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Introduction: Neoadjuvant radiotherapy is successfully used in rectal cancer to improve overall survival. However, treatment response is both unpredictable and variable. There is strong evidence to show that the phenomenon of tumour hypoxia is associated with radioresistance, however the mechanism(s) behind this are poorly understood. Consequently, there have only been a small number of studies evaluating methods targeting hypoxia-induced radioresistance. The purpose of this systematic review is to evaluate the potential effectiveness of targeting hypoxia-induced radioresistance in rectal cancer and provide recommendations for future research in this area. Methods: A comprehensive literature search was performed following the PRISMA guidelines. This study was registered on the Prospero database (CRD42023441983). Results: Eight articles met the inclusion criteria. All studies identified were in vitro or in vivo studies, there were no clinical trials. Of the 8 studies identified, 5 assessed the efficacy of drugs which directly or indirectly targeted hypoxia and three that identified potential targets. There was conflicting in vivo evidence for the use of metformin to overcome hypoxia induced radioresistance. Vorinostat, atovaquone, and evofosfamide showed promising preclinical evidence that they can overcome hypoxia-induced radioresistance. Discussion: The importance of investigating hypoxia-induced radioresistance in rectal cancer is crucial. However, to date, only a small number of preclinical studies exist evaluating this phenomenon. This systematic review highlights the importance of further research to fully understand the mechanism behind this radioresistance. There are promising targets identified in this systematic review however, substantially more pre-clinical and clinical research as a priority for future research is needed.

Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation.

Oxygen sensing is important in physiology but also in disease. We find that hypoxia (oxygen deficiency) triggers rapid and hypoxia-inducible factor (HIF)-independent histone methylation changes which are reversible upon reoxygenation. Hypoxia-induced histone methylation genomic distribution precedes transcriptional changes and is mimicked by specific Jumonji-C (JmjC) histone demethylase depletion. Oxygen sensing by JmjC histone demethylases is required for the cellular response to hypoxia.

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.

Small molecule probes used to trigger hypoxic response by activating hypoxia inducible factors (HIFs) often lack specificity. Here the authors report a potent small molecule inhibitor that induces hypoxic response by blocking VHL:HIF interactions, providing a selective route to probe hypoxic signalling.

Background: Hypoxia-inducible factor (HIF) transcription factors are well known to control the transcriptional response to hypoxia. Given the importance of cellular response to hypoxia, a number of pharmacological agents to interfere with this pathway have been developed and entered pre-clinical or clinical trial phases. However, how similar or divergent the transcriptional response elicited by different points of interference in cells is currently unknown. Methods: We performed RNA-sequencing to analyse the similarities and differences of transcriptional response in HeLa cells treated with hypoxia or chemical agents that stabilise HIF by inhibiting components of the hypoxia signalling pathway – prolyl hydroxylase (PHD) inhibitor or von Hippel–Lindau (VHL) inhibitor. Results: This analysis revealed that hypoxia produces the highest changes in gene transcription, with activation and repression of genes being in large numbers. Treatment with the PHD inhibitor IOX2 or the VHL inhibitor VH032 led mostly to gene activation, majorly via a HIF-dependent manner. These results were also confirmed by qRT-PCR using more specific and/or efficient inhibitors, FG-4592 (PHDs) and VH298 (VHL). Conclusion: PHD inhibition and VHL inhibition mimic gene activation promoted by hypoxia via a HIF-dependent manner. However, gene repression is mostly associated with the hypoxia response and not common to the response elicited by inhibitors of the pathway.

Hypoxia and inflammation are intimately linked. It is known that nuclear factor κB (NF-κB) regulates the hypoxia-inducible factor (HIF) system, but little is known about how HIF regulates NF-κB. Here, we show that HIF-1α represses NF-κB-dependent gene expression. HIF-1α depletion results in increased NF-κB transcriptional activity both in mammalian cells and in the model organism Drosophila melanogaster. HIF-1α depletion enhances the NF-κB response, and this required not only the TAK-IKK complex, but also CDK6. Loss of HIF-1α results in an increased angiogenic response in mammalian cancer cells and increased mortality in Drosophila following infection. These results indicate that HIF-1α is required to restrain the NF-κB response, and thus prevents excessive and damaging pro-inflammatory responses.

Within the genomes of metazoans, nucleosomes are highly organised adjacent to the binding sites for a subset of transcription factors. Here we have sought to investigate which chromatin remodelling enzymes are responsible for this. We find that the ATP-dependent chromatin remodelling enzyme SNF2H plays a major role organising arrays of nucleosomes adjacent to the binding sites for the architectural transcription factor CTCF sites and acts to promote CTCF binding. At many other factor binding sites SNF2H and the related enzyme SNF2L contribute to nucleosome organisation. The action of SNF2H at CTCF sites is functionally important as depletion of CTCF or SNF2H affects transcription of a common group of genes. This suggests that chromatin remodelling ATPase's most closely related to the Drosophila ISWI protein contribute to the function of many human gene regulatory elements.

Depois de um breve retrospecto da evolução das transferências de renda focalizadas nos pobres no Brasil, este artigo analisa a evolução recente do programa Bolsa Família no que diz respeito à focalização e cobertura da sua população alvo, utilizando informações do suplemento das PNADs 2004 e 2006. Apesar de o programa ter atingido sua meta de atendimento de 11 milhões de domicílios ao final de 2006, há evidências de que cerca de 3,4 milhões de domicílios elegíveis ainda se encontram a descoberto. Simulações evidenciam que garantir a cobertura de todos os domicílios elegíveis tem maior impacto sobre os indicadores de pobreza que conceder o novo benefício, criado em 2008, aos jovens nos domicílios já atendidos pelo programa.After a brief retrospective of the evolution of income transfer programs in Brazil, this article uses information from the 2004 and 2006 official national household survey (PNAD) in order to analyze the recent evolution of the Bolsa Familia program regarding targeting and coverage. Despite the fact that the BF met its goal of assisting 11 million households by the end of 2006, still around 3.4 million eligible households do not receive the transfer benefit. Simulations show that guaranteeing the basic income transfer to all eligible households has a stronger impact on poverty indicators than to grant the new benefit - created in 2008 - to youngsters who live in the already assisted households.

Non-canonical NF-κB signalling plays important roles in the development and function of the immune system but it also is deregulated in a number of inflammatory diseases. Although, NF-κB and HIF crosstalk has been documented, this has only been described following canonical NF-κB stimulation, involving RelA/p50 and the HIF-1 dimer. Here, we report that the non-canonical inducer TNFSF14/LIGHT leads to HIF induction and activation in cancer cells. We demonstrate that only HIF-2α is induced at the transcriptional level following non-canonical NF-κB activation, via a mechanism that is dependent on the p52 subunit. Furthermore, we demonstrate that p52 can bind to the HIF-2α promoter in cells. These results indicate that non-canonical NF-κB can lead to HIF signalling implicating HIF-2α as one of the downstream effectors of this pathway in cells.

Hypoxia or reduced oxygen availability has been studied extensively for its ability to activate specific genes. Hypoxia-induced gene expression is mediated by the HIF transcription factors, but not exclusively so. Despite the extensive knowledge about how hypoxia activates genes, much less is known about how hypoxia promotes gene repression. In this review, we discuss the potential mechanisms underlying hypoxia-induced transcriptional repression responses. We highlight HIF-dependent and independent mechanisms as well as the potential roles of dioxygenases with functions at the nucleosome and DNA level. Lastly, we discuss recent evidence regarding the involvement of transcriptional repressor complexes in hypoxia.

Este artigo tem como objetivo explorar evidências empíricas sobre a clientela beneficiária dos "novos" programas de transferência de renda do governo federal a partir da utilização dos microdados do questionário principal e do suplemento específico da Pesquisa Nacional por Amostra de Domicílios - PNAD. Além do descasamento entre os registros oficiais e as informações da pesquisa domiciliar, estas últimas revelam uma forte superposição de programas em setembro de 2004. Dados os critérios de elegibilidade do Bolsa-família, analisou-se também sua focalização e cobertura, o que permitiu dimensionar a clientela elegível e não beneficiária da ordem de 5 milhões de domicílios. A imputação simulada de transferência monetária a toda clientela elegível, mas não beneficiária, permitiu mensurar o impacto esperado sobre indicadores de pobreza e de desigualdade de renda.This article explores empirical evidences on the implementation of the "new" federal income-transfer programs, using micro-data from the National Annual Household Sample Survey. Besides the incompatibility between official registers and household information, these ones reveal a strong overlapping of federal programs in September 2004. Given the eligibility criteria of the Bolsa-família Program, its characteristics in terms of coverage and targeting were analyzed, which allowed for estimating the size of the eligible but not benefited clientele - around 5 million households. Imputing the monetary transfer to the entire eligible but not beneficiary households generated a new income distribution, which served as basis for measuring the expected impact on income-based poverty and inequality indicators.

The snoMEN (snoRNA Modulator of gene ExpressioN) vector technology was developed from a human box C/D snoRNA, HBII-180C, which contains an internal sequence that can be manipulated to make it complementary to RNA targets, allowing knock-down of targeted genes. Here we have screened additional human nucleolar snoRNAs and assessed their application for gene specific knock-downs to improve the efficiency of snoMEN vectors. We identify and characterise a new snoMEN vector, termed 47snoMEN, that is derived from box C/D snoRNA U47, demonstrating its use for knock-down of both endogenous cellular proteins and G/YFP-fusion proteins. Using multiplex 47snoMEM vectors that co-express multiple 47snoMEN in a single transcript, each of which can target different sites in the same mRNA, we document >3-fold increase in knock-down efficiency when compared with the original HBII-180C based snoMEN. The multiplex 47snoMEM vector allowed the construction of human protein replacement cell lines with improved efficiency, including the establishment of novel GFP-HIF-1α replacement cells. Quantitative mass spectrometry analysis confirmed the enhanced efficiency and specificity of protein replacement using the 47snoMEN-PR vectors. The 47snoMEN vectors expand the potential applications for snoMEN technology in gene expression studies, target validation and gene therapy.

This article presents income-based indicators using the data from the 2004 Brazilian National Household Survey regarding poverty and indigence in 2004. It refers to spatial characteristics of poverty, as well as its relation with the functioning of the labor market and the way family income is formed. The relatively sharp reduction in poverty and indigence from 2003 to 2004, the best result obtained since the Real Plan was implemented, constitutes the background for the analysis, although the impact of this reduction is spatially differentiated, more favorable in rural areas and less so in the São Paulo metropolitan area. The increase in family income is mainly due to the vigorous expansion of occupation, as the average labor income remained unchanged. Nevertheless, poor individuals benefited from the reduction in the returns to schooling, from the real increase in the minimum wage and from the wider scope of the social security net, which resulted in a more vigorous income increase at the base of distribution, thus leading to a reduction in inequality.

This article presents the basic characteristics of precocious labor in Brazil in the nineties. Since the age individuals start working does not seem to be an important determinant of future income, we examined its related aspects, such as school attendance and hard work incidence of. As precocious labor still involves large contingents of children in Brazil under quite different working conditions, it is essential to distinguish the most critical situations so as to support a social policy design targeted at a specific clientele.

Allopurinol, an inhibitor of xanthine oxidase, has been used in clinical trials of patients with cardiovascular and chronic kidney disease. These are two pathologies with extensive links to hypoxia and activation of the transcription factor hypoxia inducible factor (HIF) family. Here we analysed the effects of allopurinol treatment in two different cellular models, and their response to hypoxia. We explored the dose-dependent effect of allopurinol on Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) under hypoxia and normoxia. Under normoxia and hypoxia, high dose allopurinol reduced the accumulation of HIF-1α protein in HFF and HUVEC cells. Allopurinol had only marginal effects on HIF-1α mRNA level in both cellular systems. Interestingly, allopurinol effects over the HIF system were independent of prolyl-hydroxylase activity. Finally, allopurinol treatment reduced angiogenesis traits in HUVEC cells in an in vitro model. Taken together these results indicate that high doses of allopurinol inhibits the HIF system and pro-angiogenic traits in cells.

Cancer is often characterised by the presence of hypoxia and inflammation. Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and Nuclear Factor of κ-light-chain-enhancer of activated B cells (NF-κB). Although, a detailed understating of how these transcription factors respond to their cognate stimulus is well established, it is now appreciated that HIF and NF-κB undergo extensive crosstalk, in particular in pathological situations such as cancer. Here, we focus on the current knowledge on how HIF is activated by inflammation and how NF-κB is modulated by hypoxia. We summarise the evidence for the possible mechanism behind this activation and how HIF and NF-κB function impacts cancer, focusing on colorectal, breast and lung cancer. We discuss possible new points of therapeutic intervention aiming to harness the current understanding of the HIF-NF-κB crosstalk.

Hypoxia is not only a developmental cue but also a stress and pathological stimulus in many human diseases. The response to hypoxia at the cellular level relies on the activity of the transcription factor family, hypoxia inducible factor (HIF). HIF-1 is responsible for the acute response and transactivates a variety of genes involved in cellular metabolism, cell death, and cell growth. Here, we show that hypoxia results in increased mRNA levels for human lysine (K)-specific demethylase 2 (KDM2) family members, KDM2A and KDM2B, and also for Drosophila melanogaster KDM2, a histone and protein demethylase. In human cells, KDM2 family member’s mRNA levels are regulated by HIF-1 but not HIF-2 in hypoxia. Interestingly, only KDM2A protein levels are significantly induced in a HIF-1-dependent manner, while KDM2B protein changes in a cell type-dependent manner. Importantly, we demonstrate that in human cells, KDM2A regulation by hypoxia and HIF-1 occurs at the level of promoter, with HIF-1 binding to the KDM2A promoter being required for RNA polymerase II recruitment. Taken together, these results demonstrate that KDM2 is a novel HIF target that can help coordinate the cellular response to hypoxia. In addition, these results might explain why KDM2 levels are often deregulated in human cancers.

Desigualdade regional e pobreza no Brasil: a evolução 1981-1995

As Nuclear Factor-κB (NF-κB) is a major transcription factor responding to cellular stress, it is perhaps not surprising that is activated by hypoxia, or decreased oxygen availability. However, how NF-κB becomes activated in hypoxia is still not completely understood. Several mechanisms have been proposed and this review will focus on the main findings highlighting the molecules that have been identified in the process of hypoxia induced NF-κB. In addition, we will discuss the role of NF-κB in the control of the cellular response to hypoxia.

Hypoxia Inducible Factor-1 (HIF-1) is essential for mammalian development and is the principal transcription factor activated by low oxygen tensions. HIF-α subunit quantities and their associated activity are regulated in a post-translational manner, through the concerted action of a class of enzymes called Prolyl Hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) respectively. However, alternative modes of HIF-α regulation such as translation or transcription are under-investigated, and their importance has not been firmly established. Here, we demonstrate that NF-κB regulates the HIF pathway in a significant and evolutionary conserved manner. We demonstrate that NF-κB directly regulates HIF-1β mRNA and protein. In addition, we found that NF-κB-mediated changes in HIF-1β result in modulation of HIF-2α protein. HIF-1β overexpression can rescue HIF-2α protein levels following NF-κB depletion. Significantly, NF-κB regulates HIF-1β (tango) and HIF-α (sima) levels and activity (Hph/fatiga, ImpL3/ldha) in Drosophila, both in normoxia and hypoxia, indicating an evolutionary conserved mode of regulation. These results reveal a novel mechanism of HIF regulation, with impact in the development of novel therapeutic strategies for HIF-related pathologies including ageing, ischemia, and cancer.

This article presents income-based indicators using the data from the 2004 Brazilian National Household Survey regarding poverty and indigence in 2004. It refers to spatial characteristics of poverty, as well as its relation with the functioning of the labor market and the way family income is formed. The relativelysharp reduction in poverty and indigence from 2003 to 2004, the best result obtained since the Real Plan was implemented, constitutes the background for the analysis, although the impact of this reduction is spatially differentiated, more favorable in rural areas and less so in the São Paulo metropolitan area. The increase in family income is mainly due to the vigorous expansion of occupation, as the average labor income remained unchanged. Nevertheless, poor individuals benefited from the reduction in the returns to schooling, from the realincrease in the minimum wage and from the wider scope of the social security net, which resulted in a more vigorous income increase at the base of distribution, thus leading to a reduction in inequality.

This article presents the basic characteristics of precocious labor in Brazil in the nineties. Since the age the individual started to work do not seem to be an important determinant of future income, we examined the aspects related to it, such as school attendance and the incidence of hard labor. As precocious labor still involves large contingents of children in Brazil, under quite different working conditions, it is essential to distinguish the most critical situations in order to subsidize social policy design targeted at specific clienteles.

Este texto tem como objetivo apresentar elementos empíricos recentes sobre a inserção dos jovens no mercado de trabalho. Como ponto de partida, trata-se da transição entre escola e trabalho para o contingente amplo de indivíduos de 6 a 25 anos. Como a idade de 18 anos caracteriza um limite natural a partir do qual o trabalho é mais importante que a escola, examinam-se as mudanças de inserção no mercado de trabalho dos jovens de 18 a 25 anos entre 1996 e 2005, o que evidencia a sua situação particularmente vulnerável num quadro de mudanças estruturais, que afetam todos os trabalhadores. Considerando a baixíssima qualificação de 30% desses jovens, que não completaram o ensino fundamental, medidas de política pública voltadas para a redução drástica do seu déficit educacional se configuram como a forma mais efetiva de reduzir a vulnerabilidade dos jovens e melhorar as condições de sua inserção no mercado de trabalho.