Liver Tropism in Cancer: The Hepatic Metastatic Niche.

The liver is the largest organ in the human body and is prone for cancer metastasis. Although the metastatic pattern can differ depending on the cancer type, the liver is the organ to which cancer cells most frequently metastasize for the majority of prevalent malignancies. The liver is unique in several aspects: the vascular structure is highly permeable and has unparalleled dual blood connectivity, and the hepatic tissue microenvironment presents a natural soil for the seeding of disseminated tumor cells. Although 70% of the liver is composed of the parenchymal hepatocytes, the remaining 30% is composed of nonparenchymal cells including Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells. Recent discoveries show that both the parenchymal and the nonparenchymal cells can modulate each step of the hepatic metastatic cascade, including the initial seeding and colonization as well as the decision to undergo dormancy versus outgrowth. Thus, a better understanding of the molecular mechanisms orchestrating the formation of a hospitable hepatic metastatic niche and the identification of the drivers supporting this process is critical for the development of better therapies to stop or at least decrease liver metastasis. The focus of this perspective is on the bidirectional interactions between the disseminated cancer cells and the unique hepatic metastatic niche

The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits

BACKGROUND: Transplant rejection has been considered to occur primarily because donor antigens are not present during the development of the recipient's immune system to induce tolerance. Thus, transplantation prior to recipient immune system development (pre-immunocompetence transplants) should induce natural tolerance to the donor. Surprisingly, tolerance was often not the outcome in such 'natural tolerance models'. We explored the ability of natural tolerance to prevent immune responses to alloantigens, and the reasons for the disparate outcomes of pre-immunocompetence transplants. RESULTS: We found that internal transplants mismatched for a single minor-H antigen and 'healed-in' before immune system development were not ignored but instead induced natural tolerance. In contrast, multiple minor-H or MHC mismatched transplants did not consistently induce natural tolerance unless they carried chimerism generating passenger lymphocytes. To determine whether the systemic nature of passenger lymphocytes was required for their tolerizing capacity, we generated a model of localized vs. systemic donor lymphocytes. We identified the peritoneal cavity as a site that protects allogeneic lymphocytes from killing by NK cells, and found that systemic chimerism, but not chimerism restricted to the peritoneum, was capable of generating natural tolerance. CONCLUSION: These data provide an explanation for the variable results with pre-immunocompetence transplants and suggest that natural tolerance to transplants is governed by the systemic vs. localized nature of donor antigen, the site of transplantation, and the antigenic disparity. Furthermore, in the absence of systemic lymphocyte chimerism the capacity to establish natural tolerance to allogeneic tissue appears strikingly limited. REVIEWERS: This article was reviewed by Matthias von Herrath, Irun Cohen, and Wei-Ping Min (nominated by David Scott)

Determinación espectrofotométrica sensible del peróxido de hidrógeno en muestras de agua procedentes de procesos de oxidación avanzada : Evaluación de posibles interferencias

RESUMEN: La determinación de peróxido de hidrógeno (H2O2) en muestras de agua real se llevó a cabo de una manera sencilla y sensible. Las condiciones óptimas de funcionamiento resultantes de un diseño experimental factorial completo fueron 450 nm, 50 mm y 6 x 10-3 M de longitud de onda de absorción, longitud de trayectoria de la celda de cuarzo y concentración final de la solución de monovanadato de amonio, respectivamente; permitiendo la cuantificación de 2.94x10-3 mM de H2O2. Se validó el método analítico propuesto y se investigó el efecto de la matriz obteniendo un método selectivo. Además, se aplicó el método analítico desarrollado para estudiar la evolución de H2O2 en la descontaminación de agua que contenía 6,73x10-5 mM de antraceno y 1,19x10-5 mM de benzo[a]pireno utilizando el sistema UV/H2O2. Se encontró que el nivel óptimo de H2O2 que permitía cerca del 45% de mineralización y una eliminación de los hidrocarburos aromáticos policíclicos objeto de estudio superior al 99% fue de 2,94x10-1 mM, permaneciendo aproximadamente 1,47x10-1 mM de H2O2 después de 90 min de tratamiento.ABSTRACT: Hydrogen peroxide (H2O2) determination in real water samples was carried out in a simple and sensitive way. The resulting optimal operating conditions from a 23 full factorial experimental design were 450 nm, 50 mm and 6x10-3 M for the absorption wavelength, the quartz cell path length and the final concentration of the ammonium monovanadate solution, respectively; allowing the quantification of H2O2 up to 2.94x10-3 mM. The proposed analytical method was validated and the effect of the background matrix was investigated, obtaining a selective method. Additionally, the developed analytical method was applied for studying the evolution of H2O2 in the decontamination of water containing 6.73x10-5 mM of anthracene and 1.19x10-5 mM of benzo[a]pyrene using the UV/H2O2 system. It was found that the optimal H2O2 level enabling about 45% of mineralisation and a removal of the target polycyclic aromatic hydrocarbons higher than 99% was 2.94x10-1 mM, remaining approximately 1.47x10-1 mM of H2O2 after 90 min of treatment

Using deep learning and meteorological parameters to forecast the photovoltaic generators intra-hour output power interval for smart grid control

In recent years, the photovoltaic generation installed capacity has been steadily growing thanks to its inexhaustible and non-polluting characteristics. However, solar generators are strongly dependent on intermittent weather parameters, increasing power systems' uncertainty level. Forecasting models have arisen as a feasible solution to decreasing photovoltaic generators' uncertainty level, as they can produce accurate predictions. Traditionally, the vast majority of research studies have focused on the develop- ment of accurate prediction point forecasters. However, in recent years some researchers have suggested the concept of prediction interval forecasting, where not only an accurate prediction point but also the confidence level of a given prediction are computed to provide further information. This paper develops a new model for predicting photovoltaic generators' output power confidence interval 10 min ahead, based on deep learning, mathematical probability density functions and meteorological parameters. The model's accuracy has been validated with a real data series collected from Spanish meteorological sta- tions. In addition, two error metrics, prediction interval coverage percentage and Skill score, are computed at a 95% confidence level to examine the model's accuracy. The prediction interval coverage percentage values are greater than the chosen confidence level, which means, as stated in the literature, the proposed model is well-founded

Event-related desynchronization during movement attempt and execution in severely paralyzed stroke patients: An artifact removal relevance analysis

The electroencephalogram (EEG) constitutes a relevant tool to study neural dynamics and to develop brain-machine interfaces (BMI) for rehabilitation of patients with paralysis due to stroke. However, the EEG is easily contaminated by artifacts of physiological origin, which can pollute the measured cortical activity and bias the interpretations of such data. This is especially relevant when recording EEG of stroke patients while they try to move their paretic limbs, since they generate more artifacts due to compensatory activity. In this paper, we study how physiological artifacts (i.e., eye movements, motion artifacts, muscle artifacts and compensatory movements with the other limb) can affect EEG activity of stroke patients. Data from 31 severely paralyzed stroke patients performing/attempting grasping movements with their healthy/paralyzed hand were analyzed offline. We estimated the cortical activation as the event-related desynchronization (ERD) of sensorimotor rhythms and used it to detect the movements with a pseudo-online simulated BMI. Automated state-of-the-art methods (linear regression to remove ocular contaminations and statistical thresholding to reject the other types of artifacts) were used to minimize the influence of artifacts. The effect of artifact reduction was quantified in terms of ERD and BMI performance. The results reveal a significant contamination affecting the EEG, being involuntary muscle activity the main source of artifacts. Artifact reduction helped extracting the oscillatory signatures of motor tasks, isolating relevant information from noise and revealing a more prominent ERD activity. Lower BMI performances were obtained when artifacts were eliminated from the training datasets. This suggests that artifacts produce an optimistic bias that improves theoretical accuracy but may result in a poor link between task-related oscillatory activity and BMI peripheral feedback. With a clinically relevant dataset of stroke patients, we evidence the need of appropriate methodologies to remove artifacts from EEG datasets to obtain accurate estimations of the motor brain activity.This study was funded by the fortüne-Program of the University of Tübingen (2422-0-1 and 2452-0-0), the Bundesministerium für Bildung und Forschung BMBF MOTORBIC (FKZ 13GW0053) and AMORSA (FKZ 16SV7754), the Deutsche Forschungsgemeinschaft (DFG), the Basque Government Science Program (EXOTEK: KK 2016/00083). The work of A. Insausti-Delgado was supported by the Basque Government's scholarship for predoctoral students

Dollar Spot Fungus \u3ci\u3eSclerotinla homoeocarpa\u3c/i\u3e Produces Oxalic Acid

Dollar spot, caused by Sclerotinia homoeocarpa,. is one of the most devastating diseases of turfgrass worldwide. Many fungi belonging to the genus Sclerotinia produce oxalic acid along with pectolytic cell wall-degrading enzymes. A series of in vitro experiments showed the relationships among temperature, pH, mycelial growth and acid production. Mycelial growth and acid production were most abundant when S. homoeocarpa was grown between 20 and 30°C. Acid production by S. homoeocarpa appeared to be dependent upon the pH of the environment in which it was grown. High performance liquid chromatography analysis of spent broth revealed the presence of oxalic acid. Thus, as reported in other species of Sclerotinia, oxalic acid is produced by S. homoeocarpa. This is the first published report describing the production of oxalic acid by S. homoeocarpa

Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis

AbstractPancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers due to its aggressive and metastatic nature. PDA is characterized by a rich tumor stroma with abundant macrophages, fibroblasts and collagen deposition that can represent up to 90% of the tumor mass. Activation of the tyrosine kinase receptor AXL and expression of its ligand growth arrest-specific protein 6 (Gas6) correlate with a poor prognosis and increased metastasis in pancreatic cancer patients. Gas6 is a multifunctional protein that can be secreted by several cell types and regulates multiple processes, including cancer cell plasticity, angiogenesis and immune cell functions. However, the role of Gas6 in pancreatic cancer metastasis has not been fully investigated. In these studies we find that, in pancreatic tumors, Gas6 is mainly produced by tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) and that pharmacological blockade of Gas6 partially reverses epithelial-to-mesenchymal transition (EMT) of tumor cells and supports NK cell activation, thereby inhibiting pancreatic cancer metastasis. Our data suggest that Gas6 simultaneously acts on both the tumor cells and the NK cells to support pancreatic cancer metastasis. This study supports the rationale for targeting Gas6 in pancreatic cancer and use NK cells as a potential biomarker for response to anti-Gas6 therapy.</jats:p

Blockade of Stromal Gas6 Alters Cancer Cell Plasticity, Activates NK Cells, and Inhibits Pancreatic Cancer Metastasis.

Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers due to its aggressive and metastatic nature. PDA is characterized by a rich tumor stroma with abundant macrophages, fibroblasts, and collagen deposition that can represent up to 90% of the tumor mass. Activation of the tyrosine kinase receptor AXL and expression of its ligand growth arrest-specific protein 6 (Gas6) correlate with a poor prognosis and increased metastasis in pancreatic cancer patients. Gas6 is a multifunctional protein that can be secreted by several cell types and regulates multiple processes, including cancer cell plasticity, angiogenesis, and immune cell functions. However, the role of Gas6 in pancreatic cancer metastasis has not been fully investigated. In these studies we find that, in pancreatic tumors, Gas6 is mainly produced by tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) and that pharmacological blockade of Gas6 signaling partially reverses epithelial-to-mesenchymal transition (EMT) of tumor cells and supports NK cell activation, thereby inhibiting pancreatic cancer metastasis. Our data suggest that Gas6 simultaneously acts on both the tumor cells and the NK cells to support pancreatic cancer metastasis. This study supports the rationale for targeting Gas6 in pancreatic cancer and use of NK cells as a potential biomarker for response to anti-Gas6 therapy

Improving efficacy of interleukin-12-transfected dendritic cells injected into murine colon cancer with anti-CD137 monoclonal antibodies and alloantigens

Intralesional administration of cultured dendritic cells (DCs) engineered to produce IL-12 by in vitro infection with recombinant adenovirus frequently displays eradicating efficacy against established subcutaneous tumors derived from the CT26 murine colon carcinoma cell line. The elicited response is mainly mediated by cytolytic T lymphocytes. In order to search for strategies that would enhance the efficacy of the therapeutic procedure against less immunogenic tumors, we moved onto malignancies derived from the inoculation of MC38 colon cancer cells that are less prone to undergo complete regression upon a single intratumoral injection of IL-12-secreting DCs. In this model, we found that repeated injections of such DCs, as opposed to a single injection, achieved better efficacy against both the injected and a distantly implanted tumor; that the use of semiallogeneic DCs that are mismatched in one MHC haplotype with the tumor host showed slightly better efficacy; and that the combination of this treatment with systemic injections of immunostimulatory anti-CD137 (4-1BB) monoclonal antibody achieved potent combined effects that correlated with the antitumor immune response measured in IFN-gamma ELISPOT assays. The elicited systemic immune response eradicates concomitant untreated lesions in most cases. Curative efficacy was also found against some tumors established for 2 weeks when these strategies were used in combination. These are preclinical pieces of evidence to be considered in order to enhance the therapeutic benefit of a strategy that is currently being tested in clinical trials. Supplementary Material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html