Spatially preserved multi-region transcriptomic subtyping and biomarkers of chemoimmunotherapy outcome in extensive-stage small cell lung cancer.

BACKGROUND: 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. PATIENTS AND METHODS: We analyzed tumor samples from 58 ES-SCLC patients enrolled in two multicenter single-arm phase IIIb studies evaluating front-line chemoimmunotherapy in Spain: n=32 from the IMfirst trial, and n=26 from the CANTABRICO trial. We utilized the GeoMxTM DSP 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 similar between both cohorts, except for SCLC-P, not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple co-existing transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity were 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 ³12 months) contained an IFNg-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. Pre-existing IFNg-driven immunity and mitochondrial metabolism seem 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.

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.

Covid-19 y obesidad en pacientes admitidos en la unidad de cuidados intensivos / COVID-19 and obesity in patients admitted to Intensive Care Unit

Introduction: COVID-19 is an infectious disease, transmitted by diverse viral strains from the Coronaviridae family. It can manifest as a mild-moderate condition with general symptoms such as malaise, body aches and fever. However, when it finds a patient with other comorbidities it can enhance its virulence, potentially leading to a severe disease with pulmonary-systemic effects. Obesity recognized as a pandemic nowadays, displays and imminent increase in the risk of developing complications during the course of COVID-19 process. Objective: Identify the prevalence of obesity in patients admitted to the Intensive Care Unit (ICU) that displayed an unfavorable prognostic. Methodology: Observational, retrospective study, data was retrieved from a single medical center in Dominican Republic. In the period of time from March to December 2020 a total of 382 patients hospitalized in ICU with a positive PCR for SARS-CoV-2 was extracted from the electronic medical records. Conclusion: Obesity leads to a homeostatic imbalance that severely affects the body´s immune system, making the patient more susceptible to present severe cases of COVID-19, requiring higher levels of hospitalization and ICU admissions.

Introducción: el COVID-19 es una enfermedad de origen infeccioso viral, transmitida por diversas cepas de la familia Coronaviridae. Su manifestación puede ser leve-moderada con síntomas generales como malestar, dolor corporal y fiebre, sin embargo, la presencia de comorbilidades en pacientes la convierte potencialmente en una enfermedad severa con afectación pulmonar-sistémica. La obesidad, también reconocida como pandemia, representa un factor de riesgo inminente ante una mayor susceptibilidad de adquirir complicaciones durante la enfermedad por COVID-19. Objetivo: identificar la prevalencia de obesidad en pacientes admitidos a Unidad de Cuidados Intensivos (UCI) que mostraron un pronóstico desfavorable. Metodología: se realizó un estudio retrospectivo de tipo observacional, se recolectó la información de un solo centro de salud de la República Dominicana. Durante el período de marzo a diciembre del 2020, se recopiló de los récords médicos electrónicos un total de 382 pacientes hospitalizados en UCI con una prueba positiva de SARS-CoV-2. Conclusión: la obesidad produce un desbalance homeostático afectando especialmente la inmunidad del organismo haciendo al paciente más susceptible a presentar casos severos de COVID-19, requiriendo mayores niveles de hospitalización e ingresos a UCI.

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.

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.

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.

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.

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.

Perfil del paciente hipertenso con sospecha clínica de apnea obstructiva del sueño en el Centro de Diagnóstico y Medicina Avanzada y de Conferencias Médicas y Telemedicina (CEDIMAT) durante el período enero 2019 ­ febrero 2020, Santo Domingo, República Dominicana / Profile of the hypertensive patient with clinical suspicion of obstructive sleep apnea at the Center for Diagnosis and Advanced Medicine and Medical Conferences and Telemedicine (CEDIMAT) during the period January 2019 - February 2020, Santo Domingo, Dominican Republic

Introducción: la apnea obstructiva del sueño es una patología respiratoria caracterizada por paradas de la respiración de forma repetida durante el sueño. Esta patología está relacionada con los trastornos hipertensivos, pudiendo agravarlos. Objetivo: determinar el perfil de un paciente hipertenso bajo sospecha clínica de apnea obstructiva del sueño en el Centro de Diagnóstico y Medicina Avanzada y de Conferencias Médicas y Telemedicina (CEDIMAT) durante el periodo enero 2019 ­ febrero 2020. Material y métodos: se realizó un estudio observacional-descriptivo, transversal con datos retrospectivos. Se estudiaron 38 expedientes clínicos de pacientes hipertensos de la consulta de neumología y que cumplen con criterios de sospecha clínica de apnea obstructiva del sueño. Resultados: el rango de edad fue de 40-64 años con un 55.26 %. El 66 % son masculinos. 36.84 % son hipertensos grado I mientras que otro 34.21% tienen sus niveles tensionales normales. El 68.41 % son obesos y un 26.32 % están en sobrepeso. 63.16 % se clasifican como IV en la escala de Mallampati. Conclusión: el perfil de los pacientes hipertensos bajo sospecha clínica de apnea obstructiva del sueño es: sexo masculino, adultez media, obesidad, escala de mallampati categoría IV y el uso de múltiples fármacos en el control de la hipertensión

Introduction: Obstructive sleep apnea is a respiratory disease characterized by repeated stops of breathing during sleep. This pathology is related to hypertensive disorders, which can aggravate them. Objective: To determine the profile of a hypertensive patient under clinical suspicion of obstructive sleep apnea at the Center for Diagnosis and Advanced Medicine and Medical and Telemedicine Conferences (CEDIMAT) during the period January 2019 - February 2020. Material and methods: An observational study of descriptive, cross-sectional type with retrospective data. Thirty-eight clinical records of hypertensive patients from the pulmonology clinic and who meet the criteria for clinical suspicion of obstructive sleep apnea were studied. Results: The age range was 40-64 years with 55.26%. 66% are male. 36.84% are grade I hypertensive while another 34.21% have normal blood pressure levels. 68.41% are obese and 26.32% are overweight. 63.16% are classified as IV on the mallampati scale. Conclusion: The profile of hypertensive patients under clinical suspicion of obstructive sleep apnea is; male sex, middle adulthood, obesity, category IV of mallampati scale and the use of multiple drugs in the control of hypertension

Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer.

Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

Factores de riesgo de depresión post ictus isquémico / Risk factors for depression after and ischemic ictus

Resumen Objetivo: Identificar los factores de riesgo de depresión post ictus isquémico (DPI) en pacientes adultos. Material y métodos: Estudio tipo caso y control no pareado. Se incluyeron 81 casos y 81 controles de pacientes del consultorio externo de neurología del Hospital Santa Rosa de Lima, atendidos entre setiembre y diciembre del 2018. Se registraron variables clínicas y epidemiológicas mediante una ficha de datos. Para el diagnóstico de depresión se empleó la Hamilton Depression Rating Scale (HDRS). Se establecieron asociaciones mediante el cálculo de los Odds Ratio (OR) con intervalos de confianza del 95% (IC). Se compararon los casos y controles usando un análisis multivariado de regresión logística. Resultados: Las variables asociadas con DPI fueron: tabaquismo (OR=4,67; IC95%, 1,99-10,92, p<0,001), lesión localizada en el hemisferio izquierdo (OR=3,11; IC 95%, 1,41-6,84, p=0,005) y deterioro cognitivo (OR=3,18; IC95%, 1,42-7,10, p=0,005). Conclusiones: En pacientes con antecedente de ictus isquémico, el tabaquismo, la localización de la lesión en el hemisferio cerebral izquierdo y el deterioro cognitivo, se asociaron con un mayor riesgo de depresión. Se necesitan estudios adicionales para definir mejor la naturaleza de dichas asociaciones.

Summary Objective: To identify risk factors for depression after and ischemic ictus (DII) in adults. Methods: A non-matched case-control study was carried-out including 81 cases and controls, respectively recruited from the neurologic outpatient clinic of Hospital Santa Rosa de Lima from September to December of 2018. Clinical and epidemiological data were gathered and stored in a data base. The Hamilton Depression Rating Scale was used to diagnose depression. Odds rations and 95% CI were calculated and a multivariate logistic regression analysis was used. Results: smoking (OR=4.67; IC95%, 1.99-10.92, p<0.001), lesion located on the left hemisphere (OR=3.11; IC95%, 1.41-6.84, p=0.005) and cognitive deterioration (OR=3.18; IC95%, 1.42-7.10, p=0.005) were independently associated with DII. Conclusions: Smoking, lesions located on the left hemisphere and cognitive deterioration were associated with DII but further studies are needed to elucidate the nature of these associations.

miRNAs as radio-response biomarkers for breast cancer stem cells.

In breast cancer (BC), the presence of cancer stem cells (CSCs) has been related to relapse, metastasis, and radioresistance. Radiotherapy (RT) is an extended BC treatment, but is not always effective. CSCs have several mechanisms of radioresistance in place, and some miRNAs are involved in the cellular response to ionizing radiation (IR). Here, we studied how IR affects the expression of miRNAs related to stemness in different molecular BC subtypes. Exposition of BC cells to radiation doses of 2, 4, or 6 Gy affected their phenotype, functional characteristics, pluripotency gene expression, and in vivo tumorigenic capacity. This held true for various molecular subtypes of BC cells (classified by ER, PR and HER-2 status), and for BC cells either plated in monolayer, or being in suspension as mammospheres. However, the effect of IR on the expression of eight stemness- and radioresistance-related miRNAs (miR-210, miR-10b, miR-182, miR-142, miR-221, miR-21, miR-93, miR-15b) varied, depending on cell line subpopulation and clinicopathological features of BC patients. Therefore, clinicopathological features and, potentially also, chemotherapy regimen should be both taken into consideration, for determining a potential miRNA signature by liquid biopsy in BC patients treated with RT. Personalized and precision RT dosage regimes could improve the prognosis, treatment, and survival of BC patients.

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.

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.

Cork sheet as a sorptive phase to extract hormones from water by rotating-disk sorptive extraction (RDSE).

This work reports for the first time the use of laminar cork as a sorptive phase in a microextraction technique, rotating-disk sorptive extraction (RDSE). Typical hormones (estrone, estradiol, estriol and ethinyl estradiol) were selected as analyte models and extracted from wastewater samples on laminar cork with statistically equivalent extraction efficiency to that provided by Oasis HLB. The cork characterization was performed by confocal fluorescence microscopy (CLSM), Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM), allowing the identification of lignin, suberin and polysaccharides (cellulose and hemicellulose) as the main components of the cork. The best conditions for extraction were as follows: rotation velocity of the disk, 2000 rpm; extraction time, 45 min; and sample volume, 20 mL. The analytical features of the developed method show that calibration curves for all analytes have R2 values higher than 0.99. The absolute recoveries were higher than 63%, and the precision, expressed as relative standard deviation, ranged from 2 to 16%. The LOD and LOQ ranges were 3-19 and 10-62 ng L-1, respectively. The proposed method was applied to the analysis of wastewater, and the concentrations of hormones in a wastewater treatment plant in Santiago, Chile, ranged from

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.

Simultaneous determination of multiresidue and multiclass emerging contaminants in waters by rotating-disk sorptive extraction-derivatization-gas chromatography/mass spectrometry.

An efficient method has been developed for the multiresidue and multiclass determination of 16 emerging contaminants (parabens, hormones, anti-inflammatory drugs, triclosan and bisphenol A) in water samples using rotating-disk sorptive extraction (RDSE) and gas chromatography coupled to mass spectrometry (GC-MS). Silylation of the compounds prior to GC-MS analysis was optimized using a factorial experimental design; the optimal derivatization conditions to maximize the response of the set of analytes included 70 µL of N-methyl-N-(trimethylsilyl)trifluoroacetamide at 80 °C for 35 min. RDSE was implemented using Oasis® HLB as a sorptive phase and an extraction time of 60 min. The method was applied to Chilean environmental samples. In tap water, none of the analytes under study were detected. In the river and well waters, the concentrations of the four detected contaminants were below 0.38 µg L-1. In the effluent and influent of the wastewater treatment plant, the maximum concentrations of contaminants were 3.1 and 4.2 µg L-1, respectively. The proposed analytical strategy suggests clear improvements with respect to other methods reported in the literature, considering not only the different steps involved in the analytical process (extraction, derivatization and chromatography) but also taking into account that this method involves the determination of different families of analytes with different physicochemical and structural properties.

A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer.

PURPOSE: Fibroblasts expressing the orphan chemokine CXCL14 have been previously shown to associate with poor breast cancer prognosis and promote cancer growth. This study explores the mechanism underlying the poor survival associations of stromal CXCL14. EXPERIMENTAL DESIGN: Tumor cell epithelial-to-mesenchymal transition (EMT), invasion, and metastasis were studied in in vitro and in vivo models together with fibroblasts overexpressing CXCL14. An approach for CXCL14 receptor identification included loss-of-function studies followed by molecular and functional endpoints. The clinical relevance was further explored in publicly available gene expression datasets. RESULTS: CXCL14 fibroblasts stimulated breast cancer EMT, migration, and invasion in breast cancer cells and in a xenograft model. Furthermore, tumor cells primed by CXCL14 fibroblasts displayed enhanced lung colonization after tail-vein injection. By loss-of function experiments, the atypical G-protein-coupled receptor ACKR2 was identified to mediate CXCL14-stimulated responses. Downregulation of ACKR2, or CXCL14-induced NOS1, attenuated the pro-EMT and migratory capacity. CXCL14/ACKR2 expression correlated with EMT and survival in gene expression datasets. CONCLUSIONS: Collectively, the findings imply an autocrine fibroblast CXCL14/ACKR2 pathway as a clinically relevant stimulator of EMT, tumor cell invasion, and metastasis. The study also identifies ACKR2 as a novel mediator for CXCL14 function and thereby defines a pathway with drug target potential.See related commentary by Zhang et al., p. 3476.

Detection and assignment of inorganic aqueous polymers relevant to environmental nanogeoscience by direct infusion electrospray ionization mass spectrometry.

Inorganic polymers in aqueous solutions are being proposed as essential components in new theories concerning nonclassical nucleation and growth of nanominerals relevant to environmental nanogeosciences. The study of those complex natural processes requires multi-technique analytical approaches able to characterize the solutions and their constituents (solutes, oligomers, polymers, clusters and nanominerals) from atomic to micrometric scales. A novel analytical approach involving an electrospray ionization source (ESI) coupled to time-of-flight mass spectrometry (TOF/MS) was developed to identify inorganic polymers in aqueous solution. To this end, the presence of initial Al oligomers and their polymerization processes was studied during a nanomineral aqueous synthesis (hydrobasaluminte, Al4 SO4 (OH)10 ·12-36H2 O). Ensuring the feasibility and robustness of the methodology as well as the stability of the polymers under study (avoiding undesirable fragmentation), a meticulous study of the ESI-TOF MS working conditions was performed. Precision of the methodology was evaluated obtaining relative standard deviations below 3.3%. For the first time in the study of inorganic polymers in the earth sciences, the mass accuracy error (ppm) has been reported and the use of significant decimal figures of the m/z signal has been taken into account. Complementary to this, a four-step polymer assignment methodology and a database with the Al- and Al-SO4 2- polymers assigned were created. Several polymers have been assigned for the first time, including Al (SO4 )+ ·H2 O, Al2 O(SO4 )2+ ·H2 O, Al5 O4 (OH)5 2+ ·2H2 O, and Al3 O5 (OH)2- ·4H2 O, among others. The results obtained in the present study help create a foundation to include mass spectrometry as a routine analytical technique to study mineral formation in aqueous solution.