Reassessment of Historical Clinical Trials Supports the Effectiveness of Phage Therapy.

Phage therapy has become a hot topic in medical research due to the increasing prevalence of antibiotic-resistant bacteria strains. In the treatment of bacterial infections, bacteriophages have several advantages over antibiotics, including strain specificity, lack of serious side effects, and low development costs. However, scientists dismissed the clinical success of early clinical trials in the 1940s, slowing the adoption of this promising antibacterial application in Western countries. The current study used statistical methods commonly used in modern meta-analysis to reevaluate early 20th-century studies and compare them with clinical trials conducted in the last 20 years. Using a random effect model, the development of disease after treatment with or without phages was measured in odds ratios (OR) with 95% confidence intervals (CI). Based on the findings of 17 clinical trials conducted between 1921 and 1940, phage therapy was effective (OR = 0.21, 95% CI = 0.10 to 0.44, P value < 0.0001). The current study includes a topic review on modern clinical trials; four could be analyzed, indicating a noneffective therapy (OR = 2.84, 95% CI = 1.53 to 5.27, P value = 0.0009). The results suggest phage therapy was surprisingly less effective than standard treatments in resolving bacterial infections. However, the results were affected by the small sample set size. This work also contextualizes the development of phage therapy in the early 20th century and highlights the expansion of phage applications in the last few years. In conclusion, the current review shows phage therapy is no longer an underestimated tool in the treatment of bacterial infections.

Modulation of the replication of positive-sense RNA viruses by the natural plant metabolite xanthohumol and its derivatives.

The COVID-19 pandemic has highlighted the importance of identifying new potent antiviral agents. Nutrients as well as plant-derived substances are promising candidates because they are usually well tolerated by the human body and readily available in nature, and consequently mostly cheap to produce. A variety of antiviral effects have recently been described for the hop chalcone xanthohumol (XN), and to a lesser extent for its derivatives, making these hop compounds particularly attractive for further investigation. Noteworthy, mounting evidence indicated that XN can suppress a wide range of viruses belonging to several virus families, all of which share a common reproductive cycle. As a result, the purpose of this review is to summarize the most recent research on the antiviral properties of XN and its derivatives, with a particular emphasis on the positive-sense RNA viruses human hepatitis C virus (HCV), porcine reproductive and respiratory syndrome virus (PRRSV), and severe acute respiratory syndrome corona virus (SARS-CoV-2).

The Effects of Tyrosine Kinase Inhibitors (TKIs) in Monotherapy and with Add-on Treatments on Health-related Quality of Life of People with Chronic Myeloid Leukemia: A Systematic Review of Randomized-Controlled Trials.

Background: The era of establishing tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) changed the outcome and the course of this life-threatening malignancy. People suffering from CML have now a better prognosis and a longer life expectancy due to the development of TKIs, even if it requires long-term, often lifelong, treatments that are nonetheless associated with improved Health-related Quality of life (HRQoL). However, data on the effects of TKIs on HRQoL are not always systematic; sometimes the data have been obtained by studies different from RCTs, or without a clear definition of what HRQoL is. The main purpose of this systematic review is to summarize all randomized-controlled trials (RCTs) including HRQoL as main or secondary outcome in patients with CML treated with TKIs or with TKIs plus an add-on treatment. Methods: A systematic review has been conducted by searching the relevant papers in PubMed/Medline and Web of Science with the following keywords: "quality of life" OR "health-related quality of life" OR "QoL" OR "HRQoL" OR "H-QoL" AND "chronic myeloid leukemia". Interval was set from January 2000 to December 2020. Results: 40 papers were identified through the search. Out of them, 7 RCTs were included. All the studies used standardized measures to assess HRQoL, even not always specific for CML. 5 RCTs randomized subjects to 2 or 3 arms to evaluate the effects of TKIs of the first, second and third generation in monotherapy. 2 RCTs randomized subjects to TKI therapy plus an add-on treatment versus TKI therapy as usual. The results of all these trials were examined and discussed. Conclusion: All the included RCTs pointed out significant findings regarding the positive effects of TKIs on HRQoL of people with CML, both when they were used in monotherapy or, notably, with an add-on treatment to enhance TKIs effects.

Comparative Analysis of the Antitumor Activity of Cis- and Trans-Resveratrol in Human Cancer Cells with Different p53 Status.

Resveratrol, a natural plant phytoalexin, is produced in response to fungal infection or- UV irradiation. It exists as an isomeric pair with cis- and trans-conformation. Whereas multiple physiological effects of the trans-form, including a pronounced anti-tumoral activity, are nowadays elucidated, much less knowledge exists concerning the cis-isomer. In our work, we analyzed the antiproliferative and cytotoxic properties of cis-resveratrol in four different human tumor entities in direct comparison to trans-resveratrol. We used human cell lines as tumor models for hepatocellular carcinoma (HCC; HepG2, Hep3B), colon carcinoma (HCT-116, HCT-116/p53(-/-)), pancreatic carcinoma (Capan-2, MiaPaCa-2), and renal cell carcinoma (A498, SN12C). Increased cytotoxicity in all investigated tumor cells was observed for the trans-isomer. To verify possible effects of the tumor suppressor p53 on resveratrol-induced cell death, we used wild type and p53-deleted or -mutated cell lines for every tested tumor entity. Applying viability and cytotoxicity assays, we demonstrated a differential, dose-dependent sensitivity towards cis- or trans-resveratrol among the respective tumor types.

Limits of endorectal ultrasound in tailoring treatment of patients with rectal cancer.

BACKGROUND: Endorectal ultrasound (ERUS) is considered reliable in staging rectal cancer, but recently some critics have questioned its accuracy. The aim of this study was to evaluate how often an ERUS-based decision leads to an appropriate treatment. METHODS: Two hundred and twenty patients with rectal cancer staged with ERUS who underwent a surgical resection or a local excision without neoadjuvant therapy from 1997 to 2012 were included. According to ERUS, patients were divided into three groups of indication: (a) local excision (Tis-1 N0), (b) direct surgery (T2 N0), (c) preoperative chemoradiation (T3-4 or N+). Accuracy was explored by the correlation established with the final pathology. RESULTS: Accuracy for T and N staging was 65 and 64%, respectively. Indication to local excision and to chemoradiation was correct in 97 and 88% of patients staged by ERUS. Accuracy of indication to direct surgery was poor (37%), and 21% of patients were overtreated in this group. CONCLUSIONS: ERUS seems not able to fulfill all the needs of ideal tailored therapeutic strategies. T2 diagnosis needs to be confirmed by an excisional biopsy before a final decision is made because overstaging of early tumors may occur in a not-so-negligible proportion of patients.

Human Papillomavirus 16, 18, 31 and 45 viral load, integration and methylation status stratified by cervical disease stage.

BACKGROUND: Persistent infection with oncogenic Human Papillomavirus (HPV) is associated with the development of cervical cancer with each genotype differing in their relative contribution to the prevalence of cervical disease. HPV DNA testing offers improved sensitivity over cytology testing alone but is accompanied by a generally low specificity. Potential molecular markers of cervical disease include type-specific viral load (VL), integration of HPV DNA into the host genome and methylation of the HPV genome. The aim of this study was to evaluate the relationship between HPV type-specific viral load, integration and methylation status and cervical disease stage in samples harboring HPV16, HPV18, HPV31 or HPV45. METHODS: Samples singly infected with HPV16 (n=226), HPV18 (n=32), HPV31 (n=75) or HPV45 (n=29) were selected from a cohort of 4,719 women attending cervical screening in England. Viral load and integration status were determined by real-time PCR while 3'L1-URR methylation status was determined by pyrosequencing or sequencing of multiple clones derived from each sample. RESULTS: Viral load could differentiate between normal and abnormal cytology with a sensitivity of 75% and a specificity of 80% (odds ratio [OR] 12.4, 95% CI 6.2-26.1; p<0.001) with some variation between genotypes. Viral integration was poorly associated with cervical disease. Few samples had fully integrated genomes and these could be found throughout the course of disease. Overall, integration status could distinguish between normal and abnormal cytology with a sensitivity of 72% and a specificity of 50% (OR 2.6, 95% CI 1.0-6.8; p=0.054). Methylation levels were able to differentiate normal and low grade cytology from high grade cytology with a sensitivity of 64% and a specificity of 82% (OR 8.2, 95% CI 3.8-18.0; p<0.001). However, methylation varied widely between genotypes with HPV18 and HPV45 exhibiting a broader degree and higher magnitude of methylated CpG sites than HPV16 and HPV31. CONCLUSIONS: This study lends support for HPV viral load and CpG methylation status, but not integration status, to be considered as potential biomarkers of cervical disease.

Determination of Optimal Phage Load and Administration Time for Antibacterial Treatment.

Using phages as antibacterials is becoming a customary practice in Western countries. Nonetheless, successful treatments must consider the growth rate of the bacterial host and the degradation of the virions. Therefore, successful treatments require administering the right amount of phage (viral load, Vφ) at the right moment (administration time, Tφ). The present protocols implement a machine learning approach to determine the best combination of Vφ and Tφ to obtain the elimination of the target bacterium from a system. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: One bacterium, one phage Alternate Protocol 1: One bacterium, one phage (wrapping function) Alternate Protocol 2: One bacterium, one phage (wrapping function, alternative growing model) Basic Protocol 2: Two bacteria, one phage Alternate Protocol 3: Two bacteria, one phage (launch from terminal).

Compounds derived from Humulus lupulus inhibit SARS-CoV-2 papain-like protease and virus replication.

BACKGROUND: Selected natural compounds exhibit very good antiviral properties. Especially, the medicinal plant Humulus lupulus (hop) contains several secondary plant metabolites some of which have previously shown antiviral activities. Among them, the prenylated chalcone xanthohumol (XN) demonstrated to be a potent inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). HYPOTHESIS/PURPOSE: Following the finding that xanthohumol (XN) is a potent inhibitor of SARS-CoV-2 Mpro, the effect of XN and its major derivatives isoxanthohumol (IXN), 6-prenylnaringenin (6-PN), and 8-prenylnaringenin (8-PN) from hops on SARS-CoV-2 papain-like protease (PLpro) were investigated. STUDY DESIGN: The modulatory effect of the hop compounds on PLpro were studied first in silico and then in vitro. In addition, the actual effect of hop compounds on the replication of SARS-CoV-2 in host cells was investigated. METHODS: In silico docking analysis was used to predict the binding affinity of hop compounds to the active site of PLpro. A recombinant PLpro was cloned, purified, characterized, and analyzed by small-angle X-ray scattering (SAXS), deISGylation assays, and kinetic analyses. Antiviral activity of hop compounds was assessed using the fluorescently labeled wildtype SARS-CoV-2 (icSARS-CoV-2-mNG) in Caco-2 host cells. RESULTS: Our in silico docking suggests that the purified hop compounds bind to the active site of SARS-CoV-2 PLpro blocking the access of its natural substrates. The hop-derived compounds inhibit SARS-CoV-2 PLpro with half maximal inhibitory concentration (IC50) values in the range of 59-162 µM. Furthermore, we demonstrate that XN and 6-PN, in particular, impede viral replication with IC50 values of 3.3 µM and 7.3 µM, respectively. CONCLUSION: In addition to the already known inhibition of Mpro by XN, our results show, for the first time, that hop-derived compounds target also SARS-CoV-2 PLpro which is a promising therapeutic target as it contributes to both viral replication and modulation of the immune system. These findings support the possibility to develop new hop-derived antiviral drugs targeting human coronaviruses.

Analysis of High-Dose Ascorbate-Induced Cytotoxicity in Human Glioblastoma Cells and the Role of Dehydroascorbic Acid and Iron.

Several studies have demonstrated, both in vitro and in animal models, the anti-tumor efficacy of high-dose ascorbate treatment against a variety of tumor entities, including glioblastoma, the most common and aggressive primary malignant brain tumor. The aim of this study was to investigate the effects of high-dose ascorbate as well as dehydroascorbic acid on human glioblastoma cell lines and to evaluate different treatment conditions for the combined administration of ascorbate with magnesium (Mg2+) and iron (Fe3+). Intracellular levels of reactive oxygen species and the induction of cell death following ascorbate treatment were also investigated. We demonstrated high cytotoxicity and antiproliferative efficacy of high-dose ascorbate in human glioblastoma cells, whereas much weaker effects were observed for dehydroascorbic acid. Ascorbate-induced cell death was independent of apoptosis. Both the reduction in cell viability and the ascorbate-induced generation of intracellular reactive oxygen species could be significantly increased by incubating the cells with Fe3+ before ascorbate treatment. This work demonstrates, for the first time, an increase in ascorbate-induced intracellular ROS formation and cytotoxicity in human glioblastoma cells by pre-treatment of the tumor cells with ferric iron, as well as caspase-3 independence of cell death induced by high-dose ascorbate. Instead, the cell death mechanism caused by high-dose ascorbate in glioblastoma cells shows evidence of ferroptosis. The results of the present work provide insights into the efficacy and mode of action of pharmacological ascorbate for the therapy of glioblastoma, as well as indications for possible approaches to increase the effectiveness of ascorbate treatment.

Elevated CEA levels and low distance of the tumor from the anal verge are predictors of incomplete response to chemoradiation in patients with rectal cancer.

BACKGROUND: The objective of this study was to evaluate pretreatment clinical parameters as predictive factors for complete pathological response after long-term chemoradiotherapy (RCT) for rectal cancer. Tumor downstaging after RCT for rectal cancer can be obtained in half of cases, whereas a complete pathological response (CPR) is reported to range between 15 and 30%. It is not possible to foresee before therapies who will respond. METHODS: Patients with stage II-III rectal cancer that had undergone RCT and rectal resection between January 1995 and October 2010 were considered. Patients were divided in those who achieved a CPR, "CR" group, and those who did not achieve a CPR, "NCR" group. Univariate and multivariate analyses between groups were performed considering the clinical parameters: gender, age, ASA score, preoperative hematic CEA, tumor grading; distance of the tumor from the anal verge, maximum tumor diameter, TNM stage, and neoadjuvant treatment details. RESULTS: Among 260 patients, 43 (16.5%) achieved a CPR. The two groups resulted homogeneous for age, sex, pretreatment status, and tumor stage. A CEA <5 ng/dl and distance from anal verge >5 cm were correlated with CPR at multivariate analysis. Patients with both these conditions presented a significantly higher CPR rate (30.6%) as well as improved 5-year survival. CPR was also correlated with improved survival. CONCLUSIONS: Very low tumors with a high serum CEA are very unlikely to reach a CPR. The predictive value of these easily available clinical factors should not be underestimated, and better therapeutic strategies for these tumors are needed.

Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer.

Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.

High-Dose Ascorbate in Combination with Anti-PD1 Checkpoint Inhibition as Treatment Option for Malignant Melanoma.

Ascorbate acts as a prooxidant when administered parenterally at high supraphysiological doses, which results in the generation of hydrogen peroxide in dependence on oxygen. Most cancer cells are susceptible to the emerging reactive oxygen species (ROS). Accordingly, we evaluated high-dose ascorbate for the treatment of the B16F10 melanoma model. To investigate the effects of ascorbate on the B16F10 cell line in vitro, viability, cellular impedance, and ROS production were analyzed. In vivo, C57BL/6NCrl mice were subcutaneously injected into the right flank with B16F10 cells and tumor-bearing mice were treated intraperitoneally with ascorbate (3 g/kg bodyweight), immunotherapy (anti-programmed cell death protein 1 (PD1) antibody J43; 2 mg/kg bodyweight), or both treatments combined. The efficacy and toxicity were analyzed by measuring the respective tumor sizes and mouse weights accompanied by histological analysis of the protein levels of proliferating cell nuclear antigen (Pcna), glucose transporter 1 (Glut-1), and CD3. Treatment of B16F10 melanoma-carrying mice with high-dose ascorbate yielded plasma levels in the pharmacologically effective range, and ascorbate showed efficacy as a monotherapy and when combined with PD1 inhibition. Our data suggest the applicability of ascorbate as an additional therapeutic agent that can be safely combined with immunotherapy and has the potential to potentiate anti-PD1-based immune checkpoint blockades.

Viruses in colorectal cancer.

Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these - Epstein-Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) - have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes - such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis - not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53-/pRb-driven, epithelial-mesenchymal transition (EMT)-/EGFR-associated and especially Wnt/ß-catenin-driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.

Involvement of HHV-4 (Epstein-Barr Virus) and HHV-5 (Cytomegalovirus) in Inflammatory Bowel Disease and Colorectal Cancer: A Meta-Analysis.

Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients' chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk factor for the development of CRC. Chronic bacterial infections have been shown to promote some GDs, but the role of viruses in the etiology of these diseases is less clear. The present meta-analysis retrieved literature on the viral prevalence in GD patients, measuring the GD risk in odd ratios. By quantifying the study heterogeneity, the literature bias was fundamentally included in the analysis. The analysis also included 11 metagenomic studies. Our meta-analysis retrieved 11,413 studies, with 196 suitable for analysis. HHV-4 (Epstein-Barr virus) was identified as a significant risk factor for the development of IBD, and HHV-5 (cytomegalovirus) as a risk factor for both CRC and IBD. Polyomaviruses and the Hepatitis B virus were also, less strongly, involved in the risk of CRC and IBD. No relations withstanding the literature bias were identified for GC. The study discusses these findings, as well as the role of other viruses in the etiology of CRC and IBD.

Determination of phage load and administration time in simulated occurrences of antibacterial treatments.

The use of phages as antibacterials is becoming more and more common in Western countries. However, a successful phage-derived antibacterial treatment needs to account for additional features such as the loss of infective virions and the multiplication of the hosts. The parameters critical inoculation size (V F ) and failure threshold time (T F ) have been introduced to assure that the viral dose (V ϕ) and administration time (T ϕ) would lead to the extinction of the targeted bacteria. The problem with the definition of V F and T F is that they are non-linear equations with two unknowns; thus, obtaining their explicit values is cumbersome and not unique. The current study used machine learning to determine V F and T F for an effective antibacterial treatment. Within these ranges, a Pareto optimal solution of a multi-criterial optimization problem (MCOP) provided a pair of V ϕ and T ϕ to facilitate the user's work. The algorithm was tested on a series of in silico microbial consortia that described the outgrowth of a species at high cell density by another species initially present at low concentration. The results demonstrated that the MCOP-derived pairs of V ϕ and T ϕ could effectively wipe out the bacterial target within the context of the simulation. The present study also introduced the concept of mediated phage therapy, where targeting booster bacteria might decrease the virulence of a pathogen immune to phagial infection and highlighted the importance of microbial competition in attaining a successful antibacterial treatment. In summary, the present work developed a novel method for investigating phage/bacteria interactions that can help increase the effectiveness of the application of phages as antibacterials and ease the work of microbiologists.

Minerals and Cancer: Overview of the Possible Diagnostic Value.

Cancer is the second leading cause of death worldwide and is expected to increase by one-third over the next two decades, in parallel with the growing proportion of the elderly population. Treatment and control of cancer incidence is a global issue. Since there is no clear way to prevent or cure this deadly malignancy, diagnostic, predictive, and prognostic markers for oncological diseases are of great therapeutic value. Minerals and trace elements are important micronutrients for normal physiological function of the body. They are abundant in natural food sources and are regularly included in dietary supplements whereas highly processed industrial food often contains reduced or altered amounts of them. In modern society, the daily intake, storage pools, and homeostasis of these micronutrients are dependent on certain dietary habits and can be thrown out of balance by malignancies. The current work summarizes the data on minerals and trace elements associated with abnormal accumulation or depletion states in tumor patients and discusses their value as potential tumor-associated biomarkers that could be introduced into cancer therapy.

Vitamin C Deficiency in Blood Samples of COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) is the most notable pandemic of the modern era. A relationship between ascorbate (vitamin C) and COVID-19 severity is well known, whereas the role of other vitamins is less understood. The present study compared the blood levels of four vitamins in a cohort of COVID-19 patients with different severities and uninfected individuals. Serum concentrations of ascorbate, calcidiol, retinol, and α-tocopherol were measured in a cohort of 74 COVID-19 patients and 8 uninfected volunteers. The blood levels were statistically compared and additional co-morbidity factors were considered. COVID-19 patients had significantly lower plasma ascorbate levels than the controls (p-value < 0.001), and further stratification revealed that the controls had higher levels than fatal, critical, and severe COVID-19 cases (p-values < 0.001). However, no such trend was observed for calcidiol, retinol, or α-tocopherol (p-value ≥ 0.093). Survival analysis showed that plasma ascorbate below 11.4 µM was associated with a lengthy hospitalization and a high risk of death. The results indicated that COVID-19 cases had depleted blood ascorbate associated with poor medical conditions, confirming the role of this vitamin in the outcome of COVID-19 infection.

Dietary Modulation of Bacteriophages as an Additional Player in Inflammation and Cancer.

Natural compounds such as essential oils and tea have been used successfully in naturopathy and folk medicine for hundreds of years. Current research is unveiling the molecular role of their antibacterial, anti-inflammatory, and anticancer properties. Nevertheless, the effect of these compounds on bacteriophages is still poorly understood. The application of bacteriophages against bacteria has gained a particular interest in recent years due to, e.g., the constant rise of antimicrobial resistance to antibiotics, or an increasing awareness of different types of microbiota and their potential contribution to gastrointestinal diseases, including inflammatory and malignant conditions. Thus, a better knowledge of how dietary products can affect bacteriophages and, in turn, the whole gut microbiome can help maintain healthy homeostasis, reducing the risk of developing diseases such as diverse types of gastroenteritis, inflammatory bowel disease, or even cancer. The present review summarizes the effect of dietary compounds on the physiology of bacteriophages. In a majority of works, the substance class of polyphenols showed a particular activity against bacteriophages, and the primary mechanism of action involved structural damage of the capsid, inhibiting bacteriophage activity and infectivity. Some further dietary compounds such as caffeine, salt or oregano have been shown to induce or suppress prophages, whereas others, such as the natural sweeter stevia, promoted species-specific phage responses. A better understanding of how dietary compounds could selectively, and specifically, modulate the activity of individual phages opens the possibility to reorganize the microbial network as an additional strategy to support in the combat, or in prevention, of gastrointestinal diseases, including inflammation and cancer.

Vitamins as Possible Cancer Biomarkers: Significance and Limitations.

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as 'hidden hunger'), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.

Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors.

The paucity of microbiome studies at intestinal tissues has contributed to a yet limited understanding of potential viral and bacterial cofactors of colorectal cancer (CRC) carcinogenesis or progression. We analysed whole-genome sequences of CRC primary tumours, their corresponding metastases and matched normal tissue for sequences of viral, phage and bacterial species. Bacteriome analysis showed Fusobacterium nucleatum, Streptococcus sanguinis, F. Hwasookii, Anaerococcus mediterraneensis and further species enriched in primary CRCs. The primary CRC of one patient was enriched for F. alocis, S. anginosus, Parvimonas micra and Gemella sp. 948. Enrichment of Escherichia coli strains IAI1, SE11, K-12 and M8 was observed in metastases together with coliphages enterobacteria phage φ80 and Escherichia phage VT2φ_272. Virome analysis showed that phages were the most preponderant viral species (46%), the main families being Myoviridae, Siphoviridae and Podoviridae. Primary CRCs were enriched for bacteriophages, showing five phages (Enterobacteria, Bacillus, Proteus, Streptococcus phages) together with their pathogenic hosts in contrast to normal tissues. The most frequently detected, and Blast-confirmed, viruses included human endogenous retrovirus K113, human herpesviruses 7 and 6B, Megavirus chilensis, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), with one patient showing EBV enrichment in primary tumour and metastases. EBV was PCR-validated in 80 pairs of CRC primary tumour and their corresponding normal tissues; in 21 of these pairs (26.3%), it was detectable in primary tumours only. The number of viral species was increased and bacterial species decreased in CRCs compared with normal tissues, and we could discriminate primary CRCs from metastases and normal tissues by applying the Hutcheson t-test on the Shannon indices based on viral and bacterial species. Taken together, our results descriptively support hypotheses on microorganisms as potential (co)risk factors of CRC and extend putative suggestions on critical microbiome species in CRC metastasis.