Detailed Phytochemical Composition, Cyto-/Hepatotoxicity, and Antioxidant/Anti-Inflammatory Profile of Moroccan Spices: A Study on Coriander, Caraway, and Mystical Cumin.

Coriander, caraway, and mystical cumin are famous for their aromatic properties and widely used in Moroccan cuisine. The nutritional/phytochemical composition of their seeds (used for food flavoring and preservation) were compared. Their antioxidant, anti-inflammatory, cytotoxic and hepatotoxic effects were also explored. The fat content was similar among the samples (13%), with monounsaturated fatty acids being predominant. The coriander and mystical cumin seeds were extremely rich in C18:1n9c (81 and 85%, respectively) while, in the caraway, C18:1n12 (25%) was found together with C18:1n9c (32%). The caraway seeds also presented a higher proportion of C18:2n6c (34%) than the other seeds (13 and 8%, correspondingly). γ-Tocotrienol was the major vitamin E form in all the samples. The caraway seeds contained double the amount of protein (~18%) compared to the other seeds (~8%) but, qualitatively, the amino acid profiles among all seeds were similar. The seeds were also rich in dietary fiber (40-53%); however, differences were found in their fiber profiles. Caraway showed the highest antioxidant profile and anti-inflammatory activity and an LC-DAD-ESI/MSn analysis revealed great differences in the phenolic profiles of the samples. Cytotoxicity (NCI-H460, AGS, MCF-7, and CaCo2) and hepatotoxicity (RAW 264.7) were not observed. In sum, besides their flavoring/preservation properties, these seeds are also relevant source of bioactive compounds with health-promoting activities.

Blueberry Muffin Syndrome and Hyperleukocytosis in a Newborn: A Diagnostic Challenge.

Blueberry muffin syndrome (BMS) in neonates, characterized by widespread nodular lesions, presents diagnostic challenges due to its diverse etiologies. Hyperleukocytosis, with leukocyte counts exceeding 100,000/µL, is a rare phenomenon associated with severe complications in neonates. Congenital leukemia (CL), a rare diagnosis within the first month of life, is linked to high mortality. This case report presents a unique case of BMS with hyperleukocytosis as the initial presentation of CL. A full-term male newborn, born after an uncomplicated pregnancy, except for Kell isoimmunization, with an Apgar score of 9/10, and an irrelevant family history, showed widespread purple nodules consistent with BMS at birth. Laboratory workup revealed mild anemia, hyperleukocytosis with immature granulocytes on peripheral blood (PB) smear, positive direct antiglobulin test, and elevated alanine aminotransferase and lactate dehydrogenase, without hyperbilirubinemia. Empirical antibiotics and hyperhydration were started, and the neonate was transferred to a level 3 neonatal intensive care unit for further evaluation. A comprehensive etiological investigation was conducted, comprising infectious, immunological, metabolic, and neoplastic factors. A skin nodule biopsy revealed an infiltrate of blast cells, indicative of leukemia cutis, and a bone marrow aspirate confirmed acute myeloid leukemia (AML). The patient successfully completed the NOPHO-DBH-2012 chemotherapy protocol at five months and remains in complete remission at nine months. This case report contributes to the literature by highlighting the diagnostic approach and management strategies for CL presenting with BMS and hyperleukocytosis. This case aims to enhance awareness and understanding of BMS as an initial manifestation of CL. Additionally, the challenges of treating leukemia in neonates, coupled with the lack of specific guidelines for this age group, further underscore the complexities in managing such patients.

Effect of Different Time/Temperature Binomials on the Chemical Features, Antioxidant Activity, and Natural Microbial Load of Olive Pomace Paste.

Olive pomace is a by-product from olive oil production that can be further processed to obtain olive pomace paste. In this work, the influence of different time/temperature binomials (65 °C/30 min; 77 °C/1 min; 88 °C/15 s; and 120 °C/20 min) on the nutritional quality, chemical composition, and efficiency on control/elimination of natural microbial load of olive pomace paste was ascertained. The treatments significantly impacted the contents of ash, fat, vitamin E, phenolics (including hydroxytyrosol), flavonoids, and antioxidant activity, but not the fatty acids profile. The binomial 88 °C/15 s showed the greatest potential since it better preserved the phytochemical and antioxidant properties as well as the protein and fiber contents. This binomial is also faster and easy to be implemented at an industrial level, allowing the obtention of a safe functional ingredient to satisfy consumers' demands for novel sustainable products, simultaneously, responding to food safety and food security concerns.

Characterization of Chia Seeds, Cold-Pressed Oil, and Defatted Cake: An Ancient Grain for Modern Food Production.

The increasing demand for superfoods has resulted in an increase in chia seeds consumption. The reintroduction of this ancient crop in agriculture is useful to ensure food security since it can grow in high-stress conditions. The current study aimed to characterize chia seeds, cold-pressed oil, and defatted cake (the oil extraction by-product) to improve their value and to meet consumer's expectations (low-fat products). Chia seeds presented a significantly higher energy value than cake (444 vs. 284 kcal/100 g, respectively) due to fat removal (33 vs. 7%). The cake showed higher contents of total minerals (6 vs. 5%), protein (27 vs. 18%), and fiber (48 vs. 38%) in comparison to the seeds, and was hence considered a promising food ingredient. The major fatty acid in oil, seeds, and cake was α-linolenic acid (62-66%), and the vitamin E content was 409, 200, and 44 mg/kg, respectively. The major amino acid in the seeds and cake was glutamic acid (49 vs. 36 mg/g). The oil had a low oxidative stability (1 h), and the total phenolics content was 1.3 mg gallic acid equivalents/100 g. Chia cake incorporation in food formulations will follow consumer's interests, and the obtained oil can be used to improve the oil supply for different applications. This approach adds value to the concept of "one health" since it includes the culture, the environment, and the consumers.

LACTB induces cancer cell death through the activation of the intrinsic caspase-independent pathway in breast cancer.

BACKGROUND: LACTB was recently identified as a mitochondrial tumour suppressor that negatively affects cancer cell proliferation by inducing cell death and/or differentiation, depending on the cell type and tissue. However, the detailed mechanism underlying the LACTB-induced cancer cell death is largely unknown. METHODS: We used cell-based, either in 2D or 3D conditions, and in vivo experiments to understand the LACTB mechanisms. In this regard, protein array followed by an enrichment analysis, cell proliferation assays using different compounds, western blot analysis, flow cytometry and immunofluorescence were performed. Differences between quantitative variables following normal distribution were valuated using Student t test for paired or no-paired samples according to the experiment. For in vivo experiments differences in tumour growth were analyzed by 2-way ANOVA. RESULTS: We show, that LACTB expression leads to cell cycle arrest in G1 phase and increase of DNA oxidation that leads to activation of intrinsic caspase-independent cell death pathway. This is achieved by an increase of mitochondrial reactive oxygen species since early time points of LACTB induction. CONCLUSION: Our work provides a deeper mechanistic insight into LACTB-mediated cancer-cell death and shows the dynamics of the cellular responses a particular tumor suppressive stimulus might evoke under different genetic landscapes.

LACTB exerts tumor suppressor properties in epithelial ovarian cancer through regulation of Slug.

Epithelial-mesenchymal transition (EMT) is a cellular mechanism used by cancer cells to acquire migratory and stemness properties. In this study, we show, through in vitro, in vivo, and 3D culture experiments, that the mitochondrial protein LACTB manifests tumor suppressor properties in ovarian cancer. We show that LACTB is significantly down-regulated in epithelial ovarian cancer cells and clinical tissues. Re-expression of LACTB negatively effects the growth of cancer cells but not of non-tumorigenic cells. Mechanistically, we show that LACTB leads to differentiation of ovarian cancer cells and loss of their stemness properties, which is achieved through the inhibition of the EMT program and the LACTB-dependent down-regulation of Snail2/Slug transcription factor. This study uncovers a novel role of LACTB in ovarian cancer and proposes new ways of counteracting the oncogenic EMT program in this model system.

Nutritional and Chemical Characterization of Poppy Seeds, Cold-Pressed Oil, and Cake: Poppy Cake as a High-Fibre and High-Protein Ingredient for Novel Food Production.

Currently, society demands natural healthy foods with improved nutritional characteristics. Accordingly, poppies (Papaver somniferum) are a traditional crop, cultivated for food and pharmaceutical purposes, whose seeds meet consumers' preferences, making them a promising candidate for incorporation into the formulation of novel functional foods. This work performed an overall chemical characterization of poppy seeds, cold-pressed oil, and press cake, a by-product of the oil industry. The proximate composition, fatty acids, and vitamin E profiles of the oil fraction were analysed with respect to the whole seeds and the cake. The cold-press oil extracted from the poppy seeds was also characterized. Since poppy cake is a partially defatted product, it has a lower fat content than the seeds, but higher content of the rest of its elements, namely, ash (10%), protein (26%), and fibre (38%). Regarding protein composition, the major amino acid in the cake and seeds was determined to be glutamic acid (59 and 36 mg/g, respectively). All the samples presented α- and γ-tocopherols (>21 and >25 mg/kg, respectively) and the fatty acids profile of the oil fraction was mainly composed of unsaturated fatty acids, where linoleic acid predominates (>50%). The oil's oxidative stability was low (2.8 h), according to the predominance of unsaturated fatty acids. Thus, poppy cake may be considered as an ingredient with great potential for incorporation into products in the food industry according to its high content in protein and fibre, and the remaining fat content, where polyunsaturated fatty acids predominate.

Whole or Defatted Sesame Seeds (Sesamum indicum L.)? The Effect of Cold Pressing on Oil and Cake Quality.

Whole sesame seeds and sesame oil, which is obtained after cold pressing the seeds, are foodstuffs globally consumed due to their nutritional characteristics. The press cake that remains from the oil extraction process can be ground to form a defatted flour that can be incorporated into the human diet, contributing to the valorisation of this product. The nutritional comparison between the whole seeds and the press cake reveals the potential of this by-product to be incorporated in the formulation of diverse foodstuff, since it is richer than the seeds in proteins (30%) and fibre (25%) and still contains a proportion of oil (32%) with a fatty acid pattern characterized by the abundance of unsaturated fatty acids. The protein fraction of both the seeds and the cake shows a balanced composition regarding amino acid composition, with all the essential amino acids included. On the other hand, the oil obtained by cold pressing is shown as a high-quality oil, where the predominant fatty acids are oleic (42.66%) and linoleic (41.25%), which are essential fatty acids because they are not synthetised in the organism and must be obtained through the diet. In addition, it is rich in vitamin E, especially in γ-tocopherol, that was the main isomer found. Regarding these results, all products (sesame seeds, oil and press cake) are components suitable to be included in a healthy diet.

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance.

Therapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.

[Cutaneous Manifestations in Mastocytosis: Update]. / Manifestações Cutâneas nas Mastocitoses: Atualização.

INTRODUCTION: Mastocytosis is characterized by the clonal expansion of morphological and immunophenotypically abnormal mast cells in different organs. The skin is the most frequently affected tissue. Virtually all children and more than 80% of adult patients with mastocytosis show cutaneous lesions. MATERIAL AND METHODS: The present article describes the symptoms and signs in cutaneous mastocytosis, based on the review of recently published international consensus guidelines. DISCUSSION: According to the 2016 World Health Organization classification, mastocytosis can be divided in cutaneous mastocytosis, systemic mastocytosis and mast cell sarcoma. Cutaneous mastocytosis is subclassified in three subtypes: maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis and cutaneous astocytoma. Telangiectasia macularis eruptiva perstans is no longer considered a distinct entity. CONCLUSION: Based on the age of onset, cutaneous manifestations of mastocytosis can be variable. The classification of cutaneous mastocytosis has recently been updated. Typically, in patients with childhood-onset mastocytosis, the disease occurs as cutaneous mastocytosis and shows spontaneous resolution around puberty. In contrast, adult patients, despite having also cutaneous lesions, often show systemic involvement and the course of the disease is usually chronic.

Introdução: As mastocitoses caraterizam-se pela expansão clonal de mastócitos, com acumulação de mastócitos morfológica e imunofenotipicamente anormais em diferentes órgãos. A pele é o órgão mais frequentemente envolvido. Virtualmente, todas as crianças e mais de 80% dos adultos com mastocitose apresentam lesões cutâneas.Material e Métodos: O presente artigo descreve os sinais e sintomas associados à mastocitose na pele, tendo por base a revisão das normas de orientação de consenso internacionais, recentemente publicadas.Discussão: De acordo com a classificação proposta pela Organização Mundial de Saúde em 2016, a mastocitose divide-se em mastocitose cutânea, mastocitose sistémica e sarcoma de mastócitos. A mastocitose cutânea pode subdividir-se em três subtipos: a mastocitose cutânea maculopapular (também denominada urticária pigmentosa), mastocitose cutânea difusa e mastocitoma cutâneo. A telangiectasia macular eruptiva perstans já não é considerada uma entidade independente.Conclusão: As manifestações cutâneas da mastocitose são variáveis, dependendo da idade de início da doença. Recentemente a classificação da mastocitose cutânea foi atualizada. Nas crianças, a mastocitose ocorre como mastocitose cutânea que tende à regressão espontânea durante a adolescência. Quando tem início na idade adulta, a mastocitose é geralmente sistémica, sendo a forma mais frequente a mastocitose sistémica indolente, que normalmente também cursa com manifestações cutâneas e tem um curso crónico.

Image-based Identification of Chemical Compounds Capable of Trapping FOXO in the Cell Nucleus.

Forkhead box O (FOXO) factors are tumor suppressor proteins commonly inactivated in human tumors. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. FOXO proteins are usually inactivated by posttranslational modifications leading to cytoplasmic mislocalization. Therefore, the pharmacological activation by promoting nuclear localization of FOXOs is considered an attractive therapeutic approach to treat cancer and age-related diseases. We developed a cell-based imaging assay to screen for chemical agents capable of inhibiting the nuclear export and in turn trapping proteins that contain a nuclear export sequence including FOXO factors in the nucleus. The fluorescent signal of untreated assay cells localizes predominantly to the cytoplasm. Upon treatment with the nuclear export inhibitors the fluorescent-tagged reporter proteins appear as speckles in the nucleus. In a personalized medicine context, drugs capable of reactivating FOXO factors might be of enormous clinical value in human tumors in which these proteins are inactivated. Here, we describe the procedures for monitoring nuclear export which is suitable for high-throughput screening of compound collections.

StemMapper: a curated gene expression database for stem cell lineage analysis.

Transcriptomic data have become a fundamental resource for stem cell (SC) biologists as well as for a wider research audience studying SC-related processes such as aging, embryonic development and prevalent diseases including cancer, diabetes and neurodegenerative diseases. Access and analysis of the growing amount of freely available transcriptomics datasets for SCs, however, are not trivial tasks. Here, we present StemMapper, a manually curated gene expression database and comprehensive resource for SC research, built on integrated data for different lineages of human and mouse SCs. It is based on careful selection, standardized processing and stringent quality control of relevant transcriptomics datasets to minimize artefacts, and includes currently over 960 transcriptomes covering a broad range of SC types. Each of the integrated datasets was individually inspected and manually curated. StemMapper's user-friendly interface enables fast querying, comparison, and interactive visualization of quality-controlled SC gene expression data in a comprehensive manner. A proof-of-principle analysis discovering novel putative astrocyte/neural SC lineage markers exemplifies the utility of the integrated data resource. We believe that StemMapper can open the way for new insights and advances in SC research by greatly simplifying the access and analysis of SC transcriptomic data. StemMapper is freely accessible at http://stemmapper.sysbiolab.eu.

Hidradenitis Suppurativa in Children Treated with Finasteride-A Case Series.

BACKGROUND: Hidradenitis suppurativa (HS) is rare in childhood, with only 2% of cases in patients younger than 11 years. It is a chronic, recurrent, debilitating condition for which no universally effective treatment has been developed. We present five cases of children with HS diagnosed between the ages of 6 and 11 years. METHODS: Patients were treated with oral finasteride 1 to 5 mg/day. All had entered puberty at the time of treatment initiation. All had normal laboratory results before starting treatment. The maximum duration of treatment was 24 months. RESULTS: Four patients were female. Two were overweight. Three had been previously treated with oral antibiotics, and two of these with oral isotretinoin, with partial or no improvement. Overall improvement of the disease was observed in all patients, with a reduction of the frequency and intensity of the flares. No adverse effects were observed or reported during treatment. CONCLUSION: Treatment of HS can be challenging. The options available include antimicrobials, immunosuppressants, hormonal therapies, lasers, and surgery. The authors report the largest series of children with HS treated with finasteride. The results support the use of finasteride as monotherapy for the treatment of this disease in children. Further studies are necessary to fully understand the role of this drug in the management of this disease.

Infantile myofibromatosis - a clinical and pathological diagnostic challenge.

Infantile myofibromatosis is a rare disorder of fibroblastic/myofibroblastic proliferation and represents the most frequent type of mesenchymal tumor in the neonatal period and primary infancy.Three clinical types have been described: solitary, multicentric, and generalized (with visceral involvement). A correct characterization of the histopathology is essential to diagnose these neoplasias in early infancy. We present a case of multicentric infantile myofibromatosis with regression over time.

Chronic granulomatous disease as a risk factor for cutaneous lupus in childhood.

Chronic granulomatous disease (CGD) is a primaryimmunodeficiency disorder that affects the phagocyticcells of the innate immune system. It is characterizedby recurrent or persistent infections with granulomaformation. Lupus-like lesions have been reported incarriers of CGD and less frequently, in patients withCGD. Immunological study in these patients areusually negative. We describe the case of an 8-yearoldboy with CGD who developed chronic and acutecutaneous lupus erythematous with angular cheilitis,oral ulcers, Raynaud phenomenon, and positiveserologies for antinuclear, anticentromere, and anti-Saccharomyces cerevisiae antibodies.

TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT.

Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.

Adaptive mechanisms of resistance to anti-neoplastic agents.

Intrinsic and acquired resistance to conventional and targeted therapeutics is a fundamental reason for treatment failure in many cancer patients. Targeted approaches to overcome chemoresistance as well as resistance to targeted approaches require in depth understanding of the underlying molecular mechanisms. The anti-cancer activity of a drug can be limited by a broad variety of molecular events at different levels of drug action in a cell-autonomous and non-cell-autonomous manner. This review summarizes recent insights into the adaptive mechanisms used by tumours to resist therapy including cellular phenotypic plasticity, dynamic alterations of the tumour microenvironment, activation of redundant signal transduction pathways, modulation of drug target expression levels, and exploitation of pro-survival responses.