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Elucidation of pathways regulating parasite cell death is believed to contribute to identification of novel therapeutic targets for protozoan diseases, and in this context, apoptosis-like cell death has been reported in different groups of protozoa, in which metacaspases seem to play a role. In the genus Plasmodium, apoptotic markers have been detected in P. falciparum and P. berghei, and no study focusing on P. vivax cell death has been reported so far. In the present study, we investigated the susceptibility of P. vivax to undergo apoptotic cell death after incubating mature trophozoites with the classical apoptosis inducer staurosporine. As assessed by flow cytometry assays, staurosporine inhibited parasite intraerythrocytic development, which was accompanied by a decrease in cell viability, evidenced by reduced plasmodial mitochondrial activity. However, typical signs of apoptosis, such as DNA fragmentation, chromatin condensation, and nuclear segregation, were not detected in the parasites induced to cell death, and no significant alteration in metacaspase gene expression (PvMCA1) was observed under cell death stimulus. Interestingly, dying parasites positively modulated cell death (eryptosis) of host erythrocytes, which was marked by externalization of phosphatidylserine and cell shrinkage. Our study shows for the time that P. vivax blood stages may not be susceptible to apoptosis-like processes, while they could trigger eryptosis of parasitized cells by undergoing cell death. Further studies are required to elucidate the cellular machinery involved in cell death of P. vivax parasites as well as in the modulation of host cell death.
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Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Inhibidores de Proteínas Quinasas , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Medición de Riesgo , Resultado del Tratamiento , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Metacaspases comprise a family of cysteine proteases implicated in both cell death and cell differentiation of protists that has been considered a potential drug target for protozoan parasites. However, the biology of metacaspases in Plasmodium vivax - the second most prevalent and most widespread human malaria parasite worldwide, whose occurrence of chemoresistance has been reported in many endemic countries, remains largely unexplored. Therefore, the present study aimed to address, for the first time, the expression pattern of metacaspases in P. vivax parasites. METHODS AND RESULTS: P. vivax blood-stage parasites were obtained from malaria patients in the Brazilian Amazon and the expression of the three putative P. vivax metacaspases (PvMCA1-3) was detected in all isolates by quantitative PCR assay. Of note, the expression levels of each PvMCA varied noticeably across isolates, which presented different frequencies of parasite forms, supporting that PvMCAs may be expressed in a stage-specific manner as previously shown in P. falciparum. CONCLUSION: The detection of metacaspases in P. vivax blood-stage parasites reported herein, allows the inclusion of these proteases as a potential candidate drug target for vivax malaria, while further investigations are still required to evaluate the activity, role and essentiality of metacaspases in P. vivax biology.
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Malaria Vivax , Plasmodium vivax , Proteínas Protozoarias , Plasmodium vivax/genética , Plasmodium vivax/aislamiento & purificación , Brasil , Humanos , Malaria Vivax/parasitología , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Caspasas/genética , Caspasas/metabolismo , Expresión Génica/genéticaRESUMEN
In the original publication [...].
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OBJECTIVE: Mercury (Hg) is a toxic metal, and dietary exposure is the main one in humans, especially fish consumption. In order to reduce Hg exposure, maximum levels in fish products have been established. We aimed to describe total mercury (THg) and methylmercury (MeHg) concentrations in fish species consumed in Comunitat Valenciana, as well as factors associated and their tendency during the period 2011-2017. METHODS: A retrospective descriptive study of Hg levels in fish meat samples in Comunitat Valenciana between 2011 and 2017 and their temporal trend was carried out, both in general and by fish groups. Data comes from Generalitat Valenciana's Health Surveillance of Food Program. We created multivariate linear regression models to evaluate the association between sampling year, fish group and origin and THg (n=560) / MeHg (n=206) concentrations. The average annual trend of THg and MeHg levels throughout the period was evaluated. RESULTS: The median was 0.20 mg/kg for THg and 0.14 mg/kg for MeHg. Swordfish, fresh tuna/albacore and canned tuna, in that order, showed the highest concentrations. Global tendency of THg levels was descending when adjusting by swordfish annual percentage. When we analized the tendency in swordfish, we observed a 7% decrease on average per year. CONCLUSIONS: Global temporal trend of THg levels in fish in Comunitat Valenciana during the period 2011-2017 is descending after adjusting by the relative weight of swordfish over the total number of samples by year. We observe a descending tendency when studied by species (swordfish).
OBJETIVO: El mercurio (Hg) es un metal tóxico cuya principal fuente de exposición en humanos es la dieta, principalmente el consumo de pescado. Para reducir la exposición al Hg se han establecido unos niveles máximos permitidos en productos de pesca. El objetivo del presente trabajo fue describir las concentraciones de mercurio total (THg) y metilmercurio (MeHg) en las especies de pescado dispuestas para el consumo en la Comunitat Valenciana, así como los factores asociados a dichas concentraciones y su evolución en el período 2011-2017. METODOS: Se realizó un estudio descriptivo, retrospectivo, de los niveles de Hg en muestras de pescado y de su evolución temporal, tanto en general como por grupos de pescado. Los datos proceden del Programa de Vigilancia Sanitaria de Alimentos de la Generalitat Valenciana. Se construyeron modelos de regresión lineal multivariantes para evaluar la asociación del año de muestreo, el grupo de pescado y el origen del mismo con las concentraciones de THg (n=560) y MeHg (n=206). Se evaluó la tendencia anual media de los niveles de THg y MeHg a lo largo del período. RESULTADOS: La mediana para THg fue de 0,20 mg/kg, y de 0,14 mg/kg para MeHg. El pez espada/emperador fue el grupo de pescado que presentó niveles más altos, seguido del atún/bonito frescos y del atún en lata. La tendencia global de los niveles de THg fue descendente ajustando por el peso anual de las muestras de pez espada/emperador. Al analizar la tendencia en pez espada/emperador se observó una disminución del 7% en promedio por año. CONCLUSIONES: La evolución temporal de los niveles de THg en pescado en la Comunitat Valenciana en el período 2011-2017 presenta una tendencia global descendente cuando se ajusta por el peso relativo de pez/espada emperador sobre el total de muestras para cada año. Además, al estudiar los niveles de THg en este grupo se observa una tendencia decreciente.
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Mercurio , Compuestos de Metilmercurio , Contaminantes Químicos del Agua , Animales , Humanos , Estudios Retrospectivos , España , Mercurio/análisis , Peces , Contaminantes Químicos del Agua/análisisRESUMEN
(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1, WNK4, KLHL3, and CUL3. Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) activity with normal plasma aldosterone (PA) and sometimes failure to thrive. GS is a heterogeneous genetic syndrome, ranging from severe cases in childhood to mild and sometimes asymptomatic cases in mid-adulthood. (2) Methods: We report here a sizeable Spanish family of six patients (four adults and two children) with GS. (3) Results: They carry a novel heterozygous missense variant in exon 7 of WNK1 (p.Glu630Gly). The clinical presentation in the four adults consisted of hypertension (superimposed pre-eclampsia in two cases), hyperkalemia, short stature with low body weight, and isolated hyperkalemia in both children. All patients also presented mild hyperchloremic metabolic acidosis and low PR activity with normal PA levels. Abnormal laboratory findings and hypertension were normalized by dietary salt restriction and low doses of thiazide or indapamide retard. (4) Conclusions: This is the first Spanish family with GS with a novel heterozygous missense variant in WNK1 (p.Glu630Gly) in the region containing the highly conserved acidic motif, which is showing a relatively mild phenotype, and adults diagnosed in mild adulthood. These data support the importance of missense variants in the WNK1 acidic domain in electrolyte balance/metabolism. In addition, findings in this family also suggest that indapamide retard or thiazide may be an adequate long-standing treatment for GS.
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Acidosis , Hiperpotasemia , Hipertensión , Indapamida , Niño , Adulto , Humanos , Tiazidas , Proteína Quinasa Deficiente en Lisina WNK 1/genéticaRESUMEN
Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Neuropilinas/genética , Neuropilinas/metabolismo , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Transducción de Señal , Biomarcadores , Biomarcadores de Tumor , Microambiente TumoralRESUMEN
Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in several cellular processes associated to chemoresistance development. Since both the double-edged process of autophagy and hypoxia-derived response play crucial roles in the loss of therapeutic effectiveness, herein we investigated the interplay among NRP1, autophagy and hypoxia in development of lenvatinib resistance in HCC cell lines. We first analyzed NRP1 expression levels in human HCC samples from public databases, found significantly increased NRP1 expression in human HCC samples as well as its correlation with advanced tumor and metastasis stages. Among 3 HCC cell lines (HepG2, Huh-7 and Hep3B), Hep3B and Huh-7 cells showed significantly increased NRP1 expression levels and cell migration ability together with higher susceptibility to lenvatinib. We demonstrated that NRP1 gene silencing significantly enhanced the anticancer effects of lenvatinib on Hep3B and Huh-7 cells. Furthermore, lenvatinib suppressed NRP1 expression through promoting autophagy in Hep3B and Huh-7 cells; co-treatment with bafilomycin A1 attenuated the antitumor effects of lenvatinib, and NRP1 silencing prevented this loss of in vitro effectiveness of lenvatinib even in the presence of bafilomycin A1. In addition, exposure to a hypoxic microenvironment significantly decreased NRP1 expression through autophagy in Hep3B and Huh-7 cells. Under hypoxia, HIF-1α directly modulated NRP1 expression; HIF-1α silencing not only enhanced the anticancer effects of combined lenvatinib and hypoxia, but also prevented the loss of effectiveness caused by bafilomycin A1, highlighting the potential role of HIF-1α-derived hypoxia response in the adaptive cellular response to lenvatinib and promoting resistance acquisition by autophagy modulation. Overall, NRP1 may constitute a potential therapeutic target to prevent lenvatinib failure derived from a hypoxia-associated modulation of autophagy in advanced HCC.
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Carcinoma Hepatocelular , Resistencia a Antineoplásicos , Neoplasias Hepáticas , Neuropilina-1 , Humanos , Autofagia , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neuropilina-1/genética , Neuropilina-1/metabolismoRESUMEN
Neuropilin-1 (NRP1) is a transmembrane protein involved in numerous cellular functions which has had increasing interest from cancer researchers. Liver cancer and colorectal cancer (CRC) are two of the most frequent and deadly tumors with a complex pharmacological framework. Here, we assessed the prognostic, diagnostic and clinicopathological value of NRP1 in liver cancer and CRC patients. We searched PubMed, Scopus, Web of Science, Embase and Cochrane Library databases for articles evaluating the NRP1 correlation with survival parameters, tumor development or clinicopathological features. Hazard ratios and odds ratios with 95% confidence intervals were extracted or estimated by Parmar method and pooled to evaluate the overall effect size with STATA 16 software. Heterogeneity was analyzed by chi-square-based Q test and I2 statistic, along with meta-regression and subgroup analysis, and publication bias was assessed by funnel plot asymmetry and Egger's test. The study protocol was registered in PROSPERO (CRD42022307062). NRP1 overexpression was significantly correlated with lower survival in liver cancer patients and with tumor development in hepatocarcinoma patients, and was strongly correlated with an increased risk of vascular invasion in liver cancer and metastasis in CRC and liver tumors. These results support the role of NRP1 as a potential and useful biomarker in both types of cancer.
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Signal regulatory protein α (SIRPα) is an immunoreceptor expressed in myeloid innate immune cells that signals for inhibition of both phagocytosis and inflammatory response. Malaria parasites have evolutionarily selected multiple mechanisms that allow them to evade host immune defenses, including the modulation of cells belonging to innate immunity. Notwithstanding, little attention has been given to SIRPα in the context of immunosuppressive states induced by malaria. The present study attempted to investigate if malaria parasites are endowed with the capacity of modulating the expression of SIRPα on cells of innate immune system. Human peripheral blood mononuclear cells (PBMC) from healthy individuals were incubated in the presence of lipopolysaccharide (LPS) or crude extracts of P. falciparum or P. vivax and then, the expression of SIRPα was evaluated by flow cytometry. As expected, LPS showed an inhibitory effect on the expression of SIRPα in the population of monocytes, characterized by cell morphology in flow cytometry analysis, while Plasmodium extracts induced a significant positive modulation. Additional phenotyping of cells revealed that the modulatory potential of Plasmodium antigens on SIRPα expression was restricted to the population of monocytes (CD14+CD11c+), as no effect on myeloid dendritic cells (CD14-CD11c+) was observed. We hypothesize that malaria parasites explore inhibitory signaling of SIRPα to suppress antiparasitic immune responses contributing to the establishment of infection. Nevertheless, further studies are still required to better understand the role of SIRPα modulation in malaria immunity and pathogenesis.
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Forkhead box O3 (FOXO3), an essential transcription factor related to liver disease, has been linked to cancer progression. The most frequent primary liver tumor, hepatocellular carcinoma (HCC), has an elevated mortality rate and patient outcomes remain very poor. Here, we examined the diagnostic, prognostic and clinicopathological significance of FOXO3 expression in HCC. We systematically searched Cochrane, Embase, PubMed, Scopus and Web of Science. Articles analyzing FOXO3 levels in HCC patient samples and its relationship with tumor development, survival or clinicopathological factors were selected. Hazard ratios, odds ratios and 95% confidence intervals were extracted, estimated by Parmar method or calculated and pooled across studies. Heterogeneity was evaluated by chi-square-based Q and I2 tests, while publication bias by funnel plots and Egger's test. Subgroup analysis was performed when heterogeneity was evident. The study protocol was registered in PROSPERO (CRD42021237321), and data were meta-analyzed employing STATA 16. Five studies involving 1059 HCC cases were finally included in this meta-analysis, finding that high FOXO3 levels significantly correlate with HCC development and shorter overall survival. Moreover, subgroup analysis revealed a significant association between positive FOXO3 expression and the risk of invasion. Thus, FOXO3 could function as a novel biomarker with diagnostic and prognostic value in HCC.
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Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.
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Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Proteína Forkhead Box O3/genética , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Piridinas/farmacología , Sorafenib/farmacología , Autofagia/efectos de los fármacos , Carcinoma Hepatocelular/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: Treatment with non-selective beta-blockers (NSBBs) reduces the risk of ascites, which is the most common decompensating event in cirrhosis. This study aimed to assess the ability of a serum microRNA (miRNA) signature to predict ascites formation and the hemodynamic response to NSBBs in compensated cirrhosis. METHODS: Serum levels of miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p were analyzed in patients with compensated cirrhosis (N = 105). Hepatic venous pressure gradient (HVPG) was measured at baseline, after intravenous propranolol, and 1 year after randomization to NSBBs (n = 52) or placebo (n = 53) (PREDESCI trial). miRNAs were analyzed at baseline and at 1 year. RESULTS: Nineteen patients (18%) developed ascites, of whom 17 developed ascites after 1 year. miR-181b-5p levels at 1 year, but not at baseline, were higher in patients that developed ascites. The AUC of miR-181b-5p at 1 year to predict ascites was 0.7 (95% CI 0.59-0.78). miR-429 levels were lower at baseline in acute HVPG responders to NSBBs (AUC 0.65; 95% CI, 0.53-0.76), but levels at baseline and at 1 year were not associated with the HVPG response to NSBBs at 1 year. CONCLUSIONS: Serum miR-181b-5p is a promising non-invasive biomarker to identify patients with compensated cirrhosis at risk of ascites development. LAY SUMMARY: Ascites marks the transition from the compensated to decompensated stage in cirrhosis and indicates a worsening in prognosis. There are currently no easily accessible tools to identify patients with compensated cirrhosis at risk of developing ascites. We evaluated the levels of novel molecules termed microRNAs in the blood of patients with compensated cirrhosis and observed that miR-181b-5p can predict which patients are going to develop ascites.
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In the present study, we investigated the genetic diversity of Plasmodium vivax metacaspase 1 (PvMCA1) catalytic domain in two municipalities of the main malaria hotspot in Brazil, i.e., the Juruá Valley, and observed complete sequence identity among all P. vivax field isolates and the Sal-1 reference strain. Analysis of PvMCA1 catalytic domain in different P. vivax genomic sequences publicly available also revealed a high degree of conservation worldwide, with very few amino acid substitutions that were not related to putative histidine and cysteine catalytic residues, whose involvement with the active site of protease was herein predicted by molecular modeling. The genetic conservation presented by PvMCA1 may contribute to its eligibility as a druggable target candidate in vivax malaria.
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Malaria Vivax , Plasmodium vivax , Brasil , Dominio Catalítico , Variación Genética/genética , Humanos , Plasmodium vivax/genética , Proteínas Protozoarias/genéticaRESUMEN
Noninvasive staging of decompensated cirrhosis is an unmet clinical need. The aims of this study were to characterize and validate a novel microRNA (miRNA) signature to stage decompensated cirrhosis and predict the portal pressure and systolic cardiac response to nonselective beta-blockers (NSBBs). Serum samples from patients with decompensated cirrhosis (n = 36) and healthy controls (n = 36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p) identified in the secretome of primary human hepatocytes and for three miRNAs (miR-192-5p, miR-34a-5p, and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, which was refractory in 18 (50%), and were placed on NSBBs for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient, and an echocardiogram study were performed before and 1 month after NSBBs. Patients with cirrhosis had lower serum levels of miR-429, miR-885-5p, miR-181b-5p, miR-122-5p, miR-192-5p, and miR-29a-5p (P < 0.05). Baseline serum miR-452-5p and miR-429 levels were lower in NSBB responders (P = 0.006). miR-181b-5p levels were greater in refractory ascites than in diuretic-sensitive ascites (P = 0.008) and correlated with serum creatinine. miR-452-5p and miR-885-5p were inversely correlated with baseline systemic vascular resistance (ρ = -0.46, P = 0.007; and ρ = -0.41, P = 0.01, respectively) and with diminished systolic contractility (ρ = -0.55, P = 0.02; and ρ = -0.55, P = 0.02, respectively) in patients with refractory ascites after NSBBs. Conclusion: Analysis of a miRNA signature in serum discriminates between patients with decompensated cirrhosis who show more severe systemic circulatory dysfunction and compromised systolic function after beta-blockade and those more likely to benefit from NSBBs.
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Antagonistas Adrenérgicos beta/farmacología , Ascitis/etiología , Hipertensión Portal/etiología , Cirrosis Hepática/genética , MicroARNs/genética , Anciano , Ascitis/fisiopatología , Biomarcadores , Estudios de Casos y Controles , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/prevención & control , Femenino , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Perfilación de la Expresión Génica , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión Portal/fisiopatología , Hipertensión Portal/prevención & control , Cirrosis Hepática/complicaciones , Cirrosis Hepática/metabolismo , Masculino , MicroARNs/metabolismo , Persona de Mediana EdadRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly recurrent tumor after resection and has been closely related to hypoxia. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) have been shown to contribute to tumor progression and therapy resistance in HCC. We evaluated the prognostic and clinicopathological significance of HIF-1α and HIF-2α in HCC patients. METHODS: We systematically searched Embase, Cochrane, PubMed, Scopus and Web of Science (WOS) from inception to 1 June 2020 for studies evaluating HIF-1α and/or HIF-2α expression in HCC. Selected articles evaluate at least one factor by immunohistochemistry (IHC) in HCC patients who underwent surgical resection, and its relationship with prognosis and/or clinicopathological features. Study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CDR42020191977). We meta-analyzed the data extracted or estimated according to the Parmar method employing STATA software. We evaluated the overall effect size for the hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI), as well as heterogeneity across studies with the I 2 statistic and chi-square-based Q test. Moreover, we conducted subgroup analysis when heterogeneity was substantial. Publication bias was assessed by funnel plot asymmetry and Egger's test. RESULTS: HIF-1α overexpression was correlated with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS) and clinicopathological features including Barcelona Clinic Liver Cancer (BCLC), capsule infiltration, intrahepatic metastasis, lymph node metastasis, tumor-node-metastasis (TNM), tumor differentiation, tumor number, tumor size (3 cm), vascular invasion and vasculogenic mimicry. We also detected a possible correlation of HIF-1α with alpha-fetoprotein (AFP), cirrhosis, histological grade, tumor size (5 cm) and albumin after subgroup analysis. Initially, only DFS/RFS appeared to be associated with HIF-2α overexpression. Subgroup analysis denoted that HIF-2α overexpression was related to OS and capsule infiltration. CONCLUSIONS: HIF-1α and HIF-2α overexpression is related to poor OS, DFS/RFS and some clinicopathological features of HCC patients, suggesting that both factors could be useful HCC biomarkers.
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Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties; reduced levels of this hormone are associated with higher risk of cancer. Several beneficial effects of melatonin have been described in a broad number of tumors, including liver cancers. In this work we systematically reviewed the publications of the last 15 years that assessed the underlying mechanisms of melatonin activities against liver cancers, and its role as coadjuvant in the treatment of these tumors. Literature research was performed employing PubMed, Scopus and Web of Science (WOS) databases and, after screening, 51 articles were included. Results from the selected studies denoted the useful actions of melatonin in preventing carcinogenesis and as a promising treatment option for the primary liver tumors hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), either alone or in combination with other compounds. Different processes were modulated by the indole, such as inhibition of oxidative stress, proliferation, angiogenesis and invasion, promotion of immune system response, cell cycle arrest and apoptosis, as well as recovery of circadian rhythms and autophagy modulation. Taken together, the present systematic review highlights the evidence that document the potential role of melatonin in improving the landscape of liver tumor treatment.
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INTRODUCTION: Immune checkpoint inhibitor-related pneumonitis (ICIP) is a potentially life threatening immune-related adverse event (irAE), especially in non-small cell lung cancer (NSCLC) patients. Currently, the potential for increased irAE in patients who receive radiotherapy is scarcely known, although a connection between antitumor immune responses and irAEs has been suggested. In this study, we evaluated the development of ICIP in non-small cell lung cancer patients with prior radiotherapy, treated with immunotherapy in the second-line. METHODS: In this retrospective trial, we included patients treated with second-line immunotherapy at the National Cancer Institute in Mexico City from February 2015 to February 2018. Clinical, radiological and treatment variables were evaluated according to the presence of ICIP as defined by the Common Terminology Criteria for Adverse Events (4.0) in patients with or without a previous (≥months) history of radiotherapy. RESULTS: Among 101 NSCLC patients who received treatment with ICIs, 22 patients (21.8%) were diagnosed with ICIP, of which 73% (16/22) had a history of radiotherapy (OR 6.04, 95% CI 2.03-18.0, p < 0.001). Median progression free survival and overall survival were similar in patients who developed ICIP compared with those who did not, however, patients who presented grade ≥ 2 ICIP had an increased risk of mortality (HR 2.54, 95% CI 1.20-5.34, p = 0.014). CONCLUSION: In this real-world cohort of NSCLC patients treated with ICI, the history of prior radiotherapy was associated with increased risk for ICIP development. Unlike other irAEs, grade ≥ 2 ICIP is an independent prognostic factor for decreased survival in NSCLC patients.