RESUMEN
Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.
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Inmunoterapia , Neoplasias , Transducción de Señal , Esfingolípidos , Factor de Necrosis Tumoral alfa , Humanos , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/patología , Esfingolípidos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacosRESUMEN
Copper is an important metal micronutrient, required for the balanced growth and normal physiological functions of human organism. Copper-related toxicity and dysbalanced metabolism were associated with the disruption of intracellular respiration and the development of various diseases, including cancer. Notably, copper-induced cell death was defined as cuproptosis which was also observed in malignant cells, representing an attractive anti-cancer instrument. Excess of intracellular copper leads to the aggregation of lipoylation proteins and toxic stress, ultimately resulting in the activation of cell death. Differential expression of cuproptosis-related genes was detected in normal and malignant tissues. Cuproptosis-related genes were also linked to the regulation of oxidative stress, immune cell responses, and composition of tumor microenvironment. Activation of cuproptosis was associated with increased expression of redox-metabolism-regulating genes, such as ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoyltransferase 1 (LIPT1), dihydrolipoamide dehydrogenase (DLD), drolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), and pyruvate dehydrogenase E1 subunit beta (PDHB)). Accordingly, copper-activated network was suggested as an attractive target in cancer therapy. Mechanisms of cuproptosis and regulation of cuproptosis-related genes in different cancers and tumor microenvironment are discussed in this study. The analysis of current findings indicates that therapeutic regulation of copper signaling, and activation of cuproptosis-related targets may provide an effective tool for the improvement of immunotherapy regimens.
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Muerte Celular , Cobre , Inmunoterapia , Oxidación-Reducción , Humanos , Cobre/metabolismo , Neoplasias Torácicas/patología , Neoplasias Torácicas/genética , AnimalesRESUMEN
BACKGROUND: The latest update to the Australian adenoma surveillance guideline in 2018 introduced a novel risk stratification system with updated surveillance recommendations. The resource implications of adopting this new system are unclear. AIMS: To quanitfy the resource demands of adopting new over old adenoma surveillance guidelines. METHODS: We studied data from 2443 patients undergoing colonoscopies, in which a clinically significant lesion was identified in their latest, or previous procedure(s) across five Australian hospitals. We excluded procedures with inflammatory bowel disease, new or prior history of colorectal cancer or resection, inadequate bowel preparation and incomplete procedures. Old and new Australian surveillance intervals were calculated according to the number, size and histological characteristics of lesions identified. We used these data to compare the rate of procedures according to each guideline. RESULTS: Based on the procedures for 766 patients, the new surveillance guidelines significantly increased the number of procedures allocated an interval of 1 year (relative risk (RR): 1.57, P = 0.009) and 10 years (RR: 3.83, P < 0.00001) and reduced those allocated to half a year (RR: 0.08, P = 0.00219), 3 years (RR: 0.51, P < 0.00001) and 5 years (RR: 0.59, P < 0.00001). Overall, this reduced the relative number of surveillance procedures by 21% over 10 years (25.92 vs 32.78 procedures/100 patient-years), which increased to 22% after excluding patients 75 or older at the time of surveillance (19.9 vs 25.65 procedures/100 patient-years). CONCLUSION: The adoption of the latest Australian adenoma surveillance guidelines can reduce demand for surveillance colonoscopy by more than a fifth (21-22%) over 10 years.
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Adenoma , Pólipos del Colon , Neoplasias Colorrectales , Humanos , Australia/epidemiología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Adenoma/diagnóstico , Adenoma/epidemiología , Colonoscopía , RiesgoRESUMEN
Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs.
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Neoplasias de la Mama , MicroARNs , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/metabolismo , Tamoxifeno/farmacología , Tamoxifeno/uso terapéuticoRESUMEN
The treatment of central nervous system (CNS) malignancies, including brain cancers, is limited by a number of obstructions, including the blood-brain barrier (BBB), the heterogeneity and high invasiveness of tumors, the inaccessibility of tissues for early diagnosis and effective surgery, and anti-cancer drug resistance. Therapies employing nanomedicine have been shown to facilitate drug penetration across the BBB and maintain biodistribution and accumulation of therapeutic agents at the desired target site. The application of lipid-, polymer-, or metal-based nanocarriers represents an advanced drug delivery system for a growing group of anti-cancer chemicals. The nanocarrier surface is designed to contain an active ligand (cancer cell marker or antibody)-binding structure which can be modified to target specific cancer cells. Glioblastoma, ependymoma, neuroblastoma, medulloblastoma, and primary CNS lymphomas were recently targeted by easily absorbed nanocarriers. The metal- (such as transferrin drug-loaded systems), polymer- (nanocapsules and nanospheres), or lipid- (such as sulfatide-containing nanoliposomes)-based nano-vehicles were loaded with apoptosis- and/or ferroptosis-stimulating agents and demonstrated promising anti-cancer effects. This review aims to discuss effective nanomedicine approaches designed to overcome the current limitations in the therapy of brain cancers and age-dependent neurodegenerative disorders. To accent current obstacles for successful CNS-based cancer therapy, we discuss nanomedicine perspectives and limitations of nanodrug use associated with the specificity of nervous tissue characteristics and the effects nanocarriers have on cognition.
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Neoplasias Encefálicas , Nanopartículas , Enfermedades Neurodegenerativas , Humanos , Nanomedicina , Distribución Tisular , Nanopartículas/química , Neoplasias Encefálicas/tratamiento farmacológico , Lípidos/uso terapéutico , Polímeros/uso terapéuticoRESUMEN
Epigenetic regulation by microRNAs (miRs) demonstrated a promising therapeutic potential of these molecules to regulate genetic activity in different cancers, including colorectal cancers (CRCs). The RNA-based therapy does not change genetic codes in tumor cells but can silence oncogenes and/or reactivate inhibited tumor suppressor genes. In many cancers, specific miRs were shown to promote or stop tumor progression. Among confirmed and powerful epigenetic regulators of colon carcinogenesis and development of resistance are onco-miRs, which include let-7, miR-21, miR-22, miR-23a, miR-27a, miR-34, miR-92, miR-96, miR-125b, miR-135b, miR-182, miR-200c, miR-203, miR-221, miR-421, miR-451, and others. Moreover, various tumor-suppressor miRs (miR-15b-5b, miR-18a, miR-20b, miR-22, miR-96, miR-139-5p, miR-145, miR-149, miR-197, miR-199b, miR-203, miR-214, miR-218, miR-320, miR-375-3p, miR-409-3p, miR-450b-5p, miR-494, miR-577, miR-874, and others) were found silenced in drug-resistant CRCs. Re-expression of tumor suppressor miR is complicated by the chemical nature of miRs that are not long-lasting compounds and require protection from the enzymatic degradation. Several recent studies explored application of miRs using nanocarrier complexes. This study critically describes the most successfully tested nanoparticle complexes used for intracellular delivery of nuclear acids and miRs, including micelles, liposomes, inorganic and polymeric NPs, dendrimers, and aptamers. Nanocarriers shield incorporated miRs and improve the agent stability in circulation. Attachment of antibodies and/or specific peptide or ligands facilitates cell-targeted miR delivery. Addressing in vivo challenges, a broad spectrum of non-toxic materials has been tested and indicated reliable advantages of lipid-based (lipoplexes) and polymer-based liposomes. Recent cutting-edge developments indicated that lipid-based complexes with multiple cargo, including several miRs, are the most effective approach to eradicate drug-resistant tumors. Focusing on CRC-specific miRs, this review provides a guidance and insights towards the most promising direction to achieve dramatic reduction in tumor growth and metastasis using miR-nanocarrier complexes.
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Neoplasias Colorrectales , MicroARNs , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Epigénesis Genética , Lípidos , Liposomas/química , MicroARNs/genéticaRESUMEN
Epigenetic regulation of mitochondrial DNA (mtDNA) is an emerging and fast-developing field of research. Compared to regulation of nucler DNA, mechanisms of mtDNA epigenetic regulation (mitoepigenetics) remain less investigated. However, mitochondrial signaling directs various vital intracellular processes including aerobic respiration, apoptosis, cell proliferation and survival, nucleic acid synthesis, and oxidative stress. The later process and associated mismanagement of reactive oxygen species (ROS) cascade were associated with cancer progression. It has been demonstrated that cancer cells contain ROS/oxidative stress-mediated defects in mtDNA repair system and mitochondrial nucleoid protection. Furthermore, mtDNA is vulnerable to damage caused by somatic mutations, resulting in the dysfunction of the mitochondrial respiratory chain and energy production, which fosters further generation of ROS and promotes oncogenicity. Mitochondrial proteins are encoded by the collective mitochondrial genome that comprises both nuclear and mitochondrial genomes coupled by crosstalk. Recent reports determined the defects in the collective mitochondrial genome that are conducive to breast cancer initiation and progression. Mutational damage to mtDNA, as well as its overproliferation and deletions, were reported to alter the nuclear epigenetic landscape. Unbalanced mitoepigenetics and adverse regulation of oxidative phosphorylation (OXPHOS) can efficiently facilitate cancer cell survival. Accordingly, several mitochondria-targeting therapeutic agents (biguanides, OXPHOS inhibitors, vitamin-E analogues, and antibiotic bedaquiline) were suggested for future clinical trials in breast cancer patients. However, crosstalk mechanisms between altered mitoepigenetics and cancer-associated mtDNA mutations remain largely unclear. Hence, mtDNA mutations and epigenetic modifications could be considered as potential molecular markers for early diagnosis and targeted therapy of breast cancer. This review discusses the role of mitoepigenetic regulation in cancer cells and potential employment of mtDNA modifications as novel anti-cancer targets.
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Neoplasias de la Mama , Neoplasias de la Mama/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Epigénesis Genética , Femenino , Humanos , Mutación , Estrés Oxidativo/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a highly infectious agent associated with unprecedented morbidity and mortality. A failure to stop growth of COVID-19-linked morbidity rates is caused by SARS-CoV-2 mutations and the emergence of new highly virulent SARS-CoV-2 strains. Several acquired SARS-CoV-2 mutations reflect viral adaptations to host immune defence. Mutations in the virus Spike-protein were associated with the lowered effectiveness of current preventive therapies, including vaccines. Recent in vitro studies detected diminished neutralisation capacity of vaccine-induced antibodies, which are targeted to bind Spike receptor-binding and N-terminal domains in the emerging strains. Lower than expected inhibitory activity of antibodies was reported against viruses with E484K Spike mutation, including B.1.1.7 (UK), P.1 (Brazil), B.1.351 (South African), and new Omicron variant (B.1.1.529) with E484A mutation. The vaccine effectiveness is yet to be examined against new mutant strains of SARS-CoV-2 originating in Europe, Nigeria, Brazil, South Africa, and India. To prevent the loss of anti-viral protection in vivo, often defined as antibody resistance, it is required to target highly conserved viral sequences (including Spike protein) and enhance the potency of antibody cocktails. In this review, we assess the reported mutation-acquiring potential of coronaviruses and compare efficacies of current COVID-19 vaccines against 'parent' and 'mutant' strains of SARS-CoV-2 (Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529)).
Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , SARS-CoV-2/genéticaRESUMEN
Breast cancer (BC) continues to be one of the major causes of cancer deaths in women. Progress has been made in targeting hormone and growth factor receptor-positive BCs with clinical efficacy and success. However, little progress has been made to develop a clinically viable treatment for the triple-negative BC cases (TNBCs). The current study aims to identify potent agents that can target TNBCs. Extracts from microbial sources have been reported to contain pharmacological agents that can selectively inhibit cancer cell growth. We have screened and identified pigmented microbial extracts (PMBs) that can inhibit BC cell proliferation by targeting legumain (LGMN). LGMN is an oncogenic protein expressed not only in malignant cells but also in tumor microenvironment cells, including tumor-associated macrophages. An LGMN inhibition assay was performed, and microbial extracts were evaluated for in vitro anticancer activity in BC cell lines, angiogenesis assay with chick chorioallantoic membrane (CAM), and tumor xenograft models in Swiss albino mice. We have identified that PMB from the Exiguobacterium (PMB1), inhibits BC growth more potently than PMB2, from the Bacillus subtilis strain. The analysis of PMB1 by GC-MS showed the presence of a variety of fatty acids and fatty-acid derivatives, small molecule phenolics, and aldehydes. PMB1 inhibited the activity of oncogenic legumain in BC cells and induced cell cycle arrest and apoptosis. PMB1 reduced the angiogenesis and inhibited BC cell migration. In mice, intraperitoneal administration of PMB1 retarded the growth of xenografted Ehrlich ascites mammary tumors and mitigated the proliferation of tumor cells in the peritoneal cavity in vivo. In summary, our findings demonstrate the high antitumor potential of PMB1.
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Animales , Ratones , Neoplasias de la Mama/metabolismo , Bacillus subtilis , Exiguobacterium , Puntos de Control del Ciclo Celular , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proliferación Celular , Línea Celular Tumoral , Apoptosis , Microambiente TumoralRESUMEN
To date, a lot of nanotechnological optitions are available for targeted drug delivery. Extracellular vesicles (EVs) are membrane structures that cells use for storage, transport, communication, and signaling. Recent research has focused on EVs as natural nanoparticles for drug delivery. This review sheds light on the application of EVs in cancer therapy, such as targeted chemotherapy, gene therapy, and vaccine development. Aspects of biogenesis, isolation, targeting, and loading of EVs are discussed in detail.
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Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Vesículas Extracelulares/química , Nanomedicina , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Humanos , Nanopartículas/química , Neoplasias/patologíaRESUMEN
Breast cancer MCF-7 cell-line-derived mammospheres were shown to be enriched in cells with a CD44+/CD24- surface profile, consistent with breast cancer stem cells (BCSC). These BCSC were previously reported to express key sphingolipid signaling effectors, including pro-oncogenic sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate receptor 3 (S1P3). In this study, we explored intracellular trafficking and localization of SphK1 and S1P3 in parental MCF-7 cells, and MCF-7 derived BCSC-enriched mammospheres treated with growth- or apoptosis-stimulating agents. Intracellular trafficking and localization were assessed using confocal microscopy and cell fractionation, while CD44+/CD24- marker status was confirmed by flow cytometry. Mammospheres expressed significantly higher levels of S1P3 compared to parental MCF-7 cells (p < 0.01). Growth-promoting agents (S1P and estrogen) induced SphK1 and S1P3 translocation from cytoplasm to nuclei, which may facilitate the involvement of SphK1 and S1P3 in gene regulation. In contrast, pro-apoptotic cytokine tumor necrosis factor α (TNFα)-treated MCF-7 cells demonstrated increased apoptosis and no nuclear localization of SphK1 and S1P3, suggesting that TNFα can inhibit nuclear translocation of SphK1 and S1P3. TNFα inhibited mammosphere formation and induced S1P3 internalization and degradation. No nuclear translocation of S1P3 was detected in TNFα-stimulated mammospheres. Notably, SphK1 and S1P3 expression and localization were highly heterogenous in mammospheres, suggesting the potential for a large variety of responses. The findings provide further insights into the understanding of sphingolipid signaling and intracellular trafficking in BCs. Our data indicates that the inhibition of SphK1 and S1P3 nuclear translocation represents a novel method to prevent BCSCs proliferation.
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Neoplasias de la Mama/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Transducción de Señal , Receptores de Esfingosina-1-Fosfato/metabolismo , Neoplasias de la Mama/genética , Estrógenos/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lisofosfolípidos/metabolismo , Células MCF-7 , Transporte de Proteínas , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Lipid signaling network was proposed as a potential target for cancer prevention and treatment. Several recent studies revealed that phospholipid metabolising enzyme, phospholipase A2 (PLA2), is a critical regulator of cancer accelerating pathologies and apoptosis in several types of cancers. In addition to functioning as an enzyme, PLA2 can activate a phospholipase A2 receptor (PLA2R1) in plasma membrane. While the list of PLA2 targets extends to glucose homeostasis, intracellular energy balance, adipocyte development, and hepatic lipogenesis, the PLA2R1 downstream effectors are few and scarcely investigated. Among the most addressed PLA2R1 effects are regulation of pro-inflammatory signaling, autoimmunity, apoptosis, and senescence. Localized in glomeruli podocytes, the receptor can be identified by circulating anti-PLA2R1 autoantibodies leading to development of membranous nephropathy, a strong autoimmune inflammatory cascade. PLA2R1 was shown to induce activation of Janus-kinase 2 (JAK2) and estrogen-related receptor α (ERRα)-controlled mitochondrial proteins, as well as increasing the accumulation of reactive oxygen species, thus leading to apoptosis and senescence. These findings indicate the potential role of PLA2R1 as tumor suppressor. Epigenetic investigations addressed the role of DNA methylation, histone modifications, and specific microRNAs in the regulation of PLA2R1 expression. However, involvement of PLA2R1 in suppression of malignant growth and metastasis remains controversial. In this review, we summarize the recent findings that highlight the role of PLA2R1 in the regulation of carcinogenesis-related intracellular signaling.
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Neoplasias/etiología , Neoplasias/metabolismo , Receptores de Fosfolipasa A2/genética , Receptores de Fosfolipasa A2/metabolismo , Animales , Apoptosis , Biomarcadores , Susceptibilidad a Enfermedades , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Ligandos , Neoplasias/patología , Especificidad de Órganos , Fosfolipasas A2/metabolismo , Unión Proteica , Transducción de SeñalRESUMEN
Sphingolipids, sphingolipid metabolizing enzymes, and their receptors network are being recognized as part of the signaling mechanisms, which govern breast cancer cell growth, migration, and survival during chemotherapy treatment. Approximately 70% of breast cancers are estrogen receptor (ER) positive and, thus, rely on estrogen signaling. Estrogen activates an intracellular network composed of many cytoplasmic and nuclear mediators. Some estrogen effects can be mediated by sphingolipids. Estrogen activates sphingosine kinase 1 (SphK1) and amplifies the intracellular concentration of sphingosine-1-phosphate (S1P) in breast cancer cells during stimulation of proliferation and survival. Specifically, Estrogen activates S1P receptors (S1PR) and induces growth factor receptor transactivation. SphK, S1P, and S1PR expression are causally associated with endocrine resistance and progression to advanced tumor stages in ER-positive breast cancers in vivo. Recently, the network of SphK/S1PR was shown to promote the development of ER-negative cancers and breast cancer stem cells, as well as stimulating angiogenesis. Novel findings confirm and broaden our knowledge about the cross-talk between sphingolipids and estrogen network in normal and malignant cells. Current S1PRs therapeutic inhibition was indicated as a promising chemotherapy approach in non-responsive and advanced malignancies. Considering that sphingolipid signaling has a prominent role in terminally differentiated cells, the impact should be considered when designing specific SphK/S1PR inhibitors. This study analyzes the dynamic of the transformation of sphingolipid axis during a transition from normal to pathological condition on the level of the whole organism. The sphingolipid-based mediation and facilitation of global effects of estrogen were critically accented as a bridging mechanism that should be explored in cancer prevention.
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Neoplasias de la Mama/metabolismo , Estrógenos/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Receptores de Lisoesfingolípidos/metabolismo , Transducción de Señal , Animales , Neoplasias de la Mama/fisiopatología , Femenino , Humanos , Masculino , Ratones , Fosfotransferasas (Aceptor de Grupo Alcohol)/fisiología , Receptores de Lisoesfingolípidos/fisiología , Células Madre/metabolismo , Células Madre/fisiologíaRESUMEN
BACKGROUND: In a previous study of a Q fever outbreak in Birmingham, our group identified a non-infective complex of Coxiella burnetii (C.b.) antigens able to survive in the host and provoked aberrant humoral and cell-mediated immunity responses. The study led to recognition of a possible pathogenic link between C.b. infection and subsequent long-term post Q fever fatigue syndrome (QFS). This report presents an unusually severe case of C.b. antigen and DNA detection in post-mortem specimens from a patient with QFS. CASE PRESENTATION: We report a 19-year old female patient who became ill with an acute unexplained febrile encephalitis-like illness, followed by increasingly severe multisystem dysfunction and death 10 years later. During life, extensive clinical and laboratory investigations from different disciplinary stand points failed to deliver a definitive identification of a cause. Given the history of susceptibility to infection from birth, acute fever and the diagnosis of "post viral syndrome", tests for infective agents were done starting with C.b. and Legionella pneumophila. The patient had previously visited farms a number of times. Comprehensive neuropathological assessment at the time of autopsy had not revealed gross or microscopic abnormalities. The aim was to extend detailed studies with the post-mortem samples and identify possible factors driving severe disturbance of homeostasis and organ dysfunction exhibited by the course of the patient's ten-year illness. Immunohistochemistry for C.b. antigen and PCR for DNA were tested on paraffin embedded blocks of autopsy tissues from brain, spleen, liver, lymph nodes (LN), bone marrow (BM), heart and lung. Standard H&E staining of brain sections was unrevealing. Immuno-staining analysis for astrocyte cytoskeleton proteins using glial fibrillary acidic protein (GFAP) antibodies showed a reactive morphology. Coxiella antigens were demonstrated in GFAP immuno-positive grey and white matter astrocytes, spleen, liver, heart, BM and LN. PCR analysis (COM1/IS1111 genes) confirmed the presence of C.b. DNA in heart, lung, spleen, liver & LN, but not in brain or BM. CONCLUSION: The study revealed the persistence of C. b. cell components in various organs, including astrocytes of the brain, in a post-infection QFS. The possible mechanisms and molecular adaptations for this alternative C.b. life style are discussed.
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Coxiella burnetii/genética , Fiebre Q/diagnóstico , Enfermedad Aguda , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/metabolismo , Médula Ósea/patología , Encéfalo/metabolismo , Encéfalo/patología , Coxiella burnetii/aislamiento & purificación , Coxiella burnetii/metabolismo , ADN Bacteriano/análisis , ADN Bacteriano/genética , ADN Bacteriano/metabolismo , Femenino , Humanos , Hígado/microbiología , Hígado/patología , Pulmón/microbiología , Pulmón/patología , Reacción en Cadena de la Polimerasa , Fiebre Q/patología , Bazo/microbiología , Bazo/patología , Adulto JovenRESUMEN
BACKGROUND: It has recently been proposed that the M-type phospholipase A2 receptor (PLA2R1) acts as a tumour suppressor in certain malignancies including mammary cancer. Considering that DNA methylation is an important regulator of gene transcription during carcinogenesis, in the current study we analyzed the PLA2R1 expression, PLA2R1 promoter methylation, and selected micro RNA (miRNA) levels in normal human mammary epithelial cells (HMEC) and cancer cell lines. METHODS: Levels of PLA2R1 and DNA methyltransferases (DNMT) specific mRNA were determined using real-time RT-PCR. Methylation specific-high resolution melting (MS-HRM) analysis was utilized to quantify the methylation degree of selected CpG sites localized in the promoter region of the PLA2R1 gene. Expression of miRNA was tested using miScript Primer Assay system. RESULTS: Nearly complete methylation of the analyzed PLA2R1 promoter region along with PLA2R1 gene silencing was identified in MDA-MB-453 mammary cancer cells. In MCF-7 and BT-474 mammary cancer cell lines, a higher DNA methylation degree and reduced PLA2R1 expression were found in comparison with those in normal HMEC. Synergistic effects of demethylating agent (5-aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on PLA2R1 transcription in MDA-MB-453 cells confirmed the importance of DNA methylation and histone modification in the regulation of the PLA2R1 gene expression in mammary cells. Furthermore, significant positive correlation between the expression of DNMT1 and PLA2R1 gene methylation and negative correlation between the cellular levels of hsa-mir-141, -181b, and -181d-1 and the expression of PLA2R1 were identified in the analyzed cells. Analysis of combined z-score of miR-23b, -154 and -302d demonstrated a strong and significant positive correlation with PLA2R1 expression. CONCLUSIONS: Our data indicate that (i) PLA2R1 expression in breast cancer cells is controlled by DNA methylation and histone modifications, (ii) hypermethylation of the PLA2R1 promoter region is associated with up-regulation of DNMT1, and (iii) hsa-miR-23b, -154, and -302d, as well as hsa-miR-141, -181b, and -181d-1 are potential candidates for post-transcriptional regulation of PLA2R1 expression in mammary cancer cells.
Asunto(s)
Neoplasias de la Mama/genética , Metilación de ADN/genética , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica/genética , Receptores de Fosfolipasa A2/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Epigénesis Genética/genética , Femenino , Humanos , MicroARNs/genética , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genéticaRESUMEN
Current prostate carcinoma (PCa) biomarkers, including total prostate-specific antigen (tPSA), have unsatisfactory diagnostic sensitivity and specificity resulting in overdiagnosis and overtreatment. Previously, we described an optimised bias-based preamplification-digital droplet PCR (OBBPA-ddPCR) technique, which detects tumour DNA in blood-derived cell-free DNA (cfDNA) of cancer patients. The current study investigated the performance of newly developed OBBPA-ddPCR-based biomarkers. Blood plasma samples from healthy individuals (n = 90, controls) and PCa (n = 39) and benign prostatic hyperplasia patients (BPH, n = 40) were analysed. PCa and BPH patients had tPSA values within a diagnostic grey area of 2-15 ng/mL, for whom further diagnostic validation is most crucial. Methylation levels of biomarkers RASSF1A, MIR129-2, NRIP3, and SOX8 were found significantly increased in PCa patients compared to controls. By combining classical PCa risk factors (percentage of free PSA compared to tPSA (QfPSA) and patient's age) with cfDNA-based biomarkers, we developed PCa risk scores with improved sensitivity and specificity compared to established tPSA and QfPSA single-marker analyses. The diagnostic specificity was increased to 70% with 100% sensitivity for clinically significant PCa patients. Thus, prostate biopsies could be avoided for 28 out of 40 BPH patients. In conclusion, the newly developed risk scores may help to confirm the clinical decision and prevent unnecessary prostate biopsy.
RESUMEN
BACKGROUND: Australia's bowel cancer prevention guidelines, following a recent revision, are among the most complex in the world. Detailed decision tables outline screening or surveillance recommendations for 230 case scenarios alongside cessation recommendations for older patients. While these guidelines can help better allocate limited colonoscopy resources, their increasing complexity may limit their adoption and potential benefits. Therefore, tools to support clinicians in navigating these guidelines could be essential for national bowel cancer prevention efforts. Digital applications (DAs) represent a potentially inexpensive and scalable solution but are yet to be tested for this purpose. OBJECTIVE: This study aims to assess whether a DA could increase clinician adherence to Australia's new colorectal cancer screening and surveillance guidelines and determine whether improved usability correlates with greater conformance to guidelines. METHODS: As part of a randomized controlled crossover study, we created a clinical vignette quiz to evaluate the efficacy of a DA in comparison with the standard resource (SR) for making screening and surveillance decisions. Briefings were provided to study participants, which were tailored to their level of familiarity with the guidelines. We measured the adherence of clinicians according to their number of guideline-concordant responses to the scenarios in the quiz using either the DA or the SR. The maximum score was 18, with higher scores indicating improved adherence. We also tested the DA's usability using the System Usability Scale. RESULTS: Of 117 participants, 80 were included in the final analysis. Using the SR, the adherence of participants was rated a median (IQR) score of 10 (7.75-13) out of 18. The participants' adherence improved by 40% (relative risk 1.4, P<.001) when using the DA, reaching a median (IQR) score of 14 (12-17) out of 18. The DA was rated highly for usability with a median (IQR) score of 90 (72.5-95) and ranked in the 96th percentile of systems. There was a moderate correlation between the usability of the DA and better adherence (rs=0.4; P<.001). No differences between the adherence of specialists and nonspecialists were found, either with the SR (10 vs 9; P=.47) or with the DA (13 vs 15; P=.24). There was no significant association between participants who were less adherent with the DA (n=17) and their age (P=.06), experience with decision support tools (P=.51), or academic involvement with a university (P=.39). CONCLUSIONS: DAs can significantly improve the adoption of complex Australian bowel cancer prevention guidelines. As screening and surveillance guidelines become increasingly complex and personalized, these tools will be crucial to help clinicians accurately determine the most appropriate recommendations for their patients. Additional research to understand why some practitioners perform worse with DAs is required. Further improvements in application usability may optimize guideline concordance further.
RESUMEN
BACKGROUND: Betulinic acid (BA), which is a pentacyclic triterpenoid found in the bark of plane, birch, and eucalyptus trees, has emerged as a compound of significant interest in scientific research due to its potential therapeutic applications. BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities. Although numerous research studies have explored the potential anticancer effects of BA, there is a noticeable gap in the literature, highlighting the need for a more up-to-date and comprehensive evaluation of BA's anticancer potential. PURPOSE: The aim of this work is to critically assess the reported cellular and molecular mechanisms underlying the cancer preventive and therapeutic effects of BA. METHODS: Relevant research on the inhibitory effects of BA against cancerous cells was searched using Science Direct, Scopus, Web of Science, and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: The anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling. Emerging evidence also underscores the combined anticancer effects of BA with other natural bioactive compounds or approved drugs. Notably, several novel BA nanoformulations have been found to exhibit encouraging antineoplastic activities. CONCLUSION: BA, whether used alone or in combination, or as a form of nanoformulation, shows significant potential for cancer prevention and treatment. Nevertheless, further detailed studies are necessary to confirm the therapeutic effectiveness of this natural compound.