Microbiome and cancer: from mechanistic implications in disease progression and treatment to development of novel antitumoral strategies.

Cancer is a very aggressive disease and one of mankind's most important health problems, causing numerous deaths each year. Its etiology is complex, including genetic, gender-related, infectious diseases, dysbiosis, immunological imbalances, lifestyle, including dietary factors, pollution etc. Cancer patients also become immunosuppressed, frequently as side effects of chemotherapy and radiotherapy, and prone to infections, which further promote the proliferation of tumor cells. In recent decades, the role and importance of the microbiota in cancer has become a hot spot in human biology research, bringing together oncology and human microbiology. In addition to their roles in the etiology of different cancers, microorganisms interact with tumor cells and may be involved in modulating their response to treatment and in the toxicity of anti-tumor therapies. In this review, we present an update on the roles of microbiota in cancer with a focus on interference with anticancer treatments and anticancer potential.

The Vermiform Appendix and Its Pathologies.

The vermiform appendix is a muscular cylindrical structure originating near the junction of the cecum and ileum, averaging 9 cm (5-35 cm) in size. As the most mobile viscera, it can adopt several positions, the most common being the retrocecal position. Perceived as an atavistic organ lacking physiological relevance, the vermiform appendix appears to be involved in immune function, serving in the maturation of B lymphocytes and the production of immunoglobulin A, in endocrine function, excreting amines and hormones in the 2-3 mL of mucus secreted daily, and in digestive function, by storing beneficial bacteria from where they can recolonize the colon. With a lumen of about 6 mm, the vermiform appendix has a reduced storage capacity, so any blockage of the appendix with fecoliths (fecaliths), seeds derailed from the colon, or enlarged lymph nodes prevents drainage and intraluminal accumulation of secreted mucus. Unable to relax, the appendix wall severely limits its intraluminal volume, so mucus accumulation leads to inflammation of the appendix, known generically as appendicitis. In addition, the vermiform appendix may be the site of the development of neoplastic processes, which may or may not involve mucus production, some of which can significantly affect the standard of living and ultimately lead to death. In general, mucinous tumors may have a better prognosis than non-mucinous tumors. This review takes a comprehensive path, starting by describing the anatomy and embryology of the vermiform appendix and further detailing its inflammatory pathologies, pathologies related to congenital anomalies, and appendix tumors, thus creating an up-to-date framework for better understanding, diagnosis, and treatment of these health problems.

Landscape of Genetic Mutations in Appendiceal Cancers.

In appendiceal cancers, the most frequently mutated genes are (i) KRAS, which, when reactivated, restores signal transduction via the RAS-RAF-MEK-ERK signaling pathway and stimulates cell proliferation in the early stages of tumor transformation, and then angiogenesis; (ii) TP53, whose inactivation leads to the inhibition of programmed cell death; (iii) GNAS, which, when reactivated, links the cAMP pathway to the RAS-RAF-MEK-ERK signaling pathway, stimulating cell proliferation and angiogenesis; (iv) SMAD4, exhibiting typical tumor-suppressive activity, blocking the transmission of oncogenic TGFB signals via the SMAD2/SMAD3 heterodimer; and (v) BRAF, which is part of the RAS-RAF-MEK-ERK signaling pathway. Diverse mutations are reported in other genes, which are part of secondary or less critical signaling pathways for tumor progression, but which amplify the phenotypic diversity of appendiceal cancers. In this review, we will present the main genetic mutations involved in appendix tumors and their roles in cell proliferation and survival, and in tumor invasiveness, angiogenesis, and acquired resistance to anti-growth signals.

Role of interferons in the antiviral battle: from virus-host crosstalk to prophylactic and therapeutic potential in SARS-CoV-2 infection.

Mammalians sense antigenic messages from infectious agents that penetrate the respiratory and digestive epithelium, as well as signals from damaged host cells through membrane and cytosolic receptors. The transduction of these signals triggers a personalized response, depending on the nature of the stimulus and the host's genetics, physiological condition, and comorbidities. Interferons (IFNs) are the primary effectors of the innate immune response, and their synthesis is activated in most cells within a few hours after pathogen invasion. IFNs are primarily synthesized in infected cells, but their anti-infective effect is extended to the neighboring cells by autocrine and paracrine action. The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 2019 was a stark reminder of the potential threat posed by newly emerging viruses. This pandemic has also triggered an overwhelming influx of research studies aiming to unveil the mechanisms of protective versus pathogenic host immune responses induced by SARS-CoV-2. The purpose of this review is to describe the role of IFNs as vital players in the battle against SARS-CoV-2 infection. We will briefly characterize and classify IFNs, present the inductors of IFN synthesis, their sensors, and signaling pathways, and then discuss the role of IFNs in controlling the evolution of SARS-CoV-2 infection and its clinical outcome. Finally, we will present the perspectives and controversies regarding the prophylactic and therapeutic potential of IFNs in SARS-CoV-2 infection.

Role of probiotics in managing various human diseases, from oral pathology to cancer and gastrointestinal diseases.

The imbalance of microbial composition and diversity in favor of pathogenic microorganisms combined with a loss of beneficial gut microbiota taxa results from factors such as age, diet, antimicrobial administration for different infections, other underlying medical conditions, etc. Probiotics are known for their capacity to improve health by stimulating the indigenous gut microbiota, enhancing host immunity resistance to infection, helping digestion, and carrying out various other functions. Concurrently, the metabolites produced by these microorganisms, termed postbiotics, which include compounds like bacteriocins, lactic acid, and hydrogen peroxide, contribute to inhibiting a wide range of pathogenic bacteria. This review presents an update on using probiotics in managing and treating various human diseases, including complications that may emerge during or after a COVID-19 infection.

Implications of oral dysbiosis and HPV infection in head and neck cancer: from molecular and cellular mechanisms to early diagnosis and therapy.

Head and neck cancer (HNC) is the sixth most common type of cancer, with more than half a million new cases annually. This review focuses on the role of oral dysbiosis and HPV infection in HNCs, presenting the involved taxons, molecular effectors and pathways, as well as the HPV-associated particularities of genetic and epigenetic changes and of the tumor microenvironment occurred in different stages of tumor development. Oral dysbiosis is associated with the evolution of HNCs, through multiple mechanisms such as inflammation, genotoxins release, modulation of the innate and acquired immune response, carcinogens and anticarcinogens production, generation of oxidative stress, induction of mutations. Thus, novel microbiome-derived biomarkers and interventions could significantly contribute to achieving the desideratum of personalized management of oncologic patients, regarding both early diagnosis and treatment. The results reported by different studies are not always congruent regarding the variations in the abundance of different taxons in HNCs. However, there is a consistent reporting of a higher abundance of Gram-negative species such as Fusobacterium, Leptotrichia, Treponema, Porphyromonas gingivalis, Prevotella, Bacteroidetes, Haemophilus, Veillonella, Pseudomonas, Enterobacterales, which are probably responsible of chronic inflammation and modulation of tumor microenvironment. Candida albicans is the dominant fungi found in oral carcinoma being also associated with shorter survival rate. Specific microbial signatures (e.g., F. nucleatum, Bacteroidetes and Peptostreptococcus) have been associated with later stages and larger tumor, suggesting their potential to be used as biomarkers for tumor stratification and prognosis. On the other hand, increased abundance of Corynebacterium, Kingella, Abiotrophia is associated with a reduced risk of HNC. Microbiome could also provide biomarkers for differentiating between oropharyngeal and hypopharyngeal cancers as well as between HPV-positive and HPV-negative tumors. Ongoing clinical trials aim to validate non-invasive tests for microbiome-derived biomarkers detection in oral and throat cancers, especially within high-risk populations. Oro-pharyngeal dysbiosis could also impact the HNCs therapy and associated side-effects of radiotherapy, chemotherapy, and immunotherapy. HPV-positive tumors harbor fewer mutations, as well as different DNA methylation pattern and tumor microenvironment. Therefore, elucidation of the molecular mechanisms by which oral microbiota and HPV infection influence the HNC initiation and progression, screening for HPV infection and vaccination against HPV, adopting a good oral hygiene, and preventing oral dysbiosis are important tools for advancing in the battle with this public health global challenge.

Common themes in antimicrobial and anticancer drug resistance.

Antimicrobial and anticancer drug resistance represent two of the main global challenges for the public health, requiring immediate practical solutions. In line with this, we need a better understanding of the origins of drug resistance in prokaryotic and eukaryotic cells and the evolutionary processes leading to the occurrence of adaptive phenotypes in response to the selective pressure of therapeutic agents. The purpose of this paper is to present some of the analogies between the antimicrobial and anticancer drug resistance. Antimicrobial and anticancer drugs share common targets and mechanisms of action as well as similar mechanisms of resistance (e.g., increased drug efflux, drug inactivation, target alteration, persister cells' selection, protection of bacterial communities/malignant tissue by an extracellular matrix, etc.). Both individual and collective stress responses triggered by the chemotherapeutic agent involving complex intercellular communication processes, as well as with the surrounding microenvironment, will be considered. The common themes in antimicrobial and anticancer drug resistance recommend the utility of bacterial experimental models for unraveling the mechanisms that facilitate the evolution and adaptation of malignant cells to antineoplastic drugs.

Assessing Phenotypic Variability in Some Eastern European Insular Populations of the Climatic Relict Ilex aquifolium L.

Through its natural or cultivated insular population distribution, Ilex aquifolium L. is a paramount species which is exceptionally suitable for studying phenotypic variability and plasticity through the assessment of morphological, physiological, biochemical and genomic features with respect to acclimation and/or adaptation efficiency. The current study is focused on four insular populations of Ilex aquifolium from Eastern Europe (i.e., in Romania, Hungary, Serbia and Bulgaria), and presents an initial evaluation of phenotypic variability in order to conclude our research on phylogenetic relationships and phytochemical profiles, including several descriptive and quantitative morphological traits. Taken together, the data from different methods in this paper indicate that the Bulgarian and Romanian populations can be distinguished from each other and from Serbian and Hungarian populations, while the latter show a higher level of resemblance with regards to their quantitative morphological traits. It is likely that these morphological traits are determined through some quantitative trait loci implicated in stress responses generated by light, temperature, soil water, soil fertility and salinity conditions that will need to be analysed in terms of their physiological, genomic and metabolomics traits in future studies.

Antiviral Immunity in SARS-CoV-2 Infection: From Protective to Deleterious Responses.

After two previous episodes, in 2002 and 2012, when two highly pathogenic coronaviruses (SARS, MERS) with a zoonotic origin emerged in humans and caused fatal respiratory illness, we are today experiencing the COVID-19 pandemic produced by SARS-CoV-2. The main question of the year 2021 is if naturally- or artificially-acquired active immunity will be effective against the evolving SARS-CoV-2 variants. This review starts with the presentation of the two compartments of antiviral immunity-humoral and cellular, innate and adaptive-underlining how the involved cellular and molecular actors are intrinsically connected in the development of the immune response in SARS-CoV-2 infection. Then, the SARS-CoV-2 immunopathology, as well as the derived diagnosis and therapeutic approaches, will be discussed.

Using Social Media Data to Evaluate Urban Parks Use during the COVID-19 Pandemic.

In the context of increasing urbanization and associated economic, social and environmental challenges, cities have increasingly acknowledged the importance of urban parks in delivering social, economic and environmental benefits to the population. The importance has been demonstrated also during the COVID-19 pandemic that generated lockdowns and reduced the capacity of urban inhabitants in accessing such benefits. The present study aims to determine how the presence in urban parks was reflected on social media during the pandemic period of 2020. We examined Instagram posts associated with a sample of eight urban parks in Bucharest, Romania and also the entire history of Google reviews between January and August 2020. The selection of parks was made according to their size, location in Bucharest, previous reported number of visitors and profile of attractiveness. Results revealed that the peak period of the COVID-19 pandemic and the first initiation of the lockdowns strongly affected the recreation and leisure activities that people performed almost daily in the parks of Bucharest. Reviews and comments of the population were not that focused on the pandemic even after the restrictions were lifted, but they evidenced the positive and negative aspects of each park. Our results can represent a useful instrument for local administrations in determining both the flow of visitors but also their perceptions towards the endowments, landscape and most important management of urban parks.

SARS-CoV-2: From Structure to Pathology, Host Immune Response and Therapeutic Management.

Coronaviruses are large, enveloped viruses with a single-stranded RNA genome, infecting both humans and a wide range of wild and domestic animals. SARS-CoV-2, the agent of the COVID-19 pandemic, has 80% sequence homology with SARS-CoV-1 and 96-98% homology with coronaviruses isolated from bats. The spread of infection is favored by prolonged exposure to high densities of aerosols indoors. Current studies have shown that SARS-CoV-2 is much more stable than other coronaviruses and viral respiratory pathogens. The severe forms of infection are associated with several risk factors, including advanced age, metabolic syndrome, diabetes, obesity, chronic inflammatory or autoimmune disease, and other preexisting infectious diseases, all having in common the pre-existence of a pro-inflammatory condition. Consequently, it is essential to understand the relationship between the inflammatory process and the specific immune response in SARS-CoV-2 infection. In this review, we present a general characterization of the SARS-CoV-2 virus (origin, sensitivity to chemical and physical factors, multiplication cycle, genetic variability), the molecular mechanisms of COVID-19 pathology, the host immune response and discuss how the inflammatory conditions associated with different diseases could increase the risk of COVID-19. Last, but not least, we briefly review the SARS-CoV-2 diagnostics, pharmacology, and future approaches toward vaccine development.

National environmental quality assessment and monitoring of atmospheric heavy metal pollution - A moss bag approach.

As airborne pollution is recognised as the single largest environmental health hazard in Europe, the necessity to develop effective systems for monitoring and reducing the level of air pollutants, becomes imperative. The paper describes a tested and implemented long-term biomonitoring system for airborne heavy metals at a national scale. Moss bags (Hylocomium splendens) were exposed in 142 monitoring stations designated in Romania, and the content of Pb, Cd, Ni and As was quantified using inductively coupled plasma mass spectrometry. The results revealed that the accumulation of heavy metals exceeded the established thresholds, marking high pollution levels in 8.8% of samples for As, in 5.63% samples for Cd, in 3.17% samples for Pb, and in 0.35% samples for Ni. The maximum heavy metal concentration was 113.77 mg kg-1 dry weight for Pb, 44.93 mg kg-1 dry weight for Ni, 14.68 mg kg-1 dry weight for As, and 3.88 mg kg-1 dry weight for Cd, with several overlaps for at least two metals, thus marking pollution hotspots. In order to process, summarise and communicate the obtained data, a software named BioMonRo has been developed as the core part of a complex monitoring and warning-informative system. The software is able to generate heavy metal pollution maps and specific reports, depicting the levels and patterns of distribution, which can be automatically sent to a number of interested recipients. The results show that the developed national system is functional, cost-effective, and could be successfully used for long-term monitoring of airborne heavy metals.