RESUMEN

Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors.

Asunto(s)

Carcinogénesis/inmunología , Inmunidad Innata/inmunología , Transducción de Señal/inmunología , Proteína p53 Supresora de Tumor/genética , Animales , Carcinogénesis/metabolismo , Transformación Celular Neoplásica/metabolismo , Citosol/metabolismo , Expresión Génica/genética , Expresión Génica/inmunología , Proteínas de la Membrana/genética , Ratones , Nucleotidiltransferasas/genética , Proteína p53 Supresora de Tumor/inmunología

RESUMEN

Since its discovery as an oncoprotein in 1979, investigation into p53's many identities has completed a full circle and today it is inarguably the most extensively studied tumor suppressor (wild-type p53 form or WTp53) and oncogene (mutant p53 form or mtp53) in cancer research. After the p53 protein was declared "Molecule of the Year" by Science in 1993, the p53 field exploded and a plethora of excellent reviews is now available on every aspect of p53 genetics and functional repertoire in a cell. Nevertheless, new functions of p53 continue to emerge. Here, we discuss a novel mechanism that contributes to mtp53's Gain of Functions GOF (gain-of-function) activities and involves the upregulation of both nucleotide de novo synthesis and nucleoside salvage pathways.

Asunto(s)

Mutación con Ganancia de Función , Nucleótidos/metabolismo , Proteína p53 Supresora de Tumor/genética , Animales , Humanos , Proteína p53 Supresora de Tumor/metabolismo

RESUMEN

Incidence of sickle cell trait in India is high in peninsular south, south-eastern, central and south-western India, while in north and north-eastern India, it is absent. Unicentric origin of SCD in the tribals of nilgiri hills in southern India has been proposed. The present study on the frequency of HbS trait and beta-globin gene haplotypes was conducted in the tribal-rich states of Chhattisgarh and Jharkhand to get an insight into the uneven distribution of HbS in India. Jharkhand borders with the HbS-high Odisha and Chhattisgarh, and HbS-low UP, Bihar and Bengal. Cellulose acetate gel electrophoresis was performed on the collected blood samples, to detect sickle haemoglobin (HbS) followed by DNA analysis. HbS associated beta-gene haplotype was constructed for the samples positive for HbS and all the tribals by PCR-RFLP. Out of 805 (Chhattisgarh - 261, Jharkhand - 544; greater than 36 percent tribals) samples analysed HbS frequency was 13 percent in Chhattisgarh and 3.3 percent in Jharkhand. Within Jharkhand, frequencies varied considerably from 10 percent in Tatanagar to nil in Sahibganj. The Arab-India (AI) haplotype of beta-globin cluster occurred in low frequency, confined mainly to Chhattisgarh. The most abundant haplotype in all the populations was the East Asian, + - - - - - +, rare in HbS, mainly in Sahibganj in east Jharkhand, which lacked AI. Our results indicate that besides the heterozygote advantage againstmalaria, the uneven regional distribution of HbS trait is because of restricted movement of two different populations, Dravidian from the south and Tibeto-Burman from the east into the Indianmainland which failed tomeet, we conjecture, due to severe climatic conditions (deserts and heat) prevailing through parts of central India. Apparently, Jharkhand became a zone of contact between them in recent times.

Asunto(s)

Frecuencia de los Genes/genética , Hemoglobina Falciforme/genética , Rasgo Drepanocítico/epidemiología , Rasgo Drepanocítico/genética , Análisis por Conglomerados , Etnicidad/genética , Geografía , Haplotipos/genética , Humanos , India/epidemiología , Malaria/epidemiología , Globinas beta/genética

RESUMEN

Heterogeneity in thalassemia is due to various modifying factors viz. coinheritance of α-gene defects, abnormal hemoglobin, XmnI polymorphism, variation in repeat sequences present in LCR, and silencer region of the gene. The present work on populations from eastern regions of India was undertaken to study the genetic profile of heterogeneity in thalassemia patients. Mutation analysis in 126 index families revealed the presence of 3 novel mutations: CD2 (-A) in the 1st exon, -42 (C-G), and -223 (T-C) in the promoter region of ß-globin gene. The modifying effect of coexisting α-gene defects, and abnormal Hb (HbS) was clearly observed in our study, however ameliorating effect of T allele of XmnI polymorphism was not found. Analysis of the regulatory regions (LCR) exhibited new combinations (CA(15)TA(5) and CA(13)TA(8)) in HS1 region and one (AT)(10)T(3) in (AT)(x)T(y )silencer region. Thus disparate factors, when considered together, were able to explain several of the thalassemic phenotypes, otherwise not explained by the ß globin mutations. However, there were still some cases in this group whose molecular origin could not be ascertained. Our findings confirm not only the extensive genotypic and clinical heterogeneity in ß thalassemia but also the need to look for more modulators and modifiers to better understand the genotype-phenotype correlation in thalassemia.

Asunto(s)

Estudios de Asociación Genética , Mutación , Talasemia/genética , Globinas alfa/genética , Globinas beta/genética , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Alelos , Secuencia de Bases , Proteínas Sanguíneas/genética , Análisis Mutacional de ADN , Desoxirribonucleasas de Localización Especificada Tipo II/genética , Exones , Femenino , Frecuencia de los Genes , Genotipo , Humanos , India , Lactante , Masculino , Repeticiones de Microsatélite , Datos de Secuencia Molecular , Fenotipo , Polimorfismo Genético , Regiones Promotoras Genéticas , Elementos Silenciadores Transcripcionales , Talasemia/diagnóstico , Talasemia/patología

RESUMEN

Haemoglobinopathies are a leading cause of child mortality worldwide, although with a variable geographical incidence. A reliable estimate of prevalence of the disease is necessary for reducing its burden. However, most studies in India are either hospital based or from certain regions of the country and hence may not realistically reflect the disease burden. The eastern Indian states of Bihar, Chhattisgarh and Jharkhand and eastern region of Uttar Pradesh, which comprise ~25 % population of the country, are poorly studied with respect to haemoglobinopathies. The present study, conducted on 1,642 individuals from this region, shows a frequency of 3.4 % for ß-thalassaemia trait (BTT), 3.4 % for sickle cell haemoglobin trait (HbS)/haemoglobin E trait (HbE) and 18 % for α-globin defects. While BTT mutations are distributed rather uniformly across the region, HbS occurs only in Chhattisgarh and Jharkhand, the regions rich in tribal populations. The frequency of α-gene mutation is strikingly high, occurring even in individuals with normal blood count, in tribal as well as non-tribal groups. The mutation spectrum of BTT is also distinct since the common mutations, IVS1-1 (G-T) and 619 bp del, are absent while CD15 (G-A) is the second most frequent. The HbA2 level in the suspected cases is strikingly low. We demonstrate association of the low HbA2 level with vitamin B12 and folate deficiency in this cohort. Thus, the present report besides providing an estimate of the carrier frequency of ß-thalassaemia traits also confirms high prevalence of α-gene defects and regional heterogeneity in distribution of HbS in the eastern parts of India.

RESUMEN

Drinking-water treatment residual (WTR) have been proposed as a low-cost alternative sorbent for arsenic (As) - contaminated aquatic and soil systems. However, limited information exists regarding the effect of solution chemistry on As sorption by WTR. A batch incubation study was carried out to investigate the effect of solution pH (3-9) on As(V) sorption by Al- and Fe-based WTR as a function of solid: solution ratio (SSR) and initial As concentration. The effect of competing ligands (phosphate-P(V) and sulfate), and complexing metal (calcium) on As(V) sorption envelopes at the optimum SSR (200gL(-1)) was also evaluated. At 200gL(-1) SSR, maximum As(V) sorption ( approximately 100%) exhibited by the Fe-WTR was limited at the pH range of 3-7, whereas, the Al-WTR demonstrated approximately 100% As(V) sorption in the entire pH range. The negative pH effect on As(V) sorption became more pronounced with increasing initial As concentrations and decreasing SSR. Sorption of As(V) by surfaces of both WTR decreased in the presence of P(V), exhibiting strong pH dependence. Only for the Fe-WTR, increased dissolved iron concentrations at pH>7 supported a Fe-hydroxide reductive dissolution mechanism to account for the enhanced As sorption at alkaline pH. Addition of sulfate did not influence As(V) sorption by both WTR. A cooperative effect of calcium on As(V) sorption was observed at alkaline pH due to the formation of a calcium-arsenate phase. The constant capacitance model provided reasonable fits to the sorption envelope data for both single ion and binary ion (As and P) systems, but it was unable to explain the enhanced As sorption by the Fe-WTR at pH>7.

Asunto(s)

Arsénico/química , Hierro/química , Fosfatos/química , Purificación del Agua/métodos , Abastecimiento de Agua , Adsorción , Concentración de Iones de Hidrógeno , Modelos Químicos , Sulfatos/química , Contaminantes Químicos del Agua

RESUMEN

Earlier incubation and greenhouse studies in our laboratory confirmed the effectiveness of drinking-water treatment residual (WTR) in decreasing soil arsenic (As) bioaccessibility as determined with in vitro tests, which led us to hypothesize a similar outcome if animal studies were to be conducted. Our objective was to evaluate the potential of WTR in lowering soil As bioavailability by conducting in vivo experiments and compare the in vitro to the in vivo As data. This study was performed using 6-week-old male BALB/c mice that were fed with an As-contaminated soil slurry using the gavage method. Blood and stomach contents were collected at 1 and 24 h after feeding. Urine and excreta were collected at time 0 (before feeding) and 24 h after feeding. Relative As bioavailability (RBA) values calculated from the blood samples of mice fed with WTR and WTR-amended soil samples ranged from 13% to 24% and from 25% to 29%, respectively; both were significantly (p < 0.001) lower than that of the unamended (no-WTR) soil (approximately 100% RBA). Absolute As bioavailability (ABA) in the gastric phase was significantly (p < 0.001) lowered, to 7-16%, in the WTR-amended soil compared with that of the unamended control (26%). A significant (p < 0.001) linear correlation (r = 0.94) was observed between the in vitro (stomach-phase) and the in vivo RBA data. Percentage recovery of As obtained from four mice tissue compartments (i.e., blood, stomach, urine, and fecal matter) after oral and intramuscular administrations was 63-80%. Results illustrate the effectiveness of in situ WTR amendment in decreasing in vivo soil As bioavailability, thereby lowering the potential cancer risk via an oral ingestion pathway.

Asunto(s)

Arsénico/farmacocinética , Contaminantes del Suelo/farmacocinética , Suelo/análisis , Purificación del Agua/métodos , Animales , Arsénico/sangre , Disponibilidad Biológica , Masculino , Ratones , Ratones Endogámicos BALB C , Contaminantes del Suelo/sangre , Estómago , Distribución Tisular

RESUMEN

There is a strong interest in developing an in vitro arsenic (As) model that satisfactorily estimates the variability in in vivo relative oral bioavailability (RBA) measurements. Several in vitro tests have been developed, but none is universally accepted due to their limited success in predicting soil As RBA. A suite of amorphous and crystalline solid As phases were chosen, utilizing a worst-case scenario (WCS) that simulated fasting children's gastric solution chemistry. The objectives of this study were to (i) determine the effects of residence time, pH, and solid-to-solution ratio on As bioaccessibility and speciation in the in vitro gastric test; (ii) provide the fundamental basis for an optimized in vitro model constrained by the WCS; and (iii) validate the optimized in vitro test with the in vivo RBA obtained with BALB/c mice. The gastric pH was the only significant (p < 0.05) factor influencing solid As bioaccessibility. Bioaccessible As retained the oxidation state after its release from the solid into the gastric solution. The optimized in vitro model adequately predicted RBA values for a suite of solid As phases typically encountered in soils, with the exception of aluminum-based solids. This study is an excellent starting point for developing an in vitro test applicable to different As-contaminated soils.

Asunto(s)

Arsénico/farmacocinética , Contaminantes del Suelo/farmacocinética , Animales , Ácido Ascórbico , Disponibilidad Biológica , Colecalciferol , Deshidroepiandrosterona/análogos & derivados , Ecosistema , Exposición a Riesgos Ambientales , Ácido Gástrico/química , Concentración de Iones de Hidrógeno , Ratones , Ratones Endogámicos BALB C , Modelos Biológicos , Ácidos Nicotínicos , Oryza/metabolismo , Extractos Vegetales , Reproducibilidad de los Resultados