Triple-negative breast cancer (TNBC) is a poor prognostic breast cancer with the highest mutations and limited therapeutic choices. Cytokine networking between cancer cells and the tumor ...microenvironment (TME) maintains the self-renewing subpopulation of breast cancer stem cells (BCSCs) that mediate tumor heterogeneity, resistance and recurrence. Immunotherapy of those factors combined with targeted therapy or chemoagents may advantage TNBC treatment.
We found that the oncogene Multiple Copies in T-cell Malignancy 1 (MCT-1/MCTS1) expression is a new poor-prognosis marker in patients with aggressive breast cancers. Overexpressing MCT-1 perturbed the oncogenic breast epithelial acini morphogenesis and stimulated epithelial-mesenchymal transition and matrix metalloproteinase activation in invasive TNBC cells, which were repressed after MCT-1 gene silencing. As mammary tumor progression was promoted by oncogenic MCT-1 activation, tumor-promoting M2 macrophages were enriched in TME, whereas M2 macrophages were decreased and tumor-suppressive M1 macrophages were increased as the tumor was repressed via MCT-1 knockdown. MCT-1 stimulated interleukin-6 (IL-6) secretion that promoted monocytic THP-1 polarization into M2-like macrophages to increase TNBC cell invasiveness. In addition, MCT-1 elevated the soluble IL-6 receptor levels, and thus, IL-6R antibodies antagonized the effect of MCT-1 on promoting M2-like polarization and cancer cell invasion. Notably, MCT-1 increased the features of BCSCs, which were further advanced by IL-6 but prevented by tocilizumab, a humanized IL-6R antibody, thus MCT-1 knockdown and tocilizumab synergistically inhibited TNBC stemness. Tumor suppressor miR-34a was induced upon MCT-1 knockdown that inhibited IL-6R expression and activated M1 polarization.
The MCT-1 pathway is a novel and promising therapeutic target for TNBC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypoxia, the most commonly observed characteristic in cancers, is implicated in the establishment of an immunosuppressive niche. Recent studies have indicated that extracellular vesicle (EV)-mediated ...cancer-stroma interactions are considered to play a critical role in the regulation of various cellular biological functions, with phenotypic consequences in recipient cells. However, the mechanisms underlying the relationship between EVs and hypoxia during cancer progression remain largely unknown. In this study, we found that EVs derived from hypoxic lung cancers increased M2-type polarization by miR-103a transfer. Decreased PTEN levels caused by hypoxic cancer-cell-derived EV miR-103a increased activation of AKT and STAT3 as well as expression of several immunosuppressive and pro-angiogeneic factors. In contrast, inhibition of miR-103a by an miRNA inhibitor effectively decreased hypoxic cancer-mediated M2-type polarization, improving the cytokine prolife of tumor infiltration macrophages. Macrophages received cancer-cell-derived EV miR-103a feedback to further enhance cancer progression and tumor angiogenesis. Finally, circulating EV miR-103a levels were higher in patients with lung cancer and closely associated with the M2 polarization. In conclusion, our results delineate a novel mechanism by which lung cancer cells induce immunosuppressive and pro-tumoral macrophages through EVs and inspire further research into the clinical application of EV inhibition or PTEN restoration for immunotherapy.
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Extracellular vesicle (EV) miR-103 can be transferred from hypoxic cancer cells to macrophages, resulting in the enhancement of M2 polarization by the downregulation of miR-103a’s direct target PTEN. EV miR-103a increases the stimulatory effects of macrophages on cancer progression and angiogenesis.
High hydrostatic pressure processing (HPP) is a non-thermal pasteurization technology which has already been applied in the food industries. Besides maintaining the food safety and quality, HPP also ...has potential applications in the enhancement of the health benefits of food products. This study examines the current progress of research on the use of HPP in the development of health foods. Through HPP, the nutritional value of food products can be enhanced or retained, including promotes the biosynthesis of γ-aminobutyric acid (GABA) in the food materials, retains immunoglobulin components in dairy products, increases resistant starch content in cereals, and reduces the glycemic index of fruit and vegetable products, which facilitates better control of blood glucose levels and decreases calorie intake. HPP can also be utilized as a hurdle technology in combination with existing processing technologies for the development of low-sodium food products and the maintenance of microbial safety, thereby lowering the risk of triggering cardiovascular disease. Additionally, HPP can be used to enhance the diversity of probiotic food products. Appropriate sporogenous probiotics can be screened and added to various high-pressure processed food products as a certain bacterial count is still retained in the products after HPP. As HPP causes physical damage to the structures of food products, it can also be used as a synergistic extraction technology to enhance the extraction efficiency of functional components, thereby reducing extraction time. By applying HPP in the extraction of functional components from food waste, the production costs of such components can be effectively reduced. This study provides a summary of the mechanisms by which HPP enhances the health benefits of food products and the current progress of relevant research. HPP possesses huge potential in the development of novel health foods and may provide an abundance of benefits to human health in the future.
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•HPP has potential applications in the enhancement of the health benefits of food products.•The nutritional value of food material and products can be enhanced or retained by HPP.•HPP can be a hurdle in combination with existing processing for the development of low-sodium food products.•HPP causes physical damage to the foods, enhance the extraction efficiency of functional components.
The programmable one-pot oligosaccharide synthesis method was designed to enable the rapid synthesis of a large number of oligosaccharides, using the software Optimer to search Building BLocks (BBLs) ...with defined relative reactivity values (RRVs) to be used sequentially in the one-pot reaction. However, there were only about 50 BBLs with measured RRVs in the original library and the method could only synthesize small oligosaccharides due to the RRV ordering requirement. Here, we increase the library to include 154 validated BBLs and more than 50,000 virtual BBLs with predicted RRVs by machine learning. We also develop the software Auto-CHO to accommodate more data handling and support hierarchical one-pot synthesis using fragments as BBLs generated by the one-pot synthesis. This advanced programmable one-pot method provides potential synthetic solutions for complex glycans with four successful examples demonstrated in this work.
Carbohydrates have been shown to play important roles in biological processes. The pace of development in carbohydrate research is, however, relatively slow due to the problems associated with the ...complexity of carbohydrate structures and the lack of general synthetic methods and tools available for the study of this class of biomolecules. Recent advances in synthesis have demonstrated that many of these problems can be circumvented. In this Review, we describe the methods developed to tackle the problems of carbohydrate‐mediated biological processes, with particular focus on the issue related to the development of the automated synthesis of oligosaccharides. Further applications of carbohydrate microarrays and vaccines to human diseases are also highlighted.
Sweet dreams: Carbohydrates play important roles in biological processes. The pace of carbohydrate research is, however, relatively slow due, amongst other things, to the lack of general synthetic methods. Current developments in the automated synthesis of oligosaccharides can help overcome many of these problems and to pave the way for biomedical applications.
High hydrostatic pressure is an emerging non-thermal technology that can achieve the same standards of food safety as those of heat pasteurization and meet consumer requirements for fresher tasting, ...minimally processed foods. Applying high-pressure processing can inactivate pathogenic and spoilage microorganisms and enzymes, as well as modify structures with little or no effects on the nutritional and sensory quality of foods. The U.S. Food and Drug Administration (FDA) and the U.S. Department of Agriculture (USDA) have approved the use of high-pressure processing (HPP), which is a reliable technological alternative to conventional heat pasteurization in food-processing procedures. This paper presents the current applications of HPP in processing fruits, vegetables, meats, seafood, dairy, and egg products; such applications include the combination of pressure and biopreservation to generate specific characteristics in certain products. In addition, this paper describes recent findings on the microbiological, chemical, and molecular aspects of HPP technology used in commercial and research applications.
Critically-ill surgical patients are at higher risk for sarcopenia, which is associated with worse survival. Sarcopenia may impair the respiratory musculature, which can subsequently influence the ...outcome of ventilator weaning. Although there are a variety of weaning parameters predictive of weaning outcomes, none have tried to incorporate "muscle strength" or "sarcopenia". The aim of the current study was to explore the association between sarcopenia and difficult-to-wean (DtW) in critically-ill surgical patients. The influence of sarcopenia on ICU mortality was also analyzed.
Ninety-six patients undergoing mechanical ventilation in the surgical intensive care unit (ICU) were enrolled. Demographic data and weaning parameters were recorded from the prospectively collected database, and the total psoas muscle area (TPA) was determined at the level of the 3rd lumbar vertebra by computed tomography. Sarcopenia was defined by previously established cut-off points and its influence on clinical outcomes was examined. Receiver operating characteristic (ROC) curve analysis was conducted to investigate the predictive capability of TPA and weaning parameters for predicting weaning outcomes.
The median age of the studied patients was 73 years. Thirty patients (31.3%) were sarcopenic and 30 (31.3%) were defined as DtW. Eighteen patients (18.8%) had ICU mortality. Multivariate logistic regression analyses revealed that sarcopenia was an independent risk factor for DtW and ICU mortality. The area under the ROC curve (AUC) of TPA for predicting successful weaning was 0.727 and 0.720 in female and male patients, respectively. After combining TPA and conventional weaning parameters, the AUC for DtW increased from 0.836 to 0.911 and from 0.835 to 0.922 in female and male patients, respectively.
Sarcopenia is an independent risk factor for DtW and ICU mortality. TPA has predictive value when assessing weaning outcomes and can be used as an effective adjunct predictor along with conventional weaning parameters.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The roles and regulatory mechanisms of transcriptome changes during aging are unclear. It has been proposed that the transcriptome suffers decay during aging owing to age‐associated down‐regulation ...of transcription factors. In this study, we characterized the role of a transcription factor DAF‐16, which is a highly conserved lifespan regulator, in the normal aging process of Caenorhabditis elegans. We found that DAF‐16 translocates into the nucleus in aged wild‐type worms and activates the expression of hundreds of genes in response to age‐associated cellular stress. Most of the age‐dependent DAF‐16 targets are different from the canonical DAF‐16 targets downstream of insulin signaling. This and other evidence suggest that activation of DAF‐16 during aging is distinct from activation of DAF‐16 due to reduced signaling from DAF‐2. Further analysis showed that it is due in part to a loss of proteostasis during aging. We also found that without daf‐16, dramatic gene expression changes occur as early as on adult day 2, indicating that DAF‐16 acts to stabilize the transcriptome during normal aging. Our results thus reveal that normal aging is not simply a process in which the gene expression program descends into chaos due to loss of regulatory activities; rather, there is active transcriptional regulation during aging.
We present a four-layer transmitarray antenna using small and dense frequency selective surface (FSS) cells and a horn antenna operated in a Ku band satellite downlink (10.7 to 12.75 GHz in Europe). ...The FSS offers a full transmission phase range of 360° and low loss between the incident and the transmitted waves: the magnitudes of the transmitted waves were equal to or better than -3.5 dB for incident transverse electric and transverse magnetic waves up to 30° in oblique angle. The transmitarray was fabricated using FR-4 boards with a loss tangent of about 0.02. FR-4 boards with lower loss tangents at the operating Ku band were not used because of the requirement for low cost. We also present the design of the horn antenna used to illuminate the transmitarray. The design applies discrete Jones matrix analysis; the final full transmitarray (333 unit cells) with the horn antenna were co-simulated using a full-wave simulation tool. The measured and simulation results are in excellent agreement. With a cell pitch of 0.39 λ 0 , the transmitarray achieves a dynamic range of 20 dB. The measured gain of the transmitarray prototype is 26.2 dB at a center frequency of 11.7 GHz, resulting in an aperture efficiency of about 62%. The measured results were achieved with a very small transmitarray (backpack-fit versus truck-carried). The -1 dB gain bandwidth of the transmitarray antenna is 12.6% at the center frequency (11.7 GHz).
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