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Weltweit sind die Volkswirtschaften mit hohen Preissteigerungen konfrontiert. Unter anderem beeinflusst die Inflation den Staatshaushalt sowie die Tragfähigkeit der öffentlichen Schulden. Wie und in welchem Ausmaß wird die Staatsschuldenquote durch die höhere Inflationsrate beeinflusst? Es wird gezeigt, dass eine hohe Inflation kein Heilmittel gegen eine hohe Staatsschuldenquote ist. Economies around the world are facing high price increases. Inflation affects government budgets as well as the sustainability of public debt. How and to what extent is the public debt ratio affected by higher inflation rates? High inflation is not a lasting remedy for a high public debt ratio. Only under very specific conditions - and by simultaneously ignoring the manifold knock-on effects of inflation - does a higher inflation rate bring about a decline in the government debt ratio. In the longer term, it may be dangerous if inflation expectations are de-anchored and interest rates rise for a prolonged time so that debt sustainability is ultimately jeopardised.

The novel nature of the economic and social crisis, due to the spread of COVID-19, requires new rules and a drastic change in the economic measures to be adopted. The pandemic has caused a spiral of supply–demand shocks that brings about several market failures that make necessary a public intervention to assure the return to health security in the first place and then to restore economic growth and reduce unemployment. Fiscal policy has to intervene both to cover health expenses and sustain families’ income and firms’ fixed costs, and to create the basis for a future recovery through investment. To guarantee the stability of the resulting higher public debt, expansionary monetary policies have been implemented even in a non-conventional way. In the euro area, among other measures, a pandemic emergency purchase programme (PEPP) has been adopted, through which the European Central Bank (ECB) has been buying temporarily existing public debt on the secondary market. We ask whether the ECB should go even further monetising permanently on the primary markets the public debt of euro area countries or relieving a fraction of the debt that they are currently holding. An alternative possibility would be the issuance of perpetual bonds to be bought by the central bank. Needless to say, such measures are rather controversial, not only considering their political feasibility, but also for the feared effects on the central bank’s anti-inflationary credibility and on moral hazard. We argue that a sufficiently strong political will might help overcoming the objection regarding feasibility. Central bank’s anti-inflationary credibility may not necessarily be a concern: according to the credibility theory, in the case of unexpected shocks, no credibility can be gained by following policies that are not credible themselves. On the other hand, moral hazard cannot be an issue when a given measure is fully justified by the occurrence of extraordinary circumstances. Finally, we show that when the economy is hit by a stochastic shock, a moderate inflation might well be optimal, as it would allow a reduction of the unemployment rate.

The article presents the results of an analysis that compares changes in Poland’s competitive position against the backdrop of the Visegrad Group (V4) countries and the Baltic States (BS3) in the post-accession period (2006–2017). This type of study has not been presented in detail in the available literature before. Therefore, the article may significantly contribute to bridging the gap. The study employs a comparative analysis of secondary data concerning the indices and pillars of economic competitiveness described in The Global Competitiveness Reports prepared by the World Economic Forum. An important element of the examination was the endeavour to identify major determinants of those developments. The article ends with a summary of the most significant conclusions from the analysis presented. As confirmed by the examination, the countries covered differed widely regarding the improvement of their competitive positions in the post-accession period. Artykuł jest prezentacją wyników analizy, w ramach której podjęto próbę porównania zmian pozycji konkurencyjnej Polski na tle państw Grupy Wyszehradzkiej (GW–4) oraz Krajów Bałtyckich (KB–3) w okresie poakcesyjnym (lata 2006–2017). Należy podkreślić, że tego typu badanie nie było jeszcze szerzej prezentowane w dostępnej literaturze. Artykuł może być więc ważnym uzupełniniem tej luki. W badaniu zastosowano metodę analizy porównawczej danych wtórnych, dotyczących wskaźników konkurencyjności gospodarki oraz czynników ją determinujących wyodrębnionych w Raportach „Global Competitiveness Report”, opracowywanych przez Światowe Forum Ekonomiczne. Ważnym elementem prezentowanej analizy było podjęcie próby zidentyfikowania najważniejszych czynników determinujących te zmiany. Artykuł kończy zestawienie najważniejszych wniosków wynikających z prezentowanej analizy. Analiza potwierdziła, że badane kraje cechowały się dość istotnymi różnicami w zakresie poprawy ich pozycji konkurencyjnej w okresie poakcesyjnym.

ZusammenfassungDas Jahr 2020 war geprägt von der COVID-19-Pandemie und ihren wirtschaftlichen Folgen. In Deutschland stiegen staatliches Defizit sowie die Schuldenquote infolge des Rückgangs der Wirtschaftsleistung auf geschätzt 5 % bzw. 75 % des BIP an. Um die wirtschaftliche Erholung von der Pandemie nicht durch die Rückkehr zu einem rigiden Sparkurs zu gefährden, ist es jetzt von besonderer Bedeutung, sich von falschen Vorstellungen bezüglich der Finanzierung sowie der Nachhaltigkeit staatlicher Ausgabenüberschüsse zu verabschieden. Nur so können die Weichen für eine Wirtschaftspolitik des 21. Jahrhunderts richtig gestellt werden.

The human papillomavirus E6 and E7 oncoproteins interact with a different subset of host proteins, leading to dysregulation of the apoptotic, cell cycle, and signaling pathways. In this study, we identified, for the first time, that Aurora kinase B (AurB) is a bona fide interacting partner of E6. We systematically characterized the AurB-E6 complex formation and its consequences in carcinogenesis using a series of in vitro and cell-based assays. We also assessed the efficacy of Aurora kinase inhibitors in halting HPV-mediated carcinogenesis using in vitro and in vivo models. We showed that AurB activity was elevated in HPV-positive cells, and this correlated positively with the E6 protein level. E6 interacted directly with AurB in the nucleus or mitotic cells. A previously unidentified region of E6, located upstream of C-terminal E6-PBM, was important for AurB-E6 complex formation. AurB-E6 complex led to reduced AurB kinase activity. However, the AurB-E6 complex increased the hTERT protein level and its telomerase activity. On the other hand, AurB inhibition led to the inhibition of telomerase activity, cell proliferation, and tumor formation, even though this may occur in an HPV-independent manner. In summary, this study dissected the molecular mechanism of how E6 recruits AurB to induce cell immortalization and proliferation, leading to the eventual cancer development. Our findings revealed that the treatment of AZD1152 exerted a non-specific anti-tumor effect. Hence, a continuous effort to seek a specific and selective inhibitor that can halt HPV-mediated carcinogenesis should be warranted.

This study is designed to evaluate soil organic matter (SOM) quality indicators: molecular indicators of dissolved organic matter (DOM) and hydrophobicity of humic acid (HA), distribution of quantity in humified and labile fractions of histosols during renaturalization. The aim is to determine the differences in the qualitative composition of humic acids at the molecular level, which are decided by the previous tillage and genesis, and to evaluate the impact of anthropogenization on the peat soil according to hydrophobicity, as well as to estimate the impact of soil genesis and removing peat layer. Soil samples were taken from the three Sapric Histosol (according to WRB2022) profiles and the 0–30 cm layer in three field replicates (Lithuania, Radviliskis mun.). Our study suggested that in the differently managed drained Sapric Histosol under renaturalization, the most significant changes occurred in the topsoil layer (0–30 cm), in which an increase in the content of SOM particles 106–2 µm in size. It is expedient to grow perennial grasses and legumes to maintain the soil organic carbon stability mobile humic acids to mobile fulvic acids ratio (MHA:MFA 0.83 to 0.86). An evaluation of the quality of HA (E4:E6) revealed their highest maturity in the unfertilized perennial grasses (3.88) and crop rotation (3.87) with grasses. The highest concentrations of hydrophilic groups (ratio of the C=O to O-H) were found in Sapric Histosol under deciduous hardwood forest (12.33). The lowest hydrophilicity (9.25 and 9.36) was of the crop rotation Sapric Histosol with removed peat layer. The most sustainable use of drained Sapric Histosol in the context of the sustainability and quality of its humus substances should be associated with the formation of perennial grass and clover grassland and the cultivation of deciduous hardwood. Therefore, the horizon forms on the top part of the profile, which protects deeper Histosolic material layers from its mineralization.

We consider the aggregate and distributional impact of Universal Basic Income (UBI). We develop a model to study a wide range of UBI programs and financing schemes and to highlight the key mechanisms behind their impact. The most crucial channel is the rise in distortionary taxation (required to fund UBI) on labor force participation. Second in importance is the decline in self-insurance due to the insurance UBI provides, resulting in lower aggregate capital. Third, UBI creates a positive income effect lowering labor force participation. Alternative tax-transfer schemes mitigate the impact on labor force participation and the cost of UBI.

This study focuses on: (1) finding the causes of inflation which follows the inflation theories such as Demand-Pull, Cost-Push and Structural inflation.(2) measuring the degree of inflation persistence in order to evaluate the ability of monetary policies to control inflation. Engle- Granger test and the Autoregressive Distributed Lag are applied to analyze the response of inflation to its determinants. The Grid bootstrap Method and Impulse Response Functions measure the inflation persistence. The results suggest that controlling the money supply is a key factor in controlling inflation. The appreciation of Rial exchange rate is an important factor of low inflation. It is increased as a result of Budget deficit while decreased due to oil price and real GDP. Inflation persistence follows the structural changes and finally permanent shocks die out after some horizons. Therefore, monetary authorities control inflation but their policies are yet far from optimal level.

Macroeconomic uncertainties are expected to affect investment decisions. This study analyzes the effect of the real exchange rate, inflation, and growth uncertainties on private investment in Turkey, an emerging country. While a generalized autoregressive conditional heteroskedasticity (GARCH) model is adopted to measure uncertainties, the existence of a long-run relationship of the variables is assessed using the bound testing approach. Finally, an error correction model is estimated to capture the dynamic relationship. Findings/Originality : The results for the short-run dynamic estimation show that both inflation and real exchange rate uncertainties have a significant negative effect on investments. As for the long-run equilibrium, exchange rate, inflation, and growth uncertainties have a negative impact on private investments. The application of inflation targeting and exchange rate stabilization policy might effectively reduce uncertainty on investments, thus supporting economic growth in the short term.

In the recent theory of economic growth, there are multiple explanations for the “downward trend of economic growth”, which is already happening during the past decade in developed and emerging markets. Almost all economists have avoided researching the “hypothesis of a world without growth”, dealing with Krugman’s rhetoric of “secular stagnation is probable” or thinking about Koehn’s rhetoric get rid of dependence on growth”. The cult of growth is embedded in the economic, political and social heads so deeply that for each of them growth is an imperative of life and death. By reviewing certain literature and papers, we can draw a conclusion about trends in the world economy, the dominant macroeconomic mainstream and reconsider and we can a critically resist the role of “rule taker” in the economic policy of post-transition countries in the past ten years. This paper does not investigate or establish a research gap, and does not offer a solutions to current problems that may arise from comparative analyzes, but give a qualitative assessment of the neoliberal tone of global economic policy, note the controversies of economic growth and financial stability and reinterprets earlier doctrinal conflicts in the global economy, which can give perspective possible solutions or policies for post-transition countries today. The key goal of this paper is to give rise to future research.

In this paper we have worked on a number of documents and articles published to find a relationship between patents and the economic growth of countries. We have found that patents and their applications are important for economic growth. The patent is not always a global indicator of all the technological knowledge produced, since a considerable number of technological know-how remains in the form of business secrets or sometimes the technology is published in scientific articles. The patent can be an economic policy instrument to encourage investment in research and development. More patents lead to more innovations and vice versa. The patent is a vector of economic growth through the promotion of innovation.

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a growing global health problem. HPV16 has been attributed to a majority of HPV-associated HNSCCs. In order to test candidate immunotherapies, we developed a spontaneous HPV16-driven HNSCC model in HLA-A2 (AAD) transgenic mice. We sought to eliminate the confounding effects of dominant HPV antigen presentation through murine major histocompatibility complex class I (MHC-I) via epitope mutagenesis (without compromising tumorigenicity). We generated HPV16 E6(R55K)(delK75) and E7(N53S) expression constructs with mutations in known dominant H-2Db epitopes and characterized their presentation through murine and human MHC-I molecules using in vitro and in vivo activation of HPV16 E6/E7 antigen-specific CD8+ T cells. In addition, we tested the ability of E6(R55K)(delK75) and E7(N53S) for oncogenicity. The mutated E7(N53S) abolished the presentation of murine H-2Db-restricted HPV16 E7 peptide (i.e., amino acids [aa] 49 to 57) cytotoxic T lymphocyte (CTL) epitope and resulted in HLA-A2-restricted presentation of the HPV16 E7 (aa 11 to 20)-specific CTL epitope. The mutated E6(R55K)(delK75) abolished the activation of murine MHC-I-restricted E6-specific CD8+ T cell-mediated immune responses in C57BL/6 mice. In addition, the vaccination led to the activation of human HLA-A2-restricted E6-specific CD8+ T cell-mediated immune responses in HLA-A2 (AAD) transgenic mice. Injection of DNA plasmids encoding LucE7(N53S)E6(R55K)(delK75), AKT, c-Myc, and SB100 followed by electroporation results in development of squamous cell carcinoma in the oral/pharyngeal cavity of all of the HLA-A2 (AAD) transgenic mice (5/5), with 2/5 tumor-bearing mice developing metastatic carcinoma in the neck lymph nodes.

Cervical cancer caused by persistent infection with HR HPV genotypes is the second leading cause of death in women aged 15 to 44 in Serbia. The expression of the E6 and E7 HPV oncogenes is considered as a promising biomarker in diagnosing high-grade squamous intraepithelial lesions (HSIL). This study aimed to evaluate HPV mRNA and DNA tests, compare the results according to the severity of the lesions, and assess the predictive potential for the diagnosis of HSIL. Cervical specimens were obtained at the Department of Gynecology, Community Health Centre Novi Sad, Serbia, and the Oncology Institute of Vojvodina, Serbia, during 2017–2021. The 365 samples were collected using the ThinPrep Pap test. The cytology slides were evaluated according to the Bethesda 2014 System. Using a real-time PCR test, HPV DNA was detected and genotyped, while the RT-PCR proved the presence of E6 and E7 mRNA. The most common genotypes in Serbian women are HPV 16, 31, 33, and 51. Oncogenic activity was demonstrated in 67% of HPV-positive women. A comparison of the HPV DNA and mRNA tests to assess the progression of cervical intraepithelial lesions indicated that higher specificity (89.1%) and positive predictive value (69.8–78.7%) were expressed by the E6/E7 mRNA test, while higher sensitivity was recorded when using the HPV DNA test (67.6–88%). The results determine the higher probability of detecting HPV infection by 7% provided by the mRNA test. The detected E6/E7 mRNA HR HPVs have a predictive potential in assessing the diagnosis of HSIL. The oncogenic activity of HPV 16 and age were the risk factors with the strongest predictive values for the development of HSIL.

The reflections which follow build on two interrelated questions, namely, first, whether we are witnessing another "industrial revolution", and second, what is the impact of technological transformations upon the current dynamics of the socio-economic fabric, especially with respect to employment, income distribution, working conditions and labour relations. We argue that the processes of innovation and diffusion of what we could call "intelligent automation" are likely to change, or more likely reinforce, the patterns of distribution of income and power, which have been there well before the arrival of the technologies we are concerned about: some are indeed intrinsic features of capitalism since its inception, while others are features of the last thirtyforty years. First, we shall offer a fresco of such tendencies which certainly preceded any potential "Fourth Industrial Revolution" but are going to be amplified by the latter. Second, we discuss the features of such possible new techno-economic paradigms. Third, we examine the relationships between technology, productivity and growth, and the ensuing impact on jobs, division of labour, distribution of knowledge, power, and control. Finally, we address some policy implications.

The current globalized economic environment has made Emerging Market Economies (EMEs) highly exposed to global economic shocks. During the Covid-19 pandemic, EMEs have been facing increased health costs and heightened demand for fiscal stimulus. In addition, most EMEs experienced currency depreciation, reversal in capital flow, decrease in global demand and significant decline in domestic revenue, leading to a potential increase in sovereign bond risk premiums (SRP). Using dynamic panel estimations and focusing on 12 countries, we find that the Covid-19 pandemic impacts SRP primarily through GDP growth and political stability indicators. In addition, we find the real exchange rate and net export to GDP ratio have a statistically significant impact on sovereign bond risk premium.

This current study seeks to investigate the policy implication of Turkey’s recent energy policies on its sustainable development. This study uses Turkey’s country-specific data and series of 1974 to 2018 for effective investigation and justification of the findings of this study with emphasis on both short-run and long-run implications. Three models were fitted to achieve study objectives to accommodate both environmental sustainability and economic impacts. Ecological footprint was considered better measure and used as proxy for the environment related model. In summary, with environment models, the selected series (per capita GDP, industrialization, agriculture, coal as a single energy use, and mixed energy use) except per capita GDP2 were found positively and significantly related to ecological footprint in both short run and long run which translates to poor performance of Turkey’s environment. Also, using economic growth model, the selected series (industrialization, energy use, and agriculture) were all confirmed positively and significantly related to the economic growth (per capita GDP). Additionally, environmental Kuznets curve (EKC) was established for Turkey’s environment and economic performance. Furthermore, using Granger causality as robust check to these findings, a nexus was found among the series confirming the validity of the cointegration (short- and long-run policies) estimations and results. In congruence with literature and hypotheses, the results from cointegration estimation shows that the twin polices may be good to the economic performance but will spark off adverse effect on environment.

Simple Summary The process of HPV-mediated oncogenesis in HNSCCs is not fully understood. DLG1 and SCRIB protein expression levels and localization changes were evaluated in a number of HPV16-positive and HPV-negative OPSCCs and seem to be associated with malignant transformation. Moreover, loss of SCRIB expression inversely correlates with higher grade tumors, and this is much more evident in the presence of HPV16 E6. This could serve as a potential marker in predicting development of OPSCCs. Abstract The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16-positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cell–cell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cell–cell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs.

In this paper, I use a simple SIR Macro model to examine Japan’s soft lockdown policies in 2021 under the COVID-19 crisis. As real-time research, this paper consists of two parts written during two different research periods. The first part, which was originally reported in February 2021, studies the Japan’s second soft lockdown policy (state of emergency declaration) from January to March 2021. After the model is calibrated using 2020 data, the results show that a long enough lockdown can avoid future lockdowns, improving both the infection and the economy. In addition, I propose the ICU targeting policy, which keeps the number of severe patients at a constant level, mimicking the monetary policy’s inflation targeting. The model’s prediction is evaluated from an ex-post perspective in the second part, written in July 2021. I find that the model broadly captures the realized consequences of the second soft lockdown and the subsequent paths. Furthermore, the simulation is projected to the end of the pandemic under a revised scenario, incorporating the proliferation of COVID-19 variants. Finally, I discuss the effectiveness of the inverse lockdown (economic stimulus) policy in the fall of 2021 under the dynamic infection externality.

Um dos elementos desestabilizadores da crise financeira internacional de2008 foi a amplificação de choques financeiros. A tendência natural dos agentes secomportarem de forma procíclica foi reforçada por meio de outros canais. Dessa forma,as medidas macroprudenciais ganharam maior destaque na busca pela estabilidadefinanceira. Este trabalho traz contribuições que buscam esclarecer os efeitos de determinados instrumentos de regulação macroprudencial sobre variáveis macroeconômicas e financeiras, com base em um modelo que introduz fricções na oferta de créditoem um arcabouço DSGE novo-keynesiano, estimado para a economia brasileira. Osresultados sugerem uma maior adequação do instrumento de política macroprudencial contracíclico no caso de choques que se originam no próprio sistema financeiroe choques de política monetária. No caso dos choques de oferta e de demanda, autilização do instrumento prudencial revela, na maioria das vezes, papel conflitanteaos objetivos da autoridade monetária e resultado não conclusivo a respeito dos benefícios sobre a estabilidade financeira. Na comparação entre os diferentes conceitos deciclo econômico, observa-se que uma maior cooperação da autoridade prudencial emrelação aos objetivos da política monetária é proporcionada quando se utiliza a relaçãoentre crédito e produto como referência para o acompanhamento do ciclo econômico., The international financial crisis of 2008 has made clear that the academicdebate should incorporate financial frictions to investigate business cycle fluctuationsand allocative efficiency. At the financial regulation side, macroprudential measureshave gained a growing importance as an instrument in the search for financial stability.The main objective of this thesis consists in the evaluation of the role of specific macroprudential policies within a new keynesian model incorporating a financial system withfrictions and adjustment costs estimated with Brazilian data. Parameters are estimated based on bayesian methods and time series from the Brazilian economy. As a relativelynew literature, the debate is more populated by questions and challenges than by conclusive answers. In this broad debate, this work aims to contribute for the understanding of the effects of some macroprudential policy instruments over relevant macroeconomic and financial variables. In what concerns specifically the countercyclical capitalbuffer, the analysis is extended to evaluate its contributions to the objectives pursuedby the prudenctial authority and, also, its coordination with monetary authority ones.

Die Modern Monetary Theory (MMT) ist eine empirische Geldtheorie und nutzt insbesondere Bilanzen und Buchungen als methodische Grundlage zur Erkenntnisgewinnung. Nach der funktionalen Ausgestaltung moderner Geldsysteme, in denen die Regierung keine Schulden in Auslandswährung hat oder einen festen Wechselkurs garantiert, handelt es sich bei modernem Geld im Grunde genommen um Steuergutschriften. Diese werden durch die Zentralbank als Monopolistin der Währung den teilnehmenden Banken gutgeschrieben, wenn z. B. die Regierung ihre Ausgaben erhöht. Damit fällt der Regierung eine fundamentale Rolle in der Wirtschaft zu. Vollbeschäftigung, Preisstabilität und nachhaltige Ressourcenbewirtschaftung sind ohne eine Theorie der fiskalpolitischen Steuerung wohl nicht zu erreichen. Einige Reformvorschläge mit dem Ziel der Erhöhung des Gemeinwohls, wie der Green New Deal oder das Euro Treasury, basieren auf MMT und könnten sich auch in der Eurozone relativ einfach umsetzen lassen. Modern Monetary Theory (MMT) is an empirical monetary theory and makes special use of balance sheets and booking entries as the methodological foundation of scientific progress. Regarding the functional design of modern monetary systems, in which the government has no debts in foreign currency nor guarantees a fixed exchange rate, modern money is essentially a tax credit. This is credited by the central bank as monopolist of the currency to the participating banks when, for example, the government increases spending. This means that the government has a fundamental role to play in the economy. Full employment, price stability and sustainable resource management are unlikely to be achieved without a theory of fiscal governance. Some reform proposals targeting the public purpose, such as the Green New Deal or the Euro Treasury, are based on MMT and could easily be implemented in the Eurozone.

Background: Human Papilloma Virus has been considered as the main cause for cervical cancer. In this study we investigated epigenetic changes and especially methylation of specific sites of HPV genome. The main goal was to correlate methylation status with histological grade as well as to determine its accuracy in predicting the disease severity by establishing optimum methylation cutoffs. Methods: In total, sections from 145 cases genotyped as HPV16 were obtained from formalin- fixed, paraffin-embedded tissue of cervical biopsies, conization or hysterectomy specimens. Highly accurate pyrosequencing of bisulfite converted DNA, was used to quantify the methylation percentages of UTR promoter, enhancer and 5' UTR, E6 CpGs 494, 502, 506 and E7 CpGs 765, 780, 790. The samples were separated in different groupings based on the histological outcome. Statistical analysis was performed by SAS 9.4 for Windows and methylation cutoffs were identified by MATLAB programming language. Results: The most important methylation sites were at the enhancer and especially UTR 7535 and 7553 sites. Specifically for CIN3+ (i.e. HSIL or SCC) discrimination, a balanced sensitivity vs. specificity (68.1%, 66.2% respectively) with positive predictive value (PPV) and negative predictive value (NPV) (66.2%, 68.2% respectively) was achieved for UTR 7535 methylation of 6.1% cutoff with overall accuracy 67.1%, while for UTR 7553 a sensitivity 60.9%, specificity 69.0%, PPV=65.6%, NPV=64.5% and overall accuracy=65.0% at threshold 10.1% was observed. Conclusion: Viral HPV16 genome was found methylated in NF-1 binding sites of UTR in cases with high grade disease. Methylation percentages of E6 and E7 CpG sites were elevated at the cancer group.

Ror2 (receptor tyrosine kinase like orphan receptor 2) is highly expressed in various types of cancers; in the majority of these cancers, Ror2 expression is associated with more aggressive disease states. Recently, it has been reported that Ror2 is highly expressed in human papilloma virus (HPV)‑positive head and neck squamous cell cancer (HNSCC) cell lines, presumably indicating that Ror2 plays a critical role in HPV‑related cancers. However, the function of Ror2 in HPV‑positive HNSCC is currently unknown. Here, we first examined the expression levels of Ror2 in clinical specimens from patients with HPV‑negative and HPV‑positive oropharyngeal squamous cell cancer (OPSCC) via immunohistochemical analysis. We found that Ror2 was expressed in both HPV‑negative and HPV‑positive OPSCC tissues. We then confirmed that HPV‑positive HNSCC cell line, UPCI:SCC152 cells, express Ror2 higher than HPV‑negative cell lines as previously reported. Suppressed expression of HPV E6/7 resulted in reduced expression levels of Ror2. We also revealed that Ror2 downregulation significantly inhibited the proliferation of UPCI:SCC152 cells without inducing apoptosis. Moreover, Ror2 knockdown decelerated G1/S phase progression and abrogated invasive migration of UPCI:SCC152 cells. These results provide strong evidence that E6 and/or E7 oncoproteins regulate the progression of HPV‑positive HNSCC by upregulating Ror2 expression, suggesting that Ror2 could potentially be a novel target in HPV‑related cancers.

Simple Summary Among the over 200 human papillomavirus (HPV) genotypes identified, approximately 15 of them can cause human cancers. In this review, we provided an updated overview of the distribution of cancer-causing HPV genotypes by countries in East, Southeast and South Asia. Besides the standard screening and treatment methods employed in these regions, we unravel HPV detection methods and therapeutics utilised in certain countries that differ from other part of the world. The discrepancies may be partly due to health infrastructure, socio-economy and cultural diversities. Additionally, we highlighted the area lack of study, particularly on the oncogenicity of HPV genotype variants of high prevalence in these regions. Abstract Human papillomavirus (HPV) infection remains one of the most prominent cancer-causing DNA viruses, contributing to approximately 5% of human cancers. While association between HPV and cervical cancers has been well-established, evidence on the attribution of head and neck cancers (HNC) to HPV have been increasing in recent years. Among the cancer-causing HPV genotypes, HPV16 and 18 remain the major contributors to cancers across the globe. Nonetheless, the distribution of HPV genotypes in ethnically, geographically, and socio-economically diverse East, Southeast, and South Asia may differ from other parts of the world. In this review, we garner and provide updated insight into various aspects of HPV reported in recent years (2015–2021) in these regions. We included: (i) the HPV genotypes detected in normal cancers of the uterine cervix and head and neck, as well as the distribution of the HPV genotypes by geography and age groups; (ii) the laboratory diagnostic methods and treatment regimens used within these regions; and (iii) the oncogenic properties of HPV prototypes and their variants contributing to carcinogenesis. More importantly, we also unveil the similarities and discrepancies between these aspects, the areas lacking study, and the challenges faced in HPV studies.

Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7., Immunotherapy for cervical cancer should target high-risk human papillomavirus types 16 and 18, which cause 50% and 20% of cervical cancers, respectively. Here, we describe the construction and characterization of the pBI-11 DNA vaccine via the addition of codon-optimized human papillomavirus 18 (HPV18) E7 and HPV16 and 18 E6 genes to the HPV16 E7-targeted DNA vaccine pNGVL4a-SigE7(detox)HSP70 (DNA vaccine pBI-1). Codon optimization of the HPV16/18 E6/E7 genes in pBI-11 improved fusion protein expression compared to that in DNA vaccine pBI-10.1 that utilized the native viral sequences fused 3′ to a signal sequence and 5′ to the HSP70 gene of Mycobacterium tuberculosis. Intramuscular vaccination of mice with pBI-11 DNA better induced HPV antigen-specific CD8+ T cell immune responses than pBI-10.1 DNA. Furthermore, intramuscular vaccination with pBI-11 DNA generated stronger therapeutic responses for C57BL/6 mice bearing HPV16 E6/E7-expressing TC-1 tumors. The HPV16/18 antigen-specific T cell-mediated immune responses generated by pBI-11 DNA vaccination were further enhanced by boosting with tissue-antigen HPV vaccine (TA-HPV). Combination of the pBI-11 DNA and TA-HPV boost vaccination with PD-1 antibody blockade significantly improved the control of TC-1 tumors and extended the survival of the mice. Finally, repeat vaccination with clinical-grade pBI-11 with or without clinical-grade TA-HPV was well tolerated in vaccinated mice. These preclinical studies suggest that the pBI-11 DNA vaccine may be used with TA-HPV in a heterologous prime-boost strategy to enhance HPV 16/18 E6/E7-specific CD8+ T cell responses, either alone or in combination with immune checkpoint blockade, to control HPV16/18-associated tumors. Our data serve as an important foundation for future clinical translation.

The incidence of human papillomavirus-positive head and neck squamous cell carcinoma (HPV+-HNSCC) has increased dramatically over the past decades due to an increase in infection of the oral mucosa by HPV. The etiology of HPV+-HNSCC is linked to expression of the HPV oncoprotein, E6, which influences tumor formation, growth and survival. E6 effects this oncogenic phenotype in part through inhibitory protein-protein interactions (PPIs) and accelerated degradation of proteins with tumor suppressor properties, such as p53 and caspase 8. Interfering with the binding between E6 and its cellular partners may therefore represent a reasonable pharmacological intervention in HPV+ tumors. In this study, we probed a small-molecule library using AlphaScreen™ technology to discover novel E6 inhibitors. Following a cascade of screens we identified and prioritized one hit compound. Structure activity relationship (SAR) studies of this lead uncovered an analog, 30-hydroxygambogic acid (GA-OH), that displayed improved activity. Further testing of this analog in a panel of HPV+ and HPV– cell lines showed good potency and a large window of selectivity as demonstrated by apoptosis induction and significant inhibition of cell growth, cell survival in HPV+ cells. In summary, GA-OH may serve as a starting point for the development of potent E6-specific inhibitors.

Background The E6 oncoproteins of human papillomavirus (HPV) 16/18 are the critical drivers of cervical cancer (CC) progression. Extracellular vesicles (EVs) are emerging as critical mediators of cancer-tumor microenvironment (TME) communication. However, whether EVs contribute to HPV 16/18 E6-mediated impacts on CC progression remains unclear. Methods A series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of EV-Wnt7b in HPV E6-induced CC angiogenesis. The prognostic value of serum EV-Wnt7b was determined and a predictive nomogram model was established. Results HPV 16/18 E6 upregulated Wnt7b mRNA expression in four HPV 16/18-positive CC cell lines and their EVs. In vitro and in vivo experiments demonstrated that EV-Wnt7b mRNA was transferred to and modulated human umbilical vein endothelial cells (HUVECs) toward more proliferative and proangiogenic behaviors by impacting β-catenin signaling. Clinically, serum EV-Wnt7b levels were elevated in CC patients and significantly correlated with an aggressive phenotype. Serum EV-Wnt7b was determined to be an independent prognostic factor for CC overall survival (OS) and recurrence-free survival (RFS). Notably, we successfully established a novel predictive nomogram model using serum EV-Wnt7b, which showed good prediction of 1- and 3-year OS and RFS. Conclusions Our results illustrate a potential crosstalk between HPV 16/18-positive CC cells and HUVECs via EVs in the TME and highlight the potential of circulating EV-Wnt7b as a novel predictive biomarker for CC prognosis.

Coronavirus (COVID‐19) pandemic has created an unprecedented loss and disruptions over all across the world. From developed to developing, no country has been spared from its brunt. In this paper, we have analyzed the implications of COVID‐19 on the economy and society of India so far. An impact assessment on the basis of available lietrature is made on all the three sectors—primary, secondary and service sector along with the impact on migrants, health, poverty, job losses, informal sector, environment, and so forth. The all sectors of the economy has been disproportionately affected and even within a sector, there is a disproportionate loss. The societal impacts are dire too with job losses, mental illness, increased domestic violence, and so forth. Some positive effects can be seen in terms of improved air quality, water quality, wildlife but the sustainability of such impact is conditional upon post‐COVID and people's habits and future policies related to the environment.

Background Variations in human papillomavirus (HPV) E6 and E7 have been shown to be closely related to the persistence of the virus and the occurrence and development of cervical cancer. Long control region (LCR) of HPV has been shown multiple functions on regulating viral transcription. In recent years, there have been reports on E6/E7/LCR of HPV-16 and HPV-58, but there are few studies on HPV-52, especially for LCR. In this study, we focused on gene polymorphism of the HPV-52 E6/E7/LCR sequences, assessed the effects of variations on the immune recognition of viral E6 and E7 antigens, predicted the effect of LCR variations on transcription factor binding sites and provided more basic date for further study of E6/E7/LCR in Chengdu, China. Methods LCR/E6/E7 of the HPV-52 were amplified and sequenced to do polymorphic and phylogenetic analysis. Sequences were aligned with the reference sequence by MEGA 7.0 to identify SNP. A neighbor-joining phylogenetic tree was constructed by MEGA 7.0, followed by the secondary structure prediction of the related proteins using PSIPRED 4.0. The selection pressure of E6 and E7 coding regions were estimated by Bayes empirical Bayes analysis of PAML 4.9. The HLA class-I and II binding peptides were predicted by the Immune Epitope Database server. The B cell epitopes were predicted by ABCpred server. Transcription factor binding sites in LCR were predicted by JASPAR database. Results 50 SNP sites (6 in E6, 10 in E7, 34 in LCR) were found. From the most variable to the least variable, the nucleotide variations were LCR > E7 > E6. Two deletions were found between the nucleotide sites 7387–7391 (TTATG) and 7698–7700 (CTT) in all samples. A deletion was found between the nucleotide sites 7287–7288 (TG) in 97.56% (40/41) of the samples. The combinations of all the SNP sites and deletions resulted in 12 unique sequences. As shown in the neighbor-joining phylogenetic tree, except for one belonging to sub-lineage C2, others sequences clustered into sub-lineage B2. No positive selection was observed in E6 and E7. 8 non-synonymous amino acid substitutions (including E3Q and K93R in the E6, and T37I, S52D, Y59D, H61Y, D64N and L99R in the E7) were potential affecting multiple putative epitopes for both CD4+ and CD8+ T-cells and B-cells. A7168G was the most variable site (100%) and the binding sites for transcription factor VAX1 in LCR. In addition, the prediction results showed that LCR had the high probability binding sites for transcription factors SOX9, FOS, RAX, HOXA5, VAX1 and SRY. Conclusion This study provides basic data for understanding the relation among E6/E7/LCR mutations, lineages and carcinogenesis. Furthermore, it provides an insight into the intrinsic geographical relatedness and biological differences of the HPV-52 variants, and contributes to further research on the HPV-52 therapeutic vaccine development.

Este trabalho analisa o nível de bem-estar dos brasileiros por meio de informações contidas napesquisa de opinião pública Latinobarómetro. Com uma amostra de 11.767 brasileiros, estima-se modelos Logit ordenado considerando o plano amostral e uma possível heterogeneidade regional.Os resultados vão ao encontro da literatura nacional e internacional, em que a taxa de desemprego e taxa de inflação são relevantes na determinação do bem-estar sendo que a taxa de desempregado é relativamente mais importante para os brasileiros. Já a consideração do plano amostral mostrou-se relevante ao evitar valores superestimados e efeitos sobre os trade-off inflação-desemprego, e uma inexistente diferença relativa à região nordeste., This paper analyzes the level of well-being of Brazilians through informationcontained in the Latinobarómetro public opinion survey. We use a sample of 11,767Brazilians to estimate ordered Logit models, considering the sampling plan and a possibleregional heterogeneity. The results are in line with the national and internationalliterature, where the unemployment rate and inflation rate are relevant in determiningwell-being, and the unemployment rate is relatively more important for Brazilians. Alreadythe consideration of the sample plan was relevant, avoiding overestimated valuesand effects on inflation-unemployment trade-off, and a nonexistent difference relativeto the Brazilian region Nordeste.

Cutaneous papillomaviruses can cause severe, persistent infections and skin cancer in immunodeficient patients, including people with X-linked severe combined immunodeficiency (XSCID). A similar phenotype is observed in a canine model of XSCID, these dogs acquire severe cutaneous papillomavirus infections that can progress to cancer in association with canine papillomavirus type 2 (CPV2). This canine model system provides a natural spontaneous animal model for investigation of papillomavirus infections in immunodeficient patients. Currently, it is unknown if CPV2 can subvert the innate immune system and interfere with its ability to express antiviral cytokines, which are critical in the host defense against viral pathogens. The aim of the current study was to determine if the oncogenes E6 and E7 from CPV2 interfere with expression of antiviral cytokines in keratinocytes, the target cells of papillomavirus infections. We determined that E6 but not E7 interferes with the constitutive expression of some antiviral cytokines, including interferon (IFN)-&beta, and the IFN-stimulated gene IFIT1. Both E6 and E7 interfere with the transcriptional upregulation of the antiviral cytokines in response to stimulation with the dsDNA Poly(dA:dT). In contrast, while E6 also interferes with the transcriptional upregulation of antiviral cytokines in response to stimulation with the dsRNA Poly(I:C), E7 interferes with only a subset of these antiviral cytokines. Finally, we demonstrated that E7 but not E6 abrogates signaling through the type I IFN receptor. Taken together, CPV2 E6 and E7 both impact expression of antiviral cytokines in canine keratinocytes, albeit likely through different mechanisms.

The explosion of the pandemic has been optimistically considered as the “last straw that breaks the camel’s back”. At the time of writing, after three months since its outburst, we can hardly find any sign of a “broken camel”: indeed, it could have been the opportunity to collectively question the current regime of production and appropriation, exclusion and marketization characterizing this phase of unjust “rentified capitalism”, but the route taken has largely seen a frightening combination of “business as usual” on the production side and pervasive forms of social control, limitations of individual and collective rights and the perpetuation of a false dichotomy between economic and health security. This pandemic, which under decent public health provisions might have been a controlled disease, is producing the most severe crisis after the Great Depression and has been used to implement forms of massive social control hardly conceivable in “advanced democracies”. Butterfly effects are well-known in complexity sciences. However, social scientists have still difficulties in understanding how a grain can make the sandcastle fall down. On the contrary, we are now under the actual risk of starting a “new normal” without dealing with the deep routes and origins of this crisis, with the dominant intellectual discourse pushing for maintaining and indeed reinforcing the status quo, established power and social blocks. This myopic strategy might end up in collectively disruptive socio-political transformations.

Human papillomavirus refers to DNA-containing viruses and infects the skin and mucosal epithelium. One common way is to change the expression of cellular genes by integrating the viral genome into cellular DNA. The reason for the resistance of HPV infection is the presence of complex mechanisms of inhibiting the immune response of the macroorganism. An important infectious agent involved in carcinogenesis are human papillomavirus (HPV) viruses, which cause a significant part of oncological diseases. Viruses create the prerequisites for malignant cells by introducing an oncogene or blockade of suppressor proteins in cells to disrupt the regulation of cell division. Two proteins, E6 and E7, encoded by the DNA of the virus, play a leading role in this process. More than 100 different types of HPV have been identified, and approximately one- third of them infect epithelial cells in the genital tract. HPV is also the cause of carcinoma of the penis, vulva, anus and contribute to the occurrence of more than 40 % of oropharyngeal cancer. To date, the most effective way to combat HPV infection is immunoprophylaxis. To date, there are three commercially available HPV vaccines: Cervarix®, Gardasil®, Gardasil®9. These three vaccines effectively prevent HPV infections, causing the production of neutralizing antibodies that bind to viral particles and block their entry into host cells. However, these vaccines are not effective in eliminating pre-existing infections. Currently, there are no therapeutic vaccines against HPV, approved for use in humans. The review discusses the types of vaccines against HPV infection and the effectiveness of vaccination.

Infection with HPV starts with the access of the viral particles to basal cells in the epidermis, potentially via microtraumas to the skin. The basal cells are able to keep away these pathogens in normal circumstances through a robust immune response from the host, as HPV infections are, in general, cleared within 2 to 3 weeks. However, the rare instances of persistent infection and/or in cases where the host immune system is compromised are major risk factors for the development of lesions potentially leading to malignancy. Evolutionarily, obligatory pathogens such as HPVs would not be expected to risk exposing the host to lethal cancer, as this would entail challenging their own life cycle, but infection with these viruses is highly correlated with cancer and malignancy—as in cancer of the cervix, which is almost always associated with these viruses. Despite this key associative cause and the availability of very effective vaccines against these viruses, therapeutic interventions against HPV-induced cancers are still a challenge, indicating the need for focused translational research. In this review, we will consider the key roles that the viral proteins play in driving the host cells to carcinogenesis, mainly focusing on events orchestrated by early proteins E5, E6 and E7—the not-so-good, the bad and the ugly—and discuss and summarize the major events that lead to these viruses mechanistically corrupting cellular homeostasis, giving rise to cancer and malignancy.

Persistent infection with the human papillomavirus 16 (HPV 16) is the cause of half of all cervical carcinomas (CC) cases. Moreover, mutations in the oncoproteins E6 and E7 are associated with CC development. In this study, E6/E7 variants circulating in southern Mexico and their association with CC and its precursor lesions were evaluated. In total, 190 DNA samples were obtained from scrapes and cervical biopsies of women with HPV 16 out of which 61 are from patients with CC, 6 from patients with high-grade squamous intraepithelial lesions (HSIL), 68 from patients with low-grade squamous intraepithelial lesions (LSIL), and 55 from patients without intraepithelial lesions. For all E7 variants found, the E7-C732/C789/G795 variant (with three silent mutations) was associated with the highest risk of CC (odd ratio (OR) = 3.79, 95% confidence interval (CI) = 1.46–9.85). The analysis of E6/E7 bicistron conferred to AA-a*E7-C732/C789/G795 variants revealed the greatest increased risk of CC (OR = 110, 95% CI = 6.04–2001.3), followed by AA-c*E7-C732/C789/G795 and A176/G350*E7-p. These results highlight the importance of analyzing the combinations of E6/E7 variants in HPV 16 infection and suggest that AA-a*E7-C732/C789/G795, AA-c*E7-C732/C789/G795, and A176/G350*E7-p can be useful markers for predicting CC development.

Decades of research on the human papillomavirus oncogenes, E6 and E7, have given us huge amounts of data on their expression, functions and structures. We know much about the very many cellular proteins and pathways that they influence in one way or another. However, much of this information is quite discrete, referring to one activity examined under one condition. It is now time to join the dots to try to understand a larger picture: how, where and when do all these interactions occur... and why? Examining these questions will also show how many of the yet obscure cellular processes work together for cellular and tissue homeostasis in health and disease.

We propose a dynamic non-cooperative framework for long-term-care (LTC) decisions of families and use it to evaluate LTC policy options for the U.S. We firs document the importance of informal caregiving and economic determinants of care arrangements. We then build a heterogeneous-agents model with imperfectly-altruistic overlapping generations to account for the patterns we find A key innovation is the availability of informal care (IC), which is determined through intra-family bargaining. This opens up a new margin in response to policy and allows for informal insurance through home-production of care. Our calibrated model captures the observed care arrangements well. We study the implications of non-means-tested IC and formal care (FC) subsidies as well as changes to means-tested Medicaid. We fin that IC responds strongly to these policies. An IC subsidy substantially reduces reliance on Medicaid, while the reduction of tax revenues due to lower labour supply by caregivers is modest. There are large welfare gains from a combination of IC and FC subsidies, even when combined with a reduction of the Medicaid program. M.K. acknowledges research funding by the Fundación Ramón Areces, by the Spanish Ministerio de Economía y Competitividad, grants [ECO2012-34581], [ECO2015-68615-P], and [MDM 2014-0431], and Comunidad de Madrid, MadEco-CM (S2015/HUM-3444).

This study empirically investigates the short- to medium-term effects of fiscal policy on output and other macroeconomic variables in European Union countries between 1995 and 2012, with particular reference to transition countries. It applies Panel Vector Auto Regression with recursive identification of government spending shocks as the most appropriate method for the aim of the study and the sample used. The main results indicate that expansionary spending shocks have a positive, but a relatively low effect on output, with the fiscal multiplier around one in the year of the shock and the following year, and lower thereinafter. There are indications that this result is driven by the recent crisis, as multipliers are considerably lower in the pre-crisis period. Effects of fiscal policy are strongly dependent on country structural characteristics. Fiscal multipliers are higher in new European Union member states, in countries with low public debt and low trade openness. Further, spending shocks are followed by rising debt levels in old member states, which could be related well to the recent European debt crisis. Finally, the analysis of the transmission mechanism of fiscal policy yields results that are consistent with both extended Real Business Cycle models and extended New Keynesian models.

// Lu Dai 1, 2, 4 , Yueyu Cao 2 , Wei Jiang 3 , Jovanny Zabaleta 5 , Zhongmin Liu 2 , Jing Qiao 1 , Zhiqiang Qin 1, 2, 4 1 Department of Pediatrics, East Hospital, Tongji University School of Medicine, Shanghai 200120, China 2 Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai 200120, China 3 Department of Microbiology and Immunology, Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA 4 Departments of Genetics Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA 70112, USA 5 Pediatrics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA 70112, USA Correspondence to: Jing Qiao, email: qiaoj123@hotmail.com Zhiqiang Qin, email: zqin@lsuhsc.edu Keywords: HPV, KSHV, E6, E7, microRNA Received: February 14, 2017 Accepted: March 07, 2017 Published: March 15, 2017 ABSTRACT High-risk human papillomavirus (HPV) infection is the etiological agent of some malignancies such as cervical, oral and oropharyngeal cancers. Kaposi sarcoma-associated herpesvirus (KSHV) represents a principal causative agent of several human cancers arising in those immunocompromised patients. Interestingly, KSHV DNA has been detected in the oral cavity and the female genital tract, although its detection rate in cervical samples is very low and few reports are about KSHV/HPV co-infection. Therefore, it remains unclear about the role of KSHV co-infection in the development of HPV-related neoplasias. In the current study, we report that HPV16-integrated cervical cancer cell-line SiHa is susceptible to KSHV latent infection and replication. We also have found that KSHV infection or viral latent proteins are capable of reducing HPV16 E6/E7 expression through the manipulation of cellular microRNA function. Array analysis indicates that KSHV infection induces some inflammatory cytokines/chemokines production as well as up-regulates a series of interferon-induced genes expression, which may facilitate host immune defense system attacking these co-infected cells and clearance of viruses. Together, our data have provided possible explanations for very low detection rate of KSHV shedding as well as of KSHV/HPV co-infection in cervical samples and/or cervical cancer cells.

Cellular immune responses play a critical role in the eradication of intracellular infections and malignant cells through the recognition and subsequent removal of the infection or malignant cells. Effective antigen presentation is crucial for stimulating the immune system against malignant cells. Calreticulin (CRT) has been used to improve antigen presentation. However, CRT overexpression has been previously associated with the development of pancreatic and breast cancer. The import and retention signals of CRT in the endoplasmic reticulum (ER) can be used to overcome CRT overexpression. The present study describes the potent antitumor effect of a DNA vaccine encoding human papillomavirus type 16 E6 and E7 antigens flanked by ER import and retention signals (SP-E6E7m-KDEL). The effect of this vaccine was compared with that of E6 and E7 antigens fused to human full-length CRT (hCRT-E6E7m). In the present study, the effectiveness of SP-E6E7m-KDEL for inducing an interferon-γ antigen-specific, response and its therapeutic effect against tumors was demonstrated, which was as effective as immunization against those antigens fused to CRT. This simplified strategy, using ER import and retention signal peptides to direct antigens to this organelle, provides an efficient alternative to traditional vaccines and, more importantly, a safe and potent system to induce a therapeutic antitumor response.

Background Increasing evidence indicates an etiological role of human papillomavirus (HPV) in head and neck cancers, particularly oropharyngeal squamous cell carcinoma (OPSCC). However, the association between HPV and other cancers, including esophageal and tongue remains unclear. This study delineated the molecular characteristics of HPV18 E6 and E7 in esophageal (EC109 and EC9706) and tongue (Tca83) cancer cell lines with reference to cervical cancer (HeLa). Methods We analysed the HPV transcription profiles of esophageal and tongue cancer cells through Next-generation RNA sequencing, and the role of HPV18 E6 and E7 in these cells was assessed via siRNA approach, Western blotting and immunofluorescence assays. Results Overall, the HPV transcription profiles of esophageal and tongue cancer cells mimicked that of cervical cancer cells, with notable disruption of E2, and expression of E6, spliced E6 (E6*), E7, E1 and L1 transcripts. As with cervical cancer cells, p53 and its downstream transactivation target, p21, were found to be the major targets of E6 in esophageal and tongue cancer cell lines. Intriguingly, E7 preferentially targeted p130 in the two esophageal cancer cell lines, instead of pRb as in cervical cancer. Tca83 exhibited an E7 to E6 transcript ratio comparable to HeLa (cervix), targeted the ERK1/2 and MMP2 pathways, and was dependent on E6 and E7 to survive and proliferate. In contrast, both the esophageal cancer cell lines were distinct from HeLa in these aspects. Conclusions This is the first study that delineates transcript expression and protein interaction of HPV18 E6 and E7 in esophageal and tongue cancer cell lines, suggesting that HPV plays a role in inducing these cancers, albeit via distinct pathways than those observed in cervical cancer.

Continuous human papillomavirus (HPV) infection is a critical cause of cervical lesions; however, the specific mechanism is currently not clear. E6 is one of the most important oncoproteins associated with HPV, which regulates synthases in the production of prostaglandin E2 (PGE2). Notably, PGE2 has been reported to be upregulated in cervical lesions. An insufficient number of mature dendritic cells (DCs), which is unable to cause an effective immune response, is an important cause of cervical lesions. Therefore, this study explored the possible causes of HPV16-positive cervical lesions by identifying the relationship between E6, PGE2 and DCs. Firstly, the distribution and status of DCs in clinical biopsy specimens and animal models were analyzed with immuno-histochemistry and flow cytometry, which demonstrated that the migratory ability of DCs was inhibited in HPV16-positive cervical lesions. Furthermore, using immunohistochemistry, western blotting and ELISA, it was revealed that as the degree of cervical lesions increased, the expression of PGE2 and its synthases increased. Subsequently, as determined using Transwell and 3D migration assays, it was revealed that a high concentration of PGE2 inhibited the migration of DCs, which may explain the phenomenon observed in cervical lesions. Notably, E6 was identified to regulate PGE2 expression. The in vivo experiments indicated that E6 may increase the expression levels of PGE2 in cervical lesions, which could eventually induce inhibition of the migration of DCs. In conclusion, the present study suggested that E6 regulated overproduction of PGE2, which may induce inhibition of DC migration in HPV16-positive cervical lesions.

Papillomaviruses infect vertebrate epithelia and induce squamous papillomas in order to replicate. The papillomavirus E6 oncoprotein is important not only in maintenance of the papillomavirus genome but also in disrupting cellular functions to enable viral genome replication. E6 proteins exert their function by interacting with cellular proteins, one of which is the E3 ubiquitin ligase E6AP via its LXXLL motif (LQELL). E6 proteins from high- risk papillomaviruses hijack E6AP ubiquitin ligase activity to target the degradation of cellular p53, along with other cellular proteins. E6 proteins from low-risk papillomaviruses can bind E6AP and stimulate its ubiquitin ligase activity, but cellular degradation targets of the low-risk E6-E6AP complex are unclear. A cellular protein targeted for degradation by both the high and low-risk E6-E6AP complex has yet to be described. Although stimulating the ubiquitin ligase activity of E6AP is an important function of these E6AP-interacting E6 proteins, little is known regarding the precise mechanism(s) responsible. Finally, although both high and low-risk E6 proteins can bind full-length E6AP, only high-risk E6 can bind the short LQELL E6AP peptide. This indicates that there may be other regions within the E6AP protein that are important in mediating the formation of the E6- E6AP complex outside of the well-characterized E6AP LQELL motif. In this dissertation we describe an E6AP-dependent degradation target common to both high and low-risk E6 proteins: NHERF1. The targeted degradation of NHERF1 by E6AP-binding E6 proteins is not only conserved among high and low-risk E6 proteins, but also among E6 proteins from papillomaviruses discovered in other vertebrate mammals. We identify a novel region within E6 that is required for NHERF1 degradation as well as a domain in NHERF1 that is both necessary and sufficient for E6-mediated degradation. We further find that E6 degradation of NHERF1 augments canonical Wnt/beta-catenin, a complex signaling pathway involved in regulating cell proliferation. In this thesis we also examine regions within E6AP, outside of the LQELL motif, that are important in mediating the E6-E6AP interaction (which we termed E6AP auxiliary regions). We further identify one of these auxiliary regions as being required for both high and low-risk E6 proteins to stimulate E6AP E3 ubiquitin ligase activity to initiate degradation of cellular proteins. Our findings indicate there are two types of E6-E6AP interactions: those that can bind the isolated E6AP LQELL motif (Type I) and those that cannot and instead depend more heavily on E6AP auxiliary regions (Type II). Overall, our work has numerous therapeutic implications as NHERF1 may serve as a viable target for both high and low-risk infections and our identification of E6AP auxiliary regions will inform the design of therapies directed at disrupting the interaction of E6 and E6AP.

Keratinocyte infection with high-risk human papillomavirus genotypes has been linked to cancer development. In cervix, the alpha HPV16 and HPV18 have been reported as the mayor causative agents of cervical cancer. Oncogenic progression and chronic inflammation are closely related processes, with IL-6 as one of the main pro-inflammatory cytokines involved. However, there are limited studies about the regulation of IL-6 by low and high risk HPVs and the HPV proteins implicated in this modulation. In this work, we report the overexpression of IL-6 in HPV infected cervical cancer derived cell lines (HeLa and SiHa) compared to non-tumorigenic keratinocytes (HaCaT), and in Cervical Intraepithelial Neoplasia grade 1 HPV16 and HPV18 positive cervical samples compared to HPV negative samples without lesions. Moreover, we generated HaCaT keratinocytes that express E5, E6, and E7 from high risk (16 or 18) or low risk (62 and 84) HPVs. E5 proteins do not modify IL-6 expression, while E7 modestly increase it. Interestingly, E6 proteins in HaCaT cells upregulate IL-6 mRNA expression and protein secretion. Indeed, in HaCaT cells that express high risk HPV16E6 or HPV18E6 proteins, only the truncated E6* isoforms were expressed, showing the stronger IL-6 overexpression, while in HaCaT cells that express low risk HPV62 and HPV84 full length E6 proteins, IL-6 was also upregulated but not so drastically. Since HaCaT cells have a mutated p53 form that is not degraded by the introduction of E6 or E6/E7, it seems that E6/E7 regulate IL-6 by an additional mechanism independent of p53. In addition, basal keratinocytes showed a strong expression of IL-6R using immunohistochemistry, suggesting an autocrine mechanism over proliferative cells. Altogether, IL-6 cytokine expression in keratinocytes is upregulated by E6 and E7 proteins from HPVs 16, 18, 62, and 84, especially by high risk HPV16 and HPV18 E6*, which may contribute to promote a pro-inflammatory and highly proliferative microenvironment that can persist over time and lead to cervical tumorigenesis.

This paper discusses three long-term forces that are acting on the global economy and their implications for companies and policy-makers., La présente étude traite de trois forces de long terme qui agissent sur l’économie mondiale, ainsi que de leurs conséquences pour les entreprises et les décideurs.

High-risk human papillomavirus (HPV) is a common cause of cervical cancer. HPV E6 oncoprotein promotes the degradation of host tumor suppressor gene p53, leading to the development of tumors. Therapeutic strategies that specifically target E6, which is constitutively expressed in tumors and is not present in normal tissues, may be highly effective and safe. CRISPR-CRISPR associated protein 9 (Cas9) is one of the genome editing technologies that has recently garnered attention, and is used to knockout target gene expression. By combining cervical cancer cell lines engineered to constitutively express Cas9 and an adeno-associated virus (AAV) vector carrying a single guide (sg) RNA targeting E6 (AAV-sgE6), the present study sought to investigate the effects of this novel therapeutic approach on cervical cancer. The Cas9 gene was transfected into three high-risk HPV-positive cervical cancer cell lines (HeLa, HCS-2, and SKG-I) to establish cell lines that constitutively expressed Cas9. Using these cell lines, genetic mutations and their frequencies, as well as the levels of protein expression, apoptosis and cell proliferation were examined in vitro. In addition, the effects of AAV-sgE6 were examined in a mouse model of cervical cancer in vivo by a single administration of AAV-sgE6 directly into subcutaneous tumors. The results demonstrated that multiple mutations occurred frequently in the targeted E6 genomic sequence in cervical cancer cells transduced with AAV-sgE6. In addition, these AAV-sgE6-transduced cells had reduced expression of E6, increased expression of p53, increased apoptosis and their growth was suppressed in a concentration-dependent manner. Furthermore, subcutaneous tumor growth was significantly suppressed in vivo following intratumoral administration of AAV-sgE6, and adverse events due to AAV-sgE6 administration were not observed. Collectively, the present results indicated that targeting E6 expression in high-risk HPV by CRISPR-Cas9 is a highly specific and effective strategy that may be effective in treating patients with cervical cancer.

Major epidemics of the last two decades (SARS, H1N1, MERS, Ebola, and Zika) have been followed by increases in inequality [Furceri et al. (2020), COVID Economics, 12, 138–157]. In this article, we show that the extent of fiscal consolidation in the years following the onset of these pandemics has played an important role in determining the extent of the increase in inequality. Episodes marked by extreme austerity—measured using either the government’s fiscal balance, health expenditures, or redistribution—have been associated with an increase in the Gini measure of inequality three times as large as in episodes where fiscal policy has been more supportive. We survey the evidence thus far on the distributional impacts of the COVID-19 pandemic, which suggests that inequality is likely to increase in the absence of strong policy actions. We review the case made by many observers [IMF (2020), Fiscal Monitor; Stiglitz (2020), Finance & Development, Fall 2020; Sandbu (2020b), Financial Times, 26 November 2020)] that fiscal support should not be withdrawn prematurely despite understandable concerns about high public debt-to-GDP ratios.

The Limits of Mexico’s Social Policy During the Sexenium of Pena Nieto Resumen ?Existia a principios de la administracion del Presidente Pena una posicion definida por parte de la Secretaria de Hacienda y Credito Publico (SHCP) respecto a los instrumentos de politica economica y social que permitirian a la economia del pais crecer a una tasa promedio anual cercana a su nivel potencial, estimado en hasta 4.5%? ?Contaba con el suficiente radio de maniobra para que esta cifra se alcanzara sin afectar aun mas las condiciones de desigualdad y mala distribucion del ingreso de la poblacion? Los documentos de politica economica y social que a partir de 2011 definieron las lineas de la administracion, y en cuya redaccion estuvo directamente involucrado el equipo que se encuentra al frente de dicha Secretaria, evidencian al menos tres limitaciones que se extenderan hasta el final del sexenio: la subordinacion del crecimiento economico a la elevacion de la productividad; la omision de una politica laboral, y el abandono definitivo, a partir de 2015, de una politica de seguridad social universal (SSU), junto con un esfuerzo serio por promover la recuperacion del salario minimo y con ello el consumo interno. Abstract Has had the Pena administration’s Secretariat of Finance and Public Credit (SHCP) a defined position regarding the economic and social policy instruments that may have allowed the economy to grow at an average annual rate close to its potential rate, estimated up to 4.5 %? Has the institution had enough room of maneuver to make this happen without more seriously affecting the conditions of inequality and maldistribution of income that people face? The economic policy documents that defined most of Pena’s administration curse from 2011 onwards, in which writing involved the team that leads such a Secretariat, show at least three limitations that have been present and will remain so up to the end of the sexenium: the subordination of economic growth to rising productivity; the lack of a labor policy, and the absolute declination, in 2015, of a universal social security policy (SSU), coupled with a serious effort to promote the recuperation of the minimum wage and then internal consumption.

Made available in DSpace on 2018-11-26T16:54:55Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-09-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Annexin 1 (ANXA1) is a substrate for E6AP mediated ubiquitylation. It has been hypothesized that HPV 16 E6 protein redirects E6AP away from ANXA1, increasing its stability and possibly contributing to viral pathogenesis. We analyzed ANXA1 expression in HPV-positive and negative cervical carcinoma-derived cells, in cells expressing HPV-16 oncogenes and in cells transduced with shRNA targeting E6AP. We observed that ANXA1 protein expression increased in HPV-16-positive tumor cells, in keratinocytes expressing HPV-16 E6wt (wild-type) or E6/E7 and C33 cells expressing HPV-16 E6wt. ANXA1 protein expression decreased in cells transfected with E6 Dicer-substrate RNAs (DsiRNA) and 03 cells co-transduced with HPV-16 E6wt and E6AP shRNA. Moreover, colony number and proliferation rate decreased in HPV16-positive cells transduced with ANXA1 shRNA. We observed that in cells infected with HPV16, the E6 binds to E6AP to degrade p53 and upregulate ANXA1. We suggest that ANXA1 may play a role in HPV-mediated carcinogenesis. (C) 2016 Elsevier Inc. All rights reserved. Sao Paulo State Univ, Dept Biol, Inst Biosci Language & Exact Sci, Sao Jose Do Rio Preto, Brazil ICESP, Ctr Translat Res Oncol, Mol Biol Lab, Sao Paulo, Brazil Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo, Brazil Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, Sao Paulo, Brazil Sao Paulo State Univ, Dept Biol, Inst Biosci Language & Exact Sci, Sao Jose Do Rio Preto, Brazil FAPESP: 2009/11203-4

Felis catus papillomavirus type 2 (FcaPV2) DNA is found in feline cutaneous squamous cell carcinomas (SCCs); however, its biological properties are still uncharacterized. In this study, we successfully expressed FcaPV2 E6 and E7 putative oncogenes in feline epithelial cells and demonstrated that FcaPV2 E6 binds to p53, impairing its protein level. In addition, E6 and E7 inhibited ultraviolet B (UVB)-triggered accumulation of p53, p21 and pro-apoptotic markers such as Cleaved Caspase3, Bax and Bak, suggesting a synergistic action of the virus with UV exposure in tumour pathogenesis. Furthermore, FcaPV2 E7 bound to feline pRb and impaired pRb levels, resulting in upregulation of the downstream pro-proliferative genes Cyclin A and Cdc2. Importantly, we demonstrated mRNA expression of FcaPV2 E2, E6 and E7 in feline SCC samples, strengthening the hypothesis of a causative role in the development of feline SCC.

Overexpression of Aurora A kinase occurs in certain types of cancer, and therefore results in chromosome instability and phosphorylation-mediated ubiquitylation and degradation of p53 for tumorigenesis. The high-risk subtype human papillomavirus (HPV)16 early oncoprotein E6 is a major contributor inducing host cell immortalization and transformation through interaction with a number of cellular factors. In the present study, co-immunoprecipitation, glutathione S-transferase pull-down and immunostaining were used to show that HPV16 E6 and Aurora A bind to each other in vivo and in vitro. Western blotting and reverse transcription-polymerase chain reaction were used to reveal that HPV16 E6 inhibited cell apoptosis by stabilizing Aurora A expression. The present study may report a new mechanism for the involvement of HPV16 E6 in carcinogenesis, as HPV16 E6 elevates Aurora A expression and the latter may be a common target for oncogenic viruses that result in cell carcinogenesis.