.pdf

Cytochrome P450 and Other Drug Metabolizing Enzymes as Therapeutic Targets.

Immunotherapy has emerged as a revolutionary approach in cancer therapy, and recent advancements hold significant promise for breast cancer (BCa) management. Employing the patient's immune system to combat BCa has become a focal point in immunotherapeutic investigations. Strategies such as immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), and targeting the tumor microenvironment (TME) have disclosed encouraging clinical outcomes. ICIs, particularly programmed cell death protein 1 (PD-1)/PD-L1 inhibitors, exhibit efficacy in specific BCa subtypes, including triple-negative BCa (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive cancers. ACT approaches, including tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy, showed promising clinical outcomes in enhancing tumor recognition and elimination. Targeting the TME through immune agonists and oncolytic viruses signifies a burgeoning field of research. While challenges persist in patient selection, resistance mechanisms, and combination therapy optimization, these novel immunotherapies hold transformative potential for BCa treatment. Continued research and clinical trials are imperative to refine and implement these innovative approaches, paving the way for improved outcomes and revolutionizing the management of BCa. This review provides a concise overview of the latest immunotherapies (2023 studies) in BCa, highlighting their potential and current status. 

Novel immunotherapies for breast cancer: Focus on 2023 findings.

Computational variant effect predictors (VEPs) are playing increasingly important roles in the interpretation of human genetic variants. We observe striking differences in the ways that many VEPs score variants from European compared to non-European populations. We advocate for the adoption of population-free VEPs, i.e. those not trained on human population or clinical variants, to improve health equity and enhance the accuracy of genetic diagnoses across diverse populations.

Pervasive ancestry bias in variant effect predictors

Human cytochrome P450 1B1 (hCYP1B1), an extrahepatic cytochrome P450 enzyme over-expressed in various tumors, has been validated as a promising target for preventing and treating cancers. Herein, two series of chalcone derivatives were synthesized to discover potent hCYP1B1 inhibitors without AhR agonist effect. Structure-activity relationship (SAR) studies demonstrated that 4'-trifluoromethyl on the B-ring strongly enhanced the anti-hCYP1B1 effects, identifying A9 as a promising lead compound. Further SAR analysis on A9 derivatives (modified A-ring of 4'-trifluoromethylchalcone) showed that introducing 2-methoxyl improved the anti-hCYP1B1 effect and selectivity, while introducing a methoxyl at the C-4 site was beneficial for avoiding AhR activation. Ultimately, five 4'-trifluoromethyl chalcones were identified as potent hCYP1B1 inhibitors (IC50 < 10 nM), while B18 exhibits the most potent anti-hCYP1B1 effect (IC50 = 3.6 nM), suitable metabolic stability and good cell-permeability. B18 also acted as an AhR antagonist and could down-regulate hCYP1B1 in living systems. Mechanistic studies showed that B18 potently inhibited hCYP1B1 in a competitive inhibition manner (Ki = 3.92 nM), while docking simulations revealed that B18 could tightly bind to the catalytic cavity of hCYP1B1 mainly via hydrophobic and hydrogen-bonding interactions. Furthermore, B18 could potently inhibit hCYP1B1 in living cells and showed remarkable anti-migration ability on MFC-7 cells. Taken together, this study deciphered the SARs of chalcones as hCYP1B1 inhibitors and provided several potent hCYP1B1 inhibitors as promising candidates for the development of more efficacious anti-migration agents. 

Discovery of 4’-trifluoromethylchalcones as novel, potent and selective hCYP1B1 inhibitors without concomitant AhR activation

Disparities in the data that underlies clinical genomic interpretation is an acknowledged problem but there is a paucity of data demonstrating it. The National Institutes of Health's All of Us Research Program aims to collect whole genome sequences, electronic health record (EHR) data, surveys and physical measurements for over a million participants of diverse ancestry and varied access to healthcare resources. We grouped participants by computed genetic ancestry and summarized the frequency of pathogenic variation within these groups. The European subgroup showed the highest rate of pathogenic variation (2.1%), with other ancestry groups ranging from 1.04% (East Asian) to 1.87% ('Other'). Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer, Hypercholesterolemia or Hemochromatosis. Variant frequencies were consistent with GnomAD and some notable exceptions were resolved using GnomAD subsets. We additionally use this data to enrich sets of participants for specific genetic findings and to calculate penetrance. Differences in the frequency of pathogenic variants observed between ancestral groups generally indicate biases of ascertainment, but some may indicate differences in disease prevalence. These analyses are available on the All of Us Researcher Workbench.

The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities

Novel RNA N6-methyladenosine regulator related signature for predicting clinical and immunological characteristics in breast cancer.

The aim of this study is to explore the pathological niche of cancer metastasis and the site-specific interactions between tumor cells and the microenvironment, understand the mechanisms driving metastasis progression and identify potential therapeutic targets. Data from four lung cancer metastasis datasets (GSE123902, GSE131907, GSE148071, and GSE186344) were downloaded and subjected to stringent quality control and filtering. Cell types were identified using canonical markers, and pseudotime trajectory analysis was performed to evaluate cell differentiation. Functional and pathway enrichment analyses, including ssGSEA and GO/KEGG, were conducted. CellphoneDB was used to analyze intercellular communication, ranking receptor-ligand interactions based on communication strength. Eleven cell types were identified after quality control, revealing significant heterogeneity and site-specific functionality in lung cancer metastases. CTLs showed notable activity in antigen presentation and T-cell differentiation pathways, with DNAJB1⁺ CTLs playing a dominant role in cytotoxicity and immune regulation. B cells, myeloid cells, and CAFs were involved in immune modulation, defense, and matrix remodeling through specific signaling pathways. Tumor cell subclusters drove proliferation, migration, and immune evasion via immune-regulatory, Hippo, and TGF-beta pathways. No overlapping pathways were observed across metastatic sites. Cell communication analysis identified PPIA-BSG and APP-CD74 as key axes in brain and lymph node metastases, while FN1-Integrin and CTLA4-CD86 dominated in bone and adrenal metastases, respectively. In summary, this study highlights the functional heterogeneity and site-specific interactions of cells in lung cancer metastases, providing insights into the mechanisms shaping metastatic niches and potential therapeutic strategies.

Single-cell profiling uncovers the intricate pathological niche diversity in brain, lymph node, bone, and adrenal metastases of lung cancer

Simple Summary Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1) is a critical metabolic enzyme of melatonin. Although melatonin has been identified to exhibit tumor suppressing activity, the role and mechanism of the clinical and immunological characteristics of CYP1B1 in cancer remain unclear. We comprehensively explored the clinical and immunological characteristics of CYP1B1. We identified that the dysregulated expression of CYP1B1 was associated with clinical characteristics and a tumor immune microenvironment, which may provide a promising predictor and molecular target for clinical immune treatment. Abstract Background: Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1) is a critical metabolic enzyme of melatonin. Although melatonin has been identified to exhibit tumor suppressing activity, the role and mechanism of the clinical and immunological characteristics of CYP1B1 in cancer remain unclear. Methods: In this study, RNA expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) across 33 solid tumors. The expression, survival, immune subtype, molecular subtype, tumor mutation burden (TMB), microsatellite instability (MSI), biological pathways, and function in vitro and vivo were evaluated. The predictive value of CYP1B1 in immune cohorts was further explored. Results: We found the dysregulated expression of CYP1B1 was associated with the clinical stage and tumor grade. Immunological correlation analysis showed CYP1B1 was positively correlated with the infiltration of lymphocyte, immunomodulator, chemokine, receptor, and cancer-associated fibroblasts (CAFs) in most cancer. Meanwhile, CYP1B1 was involved in immune subtype and molecular subtype, and was connected with TMB, MSI, neoantigen, the activation of multiple melatonergic and immune-related pathways, and therapeutic resistance. Conclusions: Together, this study comprehensively revealed the role and mechanism of CYP1B1 and explored the significant association between CYP1B1 expression and immune activity. These findings provide a promising predictor and molecular target for clinical immune treatment.

/pdf/cyp1b1-a-novel-molecular-biomarker-predicts-molecular-ptpjeie0.pdf

CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers

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The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities

Novel RNA N6-methyladenosine regulator related signature for predicting clinical and immunological characteristics in breast cancer.

Single-cell profiling uncovers the intricate pathological niche diversity in brain, lymph node, bone, and adrenal metastases of lung cancer

CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers