Emerging immune checkpoint inhibitors for the treatment of non-small cell lung cancer.

INTRODUCTION: Over the last decade, immune checkpoint inhibitors (ICIs) have impacted on the standard therapy for patients with non-small cell lung cancer (NSCLC). ICIs first showed efficacy in patients with advanced disease who had progressed after chemotherapy, later reaching the first-line therapy context alone, in combination with chemotherapy, and/or with dual-immunotherapy regimens. AREAS COVERED: Most of their benefit is, however, restricted to just 20% of patients due to primary or emergence of acquired resistance. In this review, we will describe the role of new emerging ICIs in the current panorama of NSCLC therapeutic approaches, not only in metastatic disease but also in locally advanced stage disease, with specific focus on those drugs under investigation in Phase 2/3 clinical trials. EXPERT OPINION: Several new ICIs are now under investigation to optimize NSCLC patient management; these are usually used in combination with other well-known agents, such as 'traditional' ICIs and chemotherapy, or with other newly developed drugs. Identification of better biomarkers will provide personalized treatment approaches to overcome patient-specific immune resistance.

Stroma-normalised vessel density predicts benefit from adjuvant fluorouracil-based chemotherapy in patients with stage II/III colon cancer.

BACKGROUND: Identification of biomarkers associated with benefit of adjuvant chemotherapy in stage II/III colon cancer is an important task. METHODS: Vessel density (VD) and tumour stroma were analysed in a randomised-trial-derived discovery cohort (n = 312) and in a stage II/III group of a population-based validation cohort (n = 85). VD was scored separately in the tumour centre, invasive margin and peritumoral stroma compartments and quantitated as VD/total analysed tissue area or VD/stroma area. RESULTS: High stroma-normalised VD in the invasive margin was associated with significantly longer time to recurrence and overall survival (OS) (p = 0.002 and p = 0.006, respectively) in adjuvant-treated patients of the discovery cohort, but not in surgery-only patients. Stroma-normalised VD in the invasive margin and treatment effect were significantly associated according to a formal interaction test (p = 0.009). Similarly, in the validation cohort, high stroma-normalised VD was associated with OS in adjuvant-treated patients, although statistical significance was not reached (p = 0.051). CONCLUSION: Through the use of novel digitally scored vessel-density-related metrics, this exploratory study identifies stroma-normalised VD in the invasive margin as a candidate marker for benefit of adjuvant 5-FU-based chemotherapy in stage II/III colon cancer. The findings, indicating particular importance of vessels in the invasive margin, also suggest biological mechanisms for further exploration.

A Snapshot of The Tumor Microenvironment in Colorectal Cancer: The Liquid Biopsy.

The molecular profile of liquid biopsies is emerging as an alternative to tissue biopsies in the clinical management of malignant diseases. In colorectal cancer, significant liquid biopsy-based biomarkers have demonstrated an ability to discriminate between asymptomatic cancer patients and healthy controls. Furthermore, this non-invasive approach appears to provide relevant information regarding the stratification of tumors with different prognoses and the monitoring of treatment responses. This review focuses on the tumor microenvironment components which are detected in blood samples of colorectal cancer patients and might represent potential biomarkers. Exosomes released by tumor and stromal cells play a major role in the modulation of cancer progression in the primary tumor microenvironment and in the formation of an inflammatory pre-metastatic niche. Stromal cells-derived exosomes are involved in driving mechanisms that promote tumor growth, migration, metastasis, and drug resistance, therefore representing substantial signaling mediators in the tumor-stroma interaction. Besides, recent findings of specifically packaged exosome cargo in Cancer-Associated Fibroblasts of colorectal cancer patients identify novel exosomal biomarkers with potential clinical applicability. Furthermore, additional different signals emitted from the tumor microenvironment and also detectable in the blood, such as soluble factors and non-tumoral circulating cells, arise as novel promising biomarkers for cancer diagnosis, prognosis, and treatment response prediction. The therapeutic potential of these factors is still limited, and studies are in their infancy. However, innovative strategies aiming at the inhibition of tumor progression by systemic exosome depletion, exosome-mediated circulating tumor cell capturing, and exosome-drug delivery systems are currently being studied and may provide considerable advantages in the near future.

Differential distribution and enrichment of non-coding RNAs in exosomes from normal and Cancer-associated fibroblasts in colorectal cancer.

Exosome production from cancer-associated fibroblasts seems to be an important driver of tumor progression. We report the first in-depth biotype characterization of ncRNAs, analyzed by Next Generation Sequencing and Bioinformatics, expressed in established primary human normal and cancer-associated fibroblasts (CAFs) from cancer and normal mucosa tissues from 9 colorectal cancer patients, and/or packaged in their derived exosomes. Differential representation and enrichment analyses based on these ncRNAs revealed a significant number of differences between the ncRNA content of exosomes and the expression patterns of the normal and cancer-associated fibroblast cells. ncRNA regulatory elements are specifically packaged in CAF-derived exosomes, supporting a specific cross-talk between CAFs and colon cancer cells and/or other stromal cells, mediated by exosomes. These sncRNAs are potential biomarkers present in cancer-associated fibroblast-derived exosomes, which should thereby contribute to developing new non-invasive diagnostic, prognostic and predictive methods for clinical applications in management of cancer patients.

Liquid chromatography-time-of-flight high-resolution mass spectrometry study and determination of the dansylated products of estrogens and their hydroxylated metabolites in water and wastewater.

A method combining liquid chromatography with a dual-probe ultraspray electrospray ionization (ESI) source and time-of-flight high-resolution mass spectrometry (LC-ESI-TOF/MS) was developed for the simultaneous determination of four steroidal sex hormones, estrone (E1), 17ß-estradiol (E2), 17α-ethinyl estradiol (EE2), and estriol (E3), as well as five of their hydroxylated metabolites, 2-hydroxyestrone (2-OHE1), 4-hydroxyestrone (4-OHE1), 16α-hydroxyestrone (16-OHE1), 2-hydroxyestradiol (2-OHE2), and 4-hydroxyestradiol (4-OHE2), in water samples in a short chromatographic run of 10 min. Derivatization of the analytes was optimized using dansyl chloride as the derivatizing agent. Under optimal positive ionization conditions, the following signals, which had not been previously reported, were observed (with theoretical values of m/z 377.1373 for 2- and 4-OHE1 and 378.1452 for 2- and 4-OHE2), corresponding to doubly derivatized catechol estrogens in the form of [M+2H]2+. These mass spectrometric signals were more abundant than those reported previously for the [M+H]+ forms of these hydroxylated metabolites. Solid-phase extraction (SPE) with an octadecyl-endcapped sorbent was used to pretreat tap water and effluent from a wastewater treatment plant (WWTP) in Santiago, Chile. The method achieved the simple, fast, and sensitive measurement of nine estrogens with quantitative recoveries (higher than 85.4%). Detection and quantification limits were between 1 and 17 ng L-1 and between 3 and 58 ng L-1, respectively, for all compounds in water. The estrogens E1 and E2 were found in WWTP effluent at concentrations of 7 ± 1 and 41 ± 1 ng L-1, respectively, and EE2 was detected at a concentration below the limit of quantitation. This study shows that the proposed method is suitable for the accurate, rapid, and selective determination of all these analytes at trace levels. Graphical abstract ᅟ.

Plasticity to salinity and transgenerational effects in the nonnative shrub Baccharis halimifolia: Insights into an estuarine invasion.

PREMISE OF THE STUDY: Abiotic constraints act as selection filters for plant invasion in stressful habitats. Adaptive phenotypic plasticity and transgenerational effects play a major role in colonization of heterogeneous habitats when the scale of environmental variation is smaller than that of gene flow. We investigated how plasticity and parental salinity conditions influence the performance of the invasive dioecious shrub Baccharis halimifolia, which replaces heterogeneous estuarine communities in Europe with monospecific and continuous stands. METHODS: In two greenhouse experiments, we grew plants derived from seeds and cuttings collected through interspersed patches differing in edaphic salinity from an invasive population. We estimated parental environmental salinity from leaf Na(+) content in parental plants, and we measured fitness and ion homeostasis of the offspring grown in contrasting salinity conditions. KEY RESULTS: Baccharis halimifolia tolerates high salinity but experiences drastic biomass reduction at moderate salinity. At moderate salinity, responses to salinity are affected by the parental salinity: flowering initiation in seedlings and male cuttings is positively correlated with parental leaf Na(+) content, and biomass is positively correlated with maternal leaf Na(+) in female cuttings and seedlings. Plant height, leaf production, specific leaf area, and ionic homeostasis at the low part of the gradient are also affected by parental salinity, suggesting enhanced shoot growth as parental salinity increases. CONCLUSIONS: Our results support plasticity to salinity and transgenerational effects as factors with great potential to contribute to the invasive ability of B. halimifolia through estuarine communities of high conservation value.

¹8F-Fluorocholine PET/CT as a complementary tool in the follow-up of low-grade glioma: diagnostic accuracy and clinical utility.

PURPOSE: The follow-up of treated low-grade glioma (LGG) requires the evaluation of subtle clinical changes and MRI results. When the result is inconclusive, additional procedures are required to assist decision-making, such as the use of advanced MRI (aMRI) sequences and nuclear medicine scans (SPECT and PET). The aim of this study was to determine whether incorporating (18)F-fluorocholine PET/CT in the follow-up protocol for treated LGG improves diagnostic accuracy and clinical utility. METHODS: This was a prospective case-series study in patients with treated LGG during standard follow-up with indeterminate clinical and/or radiological findings of tumour activity. All patients underwent clinical evaluation, aMRI, (201)Tl-SPECT and (18)F-fluorocholine PET/CT. Images were interpreted by visual evaluation complemented with semiquantitative analysis. RESULTS: Between January 2012 and December 2013, 18 patients were included in this study. The final diagnosis was established by histology (five surgical specimens, one biopsy specimen) or by consensus of the Neuro-Oncology Group (11 patients) after a follow-up of >6 months (mean 14.9 ± 2.72 months). The global diagnostic accuracies were 90.9% for aMRI (38.8% inconclusive), 69.2 % for (201)Tl-SPECT (11.1% inconclusive), and 100% for (18)F-fluorocholine PET/CT. (201)Tl-SPECT led correctly to a change in the initial approach in 38.9% of patients but might have led to error in 27.8%. The use of (18)F-fluorocholine PET/CT alone rather than (201)Tl-SPECT led correctly to a change in the approach suggested by routine follow-up in 72.2% of patients and endorsed the approach in the remaining 27.8%. CONCLUSION: Our results support the need to complement structural MRI with aMRI and nuclear medicine procedures in selected patients. (18)F-Fluorocholine PET/CT can be useful in the individualized management of patients with treated LGG with uncertain clinical and/or radiological evidence of tumour activity.

Protumorigenic effects of Snail-expression fibroblasts on colon cancer cells.

Snail1 is a transcriptional factor that plays an important role in epithelial-mesenchymal transition and in the acquisition of invasive properties by epithelial cells. In colon tumors, Snail1 expression in the stroma correlates with lower specific survival of cancer patients. However, the role(s) of Snail1 expression in stroma and its association with patients' survival have not been determined. We used human primary carcinoma-associated fibroblasts (CAFs) or normal fibroblasts (NFs) and fibroblast cell lines to analyze the effects of Snail1 expression on the protumorigenic capabilities in colon cancer cells. Snail1 expression was higher in CAFs than in NFs and, as well as α-SMA, a classic marker of activated CAFs. Moreover, in tumor samples from 50 colon cancer patients, SNAI1 expression was associated with expression of other CAF markers, such as α-SMA and fibroblast activation protein. Interestingly, coculture of CAFs with colon cells induced a significant increase in epithelial cell migration and proliferation, which was associated with endogenous SNAI1 expression levels. Ectopic manipulation of Snail1 in fibroblasts demonstrated that Snail1 expression controlled migration as well as proliferation of cocultured colon cancer cells in a paracrine manner. Furthermore, expression of Snail1 in fibroblasts was required for the coadjuvant effect of these cells on colon cancer cell growth and invasion when coxenografted in nude mice. Finally, cytokine profile changes, particularly MCP-3 expression, in fibroblasts are put forward as mediators of Snail1-derived effects on colon tumor cell migration. In summary, these studies demonstrate that Snail1 is necessary for the protumorigenic effects of fibroblasts on colon cancer cells.

MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells.

Vitamin D deficiency is associated with the high risk of colon cancer and a variety of other diseases. The active vitamin D metabolite 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) regulates gene transcription via its nuclear receptor (VDR), and posttranscriptional regulatory mechanisms of gene expression have also been proposed. We have identified microRNA-22 (miR-22) and several other miRNA species as 1,25(OH)(2)D(3) targets in human colon cancer cells. Remarkably, miR-22 is induced by 1,25(OH)(2)D(3) in a time-, dose- and VDR-dependent manner. In SW480-ADH and HCT116 cells, miR-22 loss-of-function by transfection of a miR-22 inhibitor suppresses the antiproliferative effect of 1,25(OH)(2)D(3). Additionally, miR-22 inhibition increases cell migration per se and decreases the antimigratory effect of 1,25(OH)(2)D(3) in both cell types. In silico analysis shows a significant overlap between genes suppressed by 1,25(OH)(2)D(3) and miR-22 putative target genes. Consistently, miR-22 inhibition abrogates the 1,25(OH)(2)D(3)-mediated suppression of NELL2, OGN, HNRPH1, RERE and NFAT5 genes. In 39 out of 50 (78%) human colon cancer patients, miR-22 expression was found lower in the tumour than in the matched normal tissue and correlated directly with that of VDR. Our results indicate that miR-22 is induced by 1,25(OH)(2)D(3) in human colon cancer cells and it may contribute to its antitumour action against this neoplasia.

Bispecific antibodies: advancing precision oncology.

Bispecific antibodies (bsAbs) are engineered molecules designed to target two different epitopes or antigens. The mechanism of action is determined by the bsAb molecular targets and structure (or format), which can be manipulated to create variable and novel functionalities, including linking immune cells with tumor cells, or dual signaling pathway blockade. Several bsAbs have already changed the treatment landscape of hematological malignancies and select solid cancers. However, the mechanisms of resistance to these agents are understudied and the management of toxicities remains challenging. Herein, we review the principles in bsAb engineering, current understanding of mechanisms of action and resistance, data for clinical application, and provide a perspective on ongoing challenges and future developments in this field.

Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer.

PURPOSE: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. EXPERIMENTAL DESIGN: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients.

Tumor epithelial cells within a tumor coexist with a complex microenvironment in which a variety of interactions between its various components determine the behavior of the primary tumors. Cancer-associated fibroblasts (CAF) and M2 macrophages, characterized by high expression of different markers, including α-SMA, FSP1 and FAP, or CD163 and DCSIGN, respectively, are involved in the malignancy of different tumors. In the present study, expression of the above markers in CAF and M2 macrophages was analyzed using RT-PCR and immunohistochemistry in the normal mucosa and tumor tissue from a cohort of 289 colorectal cancer patients. Expression of CAF and M2 markers is associated with the clinical outcome of colorectal cancer patients. Moreover, the combination of CAF and M2 markers identifies three groups of patients with clear differences in the progression of the disease. This combined variable could be a decisive factor in the survival of advanced-stage patients. Taken together, these analyses demonstrate the prognostic involvement of interrelationships between DCSIGN, CD163, α-SMA, FSP1 and FAP markers in the survival of colon cancer patients.

Early screening of suspected microplastics in bottled water in the Santiago Metropolitan Region of Chile.

Bottled water has emerged as a possible healthier alternative due to concerns about the quality of drinking water sources. However, recent studies have detected worrying concentrations of environmental contaminants in bottled water, including microplastics. Therefore, it is an emerging need to quantify their concentrations in local suppliers which could differ among countries and regions. In this work, we used fluorescence microscopy with Nile Red for the identification and quantification of potential microplastics in twelve brands of bottled water distributed in the Santiago Metropolitan Region of Chile. The average concentration of microplastics was 391 ± 125 p L-1, while the highest concentration observed was 633 ± 33 p L-1. Microplastics between 5 and 20 µm were the major contributors, a size fraction that has been reported to be susceptible to accumulate in the digestive tract or generate potential alterations in the lymphatic and circulatory systems. The estimated daily intake value for per capita was estimated to be 229 p kg-1 year-1 for people weighing 65 kg and 198 p kg-1 year-1 for those weighing 75 kg.

Use of Virtual Reality in the Reduction of Pain After the Administration of Vaccines Among Children in Primary Care Centers: Protocol for a Randomized Clinical Trial.

BACKGROUND: Pain and anxiety caused by vaccination and other medical procedures in childhood can result in discomfort for both patients and their parents. Virtual reality (VR) is a technology that is capable of entertaining and distracting the user. Among its many applications, we find the improvement of pain management and the reduction of anxiety in patients undergoing medical interventions. OBJECTIVE: We aim to publish the protocol of a clinical trial for the reduction of pain and anxiety after the administration of 2 vaccines in children aged 3 to 6 years. METHODS: We will conduct a randomized, parallel, controlled clinical trial with 2 assigned groups. The intervention group will wear VR goggles during the administration of 2 vaccines, while the control group will receive standard care from a primary care center for the procedure. Randomization will be carried out by using the RandomizedR computer system-a randomization tool of the R Studio program. This trial will be an open or unblinded trial; both the subjects and the investigators will know the assigned treatment groups. Due to the nature of the VR intervention, it will be impossible to blind the patients, caregivers, or observers. However, a blind third-party assessment will be carried out. The study population will include children aged 3 to 6 years who are included in the patient registry and cared for in a primary care center of the region of Central Catalonia. They will receive the following vaccines during the Well-Child checkup: the triple viral+varicella vaccine at 3 years of age and the hepatitis A+diphtheria-tetanus-pertussis vaccine at 6 years of age. RESULTS: The study is scheduled to begin in January 2022 and is scheduled to end in January 2023, which is when the statistical analysis will begin. As of March 2022, a total of 23 children have been recruited, of which 13 have used VR during the vaccination process. In addition, all of the guardians have found that VR helps to reduce pain during vaccination. CONCLUSIONS: VR can be a useful tool in pediatric procedures that generate pain and anxiety. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/35910.

Initial phthalates fingerprint and hydrochemical signature as key factors controlling phthalates concentration trends in PET-bottled waters during long storage times.

Phthalateacid esters (PAEs) concentration in bottled water and different factors (water pH, storage time, sunlight exposure, and temperature) that affect/control them have become hot topics during recent years. Nevertheless, quite contradictory results and disagreements on the effects of these factors have been published. In an attempt to find some consensus on this topic, a comprehensive study considering the combined effect of long storage times (longer than a year) and the water hydrochemical signature (including water pH, elemental composition and the presence/absence of dissolved CO2)was performedusing the four most commonly consumed bottled water brands on the Chilean market. Each water brand was analyzed between 10 or 14 different times, depending on the brand (in total 97 samples were studied). Following the concept ofthe hydrochemical signature typically used in hydrogeology to classify types of waters, the notion of a water phthalate fingerprint was proposed. Finally, concerning the effect of long storage times, this study demonstrates that all the trends (increase, decrease or steady) of the Total PAEs concentration are possible; and these trends are controlled by the specific hydrochemical signatureandphthalate fingerprint of the bottled water.

Genomic Landscape of Vinflunine Response in Metastatic Urothelial Cancer.

BACKGROUND AND AIMS: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. METHODS: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). RESULTS: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. CONCLUSIONS: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.

Differential regulation of TP73 isoforms by 1α,25-dihydroxyvitamin D3 and survivin in human colon and breast carcinomas.

We evaluate whether 1,25(OH)(2)D(3) downregulates TP73 variants in colon and breast carcinomas, the role of survivin in this context, and the significance of this network in the clinic. Tumor cells were treated/untreated with 1,25(OH)(2)D(3) and transiently transfected with survivin. Levels of survivin and TP73 variants were evaluated by quantitative RT-PCR and Western blotting. In 75 colon and 60 breast cancer patients, the expressions of survivin and TP73 isoforms were determined. Tumor characteristics were examined in each patient. Survivin protein levels were also evaluated in a subgroup of patients and cell lines. Decrease in survivin and TAp73 transcripts and protein and ΔNp73 mRNA was detected after 1,25(OH)(2)D(3) treatment. Ectopic survivin expression led to an increase in the TAp73, ΔNp73, ΔEx2p73, and ΔEx2-3p73 transcripts. In cancer patients, direct correlations were observed between TP73 variants and survivin levels. 1,25(OH)(2)D(3) negatively regulate survivin and TP73 variants in colon and breast cancer cells. Positive regulation of TP73 isoforms by survivin may exist, which reinforces the possibility that the downregulation of TP73 forms by 1,25(OH)(2)D(3) is survivin-dependent.

Tumor Microenvironment in Metastatic Colorectal Cancer: The Arbitrator in Patients' Outcome.

Colorectal cancer (CRC) is one of the most common cancers in western countries. Its mortality rate varies greatly, depending on the stage of the disease. The main cause of CRC mortality is metastasis, which most commonly affects the liver. The role of tumor microenvironment in tumor initiation, progression and metastasis development has been widely studied. In this review we summarize the role of the tumor microenvironment in the liver pre-metastatic niche formation, paying attention to the distant cellular crosstalk mediated by exosomes. Moreover, and based on the prognostic and predictive capacity of alterations in the stromal compartment of tumors, we describe the role of tumor microenvironment cells and related liquid biopsy biomarkers in the delivery of precise medication for metastatic CRC. Finally, we evaluate the different clinical strategies to prevent and treat liver metastatic disease, based on the targeting of the tumor microenvironment. Specifically, targeting angiogenesis pathways and regulating immune response are two important research pipelines that are being widely developed and promise great benefits.

Rapid Determination of Parabens in Water Samples by Ultra-high Performance Liquid Chromatography Coupled to Time of Flight Mass Spectrometry.

An analytical methodology has been developed and validated for the purpose of identifying and quantifying four parabens (methylparaben, ethylparaben, propylparaben and n-butylparaben) in water samples. The combination of rotating disk sorptive extraction (RDSE) technology with ultra-high performance liquid chromatography (UHPLC), along with electrospray ionization source (ESI) and time of flight mass spectrometry (TOF/MS) in trap mode, allowed for eliminating derivatization processes and a reduction of the chromatographic time required, achieving a greener analytical method. In this method, detection limits and precision (%RSD) were lower than 0.018 µg L-1 and lower than 9.7% for all the parabens, respectively, being better than similar works. Matrix effect and absolute recoveries were studied in tap and sewage water samples to observe suppressions of the signals for all analytes, and absolute recoveries were around 60%. This methodology was applied to the analysis of two sewage samples (punctual and composite) obtained from locations in Santiago, Chile.