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Nucleic Acids Research Jun 2024Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates...
Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.
PubMed: 38932701
DOI: 10.1093/nar/gkae547 -
Advanced Science (Weinheim,... Jun 2024Genetic and epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor...
Genetic and epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. It is uncovered that rs339331 resides in a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy. RFX6, an AR-regulated gene linked to rs339331, exhibits synergistic prognostic value for PCa recurrence and metastasis. This comprehensive in vitro and in vivo studies demonstrate the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) and modulating the TGFβ/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores enzalutamide sensitivity in resistant PCa cells and tumors. This findings reveal a complex interplay of genetic and epigenetic mechanisms in PCa pathogenesis and drug resistance, centered around disrupted prostate lineage AR signaling and abnormal RFX6 expression.
PubMed: 38932472
DOI: 10.1002/advs.202401492 -
Viruses Jun 2024Oncolytic virotherapy, using viruses such as vesicular stomatitis virus (VSVΔ51) and Herpes Simplex Virus-1 (HSV-1) to selectively attack cancer cells, faces challenges...
Oncolytic virotherapy, using viruses such as vesicular stomatitis virus (VSVΔ51) and Herpes Simplex Virus-1 (HSV-1) to selectively attack cancer cells, faces challenges such as cellular resistance mediated by the interferon (IFN) response. Dimethyl fumarate (DMF) is used in the treatment of multiple sclerosis and psoriasis and is recognized for its anti-cancer properties and has been shown to enhance both VSVΔ51 and HSV-1 oncolytic activity. Tepilamide fumarate (TPF) is a DMF analog currently undergoing clinical trials for the treatment of moderate-to-severe plaque psoriasis. The aim of this study was to evaluate the potential of TPF in enhancing the effectiveness of oncolytic viruses. In vitro, TPF treatment rendered 786-0 carcinoma cells more susceptible to VSVΔ51 infection, leading to increased viral replication. It outperformed DMF in both increasing viral infection and increasing the killing of these resistant cancer cells and other cancer cell lines tested. Ex vivo studies demonstrated TPF's selective boosting of oncolytic virus infection in cancer cells without affecting healthy tissues. Effectiveness was notably high in pancreatic and ovarian tumor samples. Our study further indicates that TPF can downregulate the IFN pathway through a similar mechanism to DMF, making resistant cancer cells more vulnerable to viral infection. Furthermore, TPF's impact on gene therapy was assessed, revealing its ability to enhance the transduction efficiency of vectors such as lentivirus, adenovirus type 5, and adeno-associated virus type 2 across various cell lines. This data underscore TPF's potential role in not only oncolytic virotherapy but also in the broader application of gene therapy. Collectively, these findings position TPF as a promising agent in oncolytic virotherapy, warranting further exploration of its therapeutic potential.
Topics: Humans; Oncolytic Virotherapy; Cell Line, Tumor; Oncolytic Viruses; Virus Replication; Fumarates; Neoplasms; Dimethyl Fumarate; Herpesvirus 1, Human
PubMed: 38932212
DOI: 10.3390/v16060920 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Efforts have been made to improve the therapeutic efficiency of tumor treatments, and metal-organic frameworks (MOFs) have shown excellent potential in tumor therapy....
Efforts have been made to improve the therapeutic efficiency of tumor treatments, and metal-organic frameworks (MOFs) have shown excellent potential in tumor therapy. Monotherapy for the treatment of tumors has limited effects due to the limitation of response conditions and inevitable multidrug resistance, which seriously affect the clinical therapeutic effect. In this study, we chose to construct a multiple cascade synergistic tumor drug delivery system MIL-101(Fe)-DOX-TCPP-MnO@PDA-Ag (MDTM@P-Ag) using MOFs as drug carriers. Under near-infrared (NIR) laser irradiation, 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) and Ag NPs loaded on MDTM@P-Ag can be activated to generate cytotoxic reactive oxygen species (ROS) and achieve photothermal conversion, thus effectively inducing the apoptosis of tumor cells and achieving a combined photodynamic/photothermal therapy. Once released at the tumor site, manganese dioxide (MnO) can catalyze the decomposition of hydrogen peroxide (HO) in the acidic microenvironment of the tumor to generate oxygen (O) and alleviate the hypoxic environment of the tumor. Fe/Mn will mediate a Fenton/Fenton-like reaction to generate cytotoxic hydroxyl radicals (·OH), while depleting the high concentration of glutathione (GSH) in the tumor, thus enhancing the chemodynamic therapeutic effect. The successful preparation of the tumor drug delivery system and its good synergistic chemodynamic/photodynamic/photothermal therapeutic effect in tumor treatment can be demonstrated by the experimental results of material characterization, performance testing and in vitro experiments.
PubMed: 38931479
DOI: 10.3390/ph17060812 -
Nutrients Jun 2024, a polyphenol-rich plant, holds potential for improving inflammation, but its mechanisms are not well understood. Therefore, this study employed network pharmacology...
, a polyphenol-rich plant, holds potential for improving inflammation, but its mechanisms are not well understood. Therefore, this study employed network pharmacology and molecular docking to explore the mechanism by which ameliorates inflammation. In this study, 29 kinds of active ingredients were obtained via data mining. Five main active components were screened out for improving inflammation, which were flemichin D, naringenin, chrysophanol, genistein and orobol. In total, 52 core targets were identified, including AKT serine/threonine kinase 1 (AKT1), tumor necrosis factor (TNF), B-cell lymphoma-2 (BCL2), serum albumin (ALB), and estrogen receptor 1 (ESR1). Gene ontology (GO) enrichment analysis identified 2331 entries related to biological processes, 98 entries associated with cellular components, and 203 entries linked to molecular functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis yielded 149 pathways, including those involved in EGFR tyrosine kinase inhibitor resistance, endocrine resistance, and the PI3K-Akt signaling pathway. Molecular docking results showed strong binding effects between the main active components and the core targets, with binding energies less than -5 kcal/mol. In summary, this study preliminarily elucidated the underlying mechanisms by which , through a multi-component, multi-target, and multi-pathway approach, ameliorates inflammation. This provides a theoretical foundation for the subsequent application of in inflammation amelioration.
Topics: Molecular Docking Simulation; Network Pharmacology; Inflammation; Humans; Signal Transduction; Fabaceae; Anti-Inflammatory Agents; Proto-Oncogene Proteins c-akt; Plant Extracts
PubMed: 38931205
DOI: 10.3390/nu16121850 -
Microorganisms Jun 2024In the European Union, salmonellosis is one of the most important zoonoses reported. Poultry meat and egg products are the most common food matrices associated with...
In the European Union, salmonellosis is one of the most important zoonoses reported. Poultry meat and egg products are the most common food matrices associated with presence. Moreover, wild and domestic animals could represent an important reservoir that could favour the direct and indirect transmission of pathogens to humans. spp. can infect carnivorous or omnivorous wild birds that regularly ingest food and water exposed to faecal contamination. Birds kept in captivity can act as reservoirs of spp. following ingestion of infected prey or feed. In this paper, we describe the isolation of different serovars in several species of raptors hosted in aviaries in an Italian wildlife centre and in the raw chicken necks used as their feed but intended for human consumption. Characterisations of strains were carried out by integrating classical methods and whole genome sequencing analysis. The strains of isolated in poultry meat and birds belonged to the same cluster, with some of them being multidrug-resistant (MDR) and carrying the Col(pHAD28) plasmid-borne (fluoro)quinolone resistance gene, thus confirming the source of infection. Differently, the found in feed and raptors were all MDR, carried a plasmid of emerging (pESI)-like plasmid and belonged to different clusters, possibly suggesting a long-lasting infection or the presence of additional undetected sources. Due to the high risk of fuelling a reservoir of human pathogens, the control and treatment of feed for captive species are crucial.
PubMed: 38930551
DOI: 10.3390/microorganisms12061169 -
Materials (Basel, Switzerland) Jun 2024Following publication [...].
Following publication [...].
PubMed: 38930414
DOI: 10.3390/ma17122841 -
Medicina (Kaunas, Lithuania) May 2024: Enterococci are typically found in a healthy human gastrointestinal tract but can cause severe infections in immunocompromised patients. Such infections are treated...
: Enterococci are typically found in a healthy human gastrointestinal tract but can cause severe infections in immunocompromised patients. Such infections are treated with antibiotics. This study addresses the rising concern of antimicrobial resistance (AMR) in Enterococci, focusing on the prevalence of vancomycin-resistant enterococcus (VRE) strains. : The pilot study involved 140 Enterococci isolates collected between 2021 and 2022 from two multidisciplinary hospitals (with and without local therapeutic drug monitoring protocol of vancomycin) in Latvia. Microbiological assays and whole genome sequencing were used. AMR gene prevalence with resistance profiles were determined and the genetic relationship and outbreak evaluation were made by applying core genome multi-locus sequence typing (cgMLST). : The acquired genes and mutations were responsible for resistance against 10 antimicrobial classes, including 25.0% of isolates expressing resistance to vancomycin, predominantly of the B type. Genetic diversity among and isolates was observed and seven potential outbreak clusters were identified, three of them containing sequence types ST6, ST78 and ST80. The prevalence of vancomycin resistance was highest in the hospital without a therapeutic drug-monitoring protocol and in . Notably, a case of linezolid resistance due to a mutation was documented. : The study illustrates the concerning prevalence of multidrug-resistant Enterococci in Latvian hospitals, showcasing the rather widespread occurrence of vancomycin-resistant strains. This highlights the urgency of implementing efficient infection control mechanisms and the need for continuous VRE surveillance in Latvia to define the scope and pattern of the problem, influencing clinical decision making and planning further preventative measures.
Topics: Humans; Latvia; Anti-Bacterial Agents; Pilot Projects; Enterococcus; Microbial Sensitivity Tests; Gram-Positive Bacterial Infections; Vancomycin-Resistant Enterococci; Drug Resistance, Bacterial; Multilocus Sequence Typing; Whole Genome Sequencing
PubMed: 38929467
DOI: 10.3390/medicina60060850 -
International Journal of Molecular... Jun 2024Triple-negative breast cancer (TNBC) patients are treated with traditional chemotherapy, such as the taxane class of drugs. One such drug, paclitaxel (PTX), can be...
Triple-negative breast cancer (TNBC) patients are treated with traditional chemotherapy, such as the taxane class of drugs. One such drug, paclitaxel (PTX), can be effective in treating TNBC; however, many tumors will develop drug resistance, which can lead to recurrence. In order to improve patient outcomes and survival, there lies a critical need to understand the mechanism behind drug resistance. Our lab made the novel observation that decreased expression of the Adenomatous Polyposis Coli (APC) tumor suppressor using shRNA caused PTX resistance in the human TNBC cell line MDA-MB-157. In cells lacking APC, induction of apoptosis by PTX was decreased, which was measured through cleaved caspase 3 and annexin/PI staining. The current study demonstrates that CRISPR-mediated APC knockout in two other TNBC lines, MDA-MB-231 and SUM159, leads to PTX resistance. In addition, the cellular consequences and molecular mechanisms behind APC-mediated PTX response have been investigated through analysis of the BCL-2 family of proteins. We found a significant increase in the tumor-initiating cell population and increased expression of the pro-survival family member Bcl-2, which is widely known for its oncogenic behavior. ABT-199 (Venetoclax), is a BH3 mimetic that specifically targets Bcl-2. ABT-199 has been used as a single or combination therapy in multiple hematologic malignancies and has shown promise in multiple subtypes of breast cancer. To address the hypothesis that APC-induced Bcl-2 increase is responsible for PTX resistance, we combined treatment of PTX and ABT-199. This combination treatment of CRISPR-mediated APC knockout MDA-MB-231 cells resulted in alterations in apoptosis, suggesting that Bcl-2 inhibition restores PTX sensitivity in APC knockout breast cancer cells. Our studies are the first to show that Bcl-2 functional inhibition restores PTX sensitivity in APC mutant breast cancer cells. These studies are critical to advance better treatment regimens in patients with TNBC.
Topics: Humans; Drug Resistance, Neoplasm; Cell Line, Tumor; Triple Negative Breast Neoplasms; Proto-Oncogene Proteins c-bcl-2; Apoptosis; Female; Adenomatous Polyposis Coli Protein; Gene Expression Regulation, Neoplastic; Sulfonamides; Paclitaxel; Up-Regulation; Taxoids; Bridged-Ring Compounds; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 38928449
DOI: 10.3390/ijms25126745 -
Cancers Jun 2024The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several... (Review)
Review
The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer's mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular.
PubMed: 38927964
DOI: 10.3390/cancers16122259