iScience. 2024 Nov 1;27(12):111296. doi: 10.1016/j.isci.2024.111296. eCollection 2024 Dec 20.

ABSTRACT

Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to an individually variable spectrum of cancers caused by pathogenic TP53 germline variants. We used a clustering method to assign TP53 missense variants to classes based on their functional activities in experimental assays assessing biological p53 functions. Correlations with LFS phenotypes were analyzed using the public germline TP53 mutation database and validated in three LFS clinical cohorts. Class A carriers recapitulated all phenotypic traits of fully penetrant LFS, whereas class B carriers showed a slightly less penetrant form dominated by specific cancers, consistent with the notion that these classes identify variants with distinct functional properties. Class C displayed a lower lifetime cancer risk associated with attenuated LFS features, consistent with the notion that these variants have hypomorphic features. Class D carriers showed low lifetime cancer risks inconsistent with LFS definitions. This classification of TP53 variants provides insights into structural/functional features causing pathogenicity.

PMID:39634561 | PMC:PMC11615613 | DOI:10.1016/j.isci.2024.111296

Heliyon. 2024 Nov 14;10(22):e40179. doi: 10.1016/j.heliyon.2024.e40179. eCollection 2024 Nov 30.

ABSTRACT

BACKGROUND: The goal of this bioinformatics research is to get a comprehensive understanding of the driver genes and their function in the development, progression, and treatment of cervical cancer. This study constitutes a pioneering attempt, adding to our knowledge of genetic diversity and its ramifications.

MATERIAL AND METHODS: In this project, we use bioinformatics and systems biology methods to identify candidate transcription factors and the genes they regulate in order to identify microRNAs and LncRNAs that regulate these transcription factors and lead to the discovery of new medicines for the treatment of cervical cancer. From the differentially expressed genes available via GEO's GSE63514 accession, we use driver genes to choose these candidates. We then used the WGCNA tool in R to rebuild the co-expression network and its modules. The hub genes of each module were determined using CytoHubba, a Cystoscope plugin. The biomarker potential of hub genes was analyzed using the UCSC Xena browser and the GraphPad prism program. The TRRUST database is used to locate the TFs that regulate the expression of these genes. In order to learn how drugs, MicroRNAs, and LncRNAs interact with transcription factors, we consulted the Drug Target Information Database (DGIDB), the miRWalk database, and the LncHub database. Finally, the online database Enrichr is utilized to analyze the enrichment of Gene Ontology and KEGG pathways.

RESULTS: By combining the mRNA expression levels of 2041 driver genes from 14 early-stage Cervical cancer and 24 control samples, a co-expression network was built. The cluster analysis shows that the collection of shared genes may be broken down into seven distinct groups, or "modules." According to the average linkage hierarchical clustering and Summary smaller than 2, we found five modules (represented by the colors blue, brown, red, green, and grey) in our research. Then, we identify 5 high-degree genes from these modules that may serve as diagnostic biomarkers (ZBBX, PLCH1, TTC7B, DNAH7, and ZMYND10). In addition, we identify four transcription factors (SRF, RELA, NFKB1, and SP1) that regulate the expression of genes in the co-expression module. Drugs, microRNAs, and long noncoding RNAs are then shown to cooperate with transcription factors. At last, the KEGG database's pathways were mined for information on how the co-expression module fits within them. More clinical trials are required for more trustworthy outcomes, and we collected this data using bioinformatics methods.

CONCLUSION: The major goal of this research was to identify diagnostic and therapeutic targets for cervical cancer by learning more about the involvement of driver genes in cancer's earliest stages.

PMID:39634417 | PMC:PMC11616557 | DOI:10.1016/j.heliyon.2024.e40179

Haematologica. 2024 Dec 5. doi: 10.3324/haematol.2023.283951. Online ahead of print.

ABSTRACT

Over the course of the last decade, genomic studies in the context of normal human hematopoiesis have provided new insights into the early pathogenesis of myeloproliferative neoplasms (MPN). A preclinical phase of MPN, termed clonal hematopoiesis (CH) was identified and subsequent lineage tracing studies revealed a multi-decade long time interval from acquisition of an MPN phenotypic driver mutation in a hematopoietic stem cell (HSC) to the development of overt MPN. Multiple germline variants associated with MPN risk have been identified through genome-wide association studies (GWAS) and in some cases functional interrogation of the impact of the variant has uncovered new insights into HSC biology and MPN development. Increasingly sophisticated methods to study clonal contributions to human hematopoiesis and measure HSC fitness have helped discern the biology underlying the tremendous clinical heterogeneity observed in MPN. Despite these advances, significant knowledge gaps remain particularly with respect to germline genetic contributors to both MPN pathogenesis and phenotypic diversity, as well as limitations in the ability to prospectively quantify rates of clonal expansion in individual MPN patients. Ultimately, we envisage a personalized approach to MPN care in the future, where an individualized genetic assessment can predict MPN trajectory and this information will be used to inform and guide therapy. MPN is particularly amenable to precision medicine strategies and our increased understanding of the evolution of MPN from normal blood stem cells provides a unique opportunity for early therapeutic intervention approaches and potentially MPN prevention strategies.

PMID:39633553 | DOI:10.3324/haematol.2023.283951

EMBO Rep. 2024 Dec 4. doi: 10.1038/s44319-024-00335-y. Online ahead of print.

ABSTRACT

Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling governs cell lineage identity is often missing. Here, leveraging prostate organoid technology, we show that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and specification of prostatic lumen. RA-dependent RARγ activation promotes the expression of Foxa1, which synergizes with the androgen pathway for luminal expansion, cytoarchitecture and function. FOXA1 mutations are common in prostate and breast cancers, though their pathogenic mechanism is incompletely understood. Combining functional genetics with structural modeling of FOXA1 folding and chromatin binding analyses, we discover that FOXA1F254E255 is a loss-of-function mutation compromising its transcriptional function and luminal fate commitment of prostate progenitors. Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

PMID:39633177 | DOI:10.1038/s44319-024-00335-y

Nature. 2024 Dec 4. doi: 10.1038/s41586-024-08308-w. Online ahead of print.

ABSTRACT

A central question in biology is how macromolecular machines function cooperatively. In bacteria, transcription and translation occur in the same cellular compartment, and can be physically and functionally coupled1-4. Although high-resolution structures of the ribosome-RNA polymerase (RNAP) complex have provided initial mechanistic insights into the coupling process5-10, we lack knowledge of how these structural snapshots are placed along a dynamic reaction trajectory. Here we reconstitute a complete and active transcription-translation system and develop multi-colour single-molecule fluorescence microscopy experiments to directly and simultaneously track transcription elongation, translation elongation and the physical and functional coupling between the ribosome and the RNAP in real time. Our data show that physical coupling between ribosome and RNAP can occur over hundreds of nucleotides of intervening mRNA by mRNA looping, a process facilitated by NusG. We detect active transcription elongation during mRNA looping and show that NusA-paused RNAPs can be activated by the ribosome by long-range physical coupling. Conversely, the ribosome slows down while colliding with the RNAP. We hereby provide an alternative explanation for how the ribosome can efficiently rescue RNAP from frequent pausing without requiring collisions by a closely trailing ribosome. Overall, our dynamic data mechanistically highlight an example of how two central macromolecular machineries, the ribosome and RNAP, can physically and functionally cooperate to optimize gene expression.

PMID:39633055 | DOI:10.1038/s41586-024-08308-w

Nature. 2024 Dec 4. doi: 10.1038/s41586-024-08285-0. Online ahead of print.

ABSTRACT

Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.

PMID:39633048 | DOI:10.1038/s41586-024-08285-0

Commun Biol. 2024 Dec 4;7(1):1615. doi: 10.1038/s42003-024-07302-2.

ABSTRACT

The human lung is confronted daily with thousands of microbial invaders reaching the lower respiratory tract. An efficient response by the resident type 1 and type 2 alveolar epithelial cells (AECs) and alveolar macrophages (AMs) cells during the early hours of innate immunity is a prerequisite to maintain a non-inflammatory state, but foremost to rapidly remove harmful substances. One such human-pathogenic invader is the opportunistic fungus Aspergillus fumigatus. If the spherical conidia are not cleared in time, they swell reaching approximately twice of their initial size and germinate to develop hyphae around six hours post-infection. This process of morphological change is crucial as it enables the pathogen to invade the alveolar epithelium and to reach the bloodstream, but also makes it conspicuous for the immune system. During this process, conidia are first in contact with AECs then with migrating AMs, both attempting to internalize and clear the fungus. However, the relative contribution of AMs and AECs to uptake of A. fumigatus remains an open question, especially the capabilities of the barely investigated type 1 AECs. In this study, we present a bottom-up modeling approach to incorporate experimental data on the dynamic increase of the conidial diameter and A. fumigatus uptake by AECs and AMs in a hybrid agent-based model (hABM) for the to-scale simulation of virtual infection scenarios in the human alveolus. By screening a wide range of parameters, we found that type 1 AECs, which cover approximately 95% of the alveolar surface, are likely to have a greater impact on uptake than type 2 AECs. Moreover, the majority of infection scenarios across the regime of tested parameters were cleared through uptake by AMs, whereas the contribution to conidial uptake by AECs was observed to be limited, indicating that their crucial support might mostly consist in mediating chemokine secretion for AM recruitment. Regardless, as the first host cell being confronted with A. fumigatus conidia, our results evidence the large potential impact of type 1 AECs antimicrobial activities, underlining the requirement of increasing experimental efforts on this alveolar constituent.

PMID:39632928 | DOI:10.1038/s42003-024-07302-2

Nat Commun. 2024 Dec 4;15(1):10564. doi: 10.1038/s41467-024-54724-x.

ABSTRACT

A major event in vertebrate evolution was the separation of the skull from the pectoral girdle and the acquisition of a functional neck, transitions that required profound developmental rearrangements of the musculoskeletal system. The neck is a hallmark of the tetrapod body plan and allows for complex head movements on land. While head and trunk muscles arise from distinct embryonic mesoderm populations, the origins of neck muscles remain elusive. Here, we combine comparative embryology and anatomy to reconstruct the mesodermal contribution to neck evolution. We demonstrate that head/trunk-connecting muscle groups have conserved mesodermal origins in fishes and tetrapods and that the neck evolved from muscle groups present in fishes. We propose that expansions of mesodermal populations into head and trunk domains during embryonic development underpinned the emergence and adaptation of the tetrapod neck. Our results provide evidence for the exaptation of archetypal muscle groups in ancestral fishes, which were co-opted to acquire novel functions adapted to a terrestrial lifestyle.

PMID:39632846 | DOI:10.1038/s41467-024-54724-x

Epigenomics. 2024 Dec 5:1-16. doi: 10.1080/17501911.2024.2435244. Online ahead of print.

ABSTRACT

AIMS: Epigenomics has significantly advanced through the incorporation of Systems Biology approaches. This study aims to investigate the human lysine methylome as a system, using a data-science approach to reveal its emergent properties, particularly focusing on histone mimicry and the broader implications of lysine methylation across the proteome.

METHODS: We employed a data-science-driven OMICS approach, leveraging high-dimensional proteomic data to study the lysine methylome. The analysis focused on identifying sequence-based recognition motifs of lysine methyltransferases and evaluating the prevalence and distribution of lysine methylation across the human proteome.

RESULTS: Our analysis revealed that lysine methylation impacts 15% of the known proteome, with a notable bias toward mono-methylation. We identified sequence-based recognition motifs of 13 lysine methyltransferases, highlighting candidates for histone mimicry. These findings suggest that the selective inhibition of individual lysine methyltransferases could have systemic effects rather than merely targeting histone methylation.

CONCLUSIONS: The lysine methylome has significant mechanistic value and should be considered in the design and testing of therapeutic strategies, particularly in precision oncology. The study underscores the importance of considering non-histone proteins involved in DNA damage and repair, cell signaling, metabolism, and cell cycle pathways when targeting lysine methyltransferases.

PMID:39632680 | DOI:10.1080/17501911.2024.2435244

Genome Res. 2024 Dec 4. doi: 10.1101/gr.279025.124. Online ahead of print.

ABSTRACT

Growing evidence suggests that somatic mutations may be a major cause of the aging process. However, it remains to be tested whether the predictions of the theory also apply to species with longer life spans than humans. Hydra is a genus of freshwater polyps with remarkable regeneration abilities and a potentially unlimited life span under laboratory conditions. By genome sequencing of single cells and whole animals, we found that the mutation rates in Hydra's stem cells are even slightly higher than in humans or mice. A potential explanation for this deviation from the prediction of the theory may lie in the adaptability offered by a higher mutation rate, as we were able to show that the genome of the widely studied Hydra magnipapillata strain 105 has undergone a process of strong positive selection since the strain's cultivation 50 years ago. This most likely represents a rapid adaptation to the drastically altered environmental conditions associated with the transition from the wild to laboratory conditions. Processes under positive selection in captive animals include pathways associated with Hydra's simple nervous system, its nucleic acid metabolic process, cell migration, and hydrolase activity.

PMID:39632086 | DOI:10.1101/gr.279025.124

Cell Struct Funct. 2024 Dec 4. doi: 10.1247/csf.24065. Online ahead of print.

ABSTRACT

The cellular slime mold Dictyostelium discoideum, a member of the Amoebozoa, has been extensively studied in cell and developmental biology. D. discoideum is unique in that they are genetically tractable, with a wealth of data accumulated over half a century of research. Fluorescence live-cell imaging of D. discoideum has greatly facilitated studies on fundamental topics, including cytokinesis, phagocytosis, and cell migration. Additionally, its unique life cycle places Dictyostelium at the forefront of understanding aggregative multicellularity, a recurring evolutionary trait found across the Opisthokonta and Amoebozoa clades. The use of multiple fluorescent proteins (FP) and labels with separable spectral properties is critical for tracking cells in aggregates and identifying co-occurring biomolecular events and factors that underlie the dynamics of the cytoskeleton, membrane lipids, second messengers, and gene expression. However, in D. discoideum, the number of frequently used FP species is limited to two or three. In this study, we explored the use of new-generation FP for practical 4- to 5-color fluorescence imaging of D. discoideum. We showed that the yellow fluorescent protein Achilles and the red fluorescent protein mScarlet-I both yield high signals and allow sensitive detection of rapid gene induction. The color palette was further expanded to include blue (mTagBFP2 and mTurquosie2), large Stoke-shift LSSmGFP, and near-infrared (miRFP670nano3) FPs, in addition to the HaloTag ligand SaraFluor 650T. Thus, we demonstrated the feasibility of deploying 4- and 5- color imaging of D. discoideum using conventional confocal microscopy.Key words: fluorescence imaging, organelle, cytoskeleton, small GTPase, Dictyostelium.

PMID:39631875 | DOI:10.1247/csf.24065

Br J Pharmacol. 2024 Dec 4. doi: 10.1111/bph.17395. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Gene regulation is frequently altered in diseases in unique and patient-specific ways. Hence, personalised strategies have been proposed to infer patient-specific gene-regulatory networks. However, existing methods do not scale well because they often require recomputing the entire network per sample. Moreover, they do not account for clinically important confounding factors such as age, sex or treatment history. Finally, a user-friendly implementation for the analysis and interpretation of such networks is missing.

EXPERIMENTAL APPROACH: We present DysRegNet, a method for inferring patient-specific regulatory alterations (dysregulations) from bulk gene expression profiles. We compared DysRegNet to the well-known SSN method, considering patient clustering, promoter methylation, mutations and cancer-stage data.

KEY RESULTS: We demonstrate that both SSN and DysRegNet produce interpretable and biologically meaningful networks across various cancer types. In contrast to SSN, DysRegNet can scale to arbitrary sample numbers and highlights the importance of confounders in network inference, revealing an age-specific bias in gene regulation in breast cancer. DysRegNet is available as a Python package (https://github.com/biomedbigdata/DysRegNet_package), and analysis results for 11 TCGA cancer types are available through an interactive web interface (https://exbio.wzw.tum.de/dysregnet).

CONCLUSION AND IMPLICATIONS: DysRegNet introduces a novel bioinformatics tool enabling confounder-aware and patient-specific network analysis to unravel regulatory alteration in complex diseases.

PMID:39631757 | DOI:10.1111/bph.17395

Mar Environ Res. 2024 Nov 28;204:106859. doi: 10.1016/j.marenvres.2024.106859. Online ahead of print.

ABSTRACT

Extreme climate events, such as marine heatwaves (MHWs), are expected to occur more frequently and intensely in the future, resulting in a substantial impact on marine life. The way that diatoms respond to MHWs may have crucial effects on global primary production and biogeochemical cycles. Euplanktonic diatoms appear to benefit from MHWs directly, but this phenomenon needs an explanation. As concerns tychoplanktonic and benthic diatoms, no studies have been addressed on their thermal response strategies. To address this, we investigated the responses and underlying mechanisms of three typical growth forms of diatoms, Pseudo-nitzschia multiseries (euplanktonic), Paralia guyana (tychoplanktonic) and Navicula avium (benthic), under heat stress by combining a growth experiment with transcriptomic analysis. Our results showed that the physiological responses of diatoms to MHWs and underlying molecular mechanisms are largely related to their growth forms. The euplanktonic diatom was first depressed, but then had a distinct increase in the growth rate accompanied by inducing zeatin and unsaturated fatty acid biosynthesis and repressing substance assimilation and energy metabolism. Contrarily, the benthic diatom showed elevated substance and energy demands for macromolecules accumulation by reducing cell division and increasing photosynthesis and nitrogen assimilation. The tychoplanktonic diatom exhibited higher physiological plasticity to maintain growth and cellular homeostasis. Our results indicate the increased rate of cell division in euplanktonic diatoms under heat stress is likely an emergency response strategy promoting diatom dispersal for survival, but at the cost of disturbances of metabolic balance.

PMID:39631319 | DOI:10.1016/j.marenvres.2024.106859

JMIR Form Res. 2024 Dec 4;8:e57312. doi: 10.2196/57312.

ABSTRACT

BACKGROUND: Given the multifactorial nature of type 2 diabetes (T2D), health care for this condition would benefit from a holistic approach and multidisciplinary consultation. To address this, we developed the web-based 360-degree (360°) diagnostic tool, which assesses 4 key domains: "body" (physical health parameters), "thinking and feeling" (eg, mental health and stress), "behavior" (lifestyle factors), and "environment" (eg, work and housing conditions).

OBJECTIVE: This work examines the acceptability, implementation, and potential effects of the 360° diagnostic tool and subsequent tailored treatment (360° approach) in a 6-month intervention and feasibility study conducted in standard primary health care settings in the Netherlands.

METHODS: A single-group design with baseline, 3-month, and 6-month follow-ups was used. A total of 15 people with T2D and their health care providers from 2 practices participated in a 6-month intervention, which included the 360° diagnosis, tailored treatment, and both individual and group consultations. The 360° diagnosis involved clinical measurements for the "body" domain and self-reports for the "thinking and feeling," "behavior," and "environment" domains. After multidisciplinary consultations involving the general practitioner, pharmacist, nurse practitioner (NP), and dietitian, the NP and dietitian provided tailored advice, lifestyle treatment, and ongoing support. At the end of the intervention, face-to-face semistructured interviews were conducted with health care professionals (n=6) and participants (n=13) to assess the acceptability and implementation of the 360° approach in primary health care. Additionally, data from 14 participants on the "thinking and feeling" and "behavior" domains at baseline, 3 months, and 6 months were analyzed to assess changes over time.

RESULTS: The semistructured interviews revealed that both participants with T2D and health care professionals were generally positive about various aspects of the 360° approach, including onboarding, data collection with the 360° diagnosis, consultations and advice from the NP and dietitian, the visual representation of parameters in the profile wheel, counseling during the intervention (including professional collaboration), and the group meetings. The interviews also identified factors that promoted or hindered the implementation of the 360° approach. Promoting factors included (1) the care, attention, support, and experience of professionals; (2) the multidisciplinary team; (3) social support; and (4) the experience of positive health effects. Hindering factors included (1) too much information, (2) survey-related issues, and (3) time-consuming counseling. In terms of effects over time, improvements were observed at 3 months in mental health, diabetes-related problems, and fast-food consumption. At 6 months, there was a reduction in perceived stress and fast-food consumption. Additionally, fruit intake decreased at both 3 and 6 months.

CONCLUSIONS: Our findings suggest that the 360° approach is acceptable to both people with T2D and health care professionals, implementable, and potentially effective in fostering positive health changes. Overall, it appears feasible to implement the 360° approach in standard primary health care.

TRIAL REGISTRATION: Netherlands Trial Register NL-7509/NL-OMON45788; https://onderzoekmetmensen.nl/nl/trial/45788.

PMID:39631068 | DOI:10.2196/57312

Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2407497121. doi: 10.1073/pnas.2407497121. Epub 2024 Dec 4.

ABSTRACT

Cortical condensates, transient punctate-like structures rich in actin and the actin nucleation pathway member Neural Wiskott-Aldrich syndrome protein (N-WASP), form during activation of the actin cortex in the Caenorhabditis elegans oocyte. Their emergence and spontaneous dissolution is linked to a phase separation process driven by chemical kinetics. However, the mechanisms that drive the onset of cortical condensate formation near membranes remain unexplored. Here, using a reconstituted phase separation assay of cortical condensate proteins, we demonstrate that the key component, N-WASP, can collectively undergo surface condensation on supported lipid bilayers via a prewetting transition. Actin partitions into the condensates, where it polymerizes and counteracts the N-WASP prewetting transition. Taken together, the dynamics of condensate-assisted cortex formation appear to be controlled by a balance between surface-assisted condensate formation and polymer-driven condensate dissolution. This opens perspectives for understanding how the formation of complex intracellular structures is affected and controlled by phase separation.

PMID:39630867 | DOI:10.1073/pnas.2407497121

Nucleosides Nucleotides Nucleic Acids. 2024 Dec 4:1-16. doi: 10.1080/15257770.2024.2436421. Online ahead of print.

ABSTRACT

Breast cancer is a heterogeneous disease that is ranked as one of the most common cancers worldwide. Currently, although there are existing molecules such as progesterone receptor and estrogen receptor for breast cancer treatment, discovering more effective drug targets is still in urgent need. In this study, we have obtained six sequencing datasets of breast cancer from GEO database and identified a set of differentially expressed molecules, including 67 miRNAs and 133 genes. Function enrichment analysis by miRPathDB database indicated that targets of 11 miRNAs could be enriched in breast cancer pathway with a p-value ≤ .05. A special miRNA-gene interaction network was constructed for analysis of the progression of breast cancer. We then ranked the importance of each molecule (i.e. miRNA and gene) by their node centrality indexes in the network and selected the top 10% of molecules. The statistical analysis of these molecules showed three miRNAs (hsa-miR-1275, hsa-miR-2392, hsa-miR-3141) have significant effects on the prognosis and survival of patients. By searching for potential drugs in Drugbank database, we have identified four candidates (phenethyl isothiocyanate, amuvatinib, theophylline, trifluridine) for targeting these genes. In conclusion, we believe that these drugs and their analogs could be used in the targeted therapy of breast cancer in the future.

PMID:39630693 | DOI:10.1080/15257770.2024.2436421

Mol Biol Cell. 2024 Dec 4:mbcE24060285. doi: 10.1091/mbc.E24-06-0285. Online ahead of print.

ABSTRACT

Bone is a frequent site for breast cancer metastasis. The vast majority of breast cancer-associated metastasis is osteolytic in nature, and RANKL (receptor activator for nuclear factor κB)-induced differentiation of bone marrow-derived macrophages (BMDMs) to osteoclasts (OCLs) is a key requirement for osteolytic metastatic growth of cancer cells. In this study, we demonstrate that Myocardin-related transcription factor (MRTF) in breast cancer cells plays an important role in paracrine modulation of RANKL-induced osteoclast differentiation. This is partly attributed to MRTF's critical role in maintaining the basal cellular expression of connective tissue growth factor (CTGF), findings that align with a strong positive correlation between CTGF expression and MRTF-A gene signature in the human disease context. Luminex analyses reveal that MRTF depletion in breast cancer cells has a broad impact on OCL-regulatory cell-secreted factors that extend beyond CTGF. Experimental metastasis studies demonstrate that MRTF depletion diminishes OCL abundance and bone colonization breast cancer cells in vivo, suggesting that MRTF inhibition could be an effective strategy to diminish OCL formation and skeletal involvement in breast cancer. In summary, this study highlights a novel tumor-extrinsic function of MRTF relevant to breast cancer metastasis.

PMID:39630611 | DOI:10.1091/mbc.E24-06-0285

Interdiscip Sci. 2024 Dec 4. doi: 10.1007/s12539-024-00672-5. Online ahead of print.

ABSTRACT

Computational systems biology employs computational algorithms and integrates diverse data sources, such as gene expression profiles, molecular interactions, and network modeling, to identify promising drug candidates through repurposing existing compounds in response to urgent healthcare needs. This study tackles the urgent need for rapid therapeutic development against emerging infectious diseases. We introduce a novel analytic expression for sensitivity analysis based on the Kronecker product and enhance model prediction performance using Graph Convolutional Networks (GCNs) with sensitivity-based graph reduction. Our algorithm refines prediction performance by leveraging sensitivity-based graph reduction. By integrating RNA-seq data, molecular interactions, and GCNs, we identify disease-related genes and pathways, construct heterogeneous graph models, and predict potential drugs. This approach involves novel analytical expressions that assess sensitivity to model loss, employing the Kronecker product approach. Subgraph analysis identifies nodes for removal, leading to a refined graph used for model retraining. This cost-effective pipeline focuses on computational methods for drug repurposing, targeting infectious diseases such as Zika virus and COVID-19 infection. Applied to these infections, our methodology integrates 659 proteins and 703 drugs for Zika virus, and 495 proteins and 468 drugs for COVID-19, along with their interactions derived from gene expression profiles. Top candidate drugs, such as Betamethasone phosphate and Bizelesin for Zika virus, and Chloroquine, Heparin Disaccharide, and Resveratrol for COVID-19, were validated through literature review or docking analysis. This scalable approach demonstrates promise in repurposing drugs for urgent healthcare challenges.

PMID:39630350 | DOI:10.1007/s12539-024-00672-5

Transplantation. 2024 Dec 3. doi: 10.1097/TP.0000000000005258. Online ahead of print.

ABSTRACT

BACKGROUND: Proteomic phenotyping can provide insights into rejection pathophysiology, novel biomarkers, and therapeutic targets.

METHODS: Within the prospective, multicenter Genomic Research Alliance for Transplantation study, 181 proteins were evaluated from blood drawn at the time of endomyocardial biopsy; protein fold change, logistic regression, and pathway analyses were conducted, with protein discovery adjusted for a 5% false discovery rate.

RESULTS: Among 104 adult heart transplant patients (31% female sex, 53% Black race, median age 52 y), 74 had no rejection, 18 developed acute cellular rejection (ACR), and 12 developed antibody-mediated rejection (AMR). Differential expression was found in 2 proteins during ACR (inflammatory proteins CXCL10 and CD5) and 73 proteins during AMR. The most abundant AMR proteins were the heart failure biomarkers N-terminal pro-B-type natriuretic peptide and suppression of tumorigenicity 2. In univariate logistic regression, odds of identifying ACR on endomyocardial biopsy increased with doubling of CXCL10 (odds ratio [OR] 2.2 [95% confidence interval (CI), 1.3-3.6]) and CD5 (OR 4.7 [95% CI, 1.7-12.9]) concentrations, and odds of AMR increased with doubling of N-terminal pro-B-type natriuretic peptide (OR 13.0 [95% CI, 2.7-62.7) and suppression of tumorigenicity 2 (OR 4.8 [95% CI, 2.1-10.7]) concentrations. After multivariable analysis with clinical covariates, these proteins showed similar odds of ACR or AMR on biopsy. Pathway analysis identified T cell-receptor signaling and cell differentiation as key pathways in ACR and cardiovascular disease and cell turnover in AMR.

CONCLUSIONS: Proteomic analysis reveals unique biomarkers and biological pathway expression in ACR and AMR. Cardiac injury-associated biomarkers were more pronounced in AMR, whereas inflammatory biomarkers were more pronounced in ACR. Proteomic analysis may provide insights into rejection pathophysiology, detection, and therapy.

PMID:39630098 | DOI:10.1097/TP.0000000000005258

Essays Biochem. 2024 Dec 4;68(4):555-578. doi: 10.1042/EBC20240106.

ABSTRACT

Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PG) consist of a core protein to which the glycosaminoglycan (GAG) chains, HS or CS, are attached through a common linker tetrasaccharide. In the extracellular space, they are involved in the regulation of cell communication, assuring development and homeostasis. The HSPG biosynthetic pathway has documented 51 genes, with many diseases associated to defects in some of them. The phenotypic consequences of this genetic variation in humans, and of genetic ablation in mice, and their expression patterns, led to a phenotypically centered HSPG biosynthetic pathway model. In this model, HS sequences produced by ubiquitous NDST1, HS2ST and HS6ST enzymes are essential for normal development and homeostasis, whereas tissue restricted HS sequences produced by the non-ubiquitous NDST2-4, HS6ST2-3, and HS3ST1-6 enzymes are involved in adaptative behaviors, cognition, tissue responsiveness to stimuli, and vulnerability to disease. The model indicates that the flux through the HSPG/CSPG pathways and its diverse branches is regulated by substrate preferences and protein-protein-interactions. This results in a privileged biosynthesis of HSPG over that of CSPGs, explaining the phenotypes of linkeropathies, disease caused by defects in genes involved in the biosynthesis of the common tetrasaccharide linker. Documented feedback loops whereby cells regulate HS sulfation, and hence the interactions of HS with protein partners, may be similarly implemented, e.g., protein tyrosine sulfation and other posttranslational modifications in enzymes of the HSPG pathway. Together, ubiquitous HS, specialized HS, and their biosynthesis model can facilitate research for a better understanding of HSPG roles in physiology and pathology.

PMID:39630030 | DOI:10.1042/EBC20240106