Resectable Non-Small Cell Lung Cancer Heterogeneity and Recurrence Assessed by Tissue Next-Generation Sequencing Genotyping and Circulating Tumor Cell EZH2 Characterization.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung neoplasm. Despite surgical resection, it has a high relapse rate, accounting for 30-55% of all cases. Next-generation sequencing (NGS) based on a customized gene panel and the analysis of circulating tumor cells (CTCs) can help identify heterogeneity, stratify high-risk patients, and guide treatment decisions. In this descriptive study involving a small prospective cohort, we focus on the phenotypic characterization of CTCs, particularly concerning EZH2 expression (a member of the Polycomb Repression Complex 2), as well as on the mutation profiles of the tissue using a customized gene panel and their association with poor outcomes in NSCLC. METHODS: Isolation and characterization of EZH2 on CTCs were evaluated before surgical resection (CTC1) and one month after surgery (CTC2) in resectable NSCLC patients. Targeted NGS was performed using a customized 50-gene panel on tissue samples from a subset of patients. RESULTS: 76 patients with resectable NSCLC were recruited. The top mutated genes in the cohort included TP53, FLT1, MUC5AC, EGFR, and NLRP3. Pair of genes that had mutually exclusive mutations was TP53-RIN3, and pairs of genes with co-occurring mutations were CD163-TLR4, FGF10-FOXP2, ADAMTSL3-FLT1, ADAMTSL3-MUC5AC and MUC5AC-NLRP3. CTCs decreased significantly between the two time points CTC1 and CTC2 (p<0.0001), and CTCs+ patients with high EZH2 expression had an 87% increased risk of death (p=0.018). CONCLUSIONS: Integrating molecular profiling of tumors and CTC characterization can provide valuable insights into tumor heterogeneity and improve patient stratification for resectable NSCLC.

Surprising and novel multivariate sequential patterns using odds ratio for temporal evolution in healthcare.

BACKGROUND: Pattern mining techniques are helpful tools when extracting new knowledge in real practice, but the overwhelming number of patterns is still a limiting factor in the health-care domain. Current efforts concerning the definition of measures of interest for patterns are focused on reducing the number of patterns and quantifying their relevance (utility/usefulness). However, although the temporal dimension plays a key role in medical records, few efforts have been made to extract temporal knowledge about the patient's evolution from multivariate sequential patterns. METHODS: In this paper, we propose a method to extract a new type of patterns in the clinical domain called Jumping Diagnostic Odds Ratio Sequential Patterns (JDORSP). The aim of this method is to employ the odds ratio to identify a concise set of sequential patterns that represent a patient's state with a statistically significant protection factor (i.e., a pattern associated with patients that survive) and those extensions whose evolution suddenly changes the patient's clinical state, thus making the sequential patterns a statistically significant risk factor (i.e., a pattern associated with patients that do not survive), or vice versa. RESULTS: The results of our experiments highlight that our method reduces the number of sequential patterns obtained with state-of-the-art pattern reduction methods by over 95%. Only by achieving this drastic reduction can medical experts carry out a comprehensive clinical evaluation of the patterns that might be considered medical knowledge regarding the temporal evolution of the patients. We have evaluated the surprisingness and relevance of the sequential patterns with clinicians, and the most interesting fact is the high surprisingness of the extensions of the patterns that become a protection factor, that is, the patients that recover after several days of being at high risk of dying. CONCLUSIONS: Our proposed method with which to extract JDORSP generates a set of interpretable multivariate sequential patterns with new knowledge regarding the temporal evolution of the patients. The number of patterns is greatly reduced when compared to those generated by other methods and measures of interest. An additional advantage of this method is that it does not require any parameters or thresholds, and that the reduced number of patterns allows a manual evaluation.

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster. METHODS: Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3. RESULTS: Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3. CONCLUSIONS: During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.

ADDISC lumbar disc prosthesis: Analytical and FEA testing of novel implants.

The intact intervertebral disc is a six-freedom degree elastic deformation structure with shock absorption. "Ball-and-socket" TDR do not reproduce these properties inducing zygapophyseal joint overload. Elastomeric TDRs reproduce better normal disc kinematics, but repeated core deformation causes its degeneration. We aimed to create a new TDR (ADDISC) reproducing healthy disc features. We designed TDR, analyzed (Finite Element Analysis), and measured every 500,000 cycles for 10 million cycles of the flexion-extension, lateral bending, and axial rotation cyclic compression bench-testing. In the inlay case, we weighted it and measured its deformation. ADDISC has two semi-spherical articular surfaces, one rotation centre for flexion, another for extension, the third for lateral bending, and a polycarbonate urethane inlay providing shock absorption. The first contact is between PCU and metal surfaces. There is no metal-metal contact up to 2000 N, and CoCr28Mo6 absorbs the load. After 10 million cycles at 1.2-2.0 kN loads, wear 140.96 mg (35.50 mm3), but no implant failures. Our TDR has a physiological motion range due to its articular surfaces' shape and the PCU inlay bumpers, minimizing the facet joint overload. ADDISC mimics healthy disc biomechanics and Instantaneous Rotation Center, absorbs shock, reduces wear, and has excellent long-term endurance.

Early acute kidney injury is associated with in-hospital adverse outcomes in critically ill burn patients: an observational study.

BACKGROUND: There are no studies in large series of burn patients on the relationship between acute kidney injury (AKI) and adverse outcomes using the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. METHODS: We retrospectively analysed data from a cohort of burn patients admitted to the intensive care unit (ICU) with the diagnosis of burn injury. The diagnosis of AKI over the first 7 days after injury was made according to the KDIGO guidelines. The primary outcome was ICU mortality. We used estimative models using univariable and multivariable logistic regression analyses. RESULTS: A total of 960 patients were studied and AKI was diagnosed in 50.5%. In multivariable analysis, AKI was associated, as compared with patients without AKI, with ICU mortality {adjusted odds ratio [aOR] 2.135 [95% confidence interval (CI) 1.384-3.293]} and secondary outcomes [kidney replacement therapy, aOR 4.030 (95% CI 1.838-8.835); infection, aOR 1.437 (95% CI 1.107-1.866); hospital mortality, aOR 1.652 (95% CI 1.139-2.697)]. AKI stage 1 was associated with a higher ICU [aOR 1.869 (95% CI 1.183-2.954)] and hospital mortality [aOR 1.552 (95% CI 1.050-2.296)] and infection [aOR 1.383 (95% CI 1.049-1.823)]. AKI meeting the urine output (UO) criterion alone was not associated with increased mortality. Ignoring the UO criterion would have missed 50 (10.3%) cases with AKI. CONCLUSION: The KDIGO guidelines are useful to diagnose AKI in burn patients. Even the mild form of AKI is independently associated with increased mortality. Considering the UO criterion is important to more accurately assess the incidence of AKI, but AKI meeting the UO criterion alone is not associated with increased mortality.

Hepatocellular carcinoma risk-stratification based on ASGR1 in circulating epithelial cells for cancer interception.

Purpose: Lack of diagnostic and prognostic biomarkers in hepatocellular carcinoma impedes stratifying patients based on their risk of developing cancer. The aim of this study was to evaluate phenotypic and genetic heterogeneity of circulating epithelial cells (CECs) based on asialoglycoprotein receptor 1 (ASGR1) and miR-122-5p expression as potential diagnostic and prognostic tools in patients with hepatocellular carcinoma (HCC) and liver cirrhosis (LC). Methods: Peripheral blood samples were extracted from LC and HCC patients at different disease stages. CECs were isolated using positive immunomagnetic selection. Genetic and phenotypic characterization was validated by double immunocytochemistry for cytokeratin (CK) and ASGR1 or by in situ hybridization with miR-122-5p and CECs were visualized by confocal microscopy. Results: The presence of CECs increased HCC risk by 2.58-fold, however, this was only significant for patients with previous LC (p = 0.028) and not for those without prior LC (p = 0.23). Furthermore, the number of CECs lacking ASGR1 expression correlated significantly with HCC incidence and absence of miR-122-5p expression (p = 0.014; r = 0.23). Finally, overall survival was significantly greater for patients at earlier cancer stages (p = 0.018), but this difference was only maintained in the group with the presence of CECs (p = 0.021) whereas progression-free survival was influenced by the absence of ASGR1 expression. Conclusion: Identification and characterization of CECs by ASGR1 and/or miR-122-5p expression may be used as a risk-stratification tool in LC patients, as it was shown to be an independent prognostic and risk-stratification marker in LC and early disease stage HCC patients.

Using the Diagnostic Odds Ratio to Select Patterns to Build an Interpretable Pattern-Based Classifier in a Clinical Domain: Multivariate Sequential Pattern Mining Study.

BACKGROUND: It is important to exploit all available data on patients in settings such as intensive care burn units (ICBUs), where several variables are recorded over time. It is possible to take advantage of the multivariate patterns that model the evolution of patients to predict their survival. However, pattern discovery algorithms generate a large number of patterns, of which only some are relevant for classification. OBJECTIVE: We propose to use the diagnostic odds ratio (DOR) to select multivariate sequential patterns used in the classification in a clinical domain, rather than employing frequency properties. METHODS: We used data obtained from the ICBU at the University Hospital of Getafe, where 6 temporal variables for 465 patients were registered every day during 5 days, and to model the evolution of these clinical variables, we used multivariate sequential patterns by applying 2 different discretization methods for the continuous attributes. We compared 4 ways in which to employ the DOR for pattern selection: (1) we used it as a threshold to select patterns with a minimum DOR; (2) we selected patterns whose differential DORs are higher than a threshold with regard to their extensions; (3) we selected patterns whose DOR CIs do not overlap; and (4) we proposed the combination of threshold and nonoverlapping CIs to select the most discriminative patterns. As a baseline, we compared our proposals with Jumping Emerging Patterns, one of the most frequently used techniques for pattern selection that utilizes frequency properties. RESULTS: We have compared the number and length of the patterns eventually selected, classification performance, and pattern and model interpretability. We show that discretization has a great impact on the accuracy of the classification model, but that a trade-off must be found between classification accuracy and the physicians' capacity to interpret the patterns obtained. We have also identified that the experiments combining threshold and nonoverlapping CIs (Option 4) obtained the fewest number of patterns but also with the smallest size, thus implying the loss of an acceptable accuracy with regard to clinician interpretation. The best classification model according to the trade-off is a JRIP classifier with only 5 patterns (20 items) that was built using unsupervised correlation preserving discretization and differential DOR in a beam search for the best pattern. It achieves a specificity of 56.32% and an area under the receiver operating characteristic curve of 0.767. CONCLUSIONS: A method for the classification of patients' survival can benefit from the use of sequential patterns, as these patterns consider knowledge about the temporal evolution of the variables in the case of ICBU. We have proved that the DOR can be used in several ways, and that it is a suitable measure to select discriminative and interpretable quality patterns.

IL-15/IL-15Rα in SJS/TEN: Relevant Expression of IL15 and IL15RA in Affected Skin.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening hypersensitivity reaction to medications characterized by keratinocyte apoptosis and skin detachment. IL-15 serum levels have been associated with severity and prognosis of SJS/TEN. We have measured IL-15 concentrations in serum and blister fluid (BF) from patients with SJS/TEN by ELISA and used quantitative RT-PCR to analyze the expression of IL15 and IL15RA (encoding for IL-15 Receptor-α chain) genes in peripheral blood and BF cells, including isolated monocytes, and in affected skin. A positive correlation was found between IL-15 serum levels and a percent of detached skin. BF concentrations were higher, but no correlation was found. Higher IL15 and IL15RA gene expression levels were found in skin-infiltrating blister fluid cells compared to peripheral mononuclear cells. Moreover, IL15RA transcripts were barely detected in healthy skin, being the highest expression levels found in samples from two SJS/TEN patients who did not survive. The cutaneous expression of IL-15Rα in SJS/TEN may provide an explanation to the tissue-specific immune cytotoxic response in this clinical entity, and the results suggest that the effects of IL-15 in SJS/TEN patients may be dependent on the expression of its private receptor IL-15Rα in affected skin.

Data on risk factors related to in-hospital mortality in patients less than 55 years of age with ST-segment elevation myocardial infarction.

Risk factors associated with in-hospital mortality in young patients with ST-segment elevation myocardial infarction are poorly described. In addition, it is increasingly recognized that these risk factors might differ from those of older patients. The dataset herein presented describes the association between different variables and in-hospital mortality in patients <55 years old with ST-segment elevation myocardial infarction. This data supplements the manuscript "Sex Related Differences in the Treatment of ST-Segment Elevation Acute Myocardial Infarction in Patients Aged <55 Years" (Lorente-Ros et al.) Data for this data in brief article were obtained from a prospective database of patients <55 years old with confirmed ST-segment elevation myocardial infarction admitted to a tertiary care hospital during an 11-year period. The data were collected via review of the clinical charts. The dataset describes the relative risk and 95% confidence interval of in-hospital mortality for each variable, including cardiovascular risk factors, angiographic findings, treatment received, and complications developed. Patients in this dataset represent a unique population, given that it only includes confirmed ST-segment elevation myocardial infarction while excluding other types of acute coronary syndrome, the patient's young age, and the reflection of contemporary up-to-date practices. This dataset will be valuable to further build on knowledge on the prognostic markers of acute myocardial infarction in a younger patient population.

Exchange of cellular components between platelets and tumor cells: impact on tumor cells behavior.

Background: Platelets are active players in tumorigenesis, although the exact interactive mechanisms and their direct impact on tumor cells remain largely unknown. Methods: Bidirectional transference of lipids, proteins and RNA between platelets and tumor cells and its impact on tumor cell behavior and tumor process are analyzed in this work. Phenotypic, genetic and functional modifications induced by platelets were analyzed both in tumor cell lines and in circulating tumor cells (CTCs). Results: Data from these assays showed that platelets transferred structural components to tumor cells with higher efficiency than tumor cells to platelets (p = 0.001). This biological interplay occurred by direct contact, internalization or via extracellular vesicles. As a result, tumor cells acquired platelet markers (CD61 and CD42), showed decreased EpCAM, expressed epithelial-to-mesenchymal transition markers, and increased proliferation rates. Moreover, we were able to detect CD61 in CTCs from early and advanced prostate cancer. Conclusions: Our results demonstrated, for the first time, that platelets educate tumor cells by highly efficient transference of lipids, proteins and RNA through different mechanisms. These results suggest that tumor cells and CTCs might acquire highly dynamic and aggressive phenotypes due to platelets interaction including EMT, stem-like phenotype and high proliferative rates.

SARS-CoV-2 Infection Triggers Auto-Immune Response in ARDS.

Acute respiratory distress syndrome (ARDS) is a severe pulmonary disease, which is one of the major complications in COVID-19 patients. Dysregulation of the immune system and imbalances in cytokine release and immune cell activation are involved in SARS-CoV-2 infection. Here, the inflammatory, antigen, and auto-immune profile of patients presenting COVID-19-associated severe ARDS has been analyzed using functional proteomics approaches. Both, innate and humoral responses have been characterized through acute-phase protein network and auto-antibody signature. Severity and sepsis by SARS-CoV-2 emerged to be correlated with auto-immune profiles of patients and define their clinical progression, which could provide novel perspectives in therapeutics development and biomarkers of COVID-19 patients. Humoral response in COVID-19 patients' profile separates with significant differences patients with or without ARDS. Furthermore, we found that this profile can be correlated with COVID-19 severity and results more common in elderly patients.

Sex Related Differences in the Treatment of ST-Segment Elevation Acute Myocardial Infarction in Patients Aged <55 years.

Gender-related differences after ST-segment elevation myocardial infarction (STEMI) have been reported, but studies have generally focused on high-risk groups and results are inconsistent. This study aims to determine gender-related differences in the treatment of STEMI and in-hospital mortality in a contemporary cohort of young patients. We included patients aged <55 years admitted to the Acute Cardiac Care Unit with STEMI during an 11-year period. We retrospectively reviewed the clinical charts to register information on demographics, clinical and laboratory data, angiography, treatment received, complications, and in-hospital mortality. A total of 812 patients were included (712 men and 100 women). There were no gender-related differences in age or prevalence of cardiovascular risk factors. Women, as compared with men, had higher incidence of nonobstructive angiography (14.0% vs 2.4%) and coronary tortuosity (4.0% vs 0.8%), and lower incidence of multivessel disease (35.0% vs 49.6%) (p <0.05). Less frequently than men, women received percutaneous transluminal coronary angioplasty (94.0% vs 98.2%), and stent placement (82.0% vs 93.8%), inotropic agents (2.0% vs 8.3%), hypothermia after cardiac arrest (25.0% vs 84.0%), and mechanical ventilation (4.0% vs 11.0%) (p <0.05). These differences were not explained by the different angiographic findings. In-hospital mortality was 2.0% and 3.4%, in women and men, respectively (adjusted odds ratio 0.712, 95% confidence interval 0.164 to 3.093, p = 0.650). In conclusion, women aged <55 years with STEMI were held to different treatment standards than men.

Deep Phenotypic Characterisation of CTCs by Combination of Microfluidic Isolation (IsoFlux) and Imaging Flow Cytometry (ImageStream).

The isolation of circulating tumour cells (CTCs) in colorectal cancer (CRC) mostly relies on the expression of epithelial markers such as EpCAM, and phenotypic characterisation is usually performed under fluorescence microscopy with only one or two additional markers. This limits the ability to detect different CTC subpopulations based on multiple markers. The aim of this work was to develop a novel protocol combining two platforms (IsoFluxTM and ImageStream®X) to improve CTC evaluation. Cancer cell lines and peripheral blood from healthy donors were used to evaluate the efficiency of each platform independently and in combination. Peripheral blood was extracted from 16 early CRC patients (before loco-regional surgery) to demonstrate the suitability of the protocol for CTC assessment. Additionally, peripheral blood was extracted from nine patients one month after surgery to validate the utility of our protocol for identifying CTC subpopulation changes over time. Results: Our protocol had a mean recovery efficiency of 69.5% and a limit of detection of at least four cells per millilitre. We developed an analysis method to reduce noise from magnetic beads used for CTC isolation. CTCs were isolated from CRC patients with a median of 37 CTCs (IQ 13.0-85.5) at baseline. CTCs from CRC patients were significantly (p < 0.0001) larger than cytokeratin (CK)-negative cells, and patients were stratified into two groups based on BRAFV600E and PD-L1 expression on CK-positive cells. The changes observed over time included not only the number of CTCs but also their distribution into four different subpopulations defined according to BRAFV600E and PD-L1 positivity. We developed a novel protocol for semi-automatic CTC isolation and phenotypic characterisation by combining two platforms. Assessment of CTCs from early CRC patients using our protocol allowed the identification of two clusters of patients with changing phenotypes over time.

Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential.

Extracellular vesicles (EVs) mediate intercellular communication by transferring genetic material, proteins and organelles between different cells types in both health and disease. Recent evidence suggests that these vesicles, more than simply diagnostic markers, are key mediators of the pathophysiology of acute respiratory distress syndrome (ARDS) and other lung diseases. In this review, we will discuss the contribution of EVs released by pulmonary structural cells (alveolar epithelial and endothelial cells) and immune cells in these diseases, with particular attention to their ability to modulate inflammation and alveolar-capillary barrier disruption, a hallmark of ARDS. EVs also offer a unique opportunity to develop new therapeutics for the treatment of ARDS. Evidences supporting the ability of stem cell-derived EVs to attenuate the lung injury and ongoing strategies to improve their therapeutic potential are also discussed.

Case Studies in Physiology: Physiological and clinical effects of temporary diaphragm pacing in two patients with ventilator-induced diaphragm dysfunction.

Ventilator-induced diaphragm dysfunction (VIDD) is increasingly recognized as an important side-effect of invasive ventilation in critically ill patients and is associated with poor outcomes. Whether patients with VIDD benefit from temporary diaphragm pacing is uncertain. Intramuscular diaphragmatic electrodes were implanted for temporary stimulation with a pacing device (TransAeris System) in two patients with VIDD. The electrodes were implanted via laparoscopy (first patient) or via bilateral thoracoscopy (second patient). Stimulation parameters were titrated according to tolerance. Diaphragm thickening fraction by ultrasound, maximum inspiratory pressure (Pimax) and diaphragm electromyography (EMGdi) signal analysis were used to monitor the response to diaphragm pacing. Both patients tolerated diaphragm pacing. In the first patient, improvements in diaphragm excursions were noted once pacing was initiated and diaphragm thickening fraction did not further deteriorate over time. The diaphragm thickening fraction improved in the second patient, and Pimax as well as EMGdi analysis suggested improved muscle function. This patient could be fully weaned from the ventilator. These case reports present the first experience with temporary diaphragm pacing in critically ill patients with VIDD. Our results should be taken cautiously given the reduced sample size, but provide the proof of concept to put forward the hypothesis that a course of diaphragm pacing may be associated with improved diaphragmatic function. Our findings of the tolerance to the procedure and the beneficial physiological effects are not prove of safety and efficacy, but may set the ground to design and conduct larger studies.NEW & NOTEWORTHY Diaphragmatic electrode implantation and temporary diaphragm pacing have not been previously used in ICU patients with VIDD. Patients were monitored using a multimodal monitoring approach including ultrasound of the diaphragm, measurement of maximum inspiratory pressure and EMG signal analysis. Our results suggest that diaphragm pacing may improve diaphragmatic function, with the potential to prevent and treat VIDD in critically ill patients. Safety and efficacy of this intervention is yet to be proven in larger studies.

Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation.

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.

Antioxidants for the Treatment of Breast Cancer: Are We There Yet?

Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels and tight regulation of REDOX homeostasis to maintain a low degree of oxidative stress. Traditionally antioxidants have been extensively investigated to counteract breast carcinogenesis and tumor progression as chemopreventive agents; however, there is growing evidence indicating their potential as adjuvants for the treatment of breast cancer. Aimed to elucidate whether antioxidants could be a reality in the management of breast cancer patients, this review focuses on the latest investigations regarding the ambivalent role of antioxidants in the development of breast cancer, with special attention to the results derived from clinical trials, as well as their potential use as plausible agents in combination therapy and their power to ameliorate the side effects attributed to standard therapeutics. Data retrieved herein suggest that antioxidants play an important role in breast cancer prevention and the improvement of therapeutic efficacy; nevertheless, appropriate patient stratification based on "redoxidomics" or tumor subtype is mandatory in order to define the dosage for future standardized and personalized treatments of patients.