Nuclear and mitochondrial apoptotic pathways of p53

AbstractIn contrast to p53-mediated cell cycle arrest, the mechanisms of p53-mediated apoptosis in response to cellular stresses such as DNA damage, hypoxia and oncogenic signals still remain poorly understood. Elucidating these pathways is all the more pressing since there is good evidence that the activation of apoptosis rather than cell cycle arrest is crucial in p53 tumor suppression. Moreover, the therapeutic interest in p53 as the molecular target of anticancer intervention rests mainly on its powerful apoptotic capability. This puzzling elusiveness suggests that p53 not only engages a plethora of downstream pathways but itself might possess a biochemical flexibility that goes beyond its role as a mere transcription factor. Recent evidence of a direct pro-apoptotic role of p53 protein at mitochondria suggests a synergistic effect with its transcriptional activation function and brings an unexpected new level of complexity into p53 apoptotic pathways

EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor

ACKNOWLEDGEMENTS We thank J. M. Valverde (IRB) as well as the NMR facilities of the University of Barcelona (CCiT UB) and the Instituto de Química Física Rocasolano (IQFR, CSIC) for their assistance in, respectively, protein production and NMR. This work was supported by IRB, ICREA (X.S.), Obra Social “la Caixa” (Fellowship to E.D.M. and CancerTec grants to X.S.) MICINN (CTQ2009-08850 to X.S.), MINECO (BIO2012-31043 to X.S.; CTQ2014-56361-P to A.R), Marató de TV3 (102030 to X.S. and 102031 to E.E.P) the COFUND programme of the European Commission (C.T.W.P., A. R. and X.S.), the European Research Council (CONCERT, contract number 648201, to X.S.), the Ramón y Cajal program of MICINN (RYC-2011-07873 to C.W.B.) the Serra Hunter Programme (E.E.P.) and AGAUR (SGR-2014-56RR14 to E.E.P). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain)Peer reviewedPostprin

ΔNp73, A Dominant-Negative Inhibitor of Wild-type p53 and TAp73, Is Up-regulated in Human Tumors

p73 has significant homology to p53. However, tumor-associated up-regulation of p73 and genetic data from human tumors and p73-deficient mice exclude a classical Knudson-type tumor suppressor role. We report that the human TP73 gene generates an NH2 terminally truncated isoform. ΔNp73 derives from an alternative promoter in intron 3 and lacks the transactivation domain of full-length TAp73. ΔNp73 is frequently overexpressed in a variety of human cancers, but not in normal tissues. ΔNp73 acts as a potent transdominant inhibitor of wild-type p53 and transactivation-competent TAp73. ΔNp73 efficiently counteracts transactivation function, apoptosis, and growth suppression mediated by wild-type p53 and TAp73, and confers drug resistance to wild-type p53 harboring tumor cells. Conversely, down-regulation of endogenous ΔNp73 levels by antisense methods alleviates its suppressive action and enhances p53- and TAp73-mediated apoptosis. ΔNp73 is complexed with wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and primary tumors. Thus, ΔNp73 mediates a novel inactivation mechanism of p53 and TAp73 via a dominant-negative family network. Deregulated expression of ΔNp73 can bestow oncogenic activity upon the TP73 gene by functionally inactivating the suppressor action of p53 and TAp73. This trait might be selected for in human cancers

Vaccination with an HIV T-cell immunogen induces alterations in the mouse gut microbiota

The gut microbiota is emerging as a crucial factor modulating vaccine responses; however, few studies have investigated if vaccines, in turn, can alter the microbiota and to what extent such changes may improve vaccine efficacy. To understand the effect of T-cell vaccination on the gut microbiome, we administered an HIV-1 T-cell immunogen (HTI arm) or PBS (control, Mock arm) to C57Bl/6 mice following a heterologous prime-boost scheme. The longitudinal dynamics of the mice gut microbiota was characterized by 16 S ribosomal RNA sequencing in fecal samples collected from cages, as well as from three gut sections (cecum, small and large intestine). Serum and spleen cells were obtained at the last time point of the study to assess immune correlates using IFNγ ELISPOT and cytokine Luminex ® assays. Compared with Mock, HTI-vaccinated mice were enriched in Clostridiales genera (Eubacterium xylanophilum group, Roseburia and Ruminococcus) known as primary contributors of anti-inflammatory metabolites, such as short-chain fatty acids. Such shift was observed after the first HTI dose and remained throughout the study follow-up (18 weeks). However, the enriched Clostridiales genera were different between feces and gut sections. The abundance of bacteria enriched in vaccinated animals positively correlated with HTI-specific T-cell responses and a set of pro-inflammatory cytokines, such as IL-6. This longitudinal analysis indicates that, in mice, T-cell vaccination may promote an increase in gut bacteria known to produce anti-inflammatory molecules, which in turn correlate with proinflammatory cytokines, suggesting an adaptation of the gut microbial milieu to T-cell-induced systemic inflammation

Comparison of the pathological outcome and disease progression of two Mycobacterium caprae experimental challenge models in goats: endobronchial inoculation vs. intranasal nebulization

Background: Goats are natural hosts of tuberculosis (TB) and are a valid animal model to test new vaccines and treatments to control this disease. In this study, a new experimental model of TB in goats based on the intranasal nebulization of Mycobacterium caprae was assessed in comparison with the endobronchial route of infection. Methods: Fourteen animals were divided into two groups of seven and challenged through the endobronchial (EB) and intranasal (IN) routes, respectively. Clinical signs, rectal temperature, body weight, and immunological responses from blood samples were followed up throughout the experiment. All goats were euthanized at 9 weeks post-challenge. Gross pathological examination, analysis of lung lesions using computed tomography, and bacterial load quantification in pulmonary lymph nodes (LNs) by qPCR were carried out. Results: The IN-challenged group showed a slower progression of the infection: delayed clinical signs (body weight gain reduction, peak of temperature, and apparition of other TB signs) and delayed immunological responses (IFN-γ peak response and seroconversion). At the end of the experiment, the IN group also showed significantly lower severity and dissemination of lung lesions, lower mycobacterial DNA load and volume of lesions in pulmonary LN, and higher involvement of the nasopharyngeal cavity and volume of the lesions in the retropharyngeal LN. Conclusion: The results indicated that the IN challenge with M. caprae induced pathological features of natural TB in the lungs, respiratory LN, and extrapulmonary organs but extremely exaggerating the nasopharyngeal TB pathological features. On the other hand, the EB route oversized and accelerated the pulmonary TB lesion progression. Our results highlight the need to refine the inoculation routes in the interest of faithfully reproducing the natural TB infection when evaluating new vaccines or treatments against the disease.This study was funded through a grant from the Spanish Ministry of Science and Innovation (Ref. PID2019-105155RB-C32/AEI/10.13039/501100011033). IRTA was supported by CERCA Programme/Generalitat de Catalunya. CM is the recipient of a pre-doctoral grant from the program Don Carlos Antonio López of the Republic of Paraguay (Ref. 88/2020).info:eu-repo/semantics/publishedVersio

Impact evaluation of a community-based intervention for prevention of cardiovascular diseases in the slums of Nairobi: the SCALE-UP study.

BACKGROUND: A combination of increasing urbanization, behaviour change, and lack of health services in slums put the urban poor specifically at risk of cardiovascular disease (CVD). This study aimed to evaluate the impact of a community-based CVD prevention intervention on blood pressure (BP) and other CVD risk factors in a slum setting in Nairobi, Kenya. DESIGN: Prospective intervention study includes awareness campaigns, household visits for screening, and referral and treatment of people with hypertension. The primary outcome was overall change in mean systolic blood pressure (SBP), while secondary outcomes were changes in awareness of hypertension and other CVD risk factors. We evaluated the intervention's impact through consecutive cross-sectional surveys at baseline and after 18 months, comparing outcomes of intervention and control group, through a difference-in-difference method. RESULTS: We screened 1,531 and 1,233 participants in the intervention and control sites. We observed a significant reduction in mean SBP when comparing before and after measurements in both intervention and control groups, -2.75 mmHg (95% CI -4.33 to -1.18, p=0.001) and -1.67 mmHg (95% CI -3.17 to -0.17, p=0.029), respectively. Among people with hypertension at baseline, SBP was reduced by -14.82 mmHg (95% CI -18.04 to -11.61, p<0.001) in the intervention and -14.05 (95% CI -17.71 to -10.38, p<0.001) at the control site. However, comparing these two groups, we found no difference in changes in mean SBP or hypertension prevalence. CONCLUSIONS: We found significant declines in SBP over time in both intervention and control groups. However, we found no additional effect of a community-based intervention involving awareness campaigns, screening, referral, and treatment. Possible explanations include the beneficial effect of baseline measurements in the control group on behaviour and related BP levels, and the limited success of treatment and suboptimal adherence in the intervention group

A proof‑of‑concept study to investigate the efficacy of heat‑inactivated autovaccines in Mycobacterium caprae experimentally challenged goats

This study aimed to assess the efficacy of a heat-inactivated Mycobacterium caprae (HIMC) vaccine in goats experimentally challenged with the same strain of M. caprae. Twenty-one goats were divided into three groups of seven: vaccinated with heat-inactivated Mycobacterium bovis (HIMB), with HIMC and unvaccinated. At 7 weeks post-vaccination all animals were endobronchially challenged with M. caprae. Blood samples were collected for immunological assays and clinical signs were recorded throughout the experiment. All goats were euthanized at 9 weeks post-challenge. Gross pathological examination, analysis of lung pathology using computed tomography, and bacterial load quantification in pulmonary lymph nodes (LN) by qPCR were carried out. Only HIMC vaccinated goats showed a significant reduction of lung lesions volume and mycobacterial DNA load in LN compared to unvaccinated controls. Both vaccinated groups showed also a significant reduction of the other pathological parameters, an improved clinical outcome and a higher proportion of IFN-γ-producing central memory T cells after vaccination. The results indicated that homologous vaccination of goats with HIMC induced enhanced protection against M. caprae challenge by reducing lung pathology and bacterial load compared to the heterologous vaccine (HIMB). Further large-scale trials are necessary to assess the efficacy of autovaccines under field conditions.info:eu-repo/semantics/publishedVersio

A proof‑of‑concept study to investigate the efficacy of heat‑inactivated autovaccines in Mycobacterium caprae experimentally challenged goats

This study aimed to assess the efficacy of a heat-inactivated Mycobacterium caprae (HIMC) vaccine in goats experimentally challenged with the same strain of M. caprae. Twenty-one goats were divided into three groups of seven: vaccinated with heat-inactivated Mycobacterium bovis (HIMB), with HIMC and unvaccinated. At 7 weeks post-vaccination all animals were endobronchially challenged with M. caprae. Blood samples were collected for immunological assays and clinical signs were recorded throughout the experiment. All goats were euthanized at 9 weeks post-challenge. Gross pathological examination, analysis of lung pathology using computed tomography, and bacterial load quantification in pulmonary lymph nodes (LN) by qPCR were carried out. Only HIMC vaccinated goats showed a significant reduction of lung lesions volume and mycobacterial DNA load in LN compared to unvaccinated controls. Both vaccinated groups showed also a significant reduction of the other pathological parameters, an improved clinical outcome and a higher proportion of IFN-γ-producing central memory T cells after vaccination. The results indicated that homologous vaccination of goats with HIMC induced enhanced protection against M. caprae challenge by reducing lung pathology and bacterial load compared to the heterologous vaccine (HIMB). Further large-scale trials are necessary to assess the efficacy of autovaccines under field conditions.info:eu-repo/semantics/publishedVersio

Temporal development of the humoral immune response to surface antigens of Moraxella catarrhalis in young infants

The primary Moraxella catarrha/is-specific humoral immune response, and its association with nasopharyngeal colonization, was studied in a cohort of infants from birth to 2 years of age. Results indicated that the levels of antigen-specific IgG, IgA and IgM showed extensive inter-individual variability over time, with IgM and IgA levels to all 9 recombinant domains, from 7 different OMPs, being relatively low throughout the study period. In contrast, the level of antigen-specific IgG was significantly higher for the recombinant domains Hag(385-863), MID764-913, MID962-1200, UspA1(557-704) and UspA2(165-318) in cord blood compared to 6 months of age (P <= 0.001). This was a most likely a consequence of maternal transmission of antigen-specific IgG to newborn babies, possibly indicating a future role for these 3 surface antigens in the development of an effective humoral immune response to M. catarrhalis. Finally, at 2 years of age, the levels of antigen-specific IgG still remained far below that obtained from cord blood samples, indicating that the immune response to M. catarrhalis has not matured at 2 years of age. We provide evidence that a humoral antibody response to OMPs UspA1,UspA2 and Hag/MID may play a role in the immune response to community acquired M. catarrhalis colonization events. (C) 2011 Elsevier Ltd. All rights reserved

Prediction of 7-year psychopathology from mother-infant joint attention behaviours: a nested case–control study

&lt;br&gt;Background: To investigate whether later diagnosis of psychiatric disorder can be predicted from analysis of mother-infant joint attention (JA) behaviours in social-communicative interaction at 12 months.&lt;/br&gt; &lt;br&gt;Method: Using data from a large contemporary birth cohort, we examined 159 videos of a mother-infant interaction for joint attention behaviour when children were aged one year, sampled from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Fifty-three of the videos involved infants who were later considered to have a psychiatric disorder at seven years and 106 were same aged controls. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorder, attention-deficit/hyperactivity disorder, pervasive development disorder, anxiety and depressive disorders. Psychiatric diagnoses were obtained using the Development and Wellbeing Assessment when the children were seven years old.&lt;/br&gt; &lt;br&gt;Results: None of the three JA behaviours (shared look rate, shared attention rate and shared attention intensity) showed a significant association with the primary outcome of case–control status. Only shared look rate predicted any of the exploratory sub-diagnosis outcomes and was found to be positively associated with later oppositional-conduct disorders (OR [95% CI]: 1.5 [1.0, 2.3]; p = 0.041).&lt;/br&gt;&lt;br&gt;Conclusions: JA behaviours did not, in general, predict later psychopathology. However, shared look was positively associated with later oppositional-conduct disorders. This suggests that some features of JA may be early markers of later psychopathology. Further investigation will be required to determine whether any JA behaviours can be used to screen for families in need of intervention.&lt;/br&gt