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Cryoglobulinemic Vasculitis (CV) is an autoimmune/lymphoproliferative disorder associated with HCV infection that in 5%-10% of cases evolves into a B cell Non-Hodgkin's Lymphoma (NHL). B-cell activating factor (BAFF) is a key regulator in B-cell development and survival. Particular genetic variants are responsible for BAFF signaling impairment in autoimmune and neoplastic diseases. We evaluated BAFF and BAFF-receptor (BAFF-R) polymorphisms in order to determine if they predispose to HCV-related CV and NHL. The analysis was performed on 416 HCV-chronically infected patients: 136 HCV without signs/symptoms of lymphoproliferations/autoimmunity (HCV), 166 HCV with CV (HCV-CV) and 114 HCV with NHL (HCV-NHL). Rs9514828 SNP on BAFF promoter, rs61756766 on BAFF-R and rs12428930 on the BAFF gene were evaluated by Real-Time PCR. Concerning rs9514828, the frequency of C/T genotype was significantly higher in HCV-CV than in HCV. The difference in the distribution of the T/T mutant genotype in HCV-CV compared to HCV was significant as well as the distribution of C/T and T/T genotype in HCV-NHL versus HCV. T minor allele was more frequent in HCV-NHL and HCV-CV than in HCV. The distribution of C/T + T/T (for the dominant model of penetrance C/T + T/T vs. C/C) was significantly higher in HCV-CV and HCV-NHL than in HCV. Genotyping of rs61756766 on BAFF-R coding gene, revealed C/T heterozygosis at a frequency of 11% in HCV-NHL versus 3% in HCV. The T minor allele frequency was higher in HCV-NHL than in HCV. No differences emerged by genotyping rs12428930 SNP on BAFF coding gene. Our results reinforce the hypothesis that BAFF/BAFF-R genetic pattern has a role in the pathogenesis of HCV-related lymphoproliferations. BAFF/BAFF-R variants could identify a risk haplotype for HCV related CV and NHL and a BAFF/BAFF-R genetic profile assessment could potentially contribute to tailoring anti-BAFF therapy by identifying patients with BAFF alterations in which the treatment could be more beneficial.

The severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2) poses a threat to human life worldwide. Since early March, 2020, coronavirus disease 2019 (COVID-19), characterized by an acute and often severe form of pneumonia, has been declared a pandemic. This has led to a boom in biomedical research studies at all stages of the pipeline, from the in vitro to the clinical phase. In line with this global effort, known drugs, currently used for the treatment of other pathologies, including antivirals, immunomodulating compounds and antibodies, are currently used off-label for the treatment of COVID-19, in association with the supportive standard care. Yet, no effective treatments have been identified. A new hope stems from medical oncology and relies on the use of immune-checkpoint inhibitors (ICIs). In particular, amongst the ICIs, antibodies able to block the programmed death-1 (PD-1)/PD ligand-1 (PD-L1) pathway have revealed a hidden potential. In fact, patients with severe and critical COVID-19, even prior to the appearance of acute respiratory distress syndrome, exhibit lymphocytopenia and suffer from T-cell exhaustion, which may lead to viral sepsis and an increased mortality rate. It has been observed that cancer patients, who usually are immunocompromised, may restore their anti-tumoral immune response when treated with ICIs. Moreover, viral-infected mice and humans, exhibit a T-cell exhaustion, which is also observed following SARS-CoV-2 infection. Importantly, when treated with anti-PD-1 and anti-PD-L1 antibodies, they restore their T-cell competence and efficiently counteract the viral infection. Based on these observations, four clinical trials are currently open, to examine the efficacy of anti-PD-1 antibody administration to both cancer and non-cancer individuals affected by COVID-19. The results may prove the hypothesis that restoring exhausted T-cells may be a winning strategy to beat SARS-CoV-2 infection.

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in several mechanisms, and the alteration of IL-6 signaling leads to the overactivation of various processes including immunity, inflammation, and hemostasis. Although IL-6 increase has been documented in venous thromboembolic diseases, the exact involvement of IL-6 signaling in deep vein thrombosis (DVT) has not been fully understood. Consequently, we investigated the involvement of IL-6 trans-signaling in inflammatory events occurring in DVT, focusing on the role of the interleukin-6 receptor (IL6-R) Asp358Ala variant. The circulating levels of IL-6, soluble IL6-R (sIL6-R), and soluble glycoprotein 130, as well as the Asp358Ala genotyping, were assessed in a consecutive cohort of DVT patients and healthy controls. The results indicated that IL-6 was higher in DVT compared to controls. Moreover, sIL6-R levels were strongly correlated to Asp358Ala variant in both groups, showing a high frequency of this mutation across all samples. Interestingly, our results showed a high frequency of both Asp358Ala mutation and raised IL-6 levels in DVT patients (OR = 21.32; p ≤ 0.01), highlighting that this mutation could explain the association between IL-6 overactivation and DVT outcome. Overall, this study represents a proof of concept for the targeting of IL-6 trans-signaling as a new strategy for the DVT adjuvant therapy.

The increasing use of pesticides in intensive agriculture has had a negative impact on human health. It was widely demonstrated how pesticides can induce different genetic and epigenetic alterations associated with the development of different diseases, including tumors and neurological disorders. Therefore, the identification of effective indicators for the prediction of harmful pesticide exposure is mandatory. In this context, the aim of the study was to evaluate the modification of hsa-miR-199a-5p expression levels in liquid biopsy samples obtained from healthy donors and farm workers with chronic exposure to pesticides. For this purpose, the high-sensitive droplet digital PCR assay (ddPCR) was used to detect variation in the expression levels of the selected microRNA (miRNA). The ddPCR analyses revealed a significant down-regulation of hsa-miR-199a-5p observed in individuals exposed to pesticides compared to control samples highlighting the good predictive value of this miRNA as demonstrated by statistical analyses. Overall, the obtained results encourage the analysis of miRNAs as predictive biomarkers of chronic pesticide exposure thus improving the current strategies for the monitoring of harmful pesticide exposure.

Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) is the gold standard method for the diagnosis of COVID‑19 infection. Due to pre‑analytical and technical limitations, samples with low viral load are often misdiagnosed as false‑negative samples. Therefore, it is important to evaluate other strategies able to overcome the limits of RT‑qPCR. Blinded swab samples from two individuals diagnosed positive and negative for COVID‑19 were analyzed by droplet digital PCR (ddPCR) and RT‑qPCR in order to assess the sensitivity of both methods. Intercalation chemistries and a World Health Organization (WHO)/Center for Disease Control and Prevention (CDC)‑approved probe for the SARS‑CoV‑2 N gene were used. SYBR‑Green RT‑qPCR is not able to diagnose as positive samples with low viral load, while, TaqMan Probe RT‑qPCR gave positive signals at very late Ct values. On the contrary, ddPCR showed higher sensitivity rate compared to RT‑qPCR and both EvaGreen and probe ddPCR were able to recognize the sample with low viral load as positive even at 10‑fold diluted concentration. In conclusion, ddPCR shows higher sensitivity and specificity compared to RT‑qPCR for the diagnosis of COVID‑19 infection in false‑negative samples with low viral load. Therefore, ddPCR is strongly recommended in clinical practice for the diagnosis of COVID‑19 and the follow‑up of positive patients until complete remission.

S100A7 has been suggested to interact with Ran-binding protein 9. Both proteins are nowadays considered key effectors in immune response. Functional interaction between proteins is ensured by coevolution. The mechanisms of vertebrate coevolution between S100A7 and RanBP9 remain unclear. Several approaches for studying coevolution have been developed. Protein coevolution was inferred by calculating the linear correlation coefficients between inter-protein distance matrices using Mirrortree. We found an overall moderate correlation value (R = 0.53, p

Background: Populations living in Mediterranean islands are experiencing a nutrition transition process from traditional to Westernized dietary patterns. No information on this matter regarding individuals living in Malta have been published to date. The aim of this study was to assess the level of adherence of the Maltese people to the Mediterranean diet and which factors were associated with it. Methods: A nationwide cross-sectional study was conducted in the island of Malta between 2014 and 2016. A literature-based Mediterranean diet adherence score was used to assess the level of adherence to the dietary pattern. Results: Out of 3947 adults, the overall Mediterranean diet adherence score mean was 7.19 (SD 1.91): being female, non-smoker, and having older age was associated with higher adherence to the Mediterranean diet. Less clear pattern of association was found for educational and occupational status, for which medium educational level and a high occupational level were associated with lower adherence to Mediterranean diet. Higher adherence was finally associated with consumption of healthier food groups (more rice and dark bread and less pasta and white bread, more all plant-food groups and fish, less animal-food sources, including fast foods, more light cheeses and yogurt were more frequently consumed among higher adherent individuals in spite of regular ones). Conclusions: Adherence to the Mediterranean diet in Malta is lower than in those of populations living in companion Mediterranean islands. Given the lack of data on this topic, further studies should be conducted among the Maltese people and public health nutrition interventions should be planned to improve current eating habits toward more traditional dietary patterns.

IL-6 pathway is abnormally hyperactivated in several cancers triggering tumor cell growth and immune system inhibition. Along with genomic mutation, the IL6 pathway gene expression can be affected by DNA methylation, microRNAs, and post-translational modifications. Computational analysis was performed on the Cancer Genome Atlas (TCGA) datasets to explore the role of IL6, IL6R, IL6ST, and IL6R transmembrane isoform expression and their epigenetic regulation in different cancer types. IL6 was significantly modulated in 70% of tumor types, revealing either up- or down-regulation in an approximately equal number of tumors. Furthermore, IL6R and IL6ST were downregulated in more than 10 tumors. Interestingly, the correlation analysis demonstrated that only the IL6R expression was negatively affected by the DNA methylation within the promoter region in most tumors. Meanwhile, only the IL6ST expression was extensively modulated by miRNAs including miR-182-5p, which also directly targeted all three genes. In addition, IL6 upregulated miR-181a-3p, mirR-214-3p, miR-18a-5p, and miR-938, which in turn inhibited the expression of IL6 receptors. Finally, the patients’ survival rate was significantly affected by analyzed targets in some tumors. Our results suggest the relevance of epigenetic regulation of IL6 signaling and pave the way for further studies to validate these findings and to assess the prognostic and therapeutic predictive value of these epigenetic markers on the clinical outcome and survival of cancer patients.

The aim of this study was to investigate the relation between bladder cancer risk and the use of selected drugs for cardiovascular disease (CVD) prevention, such as aspirin, statins, and calcium channel blockers (CCBs). We analyzed data from a multicentric case-control study carried out in Italy between 2003 and 2014, including 690 bladder cancer cases and 665 hospital controls. Odds ratios (ORs) of bladder cancer and corresponding 95% confidence intervals (CIs) were estimated using unconditional multiple logistic regression models. The ORs for bladder cancer were 1.21 (95% CI: 0.87-1.68) for regular use of aspirin, 0.72 (95% CI: 0.54-0.97) for use of any CCBs, and 1.32 (95% CI: 0.87-1.99) for use of any statins. A slight inverse association was found with duration of use of CCBs, whereas no consistent association was found with duration of use, age at first use, and frequency for aspirin and statin use, or with indication of use for aspirin (as an analgesic or, for CVD prevention). No significant association was found for various combinations of drugs or for all drugs combined (OR=1.23, 95% CI: 0.31-4.85). Our data indicate the lack of a relevant association between the use of selected drugs for CVD prevention and bladder cancer risk, although suggest a potential favorable role for CCBs.

The Coronavirus Disease 2019 (COVID-19) pandemic has forced the scientific community to rapidly develop highly reliable diagnostic methods in order to effectively and accurately diagnose this pathology, thus limiting the spread of infection. Although the structural and molecular characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were initially unknown, various diagnostic strategies useful for making a correct diagnosis of COVID-19 have been rapidly developed by private research laboratories and biomedical companies. At present, rapid antigen or antibody tests, immunoenzymatic serological tests and molecular tests based on RT-PCR are the most widely used and validated techniques worldwide. Apart from these conventional methods, other techniques, including isothermal nucleic acid amplification techniques, clusters of regularly inter-spaced short palindromic repeats/Cas (CRISPR/Cas)-based approaches or digital PCR methods are currently used in research contexts or are awaiting approval for diagnostic use by competent authorities. In order to provide guidance for the correct use of COVID-19 diagnostic tests, the present review describes the diagnostic strategies available which may be used for the diagnosis of COVID-19 infection in both clinical and research settings. In particular, the technical and instrumental characteristics of the diagnostic methods used are described herein. In addition, updated and detailed information about the type of sample, the modality and the timing of use of specific tests are also discussed.

Context Recent studies have outlined the potential role of dietary factors in patients who have survived cancer. Objective The aim of this study was to summarize the evidence of the relation between dietary intake of phytoestrogens and their blood biomarkers and, overall, cancer-specific mortality and recurrence in patients with cancer. Data Sources A systematic search of PubMed, EMBASE, and Web of Science databases of studies published up to September 2019 was performed. Databases were searched for prospective and retrospective cohort studies reporting on dietary phytoestrogen intake and/or blood biomarkers and the outcomes investigated. Data extraction Data were extracted from each identified study using a standardized form. Data analysis Twenty-eight articles on breast, lung, prostate, and colorectal cancer, and glioma were included for systematic review. Given the availability of studies, a quantitative meta-analysis was performed solely for breast cancer outcomes. A significant inverse association among higher dietary isoflavone intake, higher serum/plasma enterolactone concentrations, and overall mortality and cancer recurrence was found. Among other cancer types, 2 studies reported that higher serum enterolactone and higher intake of lignans were associated with cancer-specific survival for colorectal cancer and glioma, respectively. Conclusions Dietary phytoestrogens may play a role in survival from breast cancer ; evidence regarding other cancers is too limited to draw any conclusions.

The circadian clock is a conserved timekeeping mechanism that is involved in the regulation of daily oscillations of the various biological processes and behaviors of human beings. It is well established that aberrant clock gene expression is associated with increased risk of various diseases including cancer. Also, the clock genes contribute to carcinogenesis by altering the expression of tumor-associated proto-oncogenes and many other tumor suppressor genes. One example is the close association of the circadian clock with the proto-oncogene c-myc. c-myc is overexpressed in many cancers and is involved in the initiation of the oncogenic process. Herein, we report the various clock genes in the circadian clock and how each is involved in the regulation of c-myc expression. Targeting altered clock genes to inhibit the expression of c-myc may be a therapeutic approach for the prevention and treatment of various cancers.

Matrix metalloproteases are known to represent an early step in the evolution of the immune system. Similarly, neutrophil gelatinase-associated lipocalin is known to be a key effector in immune response. MMP-9 interacts with NGAL, but their interaction mechanisms remain unclear. Functional interaction between proteins is ensured by coevolution. Protein coevolution was inferred by calculating the linear correlation coefficients between inter-protein distance matrices using MirrorTree. Among examined mammal species, we found a robust signal of MMP-9/NGAL coevolution exclusively within Primates (R = 0.96, p < 1e-06). Owing to the high conservation of these proteins among Mammals, we chose to utilize a recent version of Blocks in Sequences (BIS2) algorithm implemented in BIS2Analyzer webserver. Coevolution clusters between the two proteins were identified in MMP-9 fibronectin and hemopexin domains. Our results suggest that MMP-9/NGAL interaction is a recent evolutionary acquisition in Primates. Furthermore, MMP-9 hemopexin domain would represent a promising target for drug design against these molecules.

Cancer affects millions of individuals worldwide. Thus, there is an increased need for the development of novel effective therapeutic approaches. Tumorigenesis is often coupled with immunosuppression which defeats the anticancer immune defense mechanisms activated by the host. Novel anticancer therapies based on the use of immune checkpoint inhibitors (ICIs) are very promising against both solid and hematological tumors, although still exhibiting heterogeneous efficacy, as well as tolerability. Such a differential response seems to derive from individual diversity, including the gut microbiota (GM) composition of specific patients. Experimental evidence supports the key role played by the GM in the activation of the immune system response against malignancies. This observation suggests to aim for patient‑tailored complementary therapies able to modulate the GM, enabling the selective enrichment in microbial species, which can improve the positive outcome of ICI‑based immunotherapy. Moreover, the research of GM‑derived predictive biomarkers may help to identify the selected cancer population, which can benefit from ICI‑based therapy, without the occurrence of adverse reactions and/or cancer relapse. The present review summarizes the landmark studies published to date, which have contributed to uncovering the tight link existing between GM composition, cancer development and the host immune system. Bridging this triangle of interactions may ultimately guide towards the identification of novel biomarkers, as well as integrated and patient‑tailored anticancer approaches with greater efficacy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy. Approximately 85% of pancreatic cancers are classified as PDACs. The survival of PDAC patients is very poor and only 5–10% of patients survive 5 years after diagnosis. Mutations at the KRAS and TP53 gene are frequently observed in PDAC patients. The PANC-28 cell line lacks wild-type (WT) TP53. In the following study, we have investigated the effects of restoration of WT TP53 activity on the sensitivity of PANC-28 pancreatic cancer cells to various drugs which are used to treat PDAC patients as well as other cancer patients. In addition, we have examined the effects of signal transduction inhibitors which target critical pathways frequently deregulated in cancer. The effects of the anti-diabetes drug metformin and the anti-malarial drug chloroquine were also examined as these drugs may be repurposed to treat other diseases. Finally, the effects of certain nutraceuticals which are used to treat various ailments were also examined. Introduction of WT-TP53 activity in PANC-28 PDAC cells, can increase their sensitivity to various drugs. Attempts are being made clinically to increase TP53 activity in various cancer types which will often inhibit cell growth by multiple mechanisms.

Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant PIK3CA, were examined. KD-GSK-3β increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction inhibitors. Thus, altering the levels of GSK-3β can have dramatic effects on sensitivity to drugs and signal transduction inhibitors which may be influenced by the background of the tumor.

Background: Nut consumption has been associated with cardio-metabolic health benefits. However, studies conducted in the Southern Italian population, where adherence to the Mediterranean diet has been reported being relatively high, are rather scarce. The aim of this study was to test the association between consumption of total and specific types of nuts and metabolic status among adults living in Sicily, Southern Italy. Methods: Demographic and dietary characteristics of 2044 adults living in Southern Italy were analyzed. Multivariate logistic regression analyses were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of the association between nut consumption and metabolic status adjusting for potential confounding factors. Results: The energy-adjusted model revealed that higher nut intake was inversely associated with occurrence of hypertension, type-2 diabetes, and dyslipidemia. However, the association did not remain significant for the latter after adjusting for the main background characteristics, while an inverse association was stably confirmed for hypertension (OR = 0.61, 95% CI: 0.46–0.80 and OR = 0.44, 95% CI: 0.26–0.74, respectively) even after adjusting for adherence to the Mediterranean diet. Among individual nut types, most of the associations were null except for higher almond intake, which was inversely associated with occurrence of hypertension (OR = 0.70, 95% CI: 0.49–0.99). Conclusions: Higher nut consumption is associated with overall better metabolic status in individuals living in the Mediterranean area.

B-cell non-Hodgkin lymphomas (B-NHLs) are often characterized by the development of resistance to chemotherapeutic drugs and/or relapse. During drug-induced apoptosis, Yin Yang 1 (YY1) transcription factor might modulate the expression of apoptotic regulators genes. The present study was aimed to: (1) examine the potential oncogenic role of YY1 in reversing drug resistance in B-NHLs, and (2) identify YY1 transcriptional target(s) that regulate the apoptotic pathway in B-NHLs. Predictive analyses coupled with database-deposited data suggested that YY1 binds the promoter of the BIRC5/survivin anti-apoptotic gene. Gene Expression Omnibus (GEO) analyses of several B-NHL repositories revealed a conserved positive correlation between YY1 and survivin, both highly expressed, especially in aggressive B-NHLs. Further validation experiments performed in Raji Burkitt&rsquo, s lymphomas cells, demonstrated that YY1 silencing was associated with survivin downregulation and sensitized the cells to apoptosis. Overall, our results revealed that: (1) YY1 and survivin are positively correlated and overexpressed in B-NHLs, especially in BLs, (2) YY1 strongly binds to the survivin promoter, hence survivin may be suggested as YY1 transcriptional target, (3) YY1 silencing sensitizes Raji cells to drug-induced apoptosis via downregulation of survivin, (4) both YY1 and survivin are potential diagnostic markers and therapeutic targets for the treatment of resistant/relapsed B-NHLs.

Evidence suggests a beneficial role of the Mediterranean Diet (MedDiet) on health-related quality of life (HRQoL) in healthy subjects. HRQoL is relevant in cancer therapy and disease outcomes, therefore we investigated the association between adherence to the MedDiet and HRQoL in breast cancer survivors participating in the multicentre trial DEDiCa. Diet and HRQoL were assessed at baseline in a subgroup of 309 women enrolled within 12 months of breast cancer diagnosis without metastasis (stages I-III, mean age 52±1 yrs, BMI 27±7 kg/m2). The 14-item PREDIMED questionnaire was used to analyse adherence to the MedDiet. HRQoL was assessed with three validated questionnaires measuring physical, mental, emotional and social factors: EQ-5D-3L, EORTC QLQ-C30 and EORTC QLQ-BR23. Analysis of variance (ANOVA) and multivariate analyses were performed to assess the possible role of the MedDiet on HRQoL. Patients with higher adherence to MedDiet (PREDIMED score >7) showed significantly higher scores for physical functioning (p = 0.02) and lower scores on the symptomatic pain scale (p = 0.04) assessed by the EORTC QLQ-C30 questionnaire compared to patients with a lower adherence to MedDiet (PREDIMED score ≤7). Higher scores from the EQ-5D-3L indicating higher well-being were observed mainly in participants with higher MedDiet adherence (p = 0.05). In adjusted multivariate analyses significant positive associations were found between MedDiet, physical functioning (p = 0.001) and EQ 5D-3L score (p = 0.003) while inverse associations were found with pain and insomnia symptoms (p = 0.005 and p = 0.029, respectively). These results suggest that higher adherence to the MedDiet in breast cancer survivors is associated with better aspects of quality of life, specifically higher physical functioning, better sleep, lower pain and generally higher well-being confirming findings in healthy subjects.

The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.

Background TP53 plays critical roles in sensitivity to chemotherapy, and aging. Collagen is very important in aging. The molecular structure and biochemical properties of collagen changes during aging. The discoidin domain receptor (DDR1) is regulated in part by collagen. Elucidating the links between TP53 and DDR1 in chemosensitivity and aging could improve therapies against cancer and aging. Results Restoration of WT-TP53 activity resulted in increased sensitivity to chemotherapeutic drugs and elevated expression of key components of the Raf/MEK/ERK, PI3K/Akt and DDR1 pathways. DDR1 could modulate the levels of Raf/MEK/ERK and PI3K/Akt pathways as well as sensitize the cells to chemotherapeutic drugs. In contrast, suppression of WT TP53 with a dominant negative (DN) TP53 gene, suppressed DDR1 protein levels and increased their chemoresistance. Conclusion Restoration of WT TP53 activity or increased expression of the anti-aging DDR1 collagen receptor can result in enhanced sensitivity to chemotherapeutic drugs. Our innovative studies indicate the important links between WT TP53 and DDR1 which can modulate Raf/MEK/ERK and PI3K/Akt signaling as well as chemosensitivity and aging. Methods We investigated the roles of wild type (WT) and mutant TP53 on drug sensitivity of prostate cancer cells and the induction of Raf/MEK/ERK, PI3K/Akt and DDR1 expression and chemosensitivity.

In a relatively short period of time, treatment strategies for metastatic melanoma have radically changed leading to an unprecedented improvement in patient survival. In this period, immunotherapy options have evolved from cytokine-based approaches to antibody-mediated inhibition of immune checkpoints, cancer vaccines and pharmacological modulation of the melanoma microenvironment. Combination of immunotherapy strategies and the association of immune checkpoint inhibitors (ICIs) with BRAF V600 targeted therapy show encouraging results. The future of drug development in this field is promising. The comprehension of primary and acquired resistance mechanisms to ICIs and the dissection of melanoma immunobiology will be instrumental for the development of new treatment strategies and to improve clinical trial design. Moreover, biomarker discovery will help patient stratification and management during immunotherapy treatment. In this review, we summarize landmark clinical trials of immune checkpoint inhibitors in advanced melanoma and discuss the rational for immunotherapy combinations. Immunotherapy approaches at early stage of clinical development and recent advances in melanoma immunotherapy biomarker development are also discussed.

Significance: Hematological malignancies represent the fourth most diagnosed cancer. Relapse and acquired resistance to anticancer therapy constitute two actual issues that need to be overcome. Nitric oxide (NO) plays a pivotal role in regulating cancer progression. At present, many studies are attempting to uncover the potentials of modulating NO levels to improve the efficacy of currently available treatments against lymphoma, leukemia, and myeloma. Recent Advances: It is becoming progressively clear that NO modulation may help hematological cancer management, either by targeting directly tumor cells or by driving the immune system to eliminate cancer cells. Critical Issues: NO is a dual molecule that can have a tumor-protecting or stimulating effect, depending on its local concentration. Moreover, NO is able to target a wide range of molecules involved in both cancer genesis and evolution. In this review, an overview of the recent findings regarding the pivotal role played by NO and nitric oxide synthase in cancer progression and anticancer therapy is presented, with particular focus on hematological malignancies. Future Directions: It is critical to establish the cancer-specific function of NO and critically drive its modulation to improve cancer management toward a personalized approach. This has a special importance in hematological tumors, where the urgency of finding eradicative therapies is constant. Antioxid. Redox Signal. 34, 383-401.

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.

To evaluate adherence to abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer (mCRPC). In an observational prospective cohort study, we monitored patients with mCRPC for their adherence to abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Fifty-eight patients with median age of 76 years (range 56–94), age-adjusted Charlson comorbidity score of 10 (range, 4–15), and geriatric G8 score of 14 (range, 6–17) were enrolled. Twenty-two (38%) patients were treated with abiraterone and 36 (62%) with enzalutamide, while forty-two (72%) were in the pre-chemotherapy setting. Forty-seven patients (81%) had a caregiver. Based on the pill counting, a non-adherence rate of 4.8% and 6.2% was observed for the whole period and the first 3 months, respectively, without a statistically significant difference between abiraterone and enzalutamide cohorts. A lower non-adherence rate (1.3%) was reported by patients during the whole period, mainly due to a misperception (77%) and forgetfulness (19%). Non-adherence rate to the fulfilling of the clinical diary was 38% for the whole period. Non-adherence in the whole period was related to the radiological response (p = 0.03) and geriatric G8 score (p = 0.005). By the receiver operating characteristic (ROC) curve based on the radiological response, non-adherence cut-off was 1.87% (p = 0.04). By this non-adherence cut-off, the G8 cut-off was 14.75 (p = 0.0003). Non-adherence to abiraterone or enzalutamide for mCRPC may have an impact on disease response and be related to patients’ frailty, suggesting their geriatric assessment and clinical interventions to monitor and increase their adherence.

Limited knowledge is available on dietary patterns and bladder cancer risk. We analyzed data from an Italian case-control study carried out between 2003 and 2014, including 690 incident bladder cancer cases and 665 hospital-controls. We derived nutrient-based dietary patterns applying principal component factor analysis on 28 selected nutrients. We categorized factor scores according to quartiles, and estimated the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) through logistic regression models, adjusted for major confounding factors. We identified four dietary patterns named &ldquo, Animal products&rdquo, &ldquo, Vitamins and fiber&rdquo, Starch-rich&rdquo, and &ldquo, Animal unsaturated fatty acids&rdquo, We found an inverse association between the &ldquo, pattern and bladder cancer (OR = 0.70, 95% CI: 0.48&ndash, 0.99, IV versus I quartile category). Inverse relationships of borderline significance were also found for the &ldquo, and the &ldquo, dietary patterns. No significant association was evident for the &ldquo, pattern. The current study allowed us to identify major dietary patterns in this Italian population. Our study confirms available evidence and shows that scoring high on a fruit-and-vegetables pattern provides beneficial effects on bladder cancer risk.

Approaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). A key regulatory gene frequently mutated (∼75%) in PDAC is the TP53 tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, cancer progression and other growth regulatory processes. The mouse double minute 2 homolog (MDM2) gene product is a nuclear-localized E3 ubiquitin ligase and negatively regulates the TP53 protein which results in its proteasomal degradation. Various MDM2 inhibitors have been isolated and examined in clinical trials, especially in patients with hematological malignancies. Nutlin-3a is one of the first MDM2 inhibitors isolated. Berberine (BBR) is a natural product found in many fruits and berries and used in traditional medicine for centuries. It has many biological effects, and some are anti-proliferative in nature. BBR may activate the expression of TP53 and inhibit cell cycle progression as well as other events important in cell growth. To understand more about the potential of compounds like BBR and chemical modified BBRs (NAX compounds) to sensitize PDAC cells to MDM2 inhibitors, we introduced either WT-TP53 or the pLXSN empty vector control into two PDAC cell lines, one lacking expression of TP53 (PANC-28) and one with gain-of-function mutant TP53 on both alleles (MIA-PaCa-2). Our results indicate that nutlin-3a was able to increase the sensitivity to BBR and certain NAX compounds. The effects of nutlin-3a were usually more substantial in those cells containing an introduced WT TP53 gene. These results highlight the importance of knowledge of the type of TP53 mutation that is present in cancer patients before the administration of drugs which function by stabilization of the TP53 protein.

Aim To explore the feasibility and activity of oral metronomic vinorelbine patients with advanced NSCLC not eligible to standard chemotherapy because of old age (≥70 years), and/or poor Eastern Cooperative Oncology Group performance status (≥2), and/or extensive brain or bone disease, and/or active comorbidities (≥2) requiring for pharmacological treatment. Patients and methods In a prospective phase II not randomized study, patients with stage IV NSCLC unfit to chemotherapy were treated with oral metronomic vinorelbine at 30 mg fixed dose three times a week until disease progression. Results Fifty patients were treated, 19 (38%) in the first-line setting. Five patients (11%) experienced a grade 3 toxicity; no grade 4 toxicity occurred. Overall disease control rate was 32%, 44% and 26% in first and subsequent lines, respectively (p=0.39). Median OS and PFS were 7.3 months (95% confidence interval [CI]=4.7-10.0) and 2.7 months (95%CI=2.0-3.4), respectively. Conclusion These data support the activity and safety of metronomic vinorelbine in a relevant proportion of patients usually excluded from any specific treatment.

The aim of this study is to evaluate the association between metabolic disorders and the risk of nasopharyngeal carcinoma, considering different histological subtypes. Between 1992 and 2008, we carried out a multicentre case-control study in Italy. One-hundred and ninety-seven White patients with histologically confirmed nasopharyngeal carcinoma were enrolled as cases. The control group included 592 cancer-free patients, frequency matched by study centre, area of residence, sex, age and period of interview. Odds ratios (OR) and corresponding 95% confidence intervals (CI), for nasopharyngeal carcinoma according to obesity and self-reported history of other metabolic disorders, were calculated through logistic regression models adjusted for matching variables and tobacco smoking and drinking habits. Obesity (OR=1.44; 95% CI: 0.88-2.36), diabetes mellitus (OR=0.91; 95% CI: 0.42-1.98), hypertension (OR=0.79; 95% CI: 0.48-1.32), hypercholesterolaemia (OR=1.41; 95% CI: 0.84-2.35) and metabolic syndrome (i.e. at least three among the four previously cited metabolic disorders; OR=1.11; 95% CI: 0.86-1.43) were not significantly associated with the overall risk of nasopharyngeal carcinoma. However, the associations observed for diabetes mellitus, hypercholesterolaemia and metabolic syndrome were stronger among differentiated nasopharyngeal carcinomas than among undifferentiated ones. In particular, 21.7% of differentiated nasopharyngeal carcinoma cases and 7.8% of controls reported a history of metabolic syndrome (OR=3.37; 95% CI: 1.05-10.81). The results of the study indicated no overall association between metabolic disorders and nasopharyngeal carcinoma. Nonetheless, although the small sample size calls for caution in interpretation, metabolic disorders could increase the risk of differentiated nasopharyngeal carcinoma. This finding further supports a different aetiology of the two histological subtypes.

Colorectal cancer (CRC) is characterized by genetic heterogeneity and is often diagnosed at an advanced stage. Therefore, there is a need to identify novel predictive markers. Yin Yang 1 (YY1) is a transcription factor playing a dual role in cancer. The present study aimed to investigate whether YY1 expression levels influence CRC cell response to therapy and to identify the transcriptional targets involved. The diagnostic and prognostic values of YY1 and the identified factor(s) in CRC patients were also explored. Silencing of YY1 increased the resistance to 5-Fluorouracil-induced cytotoxicity in two out of four CRC cells with different genotypes. BCL2L15/Bfk pro-apoptotic factor was found selectively expressed in the responder CRC cells and downregulated upon YY1 knockdown. CRC dataset analyses corroborated a tumor-suppressive role for both YY1 and BCL2L15 whose expressions were inversely correlated with aggressiveness. CRC single-cell sequencing dataset analyses demonstrated higher co-expression levels of both YY1 and BCL2L15 within defined tumor cell clusters. Finally, elevated levels of YY1 and BCL2L15 in CRC patients were associated with larger relapse-free survival. Given their observed anti-cancer role, we propose YY1 and BCL2L15 as candidate diagnostic and prognostic CRC biomarkers.

Carbohydrate foods with high glycaemic index (GI) and load (GL) may negatively influence cancer risk. We studied the association of dietary carbohydrates, GI, GL, intake of bread and pasta with risk of bladder cancer using data from an Italian case–control study. The study included 578 men and women with histologically confirmed bladder cancer and 608 controls admitted to the same hospitals as cases for acute, non-neoplastic conditions. OR were estimated by logistic regression models after allowance for relevant confounding factors. OR of bladder cancer for the highest v. the lowest quantile of intake were 1·52 (95 % CI 0·85, 2·69) for available carbohydrates, 1·18 (95 % CI 0·83, 1·67) for GI, 1·96 (95 % CI 1·16, 3·31, PtrendPtrend=0·03) for pasta and 1·92 (95 % CI 1·28, 2·86, Ptrend

Natural products or nutraceuticals have been shown to elicit anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of microRNA (miR) expression which results in cell death or prevents aging, diabetes, cardiovascular and other diseases. This review will focus on a few natural products, especially on resveratrol (RES), curcumin (CUR) and berberine (BBR). RES is obtained from the skins of grapes and other fruits and berries. RES may extend human lifespan by activating the sirtuins and SIRT1 molecules. CUR is isolated from the root of turmeric (Curcuma longa). CUR is currently used in the tutreatment of many disorders, especially in those involving an inflammatory process. CUR and modified derivatives have been shown to have potent anti-cancer effects, especially on cancer stem cells (CSC). BBR is also isolated from various plants (e.g., Coptis chinensis) and has been used for centuries in traditional medicine to treat diseases such as adult- onset diabetes. Understanding the benefits of these and other nutraceuticals may result in approaches to improve human health.

While dietary factors have been shown to play an important etiologic role in non-Hodgkin lymphoma (NHL), little is known about the association between inflammatory properties of diet and NHL risk. We explored the association between the dietary inflammatory index (DII) and NHL risk in a multicenter Italian case–control study conducted between 1999 and 2014. Cases were 536 subjects with incident, histologically confirmed NHL from three areas in Italy. Controls were 984 subjects admitted to the same network of hospitals as the cases for acute, nonmalignant conditions, unrelated to diet. DII scores were computed based on 30 nutrients and food items assessed using a reproducible and validated 78-item food-frequency questionnaire. Odds ratios (ORs) were estimated through logistic regression models adjusting for age, total energy intake, and other recognized confounding factors. Subjects in the highest quartile of DII scores (i.e., with the most pro-inflammatory diets) had a higher risk of NHL compared with subjects in the lowest quartile (i.e., with the most anti-inflammatory diets) (ORQuartile4vs1 1.61, 95% confidence interval CI 1.07–2.43; p-trend = 0.01). Stratified analyses produced stronger associations between DII and NHL among males (ORQuartile4vs1 2.14; 95% CI 1.25–3.67) with significant heterogeneity (p value = 0.02); when analyzed by histologic subtype, a significant association was observed with diffuse large B-cell lymphoma (ORQuartile4vs1 1.84; 95% CI 1.09–3.10). A pro-inflammatory diet, as indicated by higher DII scores, is associated with elevated odds of NHL, especially among males.

Previous studies on the relationship between fluid intake and risk of bladder cancer have generally focused on beverages, and results have been inconsistent. We investigated the relationship between water intake and bladder cancer risk, considering water from both beverages and foods. Between 2003 and 2014 we conducted a multicenter hospital-based case-control study in Italy on 690 cases and 665 frequency-matched controls. Water intake for beverages and foods was computed using the Italian food composition database. Odds ratios (ORs) and the corresponding 95% confidence intervals (95%CIs) for water intake were estimated by unconditional multiple logistic regression models, adjusting for major risk factors for bladder cancer. In the control group, the 64.7% of water intake derived from beverages and 35.4% from foods. Comparing the highest with the lowest quartile of intake, water from beverages (OR=1.14; 95%CI: 0.82-1.59) and water from foods (OR=0.88; 95%CI: 0.61-1.28) were not significantly associated with bladder cancer risk. Some specific water sources showed significant associations with bladder cancer risk (e.g. water from vegetables, OR=0.58; 95%CI: 0.40-0.86). However, these associations may be due to the effect of other components contained in beverages and foods rather than to the water content itself. Considering the intakes of water from both beverages and foods, total water intake was not associated with bladder cancer risk.

Improving the effects of chemotherapy and reducing the side effects are important goals in cancer research. Various approaches have been examined to enhance the effectiveness of chemotherapy. For example, signal transduction inhibitors or hormonal based approaches have been included with chemo- or radio-therapy. MIA-PaCa-2 and BxPC-3 pancreatic ductal adenocarcinoma (PDAC) cells both express the estrogen receptor (ER). The effects of β-estradiol on the growth of PDAC cells has not been examined yet the ER is expressed in PDAC cells. We have examined the effects of combining β-estradiol with chemotherapeutic drugs, signal transcription inhibitors, natural products and nutraceuticals on PDAC. In most cases, inclusion of β-estradiol with chemotherapeutic drugs increased chemosensitivity. These results indicate some approaches involving β-estradiol which may be used to increase the effectiveness of chemotherapeutic and other drugs on the growth of PDAC.

Glioblastoma multiforme is the most aggressive malignant tumor of the central nervous system. Due to the absence of effective pharmacological and surgical treatments, the identification of early diagnostic and prognostic biomarkers is of key importance to improve the survival rate of patients and to develop new personalized treatments. On these bases, the aim of this review article is to summarize the current knowledge regarding the application of molecular biology and proteomics techniques for the identification of novel biomarkers through the analysis of different biological samples obtained from glioblastoma patients, including DNA, microRNAs, proteins, small molecules, circulating tumor cells, extracellular vesicles, etc. Both benefits and pitfalls of molecular biology and proteomics analyses are discussed, including the different mass spectrometry-based analytical techniques, highlighting how these investigation strategies are powerful tools to study the biology of glioblastoma, as well as to develop advanced methods for the management of this pathology.

Background Since food metabolites are eliminated by the urinary tract, several studies have investigated the association between diet and bladder cancer risk. Recently, the World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) suggested a potential beneficial effect of some foods (mainly vegetables, fruit, and milk) in the development of bladder cancer. We investigated the association between food groups and bladder cancer risk, seeking insights into food diversity as well as meat cooking methods. Methods Data were derived from an Italian multicentre case–control study, conducted between 2003 and 2014, including 690 bladder cancer cases and 665 frequency-matched controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (95%CIs) for various dietary aspects were estimated by unconditional logistic regression models adjusted for energy intake and the major known risk factors for bladder cancer. Results Comparing the highest versus the lowest quartiles, consumption of vegetables (OR = 0.62; 95%CI: 0.44-0.88) and milk/yogurt (OR = 0.62; 95%CI: 0.44–0.87) reduced the risk of bladder cancer. Conversely, consumption of meat increased bladder cancer risk with an OR of 1.57 (95%CI: 1.07–2.31), particularly when the meat was stewed (OR = 1.47; 95%CI: 1.03–2.09) or roasted (OR = 1.41; 95%CI: 1.00–1.99). There was a suggestion that a diversified diet reduced the risk of bladder cancer, but this was not significant. Conclusions Our study consolidates the role of diet in bladder cancer aetiology, showing a reduced risk for vegetable and milk/yogurt consumption and an increased risk for meat consumption, especially when the meat is stewed or roasted.

Pancreatic cancer is devastating cancer worldwide with few if any truly effective therapies. Pancreatic cancer has an increasing incidence and may become the second leading cause of death from cancer. Novel, more effective therapeutic approaches are needed as pancreatic cancer patients usually survive for less than a year after being diagnosed. Control of blood sugar levels by the prescription drug metformin in diseases such as diabetes mellitus has been examined in association with pancreatic cancer. While the clinical trials remain inconclusive, there is hope that certain diets and medications may affect positively the outcomes of patients with pancreatic and other cancers. Other natural compounds may share some of the effects of metformin. One “medicinal” fruit consumed by millions worldwide is berberine (BBR). Metformin and BBR both activate AMP-activated protein kinase (AMPK) which is a key mediator of glucose metabolism. Glucose metabolism has been shown to be very important in cancer and its significance is increasing. In the following studies, we have examined the effects of metformin, BBR and a panel of modified BBRs (NAX compounds) and chemotherapeutic drugs on the growth of four different human pancreatic adenocarcinoma cell lines (PDAC). Interestingly, the effects of metformin could be enhanced by BBR and certain modified BBRs. Upon restoration of WT-TP53 activity in MIA-PaCa-2 cells, an altered sensitivity to the combination of certain NAX compounds and metformin was observed compared to the parental cells which normally lack WT-TP53. Certain NAX compounds may interact with WT-TP53 and metformin treatment to alter the expression of key molecules involved in cell growth. These results suggest a therapeutic approach by combining certain pharmaceutical drugs and nutraceuticals to suppress the growth of cancer cells.

Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic stroke. In this review, the epidemiology and pathophysiology of stroke in cancer patients is discussed, while providing vital information on the diagnosis and management of patients with cancer and stroke. Cancer may mediate stroke pathophysiology either directly or via coagulation disorders that establish a state of hypercoagulation, as well as via infections. Cancer treatment options, such as chemotherapy, radiotherapy and surgery have all been shown to aggravate the risk of stroke as well. The clinical manifestation varies greatly depending upon the underlying cause; however, in general, cancer‑associated strokes tend to appear as multifocal in neuroimaging. Furthermore, several serum markers have been identified, such as high D‑Dimer levels and fibrin degradation products. Managing cancer patients with stroke is a delicate matter. The cancer should not be considered a contraindication in applying thrombolysis and recombinant tissue plasminogen activator (rTPA) administration, since the risk of hemorrhage in cancer patients has not been reported to be higher than that in the general population. Anticoagulation, on the contrary, should be carefully examined. Clinicians should weigh the benefits and risks of anticoagulation treatment for each patient individually; the new oral anticoagulants appear promising; however, low‑molecular‑weight heparin remains the first choice. On the whole, stroke is a serious and not a rare complication of malignancy. Clinicians should be adequately trained to handle these patients efficiently.

Uveal melanoma (UM) represents the most frequent primary tumor of the eye. Despite the development of new drugs and screening programs, the prognosis of patients with UM remains poor and no effective prognostic biomarkers are yet able to identify high-risk patients. Therefore, in the present study, microRNA (miRNA or miR) expression data, contained in the TCGA UM (UVM) database, were analyzed in order to identify a set of miRNAs with prognostic significance to be used as biomarkers in clinical practice. Patients were stratified into 2 groups, including tumor stage (high-grade vs. low-grade) and status (deceased vs. alive); differential analyses of miRNA expression among these groups were performed. A total of 20 deregulated miRNAs for each group were identified. In total 7 miRNAs were common between the groups. The majority of common miRNAs belonged to the miR-506-514 cluster, known to be involved in UM development. The prognostic value of the 20 selected miRNAs related to tumor stage was assessed. The deregulation of 12 miRNAs (6 upregulated and 6 downregulated) was associated with a worse prognosis of patients with UM. Subsequently, miRCancerdb and microRNA Data Integration Portal bioinformatics tools were used to identify a set of genes associated with the 20 miRNAs and to establish their interaction levels. By this approach, 53 different negatively and positively associated genes were identified. Finally, DIANA-mirPath prediction pathway and Gene Ontology enrichment analyses were performed on the lists of genes previously generated to establish their functional involvement in biological processes and molecular pathways. All the miRNAs and genes were involved in molecular pathways usually altered in cancer, including the mitogen-activated protein kinase (MAPK) pathway. Overall, the findings of the presents study demonstrated that the miRNAs of the miR-506-514 cluster, hsa-miR-592 and hsa-miR-199a-5p were the most deregulated miRNAs in patients with high-grade disease compared to those with low-grade disease and were strictly related to the overall survival (OS) of the patients. However, further in vitro and translational approaches are required to validate these preliminary findings.

Objectives The aim of this study was to evaluate whether the association between the inflammatory potential of one's diet and cancer risk varies across age groups in a population characterized by widespread use of the Mediterranean diet. Methods We analyzed data from a network of case-control studies conducted in Italy between 1991 and 2014. The studies included cancers of the oral cavity (n = 509), pharynx (n = 436), nasopharynx (n = 198), larynx (n = 459), esophagus (n = 304), stomach (n = 230), colon (n = 1225), rectum (n = 728), liver (n = 184), pancreas (n = 326), breast (n = 2569), endometrium (n = 454), ovary (n = 1031), prostate (n = 1294), kidney (n = 767), and bladder (n = 690). Controls were 13 563 patients hospitalized for acute, non-neoplastic conditions. Dietary inflammatory index (DII) scores were computed based on 31 food parameters assessed using a reproducible and validated food frequency questionnaire. Odds ratios were estimated through logistic regression models adjusting for recognized confounding factors. Results The DII increased with age, with lower scores among men than women, in individuals located in northern rather than in central or southern Italy, and in controls more than in cancer cases. After adjustment for cancer-specific potential confounders, an increasing DII score was directly associated with cancer risk for all considered cancer sites, except for liver and endometrium. Although the DII level varied across age groups, no heterogeneity in cancer risk emerged for any of the considered cancer sites. Conclusions In the Italian population, DII scores were higher in elderly than in middle-aged individuals. Although not directly affecting cancer risk, this finding may have important implications for the older population because elevated DII scores, indicating a proinflammatory diet, also have been associated with frailty.

There is recent evidence to indicate the existence of an inverse association between the incidence of neurological disorders and cancer development. Concurrently, the transcriptional pathways responsible for the onset of glioblastoma multiforme (GBM) and Alzheimer's disease (AD) have been found to be mutually exclusive between the two pathologies. Despite advancements being made concerning the knowledge of the molecular mechanisms responsible for the development of GBM and AD, little is known about the identity of the microRNA (miRNAs or miRs) involved in the development and progression of these two pathologies and their possible inverse expression patterns. On these bases, the aim of the present study was to identify a set of miRNAs significantly de‑regulated in both GBM and AD, and hence to determine whether the identified miRNAs exhibit an inverse association within the two pathologies. For this purpose, miRNA expression profiling datasets derived from the Gene Expression Omnibus (GEO) DataSets and relative to GBM and AD were used. Once the miRNAs significantly de‑regulated in both pathologies were identified, DIANA‑mirPath pathway prediction and STRING Gene Ontology enrichment analyses were performed to establish their functional roles in each of the pathologies. The results allowed the identification of a set of miRNAs found de‑regulated in both GBM and AD, whose expression levels were inversely associated in the two pathologies. In particular, a strong negative association was observed between the expression levels of miRNAs in GBM compared to AD, suggesting that although the molecular pathways behind the development of these two pathologies are the same, they appear to be inversely regulated by miRNAs. Despite the identification of this set of miRNAs which may be used for diagnostic, prognostic and therapeutic purposes, further functional in vitro and in vivo evaluations are warranted in order to validate the diagnostic and therapeutic potential of the identified miRNAs, as well as their involvement in the development of GBM and AD.

Mutations at the TP53 gene are readily detected (approximately 50–75%) in pancreatic ductal adenocarcinoma (PDAC) patients. TP53 was previously thought to be a difficult target as it is often mutated, deleted or inactivated on both chromosomes in certain cancers. In the following study, the effects of restoration of wild-type (WT) TP53 activity on the sensitivities of MIA-PaCa-2 pancreatic cancer cells to the MDM2 inhibitor nutlin-3a in combination with chemotherapy, targeted therapy, as well as, nutraceuticals were examined. Upon introduction of the WT-TP53 gene into MIA-PaCa-2 cells, which contain a TP53 gain of function (GOF) mutation, the sensitivity to the MDM2 inhibitor increased. However, effects of nutlin-3a were also observed in MIA-PaCa-2 cells lacking WT-TP53, as upon co-treatment with nutlin-3a, the sensitivity to certain inhibitors, chemotherapeutic drugs and nutraceuticals increased. Interestingly, co-treatment with nutlin-3a and certain chemotherapeutic drug such as irinotecan and oxaliplatin resulted in antagonistic effects in cells both lacking and containing WT-TP53 activity. These studies indicate the sensitizing abilities that WT-TP53 activity can have in PDAC cells which normally lack WT-TP53, as well as, the effects that the MDM2 inhibitor nutlin-3a can have in both cells containing and lacking WT-TP53 to various therapeutic agents.

Background DNA methylation is an epigenetic mechanism of genomic regulation involved in the maintenance of homeostatic balance. Dysregulation of DNA methylation status is one of the driver alterations occurring in neoplastic transformation and cancer progression. The identification of methylation hotspots associated to gene dysregulation may contribute to discover new prognostic and diagnostic biomarkers, as well as, new therapeutic targets. Results We present EpiMethEx (Epigenetic Methylation and Expression), a R package to perform a large-scale integrated analysis by cyclic correlation analyses between methylation and gene expression data. For each gene, samples are segmented according to the expression levels to select genes that are differentially expressed. This stratification allows to identify CG methylation probesets modulated among gene-stratified samples. Subsequently, the methylation probesets are grouped by their relative position in gene sequence to identify wide genomic methylation events statically related to genetic modulation. Conclusions The beta-test study showed that the global methylation analysis was in agreement with scientific literature. In particular, this analysis revealed a negative association between promoter hypomethylation and overexpression in a wide number of genes. Less frequently, this overexpression was sustained by intragenic hypermethylation events. Electronic supplementary material The online version of this article (10.1186/s12859-018-2397-6) contains supplementary material, which is available to authorized users.

In recent years, the introduction of new molecular techniques in experimental and clinical settings has allowed researchers and clinicians to propose circulating-tumor DNA (ctDNA) analysis and liquid biopsy as novel promising strategies for the early diagnosis of cancer and for the definition of patients’ prognosis. It was widely demonstrated that through the non-invasive analysis of ctDNA, it is possible to identify and characterize the mutational status of tumors while avoiding invasive diagnostic strategies. Although a number of studies on ctDNA in patients’ samples significantly contributed to the improvement of oncology practice, some investigations generated conflicting data about the diagnostic and prognostic significance of ctDNA. Hence, to highlight the relevant achievements obtained so far in this field, a clearer description of the current methodologies used, as well as the obtained results, are strongly needed. On these bases, this review discusses the most relevant studies on ctDNA analysis in cancer, as well as the future directions and applications of liquid biopsy. In particular, special attention was paid to the early diagnosis of primary cancer, to the diagnosis of tumors with an unknown primary location, and finally to the prognosis of cancer patients. Furthermore, the current limitations of ctDNA-based approaches and possible strategies to overcome these limitations are presented.

Berberine (BBR) is a common nutraceutical consumed by millions worldwide. BBR has many different effects on human health, e.g., diabetes, diarrhea, inflammation and now more recently it has been proposed to have potent anti-cancer effects. BBR has been shown to suppress the growth of cancer cells more than normal cells. BBR has been proposed to exert its growth-inhibitory effects by many different biochemical mechanisms including: suppression of cell cycle progression, induction of reactive oxygen species, induction of apoptosis and autophagy and interactions with DNA potentially leading to DNA damage, and altered gene expression. Pancreatic cancer is a leading cancer worldwide associated with a poor prognosis. As our population ages, pancreatic cancer has an increasing incidence and will likely become the second leading cause of death from cancer. There are few truly-effective therapeutic options for pancreatic cancer. Surgery and certain chemotherapeutic drugs are used to treat pancreatic cancer patients. Novel approaches to treat pancreatic cancer patients are direly needed as they usually survive for less than a year after being diagnosed. In the following manuscript, we discuss the abilities of BBR and certain chemically- modified BBRs (NAX compounds) to suppress growth of pancreatic cancer cells.

Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients., Graphical abstract Image 1, Highlights • Respiratory system is the main target of SARS-CoV-2. • SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions. • SARS-CoV-2 can cause central and peripheral neurological manifestations. • SARS-CoV-2 can affect the cardiovascular system and promote renal dysfunction. • Cancer patients are at a higher risk of contracting the SARS-CoV-2 virus.

It is well known that pesticides are widely used compounds. In fact, their use in agriculture, forestry, fishery and the food industry has granted a huge improvement in terms of productive efficiency. However, a great number of epidemiological surveys have demonstrated that these toxic compounds can interact and exert negative effects not only with their targets (pests, herbs and fungi), but also with the rest of the environment, including humans. This is particularly relevant in the case of workers involved in the production, transportation, preparation and application of these toxicants. Accordingly, a growing body of evidence has demonstrated the correlation between occupational exposure to pesticides and the development of a wide spectrum of pathologies, ranging from eczema to neurological diseases and cancer. Pesticide exposure is often quite difficult to establish, as many currently used modules do not take into account all of the many variables that can occur in a diverse environment, such as the agricultural sector, and the assessment of the real risk for every single worker is problematic. Indeed, the use of personal protection equipment is necessary while handling these toxic compounds, but education of workers can be even more important: personal contamination with pesticides may occur even in apparently harmless situations. This review summarises the most recent findings describing the association between pesticide occupational exposure and the development of chronic diseases.

It is well known that the occupational exposure to contaminants and carcinogens leads to the development of cancer in exposed workers. In the 18th century, Percivall Pott was the first to hypothesize that chronic exposure to dust in the London chimney sweeps was associated with an increased risk of developing cancer. Subsequently a growing body of evidence indicated that other physical factors were also responsible for oncogenic mutations. Over the past decades, many carcinogens have been found in the occupational environment and their presence is often associated with an increased incidence of cancer. Occupational exposure involves several factors and the association between carcinogens, occupational exposure and cancer is still unclear. Only a fraction of factors is recognized as occupational carcinogens and for each factor, there is an increased risk of cancer development associated with a specific work activity. According to the International Agency for Research on Cancer (IARC), the majority of carcinogens are classified as 'probable' and 'possible' human carcinogens, while, direct evidence of carcinogenicity is provided in epidemiological and experimental studies. In the present review, exposures to benzene, pesticides and mineral fibers are discussed as the most important cancer risk factors during work activities.

Bladder cancer is one of the leading cancer of the urinary tract. It is often diagnosed at advanced stage of the disease. To date, no specific and effective early detection biomarkers are available. Cancer development and progression are associated with the involvement of both epithelial-mesenchymal transition (EMT) and tumor microenvironment of which NGAL/MMP-9 complex represents the main player in bladder cancer. It is known that change in microRNAs (miRNAs) expression may result in gene modulation. Therefore, the identification of specific miRNAs associated with EMT pathway and NGAL/MMP-9 complex may be useful to detect the development of bladder cancer at early stages. On this ground, the expression levels of miRNAs in public available datasets of bladder cancer containing data of non-coding RNA profiling was evaluated. This analysis revealed a group of 16 miRNAs differentially expressed between bladder cancer patients and related healthy controls. By miRNA prediction tool (mirDIP), the relationship between the identified miRNAs and the EMT genes was established. Using the DIANA-mirPath (v.2) software, miRNAs, able to modulate the expression of NGAL and MMP-9 genes, were recognized. The results of this study provide evidence that the downregulated hsa-miR-145-5p and hsa-miR-214-3p may modulate the expression of both EMT and NGAL/MMP-9 pathways. Therefore, further validation analyses may confirm the usefulness of these selected miRNAs for predicting the development of bladder cancer at the early stage of the disease.