Molecular Subtypes, microRNAs and Immunotherapy Response in Metastatic Colorectal Cancer.

Currently, only a limited set of molecular traits are utilized to direct treatment for metastatic CRC (mCRC). The molecular classification of CRC depicts tumor heterogeneity based on gene expression patterns and aids in comprehending the biological characteristics of tumor formation, growth and prognosis. Additionally, it assists physicians in tailoring the therapeutic approach. Microsatellite instability (MSI-H)/deficient mismatch repair proteins (MMRd) status has become a ubiquitous biomarker in solid tumors, caused by mutations or methylation of genes and, in turn, the accumulation of mutations and antigens that subsequently induce an immune response. Immune checkpoint inhibitors (ICI) have recently received approval for the treatment of mCRC with MSI-H/MMRd status. However, certain individuals experience either initial or acquired resistance. The tumor-programmed cell death ligand 1 (PD-L1) has been linked to the ability of CRC to evade the immune system and promote its growth. Through comprehensive research conducted via the PUBMED database, the objectives of this paper were to review the molecular characteristics linked to tumor response in metastatic CRC in light of improved patients' outcomes following ICI therapies as seen in clinical trials and to identify particular microRNAs that can modulate the expression of specific oncoproteins, such as PD-L1, and disrupt the mechanisms that allow the immune system to be evaded.

Mammographic assessment of breast density as a tool for predicting the response to neoadjuvant therapy in breast cancer patients.

Background and aims: Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. For locally advanced diseases and high-risk tumors, neoadjuvant therapy (NAT) is the treatment of choice. Some studies show that mammographic density (MD) tumor margins and the presence of microcalcifications play a prognostic role in BC patients. Hence, the objective of this retrospective study was to assess if MD could predict the response to NAT among different molecular subtypes of BC patients undergoing NAT at The "Prof. Dr I. Chiricuta" Oncology Institute of Cluj-Napoca, Romania (IOCN). Furthermore, the association between MD, tumor margins and the presence of microcalcifications with clinico-pathological data was analyzed. Methods: Eighty-four breast cancer patients diagnosed and treated at IOCN were included in this study. The morphological characteristics of the tumors were framed according to the BIRADS lexicon. The presence or absence of microcalcifications was also assessed. First, the significance of associations between breast density, margins and microcalcifications and clinico-pathological parameters of the patients were tested with Fisher or Fisher-Freeman-Halton Exact Test. Next, using multinomial logistic regression, we modelled the associations between the pathological response measured by Miller Payne and Residual cancer burden (RCB) systems and the BI-RADS. Variables having significant univariate tests were selected as candidates for the multivariable analysis (adjusted model). Results: Breast densities were significantly associated with the age of the patients (p=0.01), number of positive lymph nodes (p=0.037), margins (p=0.002) and combined categories of Miller-Payne (p=0.034) and RCB pathological response (p=0.021). Margins was significantly associated with ki67 proliferation index (p=0.029), estrogen receptor (ER) (p=0.007), progesterone receptor (PR) (p=0.019), molecular subtype (p<0.001) and the number of clinically observed positive lymph nodes at diagnosis (p=0.019). Conclusions: In our cohort, BC patients with lower MD had higher odds of achieving pCR following NAT, suggesting the role of MD as a clinical prognostic marker. Larger multicenter studies are warranted to validate the prognostic value of MD, which could aid in patients stratification based on their likelihood to respond to NAT.

Baseline Expression of Exosomal miR-92a-3p and miR-221-3p Could Predict the Response to First-Line Chemotherapy and Survival in Metastatic Colorectal Cancer.

The status of predictive biomarkers in metastatic colorectal cancer is currently underdeveloped. Our study aimed to investigate the predictive value of six circulating exosomal miRNAs derived from plasma (miR-92a-3p, miR-143-3p, miR-146a-5p, miR-221-3p, miR-484, and miR-486-5p) for chemosensitivity, resistance patterns, and survival. Thirty-one metastatic colorectal cancer patients were selected before receiving first-line irinotecan- or oxaliplatin-based chemotherapy. Blood samples were harvested at baseline and 4-6 months after the initiation of chemotherapy. The levels of exosomal expression for each miRNA were analyzed by qPCR. Our results for patients receiving first-line FOLFOX showed significantly higher baseline levels of miR-92a-3p (p = 0.007 **), miR-146a-5p (p = 0.036 *), miR-221-3p (p = 0.047 *), and miR-484 (p = 0.009 **) in non-responders (NR) vs. responders (R). Of these, miR-92a-3p (AUC = 0.735), miR-221-3p (AUC = 0.774), and miR-484 (AUC = 0.725) demonstrated a predictive ability to discriminate responses from non-responses, regardless of the therapy used. Moreover, Cox regression analysis indicated that higher expression levels of miR-92a-3p (p = 0.008 **), miR-143-3p (p = 0.009 **), miR-221-3p (p = 0.016 *), and miR-486-5p (p = 0.019 *) at baseline were associated with worse overall survival, while patients expressing higher baseline miR-92a-3p (p = 0.003 **) and miR-486-5p (p = 0.003 **) had lower rates of progression-free survival. No predictive values for candidate microRNAs were found for the post-chemotherapy period. In line with these findings, we conclude that the increased baseline exosomal expression of miR-92a-3p and miR-221-3p seems to predict a lack of response to chemotherapy and lower OS. However, further prospective studies on more patients are needed before drawing practice-changing conclusions.

The Bioactive Properties of Carotenoids from Lipophilic Sea buckthorn Extract (Hippophae rhamnoides L.) in Breast Cancer Cell Lines.

In women, breast cancer is the most commonly diagnosed cancer (11.7% of total cases) and the leading cause of cancer death (6.9%) worldwide. Bioactive dietary components such as Sea buckthorn berries are known for their high carotenoid content, which has been shown to possess anti-cancer properties. Considering the limited number of studies investigating the bioactive properties of carotenoids in breast cancer, the aim of this study was to investigate the antiproliferative, antioxidant, and proapoptotic properties of saponified lipophilic Sea buckthorn berries extract (LSBE) in two breast cancer cell lines with different phenotypes: T47D (ER+, PR+, HER2-) and BT-549 (ER-, PR-, HER2-). The antiproliferative effects of LSBE were evaluated by an Alamar Blue assay, the extracellular antioxidant capacity was evaluated through DPPH, ABTS, and FRAP assays, the intracellular antioxidant capacity was evaluated through a DCFDA assay, and the apoptosis rate was assessed by flow cytometry. LSBE inhibited the proliferation of breast cancer cells in a concentration-dependent manner, with a mean IC50 of 16 µM. LSBE has proven to be a good antioxidant both at the intracellular level, due to its ability to significantly decrease the ROS levels in both cell lines (p = 0.0279 for T47D, and p = 0.0188 for BT-549), and at the extracellular level, where the ABTS and DPPH inhibition vried between 3.38-56.8%, respectively 5.68-68.65%, and 35.6 mg/L equivalent ascorbic acid/g LSBE were recorded. Based on the results from the antioxidant assays, LSBE was found to have good antioxidant activity due to its rich carotenoid content. The flow cytometry results revealed that LSBE treatment induced significant alterations in late-stage apoptotic cells represented by 80.29% of T47D cells (p = 0.0119), and 40.6% of BT-549 cells (p = 0.0137). Considering the antiproliferative, antioxidant, and proapoptotic properties of the carotenoids from LSBE on breast cancer cells, further studies should investigate whether these bioactive dietary compounds could be used as nutraceuticals in breast cancer therapy.

Potential antitumor activity of garlic against colorectal cancer: focus on the molecular mechanisms of action.

PURPOSE: The aim of this review is to highlight the potential of garlic phytoconstituents as antitumor agents in colorectal cancer management based on their molecular mechanisms of action, while asking if their consumption, as part of the human diet, might contribute to the prevention of colorectal cancer. METHODS: To gather information on appropriate in vitro, in vivo and human observational studies on this topic, the keywords "Allium sativum", "garlic", "colorectal cancer", "antitumor effect", "in vitro", "in vivo", "garlic consumption" and "colorectal cancer risk" were searched in different combinations in the international databases ScienceDirect, PubMed and Google Scholar. After duplicate and reviews removal, 61 research articles and meta-analyses published between 2000 and 2022 in peer-reviewed journals were found and included in this review. RESULTS: Garlic (Allium sativum) proves to be a rich source of compounds with antitumor potential. Garlic-derived extracts and several of its individual constituents, especially organosulfur compounds such as allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide, diallyl tetrasulfide, allylmethylsulfide, S-allylmercaptocysteine, Z-ajoene, thiacremonone and Se-methyl-L-selenocysteine were found to possess cytotoxic, cytostatic, antiangiogenic and antimetastatic activities in different in vitro and in vivo models of colorectal cancer. The molecular mechanisms for their antitumor effects are associated with the modulation of several well-known signaling pathways involved in cell cycle progression, especially G1-S and G2-M transitions, as well as both the intrinsic and extrinsic apoptotic pathways. However, even though in various animal models some of these compounds have chemopreventive effects, based on different human observational studies, a diet rich in garlic is not consistently associated with a lower risk of developing colorectal cancer. CONCLUSION: Independent of the impact of garlic consumption on colorectal cancer initiation and promotion in humans, its constituents might be good candidates for future conventional and/or complementary therapies, based on their diverse mechanisms of action.

Hexagonal-Grid-Layout Image Segmentation Using Shock Filters: Computational Complexity Case Study for Microarray Image Analysis Related to Machine Learning Approaches.

Hexagonal grid layouts are advantageous in microarray technology; however, hexagonal grids appear in many fields, especially given the rise of new nanostructures and metamaterials, leading to the need for image analysis on such structures. This work proposes a shock-filter-based approach driven by mathematical morphology for the segmentation of image objects disposed in a hexagonal grid. The original image is decomposed into a pair of rectangular grids, such that their superposition generates the initial image. Within each rectangular grid, the shock-filters are once again used to confine the foreground information for each image object into an area of interest. The proposed methodology was successfully applied for microarray spot segmentation, whereas its character of generality is underlined by the segmentation results obtained for two other types of hexagonal grid layouts. Considering the segmentation accuracy through specific quality measures for microarray images, such as the mean absolute error and the coefficient of variation, high correlations of our computed spot intensity features with the annotated reference values were found, indicating the reliability of the proposed approach. Moreover, taking into account that the shock-filter PDE formalism is targeting the one-dimensional luminance profile function, the computational complexity to determine the grid is minimized. The order of growth for the computational complexity of our approach is at least one order of magnitude lower when compared with state-of-the-art microarray segmentation approaches, ranging from classical to machine learning ones.

Maize cytolines as models to study the impact of different cytoplasms on gene expression under heat stress conditions.

BACKGROUND: Crops are under constant pressure due to global warming, which unfolds at a much faster pace than their ability to adapt through evolution. Agronomic traits are linked to cytoplasmic-nuclear genome interactions. It thus becomes important to understand the influence exerted by the organelles on gene expression under heat stress conditions and profit from the available genetic diversity. Maize (Zea mays) cytolines allow us to investigate how the gene expression changes under heat stress conditions in three different cytoplasmic environments, but each having the same nucleus. Analyzing retrograde signaling in such an experimental set-up has never been done before. Here, we quantified the response of three cytolines to heat stress as differentially expressed genes (DEGs), and studied gene expression patterns in the context of existing polymorphism in their organellar genomes. RESULTS: Our study unveils a plethora of new genes and GO terms that are differentially expressed or enriched, respectively, in response to heat stress. We report 19,600 DEGs as responding to heat stress (out of 30,331 analyzed), which significantly enrich 164 GO biological processes, 30 GO molecular functions, and 83 GO cell components. Our approach allowed for the discovery of a significant number of DEGs and GO terms that are not common in the three cytolines and could therefore be linked to retrograde signaling. Filtering for DEGs with a fold regulation > 2 (absolute values) that are exclusive to just one of the cytolines, we find a total of 391 up- and down-DEGs. Similarly, there are 19 GO terms with a fold enrichment > 2 that are cytoline-specific. Using GBS data we report contrasting differences in the number of DEGs and GO terms in each cytoline, which correlate with the genetic distances between the mitochondrial genomes (but not chloroplast) and the original nuclei of the cytolines, respectively. CONCLUSIONS: The experimental design used here adds a new facet to the paradigm used to explain how gene expression changes in response to heat stress, capturing the influence exerted by different organelles upon one nucleus rather than investigating the response of several nuclei in their innate cytoplasmic environments.

Phytochemical Profile and Selective Cytotoxic Activity of a Solanum bulbocastanum Dun. Methanolic Extract on Breast Cancer Cells.

Solanum bulbocastanum is a wild potato species, intensively used in potato breeding programs due to its resistance to environmental factors. Thus, its biochemical profile and putative human health-related traits might be transferred into potato cultivars aimed for consumption. This study aims to assess the phytochemical profile and the selective cytotoxicity of an S. bulbocastanum extract against breast cancer cells. Dry leaves were subjected to ultrasonication-assisted extraction in methanol [70%]. The phenolic and glycoalkaloid profiles were determined by HPLC-PDA/-ESI+-MS. The volatile profile was investigated by nontargeted ITEX/GC-MS. The extract was tested against three breast cancer cell lines (MCF7, MDA-MB-231, HS578T) and a healthy cell line (HUVEC) by the MTT assay, to assess its selective cytotoxicity. The phenolic profile of the extract revealed high levels of phenolic acids (5959.615 µg/mL extract), and the presence of flavanols (818.919 µg/mL extract). The diversity of the volatile compounds was rather low (nine compounds), whereas no glycoalkaloids were identified, only two alkaloid precursors (813.524 µg/mL extract). The extract proved to be cytotoxic towards all breast cancer cell lines (IC50 values between 139.1 and 356,1 µg/mL), with selectivity coefficients between 1.96 and 4.96 when compared with its toxicity on HUVECs. Based on these results we conclude that the exerted cytotoxic activity of the extract is due to its high polyphenolic content, whereas the lack of Solanaceae-specific glycoalkaloids might be responsible for its high selectivity against breast cancer cells in comparison with other extract obtained from wild Solanum species. However, further research is needed in order to assess the cytotoxicity of the individual compounds found in the extract, as well as the anti-tumor potential of the S. bulbocastanum tubers.

Clinical Applications of Liquid Biopsy in Colorectal Cancer Screening: Current Challenges and Future Perspectives.

Colorectal cancer (CRC) represents the third most prevalent cancer worldwide and a leading cause of mortality among the population of western countries. However, CRC is frequently a preventable malignancy due to various screening tests being available. While failing to obtain real-time data, current screening methods (either endoscopic or stool-based tests) also require disagreeable preparation protocols and tissue sampling through invasive procedures, rendering adherence to CRC screening programs suboptimal. In this context, the necessity for novel, less invasive biomarkers able to identify and assess cancer at an early stage is evident. Liquid biopsy comes as a promising minimally invasive diagnostic tool, able to provide comprehensive information on tumor heterogeneity and dynamics during carcinogenesis. This review focuses on the potential use of circulating tumor cells (CTCs), circulating nucleic acids (CNAs) and extracellular vesicles as emerging liquid biopsy markers with clinical application in the setting of CRC screening. The review also examines the opportunity to implement liquid biopsy analysis during everyday practice and provides highlights on clinical trials researching blood tests designed for early cancer diagnosis. Additionally, the review explores potential applications of liquid biopsies in the era of immunotherapy.

The Role of miR-375-3p, miR-210-3p and Let-7e-5p in the Pathological Response of Breast Cancer Patients to Neoadjuvant Therapy.

Background and Objectives: Prediction of response to therapy remains a continuing challenge in treating breast cancer, especially for identifying molecular tissue markers that best characterize resistant tumours. Microribonucleic acids (miRNA), known as master modulators of tumour phenotype, could be helpful candidates for predicting drug resistance. We aimed to assess the association of miR-375-3p, miR-210-3p and let-7e-5p in breast cancer tissues with pathological response to neoadjuvant therapy (NAT) and clinicopathological data. Material and methods: Sixty female patients diagnosed with invasive breast cancer at The Oncology Institute "Ion Chiricuța", Cluj-Napoca, Romania (IOCN) were included in this study. Before patients received any treatment, fresh breast tissue biopsies were collected through core biopsy under echographic guidance and processed for total RNA extraction and miRNA quantification. The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) database was used as an independent external validation cohort. Results: miR-375-3p expression was associated with more differentiated tumours, hormone receptor presence and lymphatic invasion. According to the Miller-Payne system, a higher miR-375-3p expression was calculated for patients that presented with intermediate versus (vs.) no pathological response. Higher miR-210-3p expression was associated with an improved response to NAT in both Miller-Payne and RCB evaluation systems. Several druggable mRNA targets were correlated with miR-375-3p and miR-210-3p expression, with upstream analysis using the IPA knowledge base revealing a list of possible chemical and biological targeting drugs. Regarding let-7e-5p, no significant association was noticed with any of the analysed clinicopathological data. Conclusions: Our results suggest that tumours with higher levels of miR-375-3p are more sensitive to neoadjuvant therapy compared to resistant tumours and that higher miR-210-3p expression in responsive tumours could indicate an excellent pathological response.

Circulating Small EVs miRNAs as Predictors of Pathological Response to Neo-Adjuvant Therapy in Breast Cancer Patients.

Neo-adjuvant therapy (NAT) is increasingly used in the clinic for the treatment of breast cancer (BC). Pathological response to NAT has been associated with improved patients' survival; however, the current techniques employed for assessing the tumor response have significant limitations. Small EVs (sEVs)-encapsulated miRNAs have emerged as promising new biomarkers for diagnosis and prediction. Therefore, our study aims to explore the predictive value of these miRNAs for the pathological response to NAT in BC. By employing bioinformatic tools, we selected a set of miRNAs and evaluated their expression in plasma sEVs and BC biopsies. Twelve miRNAs were identified in sEVs, of which, miR-21-5p, 221-3p, 146a-5p and 26a-5p were significantly associated with the Miller-Payne (MP) pathological response to NAT. Moreover, miR-21-5p, 146a-5p, 26a-5p and miR-24-3p were independent as predictors of MP response to NAT. However, the expression of these miRNAs showed no correlation between sEVs and tissue samples, indicating that the mechanisms of miRNA sorting into sEVs still needs to be elucidated. Functional analysis of miRNA target genes and drug interactions revealed that candidate miRNAs and their targets, can be regulated by different NAT regimens. This evidence supports their role in governing the patients' therapy response and highlights their potential use as prediction biomarkers.

Thyroid carcinoma associated with other primary neoplasms, a single center study.

Background and aims: Thyroid carcinoma is the most frequent endocrine malignancy. It develops following a complex interaction of environmental and genetic factors. Its incidence is on the rise mostly due to the frequent diagnosis of microcarcinomas (tumor <1 cm). In most cases, it has very good prognosis and survival rates. The incidence of a second primary malignancy in thyroid cancer patients is higher than in the general population. In this article, we focus on the role of BRAF V600E mutation in the development of other primary neoplasms associated with thyroid carcinoma. Methods: This study was conducted in the department of Nuclear Medicine and Genetics of the "Prof. Dr. Ion Chiricuța" Institute of Oncology of Cluj-Napoca. We evaluated patients with thyroid carcinoma, who were diagnosed and treated for other malignancies such as breast, colorectal, lung cancer and malignant melanoma. In addition, we tested for the BRAF V600E mutation using paraffin samples of patients. Results: We identified 17 patients that had thyroid carcinoma associated with other primary malignancies. Two of the patients included in the study had three associated primary cancers. The time interval between the diagnoses of two primary neoplasms in the same patient was 6.15 years, with a standard deviation (SD) of 5.39 years. The most common primary tumor associated with thyroid carcinoma in this study was breast cancer. We applied genetic testing for the BRAF V600E mutation in 12 patients. The BRAF V600E mutation positivity rate was 26.9% and most of the cancer associations were metachronous (occurring at least 6 months after thyroid cancer). Conclusions: The BRAF V600E mutation is an important prognostic factor in the neoplasms included in this study, but its presence is not a predictive factor for the appearance of a metachronous or synchronous associated primary neoplasm to thyroid cancer.

Plant-Derived Bioactive Compounds in Colorectal Cancer: Insights from Combined Regimens with Conventional Chemotherapy to Overcome Drug-Resistance.

Acquired drug resistance represents a major clinical problem and one of the biggest limitations of chemotherapeutic regimens in colorectal cancer. Combination regimens using standard chemotherapeutic agents, together with bioactive natural compounds derived from diet or plants, may be one of the most valuable strategies to overcome drug resistance and re-sensitize chemoresistant cells. In this review, we highlight the effect of combined regimens based on conventional chemotherapeutics in conjunction with well-tolerated plant-derived bioactive compounds, mainly curcumin, resveratrol, and EGCG, with emphasis on the molecular mechanisms associated with the acquired drug resistance.

Breast Cancer-Delivered Exosomal miRNA as Liquid Biopsy Biomarkers for Metastasis Prediction: A Focus on Translational Research with Clinical Applicability.

Metastasis represents the most important cause of breast cancer-associated mortality. Even for early diagnosed stages, the risk of metastasis is significantly high and predicts a grim outcome for the patient. Nowadays, efforts are made for identifying blood-based biomarkers that could reliably distinguish patients with highly metastatic cancers in order to ensure a closer follow-up and a more personalized therapeutic method. Exosomes are nano vesicles secreted by cancer cells that can transport miRNAs, proteins, and other molecules and deliver them to recipient cells all over the body. Through this transfer, cancer cells modulate their microenvironment and facilitate the formation of the pre-metastatic niche, leading to sustained progression. Exosomal miRNAs have been extensively studied due to their promising potential as prognosis biomarkers for metastatic breast cancer. In this review, we tried to depict an overview of the existing literature regarding exosomal miRNAs that are already validated as potential biomarkers, and which could be immediately available for the clinic. Moreover, in the last section, we highlighted several miRNAs that have proven their function in preclinical studies and could be considered for clinical validation. Considering the lack of standard methods for evaluating exosomal miRNA, we also discussed the challenges and the technical aspects underlying this issue.

The Role of Circulating Tumor Cells in the Prognosis of Metastatic Triple-Negative Breast Cancers: A Systematic Review of the Literature.

Breast cancer is one of the leading causes of death in women worldwide. One subtype of breast cancer is the triple-negative, which accounts for 15% of total breast cancer cases and is known for its poor prognosis. The main cause of death is due to metastasis. Circulating tumor cells (CTCs) play a key role in the metastatic process. CTCs arise either by detaching from the primary tumor or from cancer stem cells undergoing an epithelial-to-mesenchymal transition (EMT). This review aims to present up-to-date data concerning the role of CTC numbers in relation to the prognostic and treatment response in metastatic triple-negative breast cancer (mTNBC) patients, and also to discuss the methods used for CTCs' identification. A search in the MEDLINE database was performed. A total of 234 articles were identified. The results of the 24 eligible studies showed that positive CTC status is associated with shorter overall survival (OS) and progression-free survival (PFS) in mTNBC patients. Furthermore, a decrease in number of CTCs during therapy seems to be a favorable prognostic factor, making CTCs' detection an important prognostic tool before and during therapy in mTNBC patients. The methods used for CTC detection are still developing and need further improvement.

Diagnostic Value of microRNA-375 as Future Biomarker for Prostate Cancer Detection: A Meta-Analysis.

Background and Objectives: Responding to the need for additional biomarkers for the diagnosis of prostate cancer (PCa), mounting studies show that microRNAs (miRNAs/miRs) possess great potential as future promising diagnostic tools. However, the usefulness of these miRNAs is still highly debated, as the degree of inconsistency between study designs and results is still elevated. Herein, we present a meta-analysis evaluating the diagnostic value and accuracy of circulating miR-375, as it is one of the most studied types of miRs in PCa. Materials and Methods: The diagnostic accuracy of miR-375 was evaluated using the QUADAS-2 tool, analyzing different statistical parameters. The seven studies (from six articles) that matched our selection included 422 PCa patients and 212 controls (70 healthy volunteers + 142 with benign prostate diseases). Results and Conclusion: We obtained a p-value of 0.76 for sensitivity, 0.83 for specificity, 16 for DOR, 4.6 for LR+, 0.29 for LR-, and 0.87 for AUC (95% CI 0.83-0.89). Our results confirm that miRNA-375 has high diagnostic potential for PCa, suggesting its usefulness as a powerful biomarker. More comprehensive studies are warranted to better assess its true value as a diagnostic biomarker for this urologic disease.

Current and New Challenges in the Management of Pancreatic Neuroendocrine Tumors: The Role of miRNA-Based Approaches as New Reliable Biomarkers.

Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend a poor prognosis in an advanced stages and undifferentiated tumors. Additionally, functional pancreatic neuroendocrine tumors greatly impact quality of life due to the various clinical syndromes that result from abnormal hormonal secretion. With limited therapeutic and diagnostic options, patient stratification and selection of optimal therapeutic strategies should be the main focus. Modest improvements in the management of pancreatic neuroendocrine tumors have been achieved in the last years. Therefore, it is imperative to find new biomarkers and therapeutic strategies to improve patient survival and quality of life, limiting the disease burden. MicroRNAs (miRNAs) are small endogenous molecules that modulate the expression of thousands of genes and control numerous critical processes involved in tumor development and progression. New data also suggest the implication of miRNAs in treatment resistance and their potential as prognostic or diagnostic biomarkers and therapeutic targets. In this review, we discusses the current and new challenges in the management of PanNETs, including genetic and epigenetic approaches. Furthermore, we summarize the available data on miRNAs as potential prognostic, predictive, or diagnostic biomarkers and discuss their function as future therapeutic targets.

Tetraspanins: Physiology, Colorectal Cancer Development, and Nanomediated Applications.

Tetraspanins are transmembrane proteins expressed in a multitude of cells throughout the organism. They contribute to many processes that surround cell-cell interactions and are associated with the progress of some diseases, including cancer. Their crucial role in cell physiology is often understated. Furthermore, recent studies have shown their great potential in being used as targeting molecules. Data have suggested the potential of tetraspanins as a targeting vector for nanomediated distribution and delivery for colorectal cancer applications. Our aim is to provide a review on the important part that tetraspanins play in the human organism and highlight their potential use for drug delivery systems using nanotechnology.

Next Generation Sequencing Technology in Lung Cancer Diagnosis.

Lung cancer is still one of the most commonly diagnosed cancers, and one of the deadliest. The high death rate is mainly due to the late stage of diagnosis and low response rate to therapy. Previous and ongoing research studies have tried to discover new reliable and useful cbiomarkers for the diagnosis and prognosis of lung cancer. Next generation sequencing has become an essential tool in cancer diagnosis, prognosis, and evaluation of the treatment response. This article aims to review the leading research and clinical applications in lung cancer diagnosis using next generation sequencing. In this scope, we identified the most relevant articles that present the successful use of next generation sequencing in identifying biomarkers for early diagnosis correlated to lung cancer diagnosis and treatment. This technique can be used to evaluate a high number of biomarkers in a short period of time and from small biological samples, which makes NGS the preferred technique to develop clinical tests for personalized medicine using liquid biopsy, the new trend in oncology.