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Introduction: Chemotherapy resistance remains a significant challenge in the treatment of pancreatic adenocarcinoma (PDAC), particularly in relation to gemcitabine (Gem), a commonly used chemotherapeutic agent. MicroRNAs (miRNAs) are known to influence cancer progression and chemoresistance. This study investigates the association between miRNA expression profiles and gemcitabine resistance in PDAC. Methods: The miRNA expression profiles of a gemcitabine-sensitive (GS) PDAC cell line, MIA PaCa-2, and its gemcitabine-resistant (GR) progeny, MIA PaCa-2 GR, were analyzed. miRNA sequencing (miRNA-seq) was employed to identify miRNAs expressed in these cell lines. Differential expression analysis was performed, and Ingenuity Pathway Analysis (IPA) was utilized to elucidate the biological functions of the differentially expressed miRNAs. Results: A total of 1867 miRNAs were detected across both cell lines. Among these, 97 (5.2%) miRNAs showed significant differential expression between the GR and GS cell lines, with 65 (3.5%) miRNAs upregulated and 32 (1.7%) miRNAs downregulated in the GR line. The most notably altered miRNAs were implicated in key biological processes such as cell proliferation, migration, invasion, chemosensitization, alternative splicing, apoptosis, and angiogenesis. A subset of these miRNAs was further analyzed in patient samples to identify potential markers for recurrent tumors. Discussion: The differential miRNA expression profiles identified in this study highlight the complex regulatory roles of miRNAs in gemcitabine resistance in PDAC. These findings suggest potential targets for improving prognosis and tailoring treatment strategies in PDAC patients, particularly those showing resistance to gemcitabine. Future research should focus on validating these miRNAs as biomarkers for resistance and exploring their therapeutic potential in overcoming chemoresistance. [ABSTRACT FROM AUTHOR]

Introduction: Peritoneal metastases from colorectal cancer (CRC) present a significant clinical challenge with poor prognosis, often unresponsive to systemic chemotherapy. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment approach for select patients. The use of curcumin, a natural compound with antitumor properties, in HIPEC is of interest due to its lower side effects compared to conventional drugs and potential for increased efficacy through direct delivery to the peritoneal cavity.Methods: An in vitro hyperthermic model was developed to simulate clinical HIPEC conditions. Three colon cancer cell lines (SK-CO-1, COLO205, SNU-C1) representing different genetic mutations (p53, KRAS, BRAF) were treated with either curcumin (25 μM) or mitomycin-C (1 μM) for 1, 2, or 3 hours. Post-treatment, cells were incubated at 37°C (normothermia) or 42°C (hyperthermia). Cell viability and proliferation were assessed at 24, 48 and 72 hours post-treatment using Annexin V/PI, MTT assay, trypan blue exclusion, and Hoffman microscopy.Results: Hyperthermia significantly enhanced the antitumor efficacy of curcumin, evidenced by a two-fold reduction in cell viability compared to normothermia across all cell lines. In the SNU-C1 cell line, which harbors a p53 mutation, mitomycin-C failed to significantly impact cell viability, unlike curcumin, suggesting mutation-specific differences in treatment response.Discussion: The findings indicate that hyperthermia augments the antitumor effects of curcumin in vitro, supporting the hypothesis that curcumin could be a more effective HIPEC agent than traditional drugs like mitomycin-C. Mutation-associated differences in response to treatments were observed, particularly in p53 mutant cells. While further studies are needed, these preliminary results suggest that curcumin in HIPEC could represent a novel therapeutic strategy for CRC patients with peritoneal metastases. This approach may offer improved outcomes with fewer side effects, particularly in genetically distinct CRC subtypes.Plain Language Summary: In this study, we aimed to improve treatments for peritoneal carcinomatosis (PC), a challenging form of colorectal cancer (CRC) that does not respond well to regular chemotherapy. We explored an approach called hyperthermic intraperitoneal chemotherapy (HIPEC), which involves delivering potent chemotherapy directly to the abdominal area at an elevated temperature. Our innovative idea was to enhance HIPEC's effectiveness by using curcumin, a natural compound with fewer side effects than conventional HIPEC drugs. To test our theory, we conducted experiments on colon cancer cells under high-temperature conditions, mimicking what occurs during HIPEC treatments. We also compared curcumin with the standard drug, mitomycin-C (MMC). We discovered that curcumin, when delivered under high temperatures, outperformed MMC in killing colorectal cancer cells. This is an exciting breakthrough because it suggests that curcumin in HIPEC could be a promising alternative for treating PC. While we are still working on more comparisons and further studies, this outcome represents a significant step towards better treatment options for patients with peritoneal carcinomatosis. In conclusion, our study was motivated by the need to find more effective ways to combat an aggressive form of colorectal cancer metastasis. By exploring the potential of curcumin in HIPEC, we hope to provide better treatment options for patients who face this challenging disease. [ABSTRACT FROM AUTHOR]

Background: Liquid biopsies have become an integral part of cancer management as minimally invasive options to detect molecular and genetic changes. However, current options show poor sensitivity in peritoneal carcinomatosis (PC). Novel exosome-based liquid biopsies may provide critical information on these challenging tumors. In this initial feasibility analysis, we identified an exosome gene signature of 445 genes (ExoSig445) from colon cancer patients, including those with PC, that is distinct from healthy controls. Methods: Plasma exosomes from 42 patients with metastatic and non-metastatic colon cancer and 10 healthy controls were isolated and verified. RNAseq analysis of exosomal RNA was performed and differentially expressed genes (DEGs) were identified by the DESeq2 algorithm. The ability of RNA transcripts to discriminate control and cancer cases was assessed by principal component analysis (PCA) and Bayesian compound covariate predictor classification. An exosomal gene signature was compared with tumor expression profiles of The Cancer Genome Atlas. Results: Unsupervised PCA using exosomal genes with greatest expression variance showed stark separation between controls and patient samples. Using separate training and test sets, gene classifiers were constructed capable of discriminating control and patient samples with 100% accuracy. Using a stringent statistical threshold, 445 DEGs fully delineated control from cancer samples. Furthermore, 58 of these exosomal DEGs were found to be overexpressed in colon tumors. Conclusions: Plasma exosomal RNAs can robustly discriminate colon cancer patients, including patients with PC, from healthy controls. ExoSig445 can potentially be developed as a highly sensitive liquid biopsy test in colon cancer. [ABSTRACT FROM AUTHOR]

New stem cell and extracellular-vesicle-based therapies have the potential to improve outcomes for the increasing number of patients with heart failure. Since neonates have a significantly enhanced regenerative ability, we hypothesized that extracellular vesicles isolated from Islet-1+ expressing neonatal human cardiovascular progenitors (CPCs) will induce transcriptomic changes associated with improved regenerative capability when co-cultured with CPCs derived from adult humans. In order to test this hypothesis, we isolated extracellular vesicles from human neonatal Islet-1+ CPCs, analyzed the extracellular vesicle content using RNAseq, and treated adult CPCs with extracellular vesicles derived from neonatal CPCs to assess their functional effect. AKT, ERBB, and YAP1 transcripts were elevated in adult CPCs treated with neonatal CPC-derived extracellular vesicles. YAP1 is lost after the neonatal period but can stimulate cardiac regeneration. Our results demonstrate that YAP1 and additional transcripts associated with improved cardiovascular regeneration, as well as the activation of the cell cycle, can be achieved by the treatment of adult CPCs with neonatal CPC-derived extracellular vesicles. Progenitor cells derived from neonates secrete extracellular vesicles with the potential to stimulate and potentially improve functional effects in adult CPCs used for cardiovascular repair. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis, as it is difficult to predict or circumvent, and it develops chemoresistance quickly. One cellular mechanism associated with chemoresistance is alternative splicing dysfunction, a process through which nascent mRNA is spliced into different isoforms. Survivin (Baculoviral IAP Repeat-Containing Protein 5 (BIRC5)), a member of the inhibitor of apoptosis (IAP) protein family and a cell cycle-associated oncoprotein, is overexpressed in most cancers and undergoes alternative splicing (AS) to generate six different splicing isoforms. Methods: To determine if survivin splice variants (SSV) could be involved in PDAC chemoresistance, a Gemcitabine (Gem) resistant (GR) cell line, MIA PaCa-2 GR, was created and assessed for its SSV levels and their potential association with GR. Cross-resistance was assessed in MIA-PaCa-2 GR cells to FIRINOX (5-fluorouracil (5-FU), irinotecan, and oxaliplatin). Once chemoresistance was confirmed, RT-qPCR was used to assess the expression of survivin splice variants (SSVs) in PDAC cell lines. To confirm the effect of SSVs on chemoresistance, we used siRNA to knockdown all SSVs or SSV 2β. Results: The MIA PaCa-2 GR cell line was 40 times more resistant to Gem and revealed increased resistance to FIRINOX (5-fluorouracil (5-FU), irinotecan, and oxaliplatin); when compared to the parental MIA-PaCa-2 cells. RT-qPCR studies revealed an 8-fold relative expression increase in SSV 2β and a 2- to 8-fold increase in the other five SSVs in the GR cells. Knockdown of all SSV or SSV 2β only, using small inhibitory RNA (siRNA), sensitized the GR cells to Gem, indicating that these SSVs play a role in PDAC chemoresistance. Conclusion: These findings provide evidence for the potential role of SSV 2β and other SSVs in innate and acquired PDAC chemoresistance. We also show that the expression of SSVs is not affected by the type of chemoresistance, therefore targeting survivin splice variants in combination with chemotherapy could benefit a wide range of patients. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are emerging targets for biomarker discovery. However, suitable clinical collection and storage methods for blood plasma-derived EVs have not been fully described. We investigated the long- and short-term effects of temperature and time on the plasma-derived EV concentration, size, protein, and RNA content. EVs isolated from freshly collected human blood stored for various periods of time at either room temperature (RT) or 4°C were analyzed for concentration, size, and protein content. In addition, EVs isolated from plasma stored at −80°C were compared to frozen EV pellets. We found that the number, size, protein, and RNA content of EVs were similar between blood samples stored at RT for 24h compared to samples processed shortly after collection or stored at 4°C vs. −80°C. It is therefore feasible to isolate and analyze comparable, stable EVs from blood plasma stored for varying periods of time and at various temperatures. [ABSTRACT FROM AUTHOR]

The development of research in robotics in a developing country is a challenging task. Factors such as low research funds, low trust from local companies and the government, and a small number of qualified researchers hinder the development of strong, local research groups. In this article, and as a case of study, we present our research group in robotics at the Advanced Mining Technology Center of the Universidad de Chile, and the way in which we have addressed these challenges. In 2008, we decided to focus our research efforts in mining, which is the main industry in Chile. We observed that this industry has needs in terms of safety, productivity, operational continuity, and environmental care. All these needs could be addressed with robotics and automation technology. In a first stage, we concentrate ourselves in building capabilities in field robotics, starting with the automation of a commercial vehicle. An important outcome of this project was the earn of the local mining industry confidence. Then, in a second stage started in 2012, we began working with the local mining industry in technological projects. In this article, we describe three of the technological projects that we have developed with industry support: (i) an autonomous vehicle for mining environments without global positioning system coverage; (ii) the inspection of the irrigation flow in heap leach piles using unmanned aerial vehicles and thermal cameras; and (iii) an enhanced vision system for vehicle teleoperation in adverse climatic conditions. [ABSTRACT FROM AUTHOR]

The generation of accurate terrain maps while navigating over off-road, irregular terrains is a complex challenge, due to the difficulties in the estimation of the pose of the laser rangefinders, which is required for the proper registration of the range measurements. This paper addresses this problem. The proposed methodology uses an Extended Kalman filter to estimate in real-time the instantaneous pose of the vehicle and the laser rangefinders by considering measurements acquired from an inertial measurement unit, internal sensorial data of the vehicle and the estimated heights of the four wheels, which are obtained from the terrain map and allow determination of the vehicle's inclination. The estimated 6D pose of the laser rangefinders is used to correctly project the laser measurements onto the terrain map. The terrain map is a 2.5D map that stores in each cell the mean value and variance of the terrain height. In each map's cell position, new laser observations are fused with existing height estimations using a Kalman filter. The proposed methodology is validated in the real world using an autonomous vehicle. Field trials show that the use of the proposed state estimation methodology produces maps with much higher accuracy than the standard approaches. [ABSTRACT FROM AUTHOR]

Currently, passive robots are designed following a trial and error process in which the existence of a stable walking cycle for a given passive robot's model is analyzed using Poincaré maps. The standard stability analysis procedure suffers from discretization aliasing, and it is not able to deal with complex passive models. In this paper a methodology that allows finding conditions on the robot's parameters of a given passive model in order to obtain a stable walking cycle is proposed. The proposed methodology overcomes the aliasing problem that arises when Poincaré sections are discretized. Basically, it implements a search process that allows finding stable subspaces in the parameters' space (i.e., regions with parameters' combinations that produce stable walking cycles), by simulating the robot dynamics for different parameters' combinations. After initial conditions are randomly selected, the robot's dynamics is modeled step by step, and in the Poincaré section the existence of a walking cycle is verified. The methodology includes the definition of a search algorithm for exploring the parameters' space, a method for the partition of the space in hypercubes and their efficient management using proper data structures, and the use of so-called design value functions that quantify the feasibility of the resulting parameters. Among the main characteristics of the proposed methodology are being robot independent (it can be used with any passive robot model, regardless of its complexity), and robust (stable subspaces incorporate a stability margin value that deals with differences between the robot's model and its physical realization). The methodology is validated in the design process of a complex semi-passive robot that includes trunk, knees, and non-punctual feet. The robot also considers the use of actuators, controllers and batteries for its actuation. [ABSTRACT FROM AUTHOR]