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Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.
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Neoplasias , Humanos , Monitorización Inmunológica , Neoplasias/patología , Metabolismo Energético , Redes y Vías Metabólicas , Microambiente TumoralRESUMEN
MicroRNAs (miRNAs) play an important role in gene regulation by degradation or translational inhibition of the targeted mRNAs. It has been experimentally shown that the way miRNAs interact with their targets can be used to explain the indirect interactions among their targets, i.e., competing endogenous RNA (ceRNA). However, whether the protein translated from the targeted mRNAs can play any role in this ceRNA network has not been explored. Here we propose a deterministic model to demonstrate that in a network of one miRNA interacting with multiple-targeted mRNAs, the competition between miRNA-targeted mRNAs is not sufficient for the significant change of those targeted mRNA levels, while dramatic changes of these miRNA-targeted mRNAs require transcriptional inhibition of miRNA by its target proteins. When applied to estrogen receptor signaling pathways, the miR-193a targets E2F6 (a target of estrogen receptor), c-KIT (a marker for cancer stemness), and PBX1 (a transcriptional activator for immunosuppressive cytokine, IL-10) in ovarian cancer, such that epigenetic silencing of miR-193a by E2F6 protein is required for the significant change of c-KIT and PBX1 mRNA level for cancer stemness and immunoevasion, respectively, in ovarian cancer carcinogenesis.
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Epigénesis Genética/genética , Estrógenos/genética , Redes Reguladoras de Genes/genética , MicroARNs/genética , Neoplasias Ováricas/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Carcinogénesis/genética , Línea Celular Tumoral , Epigenómica/métodos , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients therefore needed to be treated with surgery followed by chemotherapy. Development of novel therapeutics with minimal side-effect is an urgent issue. Our previous study showed that cyproheptadine (CPH), an anti-histamine, exhibited antitumor activity in UC in vitro and in an xenograft model. However, the molecular mechanism of how CPH inhibits tumor progression is not fully understood. METHODS: Genes that were upregulated after treatment with CPH in UC cells, were examined by RNA-Seq. Real-time quantitative PCR (RT-qPCR) was employed to detect IRF6 expression while COBRA assay and bisulphite pyrosequencing were used to examine promoter methylation of IRF6. Enrichment of total H3K27 acetylation and H3K4 mono-methylation were detected by western blotting. Colony formation and flow cytometry were used to examine proliferation and apoptosis in UC cells overexpressed or depleted with IRF6. Nude mice xenograft model was used to examine the effect of IRF6 in UC. RESULTS: Our result showed that several genes, including IRF6 were upregulated after treatment with CPH in BFTC905 UC cells. Further experiments found that treatment of CPH could restore the expression of IRF6 in several other UC cell lines, probably due to promoter hypomethylation and enrichment of H3K27 acetylation and H3K4 mono-methylation. These results may be due to the fact that CPH could alter the activity, but not the expression of epigenetic modifiers. Finally, re-expression of IRF6 in UC inhibited tumor growth in vitro and in an xenograft mouse model, by inducing apoptosis. CONCLUSION: In conclusion, our results suggested that CPH may be an epigenetic modifier, modulating the expression of the potential tumor suppressor IRF6, in inhibiting tumor growth in UC.
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Ovarian cancer is the most lethal cancer of the female reproductive system. In that regard, several epidemiological studies suggest that long-term exposure to estrogen could increase ovarian cancer risk, although its precise role remains controversial. To decipher a mechanism for this, we previously generated a mathematical model of how estrogen-mediated upregulation of the transcription factor, E2F6, upregulates the ovarian cancer stem/initiating cell marker, c-Kit, by epigenetic silencing the tumor suppressor miR-193a, and a competing endogenous (ceRNA) mechanism. In this study, we tested that previous mathematical model, showing that estrogen treatment of immortalized ovarian surface epithelial cells upregulated both E2F6 and c-KIT, but downregulated miR-193a. Luciferase assays further confirmed that microRNA-193a targets both E2F6 and c-Kit. Interestingly, ChIP-PCR and bisulphite pyrosequencing showed that E2F6 also epigenetically suppresses miR-193a, through recruitment of EZH2, and by a complex ceRNA mechanism in ovarian cancer cell lines. Importantly, cell line and animal experiments both confirmed that E2F6 promotes ovarian cancer stemness, whereas E2F6 or EZH2 depletion derepressed miR-193a, which opposes cancer stemness, by alleviating DNA methylation and repressive chromatin. Finally, 118 ovarian cancer patients with miR-193a promoter hypermethylation had poorer survival than those without hypermethylation. These results suggest that an estrogen-mediated E2F6 ceRNA network epigenetically and competitively inhibits microRNA-193a activity, promoting ovarian cancer stemness and tumorigenesis.
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Factor de Transcripción E2F6/genética , Células Madre Neoplásicas/patología , Neoplasias Ováricas/genética , ARN/genética , Transcripción Genética/genética , Animales , Línea Celular Tumoral , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Estrógenos/efectos adversos , Femenino , Genes Supresores de Tumor/fisiología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones SCID , MicroARNs/genética , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Ováricas/etiología , Transcripción Genética/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor ß/δ (PPARß/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARß/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARß/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARß/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.
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Linfocitos T CD8-positivos , Ratones Endogámicos C57BL , PPAR delta , PPAR-beta , Animales , PPAR-beta/metabolismo , PPAR-beta/inmunología , Linfocitos T CD8-positivos/inmunología , PPAR delta/inmunología , PPAR delta/metabolismo , Ratones , Memoria Inmunológica/inmunología , Células T de Memoria/inmunología , Ratones Noqueados , Interleucina-15/inmunología , Interleucina-15/metabolismo , Ratones Transgénicos , Reprogramación Metabólica , Receptores Citoplasmáticos y NuclearesRESUMEN
Recent experimental and observational research has suggested that childhood allergic asthma and other conditions may be the result of prenatal exposure to environmental contaminants, such as di-(2-ethylhexyl) phthalate (DEHP). In a previous epidemiological study, we found that ancestral exposure (F0 generation) to endocrine disruptors or the common plasticizer DEHP promoted allergic airway inflammation via transgenerational transmission in mice from generation F1 to F4. In the current study, we employed a MethylationEPIC Beadchip microarray to examine global DNA methylation in the human placenta as a function of maternal exposure to DEHP during pregnancy. Interestingly, global DNA hypomethylation was observed in placental DNA following exposure to DEHP at high concentrations. Bioinformatic analysis confirmed that DNA methylation affected genes related to neurological disorders, such as autism and dementia. These results suggest that maternal exposure to DEHP may predispose offspring to neurological diseases. Given the small sample size in this study, the potential role of DNA methylation as a biomarker to assess the risk of these diseases deserves further investigation.
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Asma , Dietilhexil Ftalato , Disruptores Endocrinos , Enfermedades del Sistema Nervioso , Efectos Tardíos de la Exposición Prenatal , Embarazo , Animales , Femenino , Ratones , Humanos , Niño , Dietilhexil Ftalato/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/genética , Placenta , Exposición Materna/efectos adversos , Epigénesis Genética , Asma/inducido químicamente , Asma/epidemiología , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/genéticaRESUMEN
Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson's disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8+ T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson's disease patients have a reduced frequency of CD8+ memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8+ T cell formation. We further uncovered that regulators of mitophagy, including Parkin and NIX, were up-regulated in response to interleukin-15 (IL-15) for supporting memory T cell formation. Mechanistically, Parkin suppressed VDAC1-dependent apoptosis in memory T cells. In contrast, NIX expression in T cells counteracted ferroptosis by preventing metabolic dysfunction resulting from impaired mitophagy. Together, our results indicate that the mitophagy machinery orchestrates survival and metabolic dynamics required for memory T cell formation, as well as highlight a deficit in T cell-mediated antiviral responses in Parkinson's disease patients.
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COVID-19 , Enfermedad de Parkinson , Humanos , Linfocitos T CD8-positivos , Células T de Memoria , Mitofagia , Muerte CelularRESUMEN
Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.
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Evasión Inmune , Neoplasias , Humanos , Neoplasias/patología , Interferón gamma/metabolismo , Linfocitos T/metabolismo , Carcinogénesis , Transformación Celular Neoplásica , Microambiente TumoralRESUMEN
PURPOSE: Leprosy is rarely seen in Taiwan. We herein report a foreign worker concomitantly with facial borderline tuberculoid leprosy presenting with trigeminal neuralgia. CASE REPORT: A 26-year-old male foreign labor from Indonesia, presented with 1 year history of a hypoanaesthetic erythematous plaque of right face and subsequent 6 months constant, severe pain in the right side of his face over the nasolabial groove. Biopsies and histopathological examination confirmed the diagnosis of leprosy. We treated the patient with a multidrug regimen including dapsone, clofazimine, and rifampine since April of 2012 with a good response. CONCLUSIONS: We report a rare case of new-onset leprosy presenting with trigeminal neuralgia in Taiwan and suggest leprosy should be listed in the differential diagnosis of unusual skin manifestations and neuralgia.
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Cara/patología , Lepra/complicaciones , Neuralgia del Trigémino/etiología , Adulto , Quimioterapia Combinada , Granulomatosis Orofacial/etiología , Humanos , Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Masculino , Proteínas S100/metabolismo , TaiwánRESUMEN
Congenital vertebral artery (VA) hypoplasia is an uncommon embryonic variation of posterior circulation. The frequency of this congenital variation was reported to be 2-6% from autopsy and angiograms. Is it a congenital risk factor of ischemic stroke? In this review, we gave an overview of the literature concerning vertebral artery hypoplasia. VA hypoplasia served as an independent factor of a reduction of the posterior circulation blood flow velocity. VA hypoplasia can play a negative role in cases of occlusion of a major brain vessel since it limits the potential of compensatory blood circulation. VA hypoplasia may also lead to regional hypoperfusion and complex neurovascular consequences which correspond to vestibular neuronitis and migraine pathogenesis.
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Enfermedades Vasculares/patología , Arteria Vertebral/anomalías , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular , Enfermedades Vasculares/complicaciones , Enfermedades Vasculares/epidemiología , Potenciales Vestibulares Miogénicos Evocados/fisiologíaRESUMEN
Breast cancer is among the most frequently diagnosed cancer types and the leading cause of cancer-related death in women. The mortality rate of patients with breast cancer is currently increasing, perhaps due to a lack of early screening tools. In the present study, using The Cancer Genome Atlas (TCGA) breast cancer dataset (n=883), it was determined that methylation of the protocadherin ß15 (PCDHB15) promoter was higher in breast cancer samples than that in normal tissues. A negative association between promoter methylation and expression of PCDHB15 was observed in the TCGA dataset and breast cancer cell lines. In TCGA cohort, lower PCDHB15 expression was associated with shorter relapse-free survival times. Treatment with the DNA methyltransferase inhibitor restored PCDHB15 expression in a breast cancer cell line; however, overexpression of PCDHB15 was shown to suppress colony formation. PCDHB15 methylation detected in circulating cell-free DNA (cfDNA) isolated from serum samples was higher in patients with breast cancer (40.8%) compared with that in patients with benign tumors (22.4%). PCDHB15 methylation was not correlated with any clinical parameters. Taken together, PCDHB15 is a potential tumor suppressor in cases of breast cancer, which can be epigenetically silenced via promoter methylation. PCDHB15 methylation using cfDNA is a novel minimally invasive epigenetic biomarker for the diagnosis and prognosis of breast cancer.
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BACKGROUND: Leukoaraiosis (LA) affects cognition after stroke and reversal of LA may improve cognitive performance. We aimed to determine the impact of cerebral perfusion and circle of Willis (CoW) flow patterns on the extent of LA after carotid artery revascularization. METHODS: LA was scored on fluid-attenuated inversion recovery magnetic resonance (MR) images at the levels of the centrum semiovale and frontal horns in both cerebral hemispheres of 62 contiguous patients (men/women = 38/24, mean age = 63.2 ± 8.4 years, range 44-82) before and after unilateral carotid artery revascularization. The pre- and poststenting differences in LA scores, CoW flow pattern on MR angiography, and MR perfusion parameters were analyzed. RESULTS: The total LA score decreased from 9.87 ± 0.65 to 8.33 ± 0.72 after stenting (p = 0.03). The CoW was complete in 21 subjects and incomplete in 41 subjects. The incomplete CoW group had a higher preoperative LA load and higher cerebral interhemispheric asymmetry index, both of which decreased significantly postoperatively. CONCLUSIONS: CoW anomalies may contribute to LA in patients with carotid artery stenosis, and restoration of cerebral perfusion by carotid artery revascularization can reduce LA severity.
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Arterias Carótidas/fisiopatología , Estenosis Carotídea/complicaciones , Estenosis Carotídea/terapia , Revascularización Cerebral/métodos , Leucoaraiosis/etiología , Leucoaraiosis/terapia , Flujo Sanguíneo Regional/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Estenosis Carotídea/fisiopatología , Circulación Cerebrovascular/fisiología , Círculo Arterial Cerebral/anomalías , Círculo Arterial Cerebral/fisiopatología , Trastornos del Conocimiento/etiología , Femenino , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Various cerebral pathological changes have been reported to cause leukoaraiosis (LA). We hypothesized that circle of Willis (CoW) anomalies may contribute to LA in severe carotid artery stenosis victims through impaired cerebral autoregulation. We conducted a retrospective review on cerebral magnetic resonance (MR) patterns in patients with severe symptomatic carotid artery stenosis and compared white matter lesion (WML) load between subjects with and without complete CoW. METHODS: LA on fluid attenuation inversion recovery (FLAIR) MR images at the levels of the centrum semiovale and frontal horns in both cerebral hemispheres were scored in 106 patients with unilateral carotid artery stenosis (64 men and 42 women; mean age 68.7 ± 9.2 years, range 44-82). Subjects were divided into groups of complete and incomplete CoW according to cerebral MR angiography. Differences in the LA scores between the groups of complete and incomplete CoW were further analyzed. RESULTS: Compared with those with incomplete configuration of the CoW, subjects with a complete CoW demonstrated a decreased WML load at the level of the centrum semiovale (2.78 ± 1.17 vs. 5.62 ± 2.12, p = 0.02) and frontal horns (2.21 ± 0.79 vs. 4.22 ± 1.83, p = 0.01). CONCLUSION: Our results support the importance of a complete CoW since it may protect from WML in case of carotid stenosis.
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Estenosis Carotídea/patología , Círculo Arterial Cerebral/patología , Leucoaraiosis/etiología , Adulto , Anciano , Anciano de 80 o más Años , Estenosis Carotídea/complicaciones , Estenosis Carotídea/diagnóstico por imagen , Círculo Arterial Cerebral/diagnóstico por imagen , Femenino , Humanos , Leucoaraiosis/diagnóstico por imagen , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radiografía , Estudios Retrospectivos , Factores de RiesgoRESUMEN
In a fetal variation of circle of Willis (CoW) there is an embryological defect of the primary collateral circulation. Besides the fact that collateral flow cannot develop between anterior and posterior circulation, the tentorium namely prevents cerebellar vessels from connecting to the supra-tentorium territory. Therefore patients with a fetal variation of circle of Willis could be more prone to develop vascular insufficiency. An association between the regional cerebral blood volume (rCBV) inter-hemispheric asymmetry and CoW collateralization was observed with a topographic significance of corona radiate rather than centrum semiovale. An overview of the literature is given. We propose a fetal variation of circle of Willis as a risk factor for stroke should be subject of further investigation.
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Circulación Cerebrovascular , Círculo Arterial Cerebral/anomalías , Circulación Colateral , Anciano , Círculo Arterial Cerebral/fisiopatología , Femenino , Humanos , Malformaciones Arteriovenosas Intracraneales/fisiopatología , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Stents , Accidente Cerebrovascular/etiologíaRESUMEN
Gastric cancer is one of the leading causes of cancer death worldwide. Previous studies demonstrated that activation of STAT3 is crucial for the development and progression of gastric cancer. However, the role of STAT3 in neuronal related gene methylation in gastric cancer has never been explored. In this study, by using DNA methylation microarray, we identified a potential STAT3 target, C11orf87, showing promoter hypomethylation in gastric cancer patients with lower STAT3 activation and AGS gastric cancer cell lines depleted with STAT3 activation. Although C11orf87 methylation is independent of its expression, ectopic expression of a constitutive activated STAT3 mutant upregulated its expression in gastric cancer cell line. Further bisulfite pyrosequencing demonstrated a progressive increase in DNA methylation of this target in patient tissues from gastritis, intestinal metaplasia, to gastric cancer. Intriguingly, patients with higher C11orf87 methylation was associated with better survival. Furthermore, hypermethylation of C11orf87 was also frequently observed in other GI cancers, as compared to their adjacent normal tissues. These results suggested that C11orf87 methylation may serve as a biomarker for diagnosis and prognosis of GI cancers, including gastric cancer. We further postulated that constitutive activation of STAT3 might be able to epigenetically silence C11orf87 as a possible negative feedback mechanism to protect the cells from the overactivation of STAT3. Targeted inhibition of STAT3 may not be appropriate in gastric cancer patients with promoter hypermethylation of C11orf87.
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Metilación de ADN/genética , Epigenoma/genética , Neoplasias Gastrointestinales/genética , Sistemas de Lectura Abierta/genética , Factor de Transcripción STAT3/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Supervivencia sin Enfermedad , Epigénesis Genética , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas/genéticaRESUMEN
PURPOSE: The purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer. METHODS: MBDcap-Seq and expression microarray were performed to identify genes that were epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal experiments were performed to investigate proliferation and metastasis of miR-193a and YWHAZ in gastric cancer cell lines. Bisulfite pyrosequencing and tissue microarray were performed to investigate the promoter methylation of miR-193a and expression of STAT3, YWHAZ in patients with gastritis (n = 8) and gastric cancer (n = 71). Quantitative methylation-specific PCR was performed to examine miR-193a promoter methylation in cell-free DNA of serum samples in gastric cancer patients (n = 19). RESULTS: As compared with parental cells, depletion of STAT3 resulted in demethylation of a putative STAT3 target, miR-193a, in AGS gastric cancer cells. Although bisulfite pyrosequencing and epigenetic treatment confirmed that miR-193a was epigenetically silenced in gastric cancer cell lines, ChIP-PCR found that it may be indirectly affected by STAT3. Ectopic expression of miR-193a in AGS cells inhibited proliferation and migration of gastric cancer cells. Further expression microarray and bioinformatics analysis identified YWHAZ as one of the target of miR-193a in AGS gastric cancer cells, such that depletion of YWHAZ reduced migration in AGS cells, while its overexpression increased invasion in MKN45 cells in vitro and in vivo. Clinically, bisulfite pyrosequencing revealed that promoter methylation of miR-193a was significantly higher in human gastric cancer tissues (n = 11) as compared to gastritis (n = 8, p < 0.05). Patients infected with H. pylori showed a significantly higher miR-193a methylation than those without H. pylori infection (p < 0.05). Tissue microarray also showed a positive trend between STAT3 and YWHAZ expression in gastric cancer patients (n = 60). Patients with serum miR-193a methylation was associated with shorter overall survival than those without methylation (p < 0.05). CONCLUSIONS: Constitutive activation of JAK/STAT signaling may confer epigenetic silencing of the STAT3 indirect target and tumor suppressor microRNA, miR-193a in gastric cancer. Transcriptional suppression of miR-193a may led to overexpression of YWHAZ resulting in tumor progression. Targeted inhibition of STAT3 may be a novel therapeutic strategy against gastric cancer.
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OBJECTIVES: Cerebral arteriovenous malformations (AVMs) harbor a network of abnormal vasculatures, namely the nidus between arterial and venous components. The pressure gradient between these two components results in abnormal high-velocity arteriovenous shunts flowing through the nidus and alternate intracranial hemodynamics. This study hypothesizes that the flow patterns of the circle of Willis (CoW) are modulated by the alternation of intracranial hemodynamics occurring in cerebral AVMs. The flow patterns of the CoW before and after AVMs had been corrected and the arteriovenous shunts closed by radiosurgery were assessed to validate the hypothesis. PATIENTS AND METHODS: Fifty patients (32 men and 18 women; mean age 35.8 +/- 4.2, range 23-52 years) with cerebral AVMs previously treated by radiosurgery were retrospectively investigated. This investigation used magnetic resonance angiography, performed prior to and after AVM surgery, to assess the CoW flow patterns. RESULTS: The CoW flow patterns in nearly half of the subjects (20/50, 40%) altered after the AVMs had been corrected. The alterations included: (1) decreased size or ceased flow patterns in the CoW vascular segment: ipsilateral A1 (n = 1) of the anterior cerebral artery (ACA), ipsilateral posterior communicating artery (PCoA) segment (n = 7), contralateral PCoA collateral (n = 4), bilateral PCoA (n = 2); (2) increased size or opening of the previous 'hypoplastic' segment of CoW: ipsilateral A1 of ACA (n = 1), contralateral PCoA (n = 2), bilateral PCoA (n = 1), and (3) biphasic alteration of the CoW: ceased ipsilateral PCoA segment and opening ipsilateral A1 of the ACA (n = 1), ceased ipsilateral PCoA and opening contralateral P1 of the posterior cerebral artery (n = 1). CONCLUSION: The plasticity of the flow patterns in the CoW are modulated by intracranial hemodynamics as shown by the AVM model. The calibers of CoW arterial segments are not a static feature. Willisian collateralization with recruitment of the CoW segment may cease, or hypoplastic segments may reopen after closing arteriovenous shunts of the AVM.
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Circulación Cerebrovascular , Círculo Arterial Cerebral/fisiopatología , Malformaciones Arteriovenosas Intracraneales/fisiopatología , Malformaciones Arteriovenosas Intracraneales/cirugía , Modelos Cardiovasculares , Adulto , Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Encéfalo/cirugía , Angiografía Cerebral , Arterias Cerebrales/fisiopatología , Femenino , Humanos , Estudios Longitudinales , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radiocirugia , Flujo Sanguíneo Regional , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
Breast cancer is one of the leading causes of death among cancer patients worldwide. To date, there are several drugs that have been developed for breast cancer therapy. In the 21st century, immunotherapy is considered a pioneering method for improving the management of malignancies; however, breast cancer is an exception. According to the immunoediting model, many immunosuppressive cells contribute to immunological quiescence. Therefore, there is an urgent need to enhance the therapeutic efficacy of breast cancer treatments. In the last few years, numerous combinatorial therapies involving immune checkpoint blockade have been demonstrated that effectively improve clinical outcomes in breast cancer and combining these with methods of targeting epigenetic regulators is also an innovative strategy. Nevertheless, few studies have discussed the benefits of epi-drugs in non-cancerous cells. In this review, we give a brief overview of ongoing clinical trials involving combinatorial immunotherapy with epi-drugs in breast cancer and discuss the role of epi-drugs in the tumor microenvironment, including the results of recent research.
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BACKGROUND: Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria. RESULTS: Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp. significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice. CONCLUSION: Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi, and established the latter as CRC-promoting bacteria. Video abstract.
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Clostridiaceae/patogenicidad , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Metilación de ADN , Células Epiteliales/metabolismo , Fusobacterium nucleatum/patogenicidad , Genes Supresores de Tumor , Regiones Promotoras Genéticas/genética , Anciano , Animales , Epigénesis Genética , Epigenoma , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND AND PURPOSE: The purpose of the present study was to assess whether the direction of flow via the circle of Willis (CoW) changed after stenting for severe internal carotid artery (ICA) stenosis. METHODS: 65 patients (38 men, mean age 63.2 +/- 8.4 years, range 44-82) with a symptomatic ICA occlusion were investigated. Magnetic resonance angiography was performed prior to and 1 week after carotid artery stenting (CAS). The pattern in the CoW was assessed. RESULTS: One third of the subjects (35.38%) had a significantly altered flow pattern in the CoW after unilateral CAS, including blocked ipsilateral A1 segment collateral (n = 4), blocked contralateral A1 segment collateral (n = 5), blocked ipsilateral posterior communicating artery (PCoA) segment collateral (n = 4), blocked ipsilateral A1 segment and P1 segment collateral (n = 1), opening of ipsilateral A1 segment collateral (n = 5), opening of ipsilateral PCoA segment collateral (n = 3) and opening of ipsilateral P1 segment collateral (n = 1). CONCLUSIONS: CoW segmental hypoplasia is not a static feature. Willisian collateralization with recruitment of the CoW segment (A1, P1 and PCoA) may be blocked after CAS. CAS also leads to the opening of new willisian collateralization, either for relief of reperfusion pressure or for other hypoperfused areas.