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This study explores the potential of natural bioactive peptides from animal venoms as targeted anti-cancer agents with reduced toxicity. Initially, we screened a broad collection of animal venoms for their antiproliferative activity against cancer cell lines. From this collection, we selected venoms from Naja anchietae and Naja senegalensis due to their promising activity. Utilizing reverse- phase high-performance liquid chromatography (RP HPLC), mass spectrometry (MALDI-TOF MS and MALDI-TOF TOF MSMS), and Edman degradation sequencing, we isolated and characterized three peptides named CTNanc1, CTNanc2, and CTNanc3 from Naja anchietae , and three others named CTNsen1, CTNsen2, and CTNsen3 from Naja senegalensis , each with a molecular weight of around 7 kDa. These purified peptides demonstrated inhibition of U87 glioblastoma cell proliferation, but not of U251 and T98G cells, in cell viability assays. To assess the impact of these treatments on cell viability, apoptosis, and necrosis, flow cytometry assays were conducted on U87 cells at 72 h. The results showed a decrease in cell viability and an increase in dead cells, suggesting that the treatments not only promote apoptosis, but may also lead to increased necrosis or late-stage apoptosis as the exposure time increases. These findings suggest that these peptides could be developed as leads for cancer therapy.

Objectives: To identify the diagnostic performance of clinical and radiological signs (on voiding cystourethrography [VCUG]) to detect posterior urethral valves (PUV) in the post-neonatal period., Materials and Methods: One hundred eighteen males (median age = 0.8 years, range = 1 month-14 years, 48 toilet-trained) undergoing VCUG in a 2-year period were prospectively enrolled. Direct (dilated posterior urethra) and indirect (hypertrophied bladder neck, musculus interuretericus hypertrophy, and trabeculated appearance of the bladder wall) PUV signs on VCUG were assessed. Uroflowmetry was defined pathological by patterns suggesting infravesical obstruction., Results: Twenty-two patients with direct, 28 with indirect PUV signs on VCUG, and one with normal VCUG but persisting micturition symptoms with pathological uroflowmetry underwent urethrocystoscopy and in 43/51 a PUV diagnosis was made (n = 22, 51.2%, with direct PUV signs). In 8/28 patients with indirect signs, PUV were not confirmed. Among non-toilet-trained patients, none of the clinical signs/symptoms was associated with PUV while among toilet-trained patients only pathological uroflowmetry (odds ratio, OR = 4.0 [95% confidence interval:1.2-13.2; p = 0.02]) and pathological uroflowmetry with history of urinary tract infection (OR = infinity) were significantly associated with PUV. Significant associations with PUV of direct and indirect signs on VCUG were found both in toilet-trained and non-toilet trained patients. Direct PUV sign had 100% specificity and sensitivity while indirect PUV signs showed sensitivity = 58.1% and specificity = 89.3%. The absence of any radiological sign had a negative predictive value = 98.5%., Conclusion: Only half of patients with endoscopy-confirmed PUV presents with direct sign of PUV on VCUG. Accounting for indirect PUV signs on VCUG and pathological uroflowmetry (in toilet-trained children) could improve the PUV detection rate., Clinical Relevance Statement: Indirect radiological PUV signs should be valorized when interpreting VCUG to improve the PUV detection rate. The absence of any radiological PUV (direct and indirect) sign on VCUG excludes PUV with a very high negative predictive value., Key Points: • Worldwide agreement is that a non-dilated urethra on voiding cystourethrography excludes obstruction. • Half of patients with posterior urethral valves have non-dilated urethra on voiding cystourethrography. • Accounting for indirect signs of posterior urethral valves on voiding cystourethrography improves the diagnostic performance., (© 2023. The Author(s).)

Krippendorff's Alpha is a measure for assessing inter-rater reliability, facilitating triangulated evaluations among multiple raters. Indeed, Krippendorff's Alpha is key in validating the dependability of human assessments, thereby reinforcing the robustness of human-based choices in contexts where interpretive variability could otherwise undermine the research outcomes. Despite its versatility across various data types, the procedure for computing this coefficient might limit its applicability for researchers unfamiliar with specialised statistical software. Addressing this issue, this paper introduces the "K-Alpha Calculator"-Krippendorff's Alpha Calculator-a freely accessible, user-friendly, web application available at https://www.k-alpha.org designed for easy computation of Krippendorff's Alpha. By offering a web interface without any software dependency, the K-Alpha Calculator seeks to promote the broader integration of such a reliability metric in research processes. We envisage that the tool's contribution could support researchers in enhancing methodological rigour, fostering conclusions are rooted in triangulated interpretations and assessments. The K-Alpha Calculator is both a computational tool and an educational resource, encouraging more researchers to include reliability measures in their studies.•Development of the K-Alpha Calculator.The study centres on the introduction of a web-based application: the K-Alpha Calculator. The tool is developed to simplify the calculation of Krippendorff's Alpha without any required software dependency.•User-friendly interface for diverse data types.The K-Alpha Calculator is characterised by its accessibility and user-friendliness, designed to simplify the procedures for computing the Krippendorff's Alpha. Its utility extends to various data types, which aligns with the intrinsic versatility of this coefficient., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC). Stromal syntenin deficiency, in turn, generates a pro-tumoral microenvironment. From serial transplantations in mice and co-culture experiments, we conclude that syntenin-deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro-tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML-stroma crosstalk and unsuspected tumor-suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

This article proposes the Shiny app 'CLC Estimator' -Congeneric Latent Construct Estimator- to address the problem of estimating latent unidimensional constructs via congeneric approaches. While congeneric approaches provide more rigorous results than suboptimal parallel-based scoring methods, most statistical packages do not provide easy access to congeneric approaches. To address this issue, the CLC Estimator allows social scientists to use congeneric approaches to estimate latent unidimensional constructs smoothly. The present app provides a novel solution to the challenge of limited access to congeneric estimation methods in survey research.

B-cell acute lymphoblastic leukemia (B-ALL) reflects the malignant counterpart of developing B cells in the bone marrow (BM). Despite tremendous progress in B-ALL treatment, the overall survival of adults at diagnosis and patients at all ages after relapse remains poor. Galectin-1 (GAL1) expressed by BM supportive niches delivers proliferation signals to normal pre-B cells through interaction with the pre-B cell receptor (pre-BCR). Here, we asked whether GAL1 gives non-cell autonomous signals to pre-BCR + pre-B ALL, in addition to cell-autonomous signals linked to genetic alterations. In syngeneic and patient-derived xenograft (PDX) murine models, murine and human pre-B ALL development is influenced by GAL1 produced by BM niches through pre-BCR-dependent signals, similarly to normal pre-B cells. Furthermore, targeting pre-BCR signaling together with cell-autonomous oncogenic pathways in pre-B ALL PDX improved treatment response. Our results show that non-cell autonomous signals transmitted by BM niches represent promising targets to improve B-ALL patient survival., Competing Interests: The authors declare no competing financial interests., (© 2023 The Author(s).)

Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation in vitro as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation in vitro , suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bou-Tayeh, Laletin, Salem, Just-Landi, Fares, Leblanc, Balzano, Kerdiles, Bidaut, Hérault, Olive, Aurrand-Lions, Walzer, Nunès and Fauriat.)

Exosomal transfers represent an important mode of intercellular communication. Syntenin is a small scaffold protein that, when binding ALIX, can direct endocytosed syndecans and syndecan cargo to budding endosomal membranes, supporting the formation of intraluminal vesicles that compose the source of a major class of exosomes. Syntenin, however, can also support the recycling of these same components to the cell surface. Here, by studying mice and cells with syntenin-knock out, we identify syntenin as part of dedicated machinery that integrates both the production and the uptake of secreted vesicles, supporting viral/exosomal exchanges. This study significantly extends the emerging role of heparan sulfate proteoglycans and syntenin as key components for macromolecular cargo internalization into cells.

Grasp55 is a ubiquitous Golgi stacking protein involved in autophagy, protein trafficking, and glucose deprivation sensing. The function of Grasp55 in protein trafficking has been attributed to its PDZ-mediated interaction with the C-terminal PDZ-binding motifs of protein cargos. We have recently shown that such an interaction occurs between Grasp55 and the adhesion molecule Jam-C, which plays a central role in stemness maintenance of hematopoietic and spermatogenic cells. Accordingly, we have found that Grasp55 -deficient mice suffer from spermatogenesis defects similar to Jam-C knockout mice. However, whether Grasp55 is involved in the maintenance of immunohematopoietic homeostasis through regulation of protein transport and Jam-C expression remains unknown. In this study, we show that Grasp55 deficiency does not affect hematopoietic stem cell differentiation, engraftment, or mobilization, which are known to depend on expression of Grasp55-dependent protein cargos. In contrast, using an Myc-dependent leukemic model addicted to autophagy, we show that knockdown of Grasp55 in leukemic cells reduces spleen and bone marrow tumor burden upon i.v. leukemic engraftment. This is not due to reduced homing of Grasp55-deficient cells to these organs but to increased spontaneous apoptosis of Grasp55-deficient leukemic cells correlated with increased sensitivity of the cells to glucose deprivation. These results show that Grasp55 plays a role in Myc-transformed hematopoietic cells but not in normal hematopoietic cells in vivo., (Copyright © 2020 by The American Association of Immunologists, Inc.)

In the bone marrow, CXCL12 and IL-7 are essential for B cell differentiation, whereas hematopoietic stem cell (HSC) maintenance requires SCF and CXCL12. Peri-sinusoidal stromal (PSS) cells are the main source of IL-7, but their characterization as a pro-B cell niche remains limited. Here, we characterize pro-B cell supporting stromal cells and decipher the interaction network allowing pro-B cell retention. Preferential contacts are found between pro-B cells and PSS cells, which homogeneously express HSC and B cell niche genes. Furthermore, pro-B cells are frequently located in the vicinity of HSCs in the same niche. Using an interactome bioinformatics pipeline, we identify Nidogen-1 as essential for pro-B cell retention in the peri-sinusoidal niche as confirmed in Nidogen-1 -/- mice. Finally, human pro-B cells and hematopoietic progenitors are observed close to similar IL-7 + stromal cells. Thus, a multispecific niche exists in mouse and human supporting both early progenitors and committed hematopoietic lineages., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The phenols and fatty acids profile and in vitro antioxidant and hypoglycaemic activity of seed, peel, pulp or pulp plus seeds of Colombian fruits from Solanaceae and Passifloraceae families were investigated. Ultra-High Performance Liquid Chromatography (UHPLC)-High Resolution Mass Spectrometry (HRMS) revealed the presence of chlorogenic acid as dominant phenolic compound in Solanaceae samples. Based on the Relative Antioxidant Score (RACI) and Global Antioxidant Score (GAS) values, Solanum quitoense peel showed the highest antioxidant potential among Solanaceae samples while Passiflora tripartita fruits exhibited the highest antioxidant effects among Passifloraceae samples. P. ligularis seeds were the most active as hypoglycaemic agent with IC 50 values of 22.6 and 24.8 μg/mL against α-amylase and α-glucosidase, respectively. Considering that some of the most promising results were obtained by the processing waste portion, its use as functional ingredients should be considered for the development of nutraceutical products intended for patients with disturbance of glucose metabolism.

Epidemiological studies have linked high consumption of meat with major age-related diseases including cardiovascular diseases. Abnormal postprandial increases in plasma lipids after a meat meal have been hypothesized among the pathogenetic mechanisms. However, it is still unknown if the postprandial serum derived after a normal meat meal is able to affect endothelial function, and if the type of meat and the age of the donors are critical factors. Here, we show the effects of postprandial sera derived from healthy adults and elderly volunteers who consumed meat meals on human coronary artery endothelial cell (HCAEC) oxidative stress, gene expression, DNA damage, and cellular senescence. We observed that a single exposure to postprandial serum induces a slight increase in ROS that is associated with modulation of gene expression pathways related to oxidative stress response and metabolism. The postprandial-induced increase in ROS is not associated with a measurable DNA oxidative damage. However, repeated exposure to postprandial serum induces an acceleration of cellular senescence. Taking into account the deleterious role of cellular senescence in age-related vascular diseases, the results suggest a new mechanism by which excessive meat consumption and time spent in postprandial state may affect health status during aging.

The composition and structure of triacylglycerols (TAGs) and partial glycerides of crude palm oil obtained from interspecific hybrid Elaeis oleifera×Elaeis guineensis, grown in Colombia, were fully characterised and compared to data obtained by analysing crude African palm oil. Hybridisation appears to substantially modify the biosynthesis of fatty acids (FAs) rather than their assembly in TAGs. In fact, total FAs analysis showed significant differences between these two types of oil, with hybrid palm oil having a higher percentage of oleic acid (54.6 ± 1.0 vs 41.4 ± 0.3), together with a lower saturated fatty acid content (33.5 ± 0.5 vs 47.3 ± 0.1), while the percentage of essential fatty acid, linoleic acid, does not undergo significant changes. Furthermore, 34 TAG types were identified, with no qualitative differences between African and E. guineensis×E. oleifera hybrid palm oil samples. Short and medium chain FAs (8:0, 10:0, 12:0, 14:0) were utilised, together, to build a restricted number of TAG molecular species. Oil samples from the E. guineensis×E. oleifera hybrid showed higher contents of monosaturated TAGs (47.5-51.0% vs 36.7-37.1%) and triunsaturated TAGs (15.5-15.6% vs 5.2-5.4%). The sn-2 position of TAGs in hybrid palm oil was shown to be predominantly esterified with oleic acid (64.7-66.0 mol% vs 55.1-58.2 mol% in African palm oil) with only 10-15% of total palmitic acid and 6-20% of stearic acid acylated in the secondary position. The total amount of diacylglycerols (DAGs) was in agreement with the values of free acidity; DAG types found were in agreement with the representativeness of different TAG species., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The total fatty acid compositions, especially the furan fatty acid (F-acids) profile, from edible muscle (fillet) and organ tissues (brain, eye, ovaries, and testes) of spawning and nonspawning sardine and anchovy were examined. The spawning season had no effect on F-acid profiles of the fillet and all organ tissues, for both fishes. However, differences among the F-acid fraction of the organ tissues were revealed. The F-acid portion was less than 1% of total fatty acid in all samples. Five F-acid congeners were detected in the fillet, eye, and gonads, while the brain contained only four F-acids. Unlike the F-acids, spawning season affected the docosahexaenoic acid (DHA) abundance in fillet and gonads. DHA enrichment occurred in fillets and gonads from spawning sardine and anchovy. The ratio ω3 PUFA/ω6 PUFA decreases between spawning and nonspawning fillets, thus the fillets from spawning fish have higher nutritional value.

Since the price of Arabica is currently more than twice higher than Robusta, a rapid and reliable method for the determination of the roasted coffee blend composition is fundamental for the authentication of commercial blends used for the Italian Espresso coffee. A GC-FID method based on the ratio between the integrated peak areas of kahweol (K) divided by the sum of K and 16-O-methylcafestol (16MCF) was developed. No internal/external standard was used. Moreover, the quantitation of the unsaponifiable compounds is not necessary, as well as the calculation of any response factors. The percentage of Robusta in 34 samples of coffee blends with known composition, and in 48 samples of pure varieties was used to build a cubic polynomial function with R(2)=0.998. The roasting conditions did not affect the results. Considering eight commercial blends (ranging 0-90% Robusta), no significant difference (two-tailed P=0.817) was registered between the claimed and the predicted composition., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The majority of studies demonstrating the diagnostic potential of three-dimensional (3-D) echocardiography have been conducted on selected series of patients in research laboratories., Aim: To investigate the feasibility and usefulness of real-time 3-D transthoracic echocardiography in daily routine practice., Methods: Two hundred consecutive patients underwent standard two-dimensional (2-D) transthoracic echocardiography (TTE) and real-time (RT) 3-D TTE with a commercially available ultrasound system (Sonos 7500 LIVE 3D, Philips Medical Systems). The quality of 3-D acquisitions and post-processed images was graded as: bad, satisfactory, good and demo. In each case, the results of 3-D TTE were compared with 2-D images to disclose additional qualitative information provided by 3-D examination. An additional qualitative information score was given for each cardiac structure., Results: The mean time of the 3-D examination was 11+/-4 min. The mean time of 2-D transthoracic studies in our laboratory is 25 min and the total time in this series was therefore approximately 36 min. The mean number of acquisitions in our series was 11.5 per patient. The quality was evaluated as bad/insufficient in 7.0%, satisfactory/sufficient in 29.6%, good in 40.2% and demo in 23.2% of all datasets and reconstructions. The structures with greater additional qualitative information scores comprise the anterior and posterior mitralic leaflets, antero-lateral and postero-medial papillary muscles and leaflets of tricuspid valve. The intra- and interobserver reproducibility of quality grading was good and there are few interobserver discrepancies, which were resolved by two physicians, experienced in 3-D echocardiography, not involved in the study., Conclusions: RT 3-D TTE may be used in clinical settings with high feasibility rate and may provide additional, clinically quite relevant qualitative information. This technique may expand the abilities of non-invasive cardiology and open new doors for the evaluation of cardiac disease.