It has been well documented that the tumor microenvironment (TME) plays a key role in the promotion of drug resistance, the support of tumor progression, invasiveness, metastasis, and even the ...maintenance of a cancer stem-like phenotype. Here, we reviewed TME formation presenting it as a reflection of a tumor's own organization during the different stages of tumor development. Interestingly, functionally different groups of stromal cells seem to have specific spatial distributions within the TME that change as the tumor evolves into advanced stage progression which correlates with the fact that cancer stem-like cells (CSCs) are located in the edges of solid tumor masses in advanced tumors.We also focus on the continuos feedback that is established between a tumor and its surroundings. The "talk" between tumor mass cells and TME stromal cells, marks the evolution of both interlocuting cell types. For instance, the metabolic and functional transformations that stromal cells undergo due to tumor corrupting activity.Moreover, the molecular basis of metastatic spread is also approached, making special emphasis on the site-specific pre-metastatic niche formation as another reflection of the primary tumor molecular signature.Finally, several therapeutic approaches targeting primary TME and pre-metastatic niche are suggested. For instance, a systematic analysis of the TME just adjacent to the tumor mass to establish the proportion of myofibroblasts-like cancer-associated fibroblasts (CAFs) which may in turn correspond to stemness and metastases-promotion. Or the implementation of "re-education" therapies consisting of switching tumor-supportive stromal cells into tumor-suppressive ones. In summary, to improve our clinical management of cancer, it is crucial to understand and learn how to manage the close interaction between TME and metastasis.
The increase in cancer incidences shows that there is a need to better understand tumour heterogeneity to achieve efficient treatments. Interestingly, there are several common features among almost ...all types of cancers, with chronic inflammation induction and deaminase dysfunctions singled out. Deaminases are a family of enzymes with nucleotide-editing capacity, which are classified into two main groups: DNA-based and RNA-based. Remarkably, a close relationship between inflammation and the dysregulation of these molecules has been widely documented, which may explain the characteristic intratumor heterogeneity, both at DNA and transcriptional levels. Indeed, heterogeneity in cancer makes it difficult to establish a unique tumour progression model. Currently, there are three main cancer models—stochastic, hierarchic, and dynamic—although there is no consensus on which one better resembles cancer biology because they are usually overly simplified. Here, to accurately explain tumour progression, we propose interactions among chronic inflammation, deaminases dysregulation, intratumor genetic heterogeneity, cancer phenotypic plasticity, and even the previously proposed appearance of cancer stem-like cell populations in the edges of advanced solid tumour masses (instead of being the cells of origin of primary malignancies). The new tumour development model proposed in this study does not contradict previously accepted models and it may open up a window to interesting therapeutic approaches.
Scope
The plasma metabolomics profiles of protein intake have been rarely investigated. The aim is to identify the distinct plasma metabolomics profiles associated with overall intakes of protein as ...well as with intakes from animal and plant protein sources.
Methods and results
A cross‐sectional analysis using data from 1833 participants at high risk of cardiovascular disease is conducted. Associations between 385 identified metabolites and the intake of total, animal protein (AP), and plant protein (PP), and plant‐to‐animal ratio (PR) are assessed using elastic net continuous regression analyses. A double 10‐cross‐validation (CV) procedure is used and Pearson correlations coefficients between multi‐metabolite weighted models and reported protein intake in each pair of training‐validation datasets are calculated. A wide set of metabolites is consistently associated with each protein source evaluated. These metabolites mainly consisted of amino acids and their derivatives, acylcarnitines, different organic acids, and lipid species. Few metabolites overlapped among protein sources (i.e., C14:0 SM, C20:4 carnitine, GABA, and allantoin) but none of them toward the same direction. Regarding AP and PP approaches, C20:4 carnitine and dimethylglycine are positively associated with PP but negatively associated with AP. However, allantoin, C14:0 SM, C38:7 PE plasmalogen, GABA, metronidazole, and trigonelline (N‐methylnicotinate) behave contrarily. Ten‐CV Pearson correlation coefficients between self‐reported protein intake and plasma metabolomics profiles range from 0.21 for PR to 0.32 for total protein.
Conclusions
Different sets of metabolites are associated with total, animal, and plant protein intake. Further studies are needed to assess the contribution of these metabolites in protein biomarkers’ discovery and prediction of cardiometabolic alterations.
The plasma metabolomics profile of protein intake have been rarely investigated. The aim is to identify metabolites associated with the consumption of total, animal, and plant protein. Different plasma metabolomics profiles are identified, which exhibit moderate correlations with the self‐reported protein intake. Further studies are needed to assess the contribution of these metabolites in protein biomarkers' discovery and metabolic alterations.
Recently, the influence that metabolic syndrome (MetS), hormonal alterations and inflammation might have on prostate cancer (PCa) risk has been a subject of controversial debate. Herein, we aimed to ...investigate the association between MetS‐components, C‐reactive protein (CRP) and testosterone levels, and the risk of clinically significant PCa (Sig‐PCa) at the time of prostate biopsy. For that, men scheduled for transrectal ultrasound guided biopsy of the prostate were studied. Clinical, laboratory parameters and criteria for MetS characterization just before the biopsy were collected. A total of 524 patients were analysed, being 195 (37.2%) subsequently diagnosed with PCa and 240 (45.8%) meet the diagnostic criteria for MetS. Among patients with PCa, MetS‐diagnosis was present in 94 (48.2%). Remarkably, a higher risk of Sig‐PCa was associated to MetS, greater number of MetS‐components and higher CRP levels (odds‐ratio: 1.83, 1.30 and 2.00, respectively; P < 0.05). Moreover, higher circulating CRP levels were also associated with a more aggressive Gleason score in PCa patients. Altogether, our data reveal a clear association between the presence of MetS, a greater number of MetS‐components or CRP levels >2.5 mg/L with an increased Sig‐PCa diagnosis and/or with aggressive features, suggesting that MetS and/or CRP levels might influence PCa pathophysiology.
Scope
The relationship between red wine (RW) consumption and metabolism is poorly understood. It is aimed to assess the systemic metabolomic profiles in relation to frequent RW consumption as well as ...the ability of a set of metabolites to discriminate RW consumers.
Methods and results
A cross‐sectional analysis of 1157 participants is carried out. Subjects are divided as non‐RW consumers versus RW consumers (>1 glass per day RW 100 mL per day). Plasma metabolomics analysis is performed using LC–MS. Associations between 386 identified metabolites and RW consumption are assessed using elastic net regression analysis taking into consideration baseline significant covariates. Ten‐cross‐validation (CV) is performed and receiver operating characteristic curves are constructed in each of the validation datasets based on weighted models. A subset of 13 metabolites is consistently selected and RW consumers versus nonconsumers are discriminated. Based on the multi‐metabolite model weighted with the regression coefficients of metabolites, the area under the curve is 0.83 (95% CI: 0.80–0.86). These metabolites mainly consisted of lipid species, some organic acids, and alkaloids.
Conclusions
A multi‐metabolite model identified in a Mediterranean population appears useful to discriminate between frequent RW consumers and nonconsumers. Further studies are needed to assess the contribution of these metabolites in health and disease.
The relationship between red wine (RW) consumption and metabolism is poorly understood. The aim of this study is to assess the circulating metabolomic profiles in relation to frequent RW consumption as well as the ability of a set of metabolites to discriminate RW consumers from nonconsumers. The validated 13‐multi‐metabolite model accurately discriminates those who frequently consume RW from non‐RW consumers.
Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also ...associated with lower risk of cardiometabolic diseases.
The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD.
The discovery population included 1833 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m2): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training–validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models.
A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P < 0.001).
A metabolite profile including 19 metabolites was associated with walnut consumption and with a lower risk of incident T2D and CVD in a Mediterranean population at high cardiovascular risk.
Insulin resistance is a complex metabolic disorder and is often associated with type 2 diabetes (T2D).
The aim of this study was to test whether baseline metabolites can additionally improve the ...prediction of insulin resistance beyond classical risk factors. Furthermore, we examined whether a multimetabolite model predicting insulin resistance in nondiabetics can also predict incident T2D.
We used a case-cohort study nested within the Prevención con Dieta Mediterránea (PREDIMED) trial in subsets of 700, 500, and 256 participants without T2D at baseline and 1 and 3 y. Fasting plasma metabolites were semiquantitatively profiled with liquid chromatography–tandem mass spectrometry. We assessed associations between metabolite concentrations and the homeostasis model of insulin resistance (HOMA-IR) through the use of elastic net regression analysis. We subsequently examined associations between the baseline HOMA-IR–related multimetabolite model and T2D incidence through the use of weighted Cox proportional hazard models.
We identified a set of baseline metabolites associated with HOMA-IR. One-year changes in metabolites were also significantly associated with HOMA-IR. The area under the curve was significantly greater for the model containing the classical risk factors and metabolites together compared with classical risk factors alone at baseline 0.81 (95% CI: 0.79, 0.84) compared with 0.69 (95% CI: 0.66, 0.73) and during a 1-y period 0.69 (95% CI: 0.66, 0.72) compared with 0.57 (95% CI: 0.53, 0.62). The variance in HOMA-IR explained by the combination of metabolites and classical risk factors was also higher in all time periods. The estimated HRs for incident T2D in the multimetabolite score (model 3) predicting high HOMA-IR (median value or higher) or HOMA-IR (continuous) at baseline were 2.00 (95% CI: 1.58, 2.55) and 2.24 (95% CI: 1.72, 2.90), respectively, after adjustment for T2D risk factors.
The multimetabolite model identified in our study notably improved the predictive ability for HOMA-IR beyond classical risk factors and significantly predicted the risk of T2D.
Cancer stem cells (CSCs) subpopulation within the tumour is responsible for metastasis and cancer relapse. Here we investigate in vitro and in vivo the effects of a pancreatic (pro)enzyme mixture ...composed of Chymotrypsinogen and Trypsinogen (PRP) on CSCs derived from a human pancreatic cell line, BxPC3. Exposure of pancreatic CSCs spheres to PRP resulted in a significant decrease of ALDEFLUOR and specific pancreatic CSC markers (CD 326, CD 44 and CxCR4) signal tested by flow cytometry, further CSCs markers expression was also analyzed by western and immunofluorescence assays. PRP also inhibits primary and secondary sphere formation. Three RT
Profiler PCR Arrays were used to study gene expression regulation after PRP treatment and resulted in, (i) epithelial-mesenchymal transition (EMT) inhibition; (ii) CSCs related genes suppression; (iii) enhanced expression of tumour suppressor genes; (iv) downregulation of migration and metastasis genes and (v) regulation of MAP Kinase Signalling Pathway. Finally, in vivo anti-tumor xenograft studies demonstrated high anti-tumour efficacy of PRP against tumours induced by BxPC3 human pancreatic CSCs. PRP impaired engrafting of pancreatic CSC's tumours in nude mice and displayed an antigrowth effect toward initiated xenografts. We concluded that (pro)enzymes treatment is a valuable strategy to suppress the CSC population in solid pancreatic tumours.
The aims of this study were to determine the involvement of interleukin 17 (IL-17) and IL-17-producing cells in dengue pathogenesis. Blood samples from dengue virus (DENV)-infected patients were ...collected on different days after the onset of symptoms. Patients were classified according to 1997 World Health Organization guidelines. Our study examined 152 blood samples from dengue fever (DF,
= 109) and dengue hemorrhagic fever (DHF,
= 43) patients and 90 blood samples from healthy controls (HC). High serum concentrations of IL-17A and IL-22 were also associated with DHF (IL-17A DHF vs. DF,
< 0.01; DHF vs. HC,
< 0.0001; IL-22 DHF vs. DF,
< 0.05; DHF vs. HC,
< 0.0001). Moreover, there was a positive correlation between serum levels of IL-17A and IL-23, a key cytokine that promotes IL-17-based immune responses (r = 0.4089,
< 0.0001). Consistent with the IL-17-biased immune response in DHF patients, we performed ex vivo activation of peripheral blood mononuclear cells (PBMCs) from DHF patients and flow cytometry analysis showed a robust IL-17-biased immune response, characterized by a high frequency of CD4+IL-17+ producing cells. Our results suggests IL-17-producing cells and their related cytokines can play a prominent role in this viral disease.
Introduction: The aim of this study was to analyze the situational framework (numerical equality, counterattack and numerical inequality) associated with shooting performance in women's Water polo ...considering three different levels in the final ranking (high -1st-4th-, medium -5th-8th- and worst -9th-12th-). Material and Methods: All shots (2698) made in 34th European Championship in 2020 were analyzed in the present study. The study was developed with an observational design. The reliability between three observers was verified using the Kappa concordance index. The shots were registered using Polo Direct Analysis v1.0 software. Results: There are differences between the high level teams (ranked at 1st-4th) and the rest of the teams, appreciating a greater scoring efficiency in equality lob shots (.5; 1.0; 1.2) and reverse shot .7; .5; .2) inequality short post (3.0; 1.8; 1.7) and counterattack in the situations shots from left side (1.6; .7; .5), shots from center with feint (2.9; 1.5; .7), drive (2.0; .8; .7) and rebound shot (.9; .7; .3). Discussion: The existence of differences between the top-ranked teams, those in the intermediate zones and the lowest-ranked teams are found. There is a greater scoring efficiency in the top-ranked teams. Conclusions: It is concluded that in order to achieve a higher performance in women's water polo, athletes must have the ability to withstand great efforts and perform fast swims to convert counterattack situations. Likewise, and in static situations, it is necessary to have fast ball circulation, lining up players with a great versatility of shooting in the different game situations, which therefore allows them to have more resources and take advantage of the opportunities generated by the opponent.
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