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In the gut, secretory immunoglobulin A is the predominant humoral response against commensals, although healthy hosts also produce microbiota-specific IgG antibodies. During intestinal inflammation, the content of IgG in the lumen increases along with the proportion of commensal bacteria coated with this antibody, suggesting signalling through the IgG-CD64 axis in the pathogenesis of inflammatory bowel diseases. In this work, we evaluated day by day the frequency of faecal bacteria coated with IgA and IgG during the development of DSS colitis. We studied the phenotype and phagocytic activity of F4/80

One of the most striking features of human cognition is the capacity to plan. Two aspects of human planning stand out: its efficiency and flexibility. Efficiency is especially impressive because plans must often be made in complex environments, and yet people successfully plan solutions to myriad everyday problems despite having limited cognitive resources. Standard accounts in psychology, economics, and artificial intelligence have suggested human planning succeeds because people have a complete representation of a task and then use heuristics to plan future actions in that representation. However, this approach generally assumes that task representations are fixed. Here, we propose that task representations can be controlled and that such control provides opportunities to quickly simplify problems and more easily reason about them. We propose a computational account of this simplification process and, in a series of pre-registered behavioral experiments, show that it is subject to online cognitive control and that people optimally balance the complexity of a task representation and its utility for planning and acting. These results demonstrate how strategically perceiving and conceiving problems facilitates the effective use of limited cognitive resources., 56 pages, 5 main figures, 10 extended data figures, supplementary information is included in ancillary files

An inhibitor of the pleckstrin homology domain of CNK1 selectively blocks the growth of mutant KRAS cells and tumors Supplemental Information

Cnk1 (connector enhancer of kinase suppressor of Ras 1) is a pleckstrin homology (PH) domain–containing scaffold protein that increases the efficiency of Ras signaling pathways, imparting efficiency and specificity to the response of cell proliferation, survival, and migration. Mutated KRAS (mut-KRAS) is the most common proto-oncogenic event, occurring in approximately 25% of human cancers and has no effective treatment. In this study, we show that selective inhibition of Cnk1 blocks growth and Raf/Mek/Erk, Rho and RalA/B signaling in mut-KRAS lung and colon cancer cells with little effect on wild-type (wt)-KRAS cells. Cnk1 inhibition decreased anchorage-independent mut-KRas cell growth more so than growth on plastic, without the partial "addiction" to mut-KRAS seen on plastic. The PH domain of Cnk1 bound with greater affinity to PtdIns(4,5)P2 than PtdIns(3,4,5)P3, and Cnk1 localized to areas of the plasma membranes rich in PtdIns, suggesting a role for the PH domain in the biological activity of Cnk1. Through molecular modeling and structural modification, we identified a compound PHT-7.3 that bound selectively to the PH domain of Cnk1, preventing plasma membrane colocalization with mut-KRas. PHT-7.3 inhibited mut-KRas, but not wild-type KRas cancer cell and tumor growth and signaling. Thus, the PH domain of Cnk1 is a druggable target whose inhibition selectively blocks mutant KRas activation, making Cnk1 an attractive therapeutic target in patients with mut-KRAS–driven cancer.Significance:These findings identify a therapeutic strategy to selectively block oncogenic KRas activity through the PH domain of Cnk1, which reduces its cell membrane binding, decreasing the efficiency of Ras signaling and tumor growth.

Numerous studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in chemoprevention or treatment of cancer. Nevertheless, the mechanisms underlying these antineoplastic effects remain poorly understood. Here, we report that induction of the cancer-specific proapoptotic cytokine melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) by several NSAIDs is an essential step for induction of apoptosis and G2-M growth arrest in cancer cells in vitro and inhibition of tumor growth in vivo. We also show that MDA-7/IL-24–dependent up-regulation of growth arrest and DNA damage inducible 45 α (GADD45α) and GADD45γ gene expression is sufficient for cancer cell apoptosis via c-Jun NH2-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of GADD45α and GADD45γ transcription by small interfering RNA abrogates apoptosis and growth arrest induction by the NSAID treatment, blocks JNK activation, and restores Cdc2-cyclin B kinase activity. Our results establish MDA-7/IL-24 and GADD45α and GADD45γ as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells. (Cancer Res 2006; 66(24): 11922-31)

Supplementary Figures 1-3 from Coordination of Centrosome Homeostasis and DNA Repair Is Intact in MCF-7 and Disrupted in MDA-MB 231 Breast Cancer Cells

The epithelium-specific Ets transcription factor, PDEF, plays a role in prostate and breast cancer, although its precise function has not been established. In prostate cancer, PDEF is involved in regulating prostate-specific antigen expression via interaction with the androgen receptor and NKX3.1, and down-regulation of PDEF by antiproliferative agents has been associated with reduced PDEF expression. We now report that reduced expression of PDEF leads to a morphologic change, increased migration and invasiveness in prostate cancer cells, reminiscent of transforming growth factor β (TGFβ) function and epithelial-to-mesenchymal transition. Indeed, inhibition of PDEF expression triggers a transcriptional program of genes involved in the TGFβ pathway, migration, invasion, adhesion, and epithelial dedifferentiation. Our results establish PDEF as a critical regulator of genes involved in cell motility, invasion, and adhesion of prostate cancer cells. [Cancer Res 2007;67(9):4219–26]

Supplementary Methods, Figures 1-7, Table 1 from A Novel Pathway Involving Melanoma Differentiation Associated Gene-7/Interleukin-24 Mediates Nonsteroidal Anti-inflammatory Drug–Induced Apoptosis and Growth Arrest of Cancer Cells

Supplementary Text from Reduced PDEF Expression Increases Invasion and Expression of Mesenchymal Genes in Prostate Cancer Cells

The highly infective coronavirus disease 19 (COVID-19) is caused by a novel strain of coronaviruses – the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – discovered in December 2019 in the city of Wuhan (Hubei Province, China). Remarkably, COVID-19 has rapidly spread across all continents and turned into a public health emergency, which was ultimately declared as a pandemic by the World Health Organization (WHO) in early 2020. SARS-CoV-2 presents similar aspects to other members of the coronavirus family, mainly regarding its genome, protein structure and intracellular mechanisms, that may translate into mild (or even asymptomatic) to severe infectious conditions. Although the mechanistic features underlying the COVID-19 progression have not been fully clarified, current evidence have suggested that SARS-CoV-2 may primarily behave as other β-coronavirus members. To better understand the development and transmission of COVID-19, unveiling the signaling pathways that may be impacted by SARS-CoV-2 infection, at the molecular and cellular levels, is of crucial importance. In this review, we present the main aspects related to the origin, classification, etiology and clinical impact of SARS-CoV-2. Specifically, here we describe the potential mechanisms of cellular interaction and signaling pathways, elicited by functional receptors, in major targeted tissues/organs from the respiratory, gastrointestinal (GI), cardiovascular, renal, and nervous systems. Furthermore, the potential involvement of these signaling pathways in evoking the onset and progression of COVID-19 symptoms in these organ systems are presently discussed. A brief description of future perspectives related to potential COVID-19 treatments is also highlighted.

The Autism Spectrum Disorder (ASD) consists of a prevalent and heterogeneous group of neurodevelopmental diseases representing a severe burden to affected individuals and their caretakers. Despite substantial improvement towards understanding of ASD etiology and pathogenesis, as well as increased social awareness and more intensive research, no effective drugs have been successfully developed to resolve the main and most cumbersome ASD symptoms. Hence, finding better treatments, which may act as "disease-modifying" agents, and novel biomarkers for earlier ASD diagnosis and disease stage determination are needed. Diverse mutations of core components and consequent malfunctions of several cell signaling pathways have already been found in ASD by a series of experimental platforms, including genetic associations analyses and studies utilizing pre-clinical animal models and patient samples. These signaling cascades govern a broad range of neurological features such as neuronal development, neurotransmission, metabolism, and homeostasis, as well as immune regulation and inflammation. Here, we review the current knowledge on signaling pathways which are commonly disrupted in ASD and autism-related conditions. As such, we further propose ways to translate these findings into the development of genetic and biochemical clinical tests for early autism detection. Moreover, we highlight some putative druggable targets along these pathways, which, upon further research efforts, may evolve into novel therapeutic interventions for certain ASD conditions. Lastly, we also refer to the crosstalk among these major signaling cascades as well as their putative implications in therapeutics. Based on this collective information, we believe that a timely and accurate modulation of these prominent pathways may shape the neurodevelopment and neuro-immune regulation of homeostatic patterns and, hopefully, rescue some (if not all) ASD phenotypes.

Lymphotoxin β receptor (LTβR) signaling is crucial for lymphoid tissue organogenesis and immune homeostasis. To identify novel regulatory mechanisms for signaling, we implemented a two-step screen that uses co-expression analysis of human fibroblasts undergoing LTβR stimulation and affinity-purification mass spectrometry (AP-MS) for the LTβR signaling protein, TNF receptor-associated factor 3 (TRAF3). We identify Ewing’s sarcoma (EWS) protein as a novel LTβR signaling component that associates with TRAF3, but not with TNF receptor-associated factor 2 (TRAF2). The EWS:TRAF3 complex forms under unligated conditions that is disrupted following activation of the LTβR. We conclude that EWS limits expression of pro-inflammatory molecules, GM-CSF and ERK-2, promoting immune homeostasis. • EWS functions as a modulator downstream of LTβR stimulation. • TRAF3, but not TRAF2, links EWS to receptor activation. • EWS controls inflammatory responses mediated by GM-CSF

In this work, we propose a new scheme of optical feedback using stimulated Brillouin scattering (SBS). A high-power laser diode emitting at 1450 nm stimulates Brillouin back-scattering in a 4km-long optical fibre and the back-scattered light is injected back into the laser diode for optical feedback. The experimental results with RF spectrum exhibit clearly the Brillouin frequency shift at 11.46 GHz. Although the frequency shift is very large, the laser diode subject to optical feedback using SBS shows abundant dynamics. RF spectrum maps are also established with respect to the laser drive current. The results are compared with the ones for conventional optical feedback and it is clearly shown that the dynamical behaviours for both the configurations are very different. The investigation with autocorrelation functions reveals that the time-delay signature vanishes completely using the SBS feedback scheme unlike the conventional feedback one.

The authors would like to thank the patients who participated in the study and their families, friends, caregivers and referring physicians. The authors are very grateful to Drs. Miguel Ángel Perales (Memorial Sloan Kettering Cancer Center, New York), Shannon Maude (Children's Hospital of Philadelphia), Juan José Lasarte (Centro de Investigación Médica Aplicada, Navarra) and Michael Schmitt (Universitäts Klinikum Heidelberg), members of the CART19-BE-01 trial DSMB. The authors are also indebted to the study staff and health care providers at Hospital Clínic, specifically to Anna Boronat, Raquel Martín-Ibáñez, Unai Perpiñá, Josep M. Canals, Vanina Rodríguez, Guillermo Suñé, Esteve Trias and Jordi Yagüe who participated in the development of the CART19 construct; Sara Varea, Judit Pich, Gabriela Recalde, Leticia Pereira and Joan Albert Arnáiz, from the Clinical Trials Unit; Gonzalo Calvo, Andrea Scalise, Joaquín Sáez-Peñataro, Ferran Torres and Sandra Castaño, from the Department of Pharmacology; and Josep Maria Campistol, Antoni Castells, Aurea Mira and Marc Roda as the main representatives from the institution. This study was funded by CatSalut, Projecte ARI and grants co-financed by the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria-and Fondo Europeo de Desarrollo Regional (FEDER) PICI14/122, PI13/676, PIE13/33, PI18/775; and Fundació La Caixa CP042702/LCF/PR/GN18/50310007. VO-M and JD were recipients of research grants from FEHH and Generalitat de Catalunya (PERIS IPFE SLT006/17/301), respectively. CART19 cells are emerging as an alternative therapy for patients with chronic lymphocytic leukemia (CLL). Here we report the outcome of nine consecutive patients with CLL treated with ARI-0001 CART19 cells, six of them with Richter's transformation (RT). One patient with RT never received therapy. The cytokine release syndrome rate was 87.5% (12.5% grade ≥3). Neurotoxicity was not observed in any patient. All patients experienced absolute B-cell aplasia, and seven (87.5%) responded to therapy. With a median follow-up of 5.6 months, two patients with RT experienced a CD19-negative relapse. In conclusion, ARI-0001 cell therapy was feasible, safe, and effective in patients with high-risk CLL or RT.

Simple Summary T-LGLL and CLPD-NK are two indolent lymphoproliferative syndromes whose main symptoms derive from the cytopenia(s). A proportion of patients harbor STAT3 mutations that appear to play an important role in the pathogenesis of the disease. The aim of our retrospective study was to describe the main clinicobiological characteristics, response to therapy and outcome in a large cohort of T-LGLL and CLPD-NK patients diagnosed at a single institution. The impact of STAT3 mutations on the behaviour of the disease and the survival of these patients compared to the age- and sex-matched general population are also evaluated. For the first time, we show that the survival of patients with these two diseases does not differ from that of a matched general Spanish population, confirming the indolent course of these entities. Abstract T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of STAT3 are involved in the pathogenesis of these entities. We describe the clinicobiological features, mutational status of STAT3/STAT5B, treatment and outcome of 131 patients. Neutropenia was the most frequent finding at diagnosis, followed by anemia. Concurrent hematological disorders were diagnosed in 37% of patients and autoimmune conditions and solid tumors in 17% and 15%, respectively. All patients who needed treatment belonged to the CD8+CD57+ group. Remarkably, patients included in the CD4+ group had a higher association with solid tumors (p = 0.037). STAT3 mutations were found in 17% of patients, mainly Y640F and D661Y mutations. Patients carrying STAT3 mutations more frequently presented with anemia, neutropenia, high LDH, high large granular lymphocyte counts and need for treatment (p = 0.0037). Methotrexate was the most frequently used agent (72% of cases). The overall response rate to all treatments was 50%. The 10-year overall survival of this series was 78%, with no differences according to the mutational status of STAT3. We compared the survival of these patients with the general Spanish population and no differences were found, confirming the indolent nature of these hematological malignancies. Our study further extends findings documented by others on the clinical behavior of the disease and the impact of STAT3, and for the first time analyzes survival compared to a matched general Spanish population.

Gentamicin was comparatively encapsulated within silica matrices by sol–gel processes that use a base-catalyzed gelation, base-catalyzed precipitation, or acid-catalyzed gelation route. Acid-catalyzed gelation was chosen to encapsulate several pharmaceuticals (fluoxetine, lidocaine, morphine, nifedipine, paracetamol, and tetracycline). The xerogels were characterized by their carbon content and nitrogen adsorption values. The encapsulated systems had high surface areas ranging from 280 to 650 m2 g−1. Their inhibition of Desmodesmus subspicatus growth was evaluated. The systems with bulkier pharmaceuticals and greater surface areas showed the highest drug-related algal growth inhibition. The encapsulated systems were less toxic to Desmodesmus subspicatus than the free drugs. Silica-encapsulated paracetamol was the xerogel that inhibited algal growth the least, while the encapsulated nifedipine was the most toxic to the algae. Compared with the free drugs, the encapsulated systems were 17–55% less toxic to algae based on the Desmodesmus subspicatus growth inhibition data.

The excessive sun exposure, coupled with lack of sun protection represents one of the biggest risks to the occurrence of skin cancer and photoaging. Recent strategies for photoprotection have included the incorporation of natural antioxidant and anti-inflammatory compounds, into sunscreens, and the oral administration of natural antioxidant extracts. In this work, we use Brazilian red propolis extract because its antioxidant and anti-inflammatory activities. The aim of this work was to evaluate the sun protection factor and antioxidant activity of different hydroalcoholic extracts of red propolis (70% and 75%) prepared from lyophilized red propolis at room and high temperatures. The sun protection factor in vitro was determined by a spectrophotometric method developed by Mansur. The hydroalcoholic extracts of red propolis incorporated with Filter UVA-UVB 5% Gel Permulem TR-1 presented absorption in the UVB region. Also, the in vitro capacity of the hydroalcoholic extracts of red propolis to increase photoprotective activity of Filter UVA-UVB 5% Gel was evaluated. The hydroalcoholic extracts of red propolis incorporated presented higher values of sun protection factor and showed synergism in the photoprotective activity of Filter UVA-UVB 5% Gel Permulem TR-1. The antioxidant activity and sun protection factor are correlated with total phenolics content of the extracts and the hydroalcoholic extract of red propolis 75% at room temperature was choosen. The formulation developed with Filter UVA-UVB 5% Gel Permulem TR-1 with this hydroalcoholic extract of red propolis showed safe to be applied on the skin according HET-CAM test. Suggests indication of hydroalcoholic extract of red propolis (75% – room temperature) associated to photoprotective formulations for use in photoprotective products. Keywords: Sun protection factor, Red propolis, Filter UVA-UVB, Total phenolics, HET-CAM test, Antioxidant activity

The Parent Attitudes about Childhood Vaccines (PACV) survey is a validated instrument for identifying vaccine-hesitant parents; however, a Spanish version is not available. Utilizing the WHO framework for translating survey instruments, we used an iterative process for developing the Spanish PACV that included forward translation, expert panel review, back translation and pre-testing that utilized cognitive interviewing. We made revisions to the Spanish PACV at each step, focusing on addressing inclusivity, readability, clarity and conceptual equivalence. The expert panel was comprised of 6 Spanish-speaking medical and research professionals who worked alongside 3 study team members. Pre-testing was conducted using convenience sampling of Spanish-speaking parents (N = 35) who had a child receiving care at the residents’ continuity clinic at Texas Children’s Hospital. Most pre-testing participants were married (80.6%), mothers (97.1%), ≥30 years of age (88.2%) and had a high school education or less (70.6%). While the majority of participants stated the survey was easy to complete, the translation of 5 PACV items was further revised to improve interpretability. We conclude that the final Spanish PACV is conceptually equivalent and culturally appropriate for most Hispanic populations.

Introduction To address the need for non-pharmacologic, scalable approaches for managing attention-deficit and hyperactivity disorder (ADHD) in young people, we report the results of a study of an application developed for a wearable device (Apple Watch) that was designed to track movement and provide visual and haptic feedback for ADHD. Methods Six-week, open label pilot study with structured rating scales ADHD and semi-structured qualitative interview. Apple Watch software application given to users that uses actigraphy and graphic interface as well as haptic feedback to provide feedback to users about level of movement during periods of intentional focus. Linear mixed models to estimate trajectories. Results Thirty-two participants entered the study. This application was associated with improvement in ADHD symptoms over the 6 weeks of the study. We observed an ADHD-Rating Scale change of β = −1.2 units/week (95% CI = −0.56 to −1.88, F = 13.4, P = .0004). Conclusions These positive clinical outcomes highlight the promise of such wearable applications for ADHD and the need to pursue their further development.

One of the most striking features of human cognition is the ability to plan. Two aspects of human planning stand out-its efficiency and flexibility. Efficiency is especially impressive because plans must often be made in complex environments, and yet people successfully plan solutions to many everyday problems despite having limited cognitive resources

We prove a tight and close-to-optimal lower bound on the effectiveness of local quantum measurements (without classical communication) at discriminating any two bipartite quantum states. Our result implies, for example, that any two orthogonal quantum states of a $n_A\times n_B$ bipartite quantum system can be discriminated via local measurements with an error probability no larger than $\frac12 \left(1 - \frac{1}{c \min\{n_A, n_B\}} \right)$, where $1\leq c\leq 2\sqrt2$ is a universal constant, and our bound scales provably optimally with the local dimensions $n_A,n_B$. Mathematically, this is achieved by showing that the distinguishability norm $\|\cdot\|_{LO}$ associated with local measurements satisfies that $\|\cdot\|_1\leq 2\sqrt2 \min\{n_A,n_B\} \|\cdot\|_{LO}$, where $\|\cdot\|_1$ is the trace norm.

This paper proposes and demonstrates the use of filtered microwave band-pass windows situated at 2.1 GHz and 4.2 GHz as electrical carriers to transmit digital signals. The use of an appropriate microwave photonic filter (MPF) allows for the generation of the microwave band-pass windows. The key parameters of the filtering effect are the intermodal separation of a multimode laser diode (MLD), the chromatic dispersion parameter of the optical link, and its own length. Experimentally, it is demonstrated that the filtered band-pass windows can be used as electrical carriers to transmit digital signals at frequencies of 50 MHz, 100 MHz, and 150 MHz over 25.31 km of single-mode-standard-fiber (SM-SF). The quality Q-factor, jitter, and bit-error-rate are the parameters that allow for the evaluation of the quality of the digital signal transmission. The obtained results allow for the proposition of this photonic architecture in a passive optical network (PON) to distribute services like Internet Protocol (IP) telephony, internet, streaming video, and high definition television.

BackgroundThe travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.MethodsA cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries.ResultsCapture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI −12.4 to −5.4, pConclusionsFewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.

T cells play an essential role in the immune response against the human respiratory syncytial virus (hRSV). It has been described that both CD4+ and CD8+ T cells can contribute to the clearance of the virus during an infection. However, for some individuals, such an immune response can lead to an exacerbated and detrimental inflammatory response with high recruitment of neutrophils to the lungs. The receptor of most T cells is a heterodimer consisting of α and β chains (αβTCR) that upon antigen engagement induces the activation of these cells. The αβTCR molecule displays a broad sequence diversity that defines the T cell repertoire of an individual. In our laboratory, a recombinant Bacille Calmette–Guérin (BCG) vaccine expressing the nucleoprotein (N) of hRSV (rBCG-N-hRSV) was developed. Such a vaccine induces T cells with a Th1 polarized phenotype that promote the clearance of hRSV infection without causing inflammatory lung damage. Importantly, as part of this work, the T cell receptor (TCR) repertoire of T cells expanded after hRSV infection in naïve and rBCG-N-hRSV-immunized mice was characterized. A more diverse TCR repertoire was observed in the lungs from rBCG-N-hRSV-immunized as compared to unimmunized hRSV-infected mice, suggesting that vaccination with the recombinant rBCG-N-hRSV vaccine triggers the expansion of T cell populations that recognize more viral epitopes. Furthermore, differential expansion of certain TCRVβ chains was found for hRSV infection (TCRVβ+8.3 and TCRVβ+5.1,5.2) as compared to rBCG-N-hRSV vaccination (TCRVβ+11 and TCRVβ+12). Our findings contribute to better understanding the T cell response during hRSV infection, as well as the functioning of a vaccine that induces a protective T cell immunity against this virus.

BACKGROUND: . Intravitreal administration of topotecan shows activity against tumor vitreous seeding in the conservative treatment of retinoblastoma, a malignant tumor originated in the retina of small children. Adequate storage of the intravitreal topotecan solution would allow immediate availability for patients at health care institutions. The goal of the work was to address the stability of the intravitreal topotecan formulation upon reconstitution. MATERIALS AND METHODS: . Intravitreal topotecan solutions were reconstituted (at a concentration of 0.2 mg topotecan in 1 mL saline solution vehicle, aliquoted in 1 mL plastic syringes) and stored either frozen or at room temperature for different times. Topotecan content was analyzed at time zero and at different conditions using a high performance liquid chromatography method to quantify topotecan lactone (active) and to detect its pH-dependent hydrolysis product, the open carboxylate. RESULTS: . We found that intravitreal topotecan syringes remained stable at room temperature at least for 24 h, at least for 167 days upon stored frozen at -20°C, and up to 8 h after thawing at day 6. The degradation carboxylate product did not appear in the analyzed thawed samples during the whole study. CONCLUSIONS: . This study confirms the stability of frozen intravitreal topotecan syringes and will help optimize the use of this chemotherapy modality at institutions with low resources. Storage of aliquots will also help reduce personnel exposure to chemotherapy at hospital pharmacies.

We study numerically the appearance and number of axial vortices in the outlets of X-shaped junctions of two perpendicular channels of rectangular sections with facing inlets. We explore the effect of the aspect ratio of the cross section, AR, on the number of vortices created at the center of the junction. Direct numerical simulations (DNSs) performed for different values of the Reynolds number Re and AR demonstrate that vortices with their axis parallel to the outlets, referred to as axial vortices, appear above critical Reynolds numbers Rec. As AR increases from 1 to 11, the number of vortices observed increases from 1 to 4, independently of Re. For AR = 1, the single axial vortex induces an interpenetration of the inlet fluids in the whole section; instead, for larger AR's for which more vortices appear, the two inlet fluids remain largely segregated in bands, except close to the vortices. The linear stability analysis demonstrates that only one leading eigenmode is unstable for a given set of values of AR and Re. This mode provides a simplified model of the flow field, reproducing its key features such as the number of vortices and their distance. Its determination with this method requires a much smaller computational load than the DNS. This approach is shown to allow one to determine quickly and precisely the critical Reynolds number Rec and the sensitivity function S, which characterizes the influence of variations of the base flow on the unstable one. Fil: Correa, Pablo Germán. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. - Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires; Argentina Fil: Gomba, Juan Manuel. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. - Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires; Argentina Fil: Mac Intyre, J.R.. Aalto University; Finlandia Fil: Ubal, Sebastian. Universidad Nacional de Entre Ríos. Instituto de Investigación y Desarrollo en Bioingeniería y Bioinformática - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigación y Desarrollo en Bioingeniería y Bioinformática; Argentina Fil: Perazzo, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: Hulin, J.P.. Centre National de la Recherche Scientifique; Francia Fil: Auradou, H.. Centre National de la Recherche Scientifique; Francia

[EN] Atmospheric freeze-drying (AFD) at -10 degrees C and moderate temperature convective drying (MTD) at 50 degrees C without and with ultrasound application (20.5 kW/m(3)) were carried out. Alcohol insoluble residue (AIR) and its swelling capacity (SC), water retention capacity (WRC) and fat retention capacity (FRC) were measured in the dried product. Ultrasound significantly shortened the drying time in both processes, the intensification effect being more significant in atmospheric freeze-drying (57% and 27% reduction in atmospheric freeze-drying and convective drying, respectively). As regards AIR and WRC, no effect was observed of either the drying temperature or ultrasound application. On the contrary, SC was significantly lower in AFD samples. The FRC of MTD samples was similar to that of the fresh ones and higher than the values obtained for atmospheric freeze-dried samples. Therefore, convective drying at moderate temperature preserved the AIR properties better than atmospheric freeze-drying., The authors acknowledge the financial support of INIA-ERDF through project RTA2015-00060-C04-02. We are also grateful for the economic support of the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (Capes)- Finance Code 001, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Fundacao de Amparo a Pesquisa de Minas Gerais (FAPEMIG).

Breast cancer is the most frequent and lethal neoplastic disease among women worldwide. Psidium Guajava is a promising functional food against cancer, owing to a variety of bioactive compounds. This study aimed to evaluate the anticarcinogenic potential of Pedro Sato (PS), Hitigio (HI) and Tsumori (TS) guava cultivars fruit pulp extracts in MDA-MB-435 and MCF-7 human breast cancer cells. The antioxidant capacity of the extracts and their effect on cell viability, cell cycle and apoptosis were assessed. Additionally, the concentration of carotenoids, total phenolics, ascorbic acid and other physicochemical parameters were evaluated. PS pulp extract showed the highest in vitro antioxidative activity by all tested methods, as well as the highest content of lycopene and total phenolics, while TS pulp extract presented the highest concentration of β-carotene. After 48 hours treatment, all guava cultivars’ extracts caused reduction of MDA-MB-435 and MCF-7 cells viability, with PS and HI being the most effective extracts. All guava extracts caused MDA-MB-435 and MCF-7 cell count reduction in G0/G1 and G2/M phases and increased apoptosis. The present results strongly suggest that guava pulp exerts antiproliferative effect on breast adenocarcinoma cells.

The dopaminergic system plays important roles in neuromodulation, such as motor control, motivation, reward, cognitive function, maternal, and reproductive behaviors. Dopamine is a neurotransmitter, synthesized in both central nervous system and the periphery, that exerts its actions upon binding to G protein-coupled receptors. Dopamine receptors are widely expressed in the body and function in both the peripheral and the central nervous systems. Dopaminergic signaling pathways are crucial to the maintenance of physiological processes and an unbalanced activity may lead to dysfunctions that are related to neurodegenerative diseases. Unveiling the neurobiology and the molecular mechanisms that underlie these illnesses may contribute to the development of new therapies that could promote a better quality of life for patients worldwide. In this review, we summarize the aspects of dopamine as a catecholaminergic neurotransmitter and discuss dopamine signaling pathways elicited through dopamine receptor activation in normal brain function. Furthermore, we describe the potential involvement of these signaling pathways in evoking the onset and progression of some diseases in the nervous system, such as Parkinson's, Schizophrenia, Huntington's, Attention Deficit and Hyperactivity Disorder, and Addiction. A brief description of new dopaminergic drugs recently approved and under development treatments for these ailments is also provided.

Militarization on the US–Mexico border has intensified in America’s post-9/11 War on Terror, while America’s War on Drugs has escalated militarization in America’s urban core. This infusion of military weapons and tactics along the border and within America’s urban core produces devastating effects on communities of color. Yet, to date, few critical race scholars attend to the Wars on Terror and on Drugs as two sides of the same coin. This article serves as a bridge between US–Mexico border studies and critical race studies vis-à-vis a theorization of a thickening military-police assemblage birthed by the War on Drugs, and intensified by the War on Terror. To delineate this assemblage, we respond to two key questions: how and to what degree has the US–Mexico border served as a staging ground for US (para)military and surveillance strategies at home and abroad? and how do discourses on America’s urban core compare and contrast with those on its southern border? We draw upon the cases of Esequiel Hernández, Jr. and Michael Brown, two teenagers whose lives were taken by this assemblage, to frame these questions. Our analysis reveals material, symbolic, and affective links between America’s militarization on the southwest border and within its urban core.

Di(1H-indol-3-yl)(4-trifluoromethylphenyl)methane (DIM-Ph-4-CF3) is an analog of orphan nuclear receptor 4A1 (NR4A1) ligand cytosporone B. We have synthesized several oxidation products of DIM-Ph-4-CF3, focusing on analogs with electron-withdrawing or donating groups at their phenyl ring 4-positions, and examined their anti-cancer activity and mechanism-of-action. Mesylates (DIM-Ph-4-X+ OMs-s) having CF3, CO2Me and Cl groups were more effective inhibitors of cancer cell viability than their precursors. 19F NMR spectroscopy and differential scanning calorimetry strongly indicated interactions of DIM-Ph-4-CF3+ OMs- with the NR4A1 ligand binding domain, and compound-induced apoptosis of prostate cancer cells was dependent on NR4A1. DIM-Ph-4-CF3+ OMs- showed robust inhibition of LNCaP prostate cancer xenografts with no apparent toxicity. In vitro and in vivo, DIM-Ph-4-CF3+ OMs- activated proapoptotic unfolded protein response (UPR) signaling in prostate cancer cells. Independently of DIM-Ph-4-CF3+ OMs-, the bulk of NR4A1 localized to the cytoplasm in various cancer cell lines, suggesting a cytoplasmic mechanism-of-action of DIM-Ph-4-CF3+ OMs- in UPR induction and cell death. In summary, the data suggest that oxidized analogs of DIM-Ph-4-CF3 possess potent and safe anti-cancer activity which is mediated through UPR signaling downstream of NR4A1 binding.

Objective Immune-related pathways have been frequently associated to tumorigenesis. NOD1 and NOD2 are innate immune receptors responsible for sensing a subset of bacterial-derived components, and to further translate these pathogenic signals through pro-inflammatory and survival pathways. NOD1 and NOD2 have been further associated with tumorigenesis, particularly in gastrointestinal cancers. NOD1 has also been suggested to be a tumor suppressor gene in a model of estrogen receptor-dependent breast cancer. Contrarily, NOD2 polymorphisms are associated with higher risk of breast cancer, with no tumor suppressor role being reported. To better delineate this issue, we investigated NOD1 and NOD2 expression in a panel of breast cancer cell lines, as well as their potential impact in breast tumorigenesis based on in vitro assays. Results The highly invasive Hs578T breast cell line presented the second highest NOD1 expression and the lowest NOD2 expression in our panel. Therefore, we investigated whether NOD1 and/or NOD2 might act as a tumor suppressor in this cell model. Our studies indicate that overexpression of either NOD1 or NOD2 reduces cell proliferation and increases clonogenic potential in vitro. Elucidation of NOD1 and NOD2 effects on tumor cell viability and proliferation may unveil potential targets for future therapeutic intervention.

Introduction. Adiponectin and resistin levels are increased in patients with cirrhosis, but it prognostic significance is unknown. We sought to investigate the factors associated with adiponectin and resistin levels and its clinical significance in patients with cirrhosis.Materials and methods. This was a prospective cohort study that included 122 subjects with cirrhosis who attended an outpatient clinic and were initially evaluated in 2012. Serum adiponectin and resistin levels were measured in samples collected in 2012 (adiponectin and resistin) and 2014 (adiponectin). Thirty healthy subjects served as a control group.Results. Higher adiponectin (21.59 μg/mL vs. 12.52 μg/mL, P < 0.001) and resistin levels (3.83 ng/mL vs. 2.66 ng/mL, P < 0.001) were observed among patients with cirrhosis compared to controls. Patients classified as Child-Pugh B/C had higher adiponectin levels in relation to ChildPugh A patients. At second measurement, adiponectin levels increased significantly in non-transplant patients and decreased in liver transplant recipients. Univariate Cox analysis showed that among patients with alcoholic liver disease, adiponectin levels were associated with lower transplant-free survival (HR = 1.034, 95% CI 1.006 - 1.062, P = 0.016). The transplant-free survival was significantly lower among patients with alcoholic liver disease and adiponectin ≥ 17 μg/mL (26.55 months, 95% CI 21.40-31.70) as compared to those with levels < 17 μg/mL (33.76 months, 95% CI 30.70-36.82) (P = 0.045). No relationship was found between the levels of resistin and survival.Conclusion. Adiponectin but not resistin levels were associated with intensity of liver dysfunction and worse prognosis in patients with alcoholic liver disease, suggesting a potential as a prognostic biomarker.