Communication between cells: exosomes as a delivery system in prostate cancer.

Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database (https:// pubmed. ncbi. nlm. nih. gov) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented

Effects of pegylated G-CSF on immune cell number and function in patients with gynecological malignancies

<p>Abstract</p> <p>Background</p> <p>Pegylated granulocyte colony-stimulating factor (G-CSF; pegfilgrastim) is a longer-acting form of G-CSF, whose effects on dendritic cell (DC) and regulatory T cell (Treg) mobilization, and on the <it>in vivo </it>and ex vivo release of immune modulating cytokines remain unexplored.</p> <p>Methods</p> <p>Twelve patients with gynecological cancers received carboplatin/paclitaxel chemotherapy and single-dose pegfilgrastim as prophylaxis of febrile neutropenia. Peripheral blood was collected prior to pegfilgrastim administration (day 0) and on days +7, +11 and +21, to quantify immunoregulatory cytokines and to assess type 1 DC (DC1), type 2 DC (DC2) and Treg cell mobilization. <it>In vitro</it>-differentiated, monocyte-derived DC were used to investigate endocytic activity, expression of DC maturation antigens and ability to activate allogeneic T-cell proliferation.</p> <p>Results</p> <p>Pegfilgrastim increased the frequency of circulating DC1 and DC2 precursors. In contrast, CD4⁺FoxP3⁺<it>bona fide </it>Treg cells were unchanged compared with baseline. Serum levels of hepatocyte growth factor and interleukin (IL)-12p40, but not transforming growth factor-β1 or immune suppressive kynurenines, significantly increased after pegfilgrastim administration. Interestingly, pegfilgrastim fostered <it>in vitro</it> monocytic<it/> secretion of IL-12p40 and IL-12p70 when compared with unconjugated G-CSF. Finally, DC populations differentiated <it>in vitro </it>after clinical provision of pegfilgrastim were phenotypically mature, possessed low endocytic activity, and incited a robust T-cell proliferative response.</p> <p>Conclusions</p> <p>Pegfilgrastim induced significant changes in immune cell number and function. The enhancement of monocytic IL-12 secretion portends favorable implications for pegfilgrastim administration to patients with cancer, a clinical context where the induction of immune deviation would be highly undesirable.</p

Diagnosis and Treatment of Obstructive Hypertrophic Cardiomyopathy

Left ventricular outflow obstruction (LVOTO) and diastolic dysfunction are the main pathophysiological characteristics of hypertrophic cardiomyopathy (HCM)LVOTO, may be identified in more than half of HCM patients and represents an important determinant of symptoms and a predictor of worse prognosis. This review aims to clarify the LVOTO mechanism in, diagnosis of, and therapeutic strategies for patients with obstructive HCM

Thymoglobulin, interferon-γ and interleukin-2 efficiently expand cytokine-induced killer (CIK) cells in clinical-grade cultures

<p>Abstract</p> <p>Background</p> <p>Cytokine-induced killer (CIK) cells are typically differentiated <it>in vitro </it>with interferon (IFN)-γ and αCD3 monoclonal antibodies (mAb), followed by the repeated provision of interleukin (IL)-2. It is presently unknown whether thymoglobulin (TG), a preparation of polyclonal rabbit γ immunoglobulins directed against human thymocytes, can improve the generation efficiency of CIK cells compared with αCD3 mAb in a clinical-grade culture protocol.</p> <p>Methods</p> <p>Peripheral blood mononuclear cells (PBMC) from 10 healthy donors and 4 patients with solid cancer were primed with IFN-γ on day 0 and low (50 ng/ml), intermediate (250 ng/ml) and high (500 ng/ml) concentrations of either αCD3 mAb or TG on day 1, and were fed with IL-2 every 3 days for 21 days. Aliquots of cells were harvested weekly to monitor the expression of representative members of the killer-like immunoglobulin receptor (KIR), NK inhibitory receptor, NK activating receptor and NK triggering receptor families. We also quantified the frequency of <it>bona fide </it>regulatory T cells (Treg), a T-cell subset implicated in the down-regulation of anti-tumor immunity, and tested the <it>in vitro </it>cytotoxic activity of CIK cells against NK-sensitive, chronic myeloid leukaemia K562 cells.</p> <p>Results</p> <p>CIK cells expanded more vigorously in cultures supplemented with intermediate and high concentrations of TG compared with 50 ng/ml αCD3 mAb. TG-driven CIK cells expressed a constellation of NK activating/inhibitory receptors, such as CD158a and CD158b, NKp46, NKG2D and NKG2A/CD94, released high quantities of IL-12p40 and efficiently lysed K562 target cells. Of interest, the frequency of Treg cells was lower at any time-point compared with PBMC cultures nurtured with αCD3 mAb. Cancer patient-derived CIK cells were also expanded after priming with TG, but they expressed lower levels of the NKp46 triggering receptor and NKG2D activating receptor, thus manifesting a reduced ability to lyse K562 cells.</p> <p>Conclusions</p> <p>TG fosters the generation of functional CIK cells with no concomitant expansion of tumor-suppressive Treg cells. The culture conditions described herein should be applicable to cancer-bearing individuals, although the differentiation of fully functional CIK cells may be hindered in patients with advanced malignancies.</p

Highlighting chromosome loops in DNA-picked chromatin (DPC).

"Growing evidence supports the concept that dynamic intra-and inter-chromosomal links between specific loci contribute to the creation of cell type-specific gene expression profiles. Therefore, analysis of the establishment of peculiar functional correlations between sites, also distant on linear DNA, that govern the transcriptional process appears to be of fundamental relevance. We propose here an experimental approach showing that 17 beta-estradiol-induced transcription associates to formation of loops between the promoter and termination regions of hormone-responsive genes. This strategy reveals as a tool to be also suitably used, in conjunction with automated techniques, for an extensive analysis of sites shared by multiple genes for induced expression.

Factors Affecting Patient Compliance during Orthodontic Treatment with Aligners: Motivational Protocol and Psychological Well-Being

Objective:Compliance is critical for successful outcomes in orthodontics, and personality traits may play a role in determining patient adherence. This study aimed to monitor compliance during treatment with removable clear aligners (CA) [Align Technology Inc, San José, Calif ], and evaluate the influence of motivational techniques and the patient’s profiles assessed through the psychological wellbeing (PWB) questionnaire on clinical outcomes.Methods:Thirty-nine consecutive patients in permanent dentition seeking treatment with CA were recruited from two universities. Casts were obtained before treatment and after 3, 6, and 12 months and the corresponding digital Clincheck©.STL files were used to calculate the discrepancy index to check for differences between virtual and real treatment stages. Patients were divided into two groups: the Case group, which received motivational techniques at each appointment, and the control group which received instructions only at the beginning. Psychological profiles were evaluated before treatment (T0) and after 3 (T1), 6 (T2), and 12 (T3) months.Results:There were no differences between the Case and Control groups regarding the use of motivational reminders. The analysis of the PWB showed that almost all values increased, and there was a strong correlation between dental casts and correspondent. STL files at every time point. The PWB showed increased values from T0 to T3 in the sample.Conclusion:Motivational techniques did not affect patient compliance, and treatment outcomes were achieved as planned. The PWB of all patients improved throughout the treatment with CA

RAAD: LIGHT-1 CubeSat's Payload for the Detection of Terrestrial Gamma-Ray Flashes

The Rapid Acquisition Atmospheric Detector (RAAD), onboard the LIGHT-1 3U CubeSat, detects photons between hard X-rays and soft gamma-rays, in order to identify and characterize Terrestrial Gamma Ray Flashes (TGFs). Three detector configurations are tested, making use of Cerium Bromide and Lanthanum BromoChloride scintillating crystals coupled to photomultiplier tubes or Multi-Pixel Photon Counters, in order to identify the optimal combination for TGF detection. High timing resolution, a short trigger window, and the short decay time of its electronics allow RAAD to perform accurate measurements of prompt, transient events. Here we describe the overview of the detection concept, the development of the front-end acquisition electronics, as well as the ground testing and simulation the payload underwent prior to its launch on December 21st, 2021. We further present an analysis of the detector's in-orbit system behavior and some preliminary results.Comment: 19 pages, 15 figure

Role of CD45 Signaling Pathway in Galactoxylomannan-Induced T Cell Damage

Previously, we reported that Galactoxylomannan (GalXM) activates the extrinsic and intrinsic apoptotic pathways through an interaction with the glycoreceptors on T cells. In this study we establish the role of the glycoreceptor CD45 in GalXM-induced T cell apoptosis, using CD45+/+ and CD45−/− cell lines, derived from BW5147 murine T cell lymphoma. Our results show that whereas CD45 expression is not required for GalXM association by the cells, it is essential for apoptosis induction. In CD45+/+ cells, CD45 triggering by GalXM reduces the activation of Lck, ZAP70 and Erk1/2. Conversely, in CD45−/− cells, Lck was hyperphosphorylated and did not show any modulation after GalXM stimulation. On the whole, our findings provide evidence that the negative regulation of Lck activation occurs via CD45 engagement. This appears to be related to the capacity of GalXM to antagonize T cell activation and induce T cell death. Overall this mechanism may be responsible for the immune paralysis that follows GalXM administration and could explain the powerful immunosuppression that accompanies cryptococcosis

The psychological science accelerator’s COVID-19 rapid-response dataset

In response to the COVID-19 pandemic, the Psychological Science Accelerator coordinated three large-scale psychological studies to examine the effects of loss-gain framing, cognitive reappraisals, and autonomy framing manipulations on behavioral intentions and affective measures. The data collected (April to October 2020) included specific measures for each experimental study, a general questionnaire examining health prevention behaviors and COVID-19 experience, geographical and cultural context characterization, and demographic information for each participant. Each participant started the study with the same general questions and then was randomized to complete either one longer experiment or two shorter experiments. Data were provided by 73,223 participants with varying completion rates. Participants completed the survey from 111 geopolitical regions in 44 unique languages/dialects. The anonymized dataset described here is provided in both raw and processed formats to facilitate re-use and further analyses. The dataset offers secondary analytic opportunities to explore coping, framing, and self-determination across a diverse, global sample obtained at the onset of the COVID-19 pandemic, which can be merged with other time-sampled or geographic data