43,153 research outputs found

    IDO1 and inflammatory neovascularization: bringing new blood to tumor-promoting inflammation

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    In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the ÔÇśHallmarks of CancerÔÇÖ, it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance to tumor antigens, thereby helping tumors evade adaptive immune control. Additionally, recent findings indicate that IDO1 also promotes tumor neovascularization by subverting local innate immunity. This newly recognized function for IDO1 is mediated by a unique myeloid cell population termed IDVCs (IDO1-dependent vascularizing cells). Initially identified in metastatic lesions, IDVCs may exert broader effects on pathologic neovascularization in various disease settings. Mechanistically, induction of IDO1 expression in IDVCs by the inflammatory cytokine IFN╬│ blocks the antagonistic effect of IFN╬│ on neovascularization by stimulating the expression of IL6, a powerful pro-angiogenic cytokine. By contributing to vascular access, this newly ascribed function for IDO1 aligns with its involvement in other cancer hallmark functionalities, (tumor-promoting inflammation, immune escape, altered cellular metabolism, metastasis), which may stem from an underlying role in normal physiological functions such as wound healing and pregnancy. Understanding the nuances of how IDO1 involvement in these cancer hallmark functionalities varies between different tumor settings will be crucial to the future development of successful IDO1-directed therapies

    Identifizierung pr├Ądiktiver und prognostischer Biomarker in unterschiedlichen Tumorkompartimenten des ├Âsophagealen Adenokarzinoms

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    Das ├Âsophageale Adenokarzinom zeigt eine global steigende Inzidenz und hat mit einer 5-Jahres-├ťberlebensrate von weniger als 25% eine schlechte Prognose. Personalisierte Therapieans├Ątze sind selten und prognostische/pr├Ądiktive Biomarker des Tumormikromilieus sind unzureichend charakterisiert. Die kumulative Promotion n├Ąhert sich dieser Problematik in drei unterschiedlichen Schwerpunkten. 1. Zur Identifizierung Kompartiment-spezifischer Biomarker wurde eine Methode entwickelt, welche als kosteng├╝nstige Alternative zum sc-Seq Expressionsprofile individueller Zelltypen generiert. Dabei erfolgt die Extraktion der RNA nicht aus Einzelzellen, sondern aus flowzytometrisch-getrennten Zellkompartimenten. Die Separation der Proben in Epithelzellen, Immunzellen und Fibroblasten wurde durch verschiedene Verfahren validiert und eine suffiziente Ausbeute an RNA auch f├╝r kleine Gewebemengen gezeigt. 2. Biomarker des Immunzellkompartiments als therapeutische Angriffspunkte wurden in einem Patientenkollektiv von bis zu 551 Patienten auf ihre Bedeutung beim EAC ├╝berpr├╝ft. Es zeigte sich eine Expression der Immuncheckpoints LAG3, VISTA und IDO auf TILs durch IHC und RNA-Sonden basierte Verfahren in einem relevanten Anteil (LAG3: 11,4%, VISTA: 29%, IDO: 52,6%). Es konnte eine prognostisch g├╝nstige Bedeutung der VISTA, LAG3 und IDO Expression gezeigt werden. Durch den Vergleich von Genexpressionsprofilen aus therapienaiven und vorbehandelten Tumoren konnte zudem ein immunsuppressiver Effekt von neoadjuvanten Therapiekonzepten auf das Tumormikromilieu des EACs gezeigt werden. Dabei kam es zur verminderten Expression von Checkpoints und Anzahl TILs nach (Radio-) Chemotherapie. 3. Im Tumorzellkompartiment wurde die Rolle von Amplifikationen in ErbB-Rezeptor abh├Ąngigen Signalwegen durch FISH-Technik und Immunhistochemie evaluiert. Es fanden sich KRAS Amplifikationen in 17,1%, PIK3CA Amplifikationen in 5% sowie eine HER2/neu-├ťberexpression in 14,9% der untersuchten Tumore

    Identification of natural killer cell associated subtyping and gene signature to predict prognosis and drug sensitivity of lung adenocarcinoma

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    Introduction: This research explored the immune characteristics of natural killer (NK) cells in lung adenocarcinoma (LUAD) and their predictive role on patient survival and immunotherapy response.Material and methods: Molecular subtyping of LUAD samples was performed by evaluating NK cell-associated pathways and genes in The Cancer Genome Atlas (TCGA) dataset using consistent clustering. 12 programmed cell death (PCD) patterns were acquired from previous study. Riskscore prognostic models were constructed using Least absolute shrinkage and selection operator (Lasso) and Cox regression. The model stability was validated in Gene Expression Omnibus database (GEO).Results: We classified LUAD into three different molecular subgroups based on NK cell-related genes, with the worst prognosis in C1 patients and the optimal in C3. Homologous Recombination Defects, purity and ploidy, TMB, LOH, Aneuploidy Score, were the most high-expressed in C1 and the least expressed in C3. ImmuneScore was the highest in C3 type, suggesting greater immune infiltration in C3 subtype. C1 subtypes had higher TIDE scores, indicating that C1 subtypes may benefit less from immunotherapy. Generally, C3 subtype presented highest PCD patterns scores. With four genes, ANLN, FAM83A, RHOV and PARP15, we constructed a LUAD risk prediction model with significant differences in immune cell composition, cell cycle related pathways between the two risk groups. Samples in C1 and high group were more sensitive to chemotherapy drug. The score of PCD were differences in high- and low-groups. Finally, we combined Riskscore and clinical features to improve the performance of the prediction model, and the calibration curve and decision curve verified that the great robustness of the model.Conclusion: We identified three stable molecular subtypes of LUAD and constructed a prognostic model based on NK cell-related genes, maybe have a greater potential for application in predicting immunotherapy response and patient prognosis

    Correlation between the intestinal microflora and peripheral blood Th1/Th2 balance in hypothyroidism during the first half of pregnancy

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    ObjectiveThis study aimed to investigate the relationship between intestinal microflora characteristics and the peripheral blood T helper cell (Th)1/Th2 balance in patients with hypothyroidism during the first half of pregnancy.MethodsThe Th1/Th2 ratios in the peripheral blood of pregnant women in the hypothyroidism and control groups were determined using flow cytometry. The cytometric bead array assay was used to determine the serum levels of interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-╬▒, and interferon (IFN)-╬│. Moreover, 16S rRNA amplicon sequencing was used to determine the intestinal microbial composition in the two groups. Finally, the relationships between intestinal microflora, Th1/Th2 cells, cytokines, and clinical indicators were analyzed.ResultsC-reactive protein levels were higher in the hypothyroidism group than in the control group. In contrast to the control group, the hypothyroidism group showed an increase in Th1 cells and the Th1/Th2 ratio, and a decrease in Th2 cells. The hypothyroidism group had higher serum IL-2, TNF-╬▒, and IFN-╬│ levels, and lower IL-10 levels, than the control group. The richness of the intestinal microflora in the hypothyroidism group increased whereas the diversity decreased. The linear discriminant analysis effect size revealed that the hypothyroidism group had a higher abundance of Prevotella and Faecalibacterium, but a lower abundance of Bacteroides, compared to the control group. Prevotella was positively correlated with Th1 cells, the Th1/2 ratio, and TNF-╬▒. Bacteroides was positively correlated with Th2 cells and IL-10, but negatively correlated with Th1 cells, the Th1/2 ratio, TNF-╬▒, and IFN-╬│. The thyroid peroxidase antibody level was directly proportional to TNF-╬▒.ConclusionA Th1/Th2 imbalance occurs in patients with hypothyroidism during the first half of pregnancy. Disorders of the intestinal microflora may lead to hypothyroidism during pregnancy by affecting the Th1/Th2 balance

    The potential value of Notch1 and DLL1 in the diagnosis and prognosis of patients with active TB

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    ObjectivesThe Notch signaling pathway has been implicated in the pathogenesis of active tuberculosis (TB), and Th1-type cell-mediated immunity is essential for effective control of mycobacterial infection. However, it remains unclear whether Notch signaling molecules (Notch1, DLL1, and Hes1) and Th1-type factors (T-bet and IFN-╬│) can serve as biomarkers for tracking the progression of active TB at different stages along with peripheral blood white blood cell (WBC) parameters.MethodsA total of 60 participants were enrolled in the study, including 37 confirmed TB patients (mild (n=17), moderate/severe (n=20)) and 23 healthy controls. The mRNA expression of Notch1, DLL1, Hes1, T-bet and IFN-╬│ in the peripheral blood mononuclear cells (PBMCs) of the subjects was measured by RT-qPCR, then analyzed for differences. Receiver Operating Characteristic curve (ROC) was used to assess the effectiveness of each factor as a biomarker in identifying lung injury.ResultsWe found that mRNA expression levels of Notch1, DLL1, and Hes1 were upregulated in active TB patients, with higher levels observed in those with moderate/severe TB than those with mild TB or without TB. In contrast, mRNA levels of T-bet and IFN-╬│ were downregulated and significantly lower in mild and moderate/severe cases. Furthermore, the combiROC analysis of IFN-╬│ and the percentage of lymphocytes (L%) among WBC parameters showed superior discriminatory ability compared to other factors for identifying individuals with active TB versus healthy individuals. Notably, Notch pathway molecules were more effective than Th1-type factors and WBC parameters in differentiating mild and moderate/severe cases of active TB, particularly in the combiROC model that included Notch1 and Hes1.ConclusionsOur study demonstrated that Notch1, Hes1, IFN-╬│, and L% can be used as biomarkers to identify different stages of active TB patients and to monitor the effectiveness of treatment

    Regulation of Phagocytosis in Macrophages

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    When the first line of defenceÔÇöthe integumentary system fails, the immune system protects us from infections by pathogens. Macrophages are crucial for mediating effects in the innate immune system by eliminating impaired cells and harmful micro-organisms through phagocytosis. Although other cells undergo phagocytosis, the cellular processes that regulate phagocytosis may vary from cell to cell. These include metabolic changes, signal transduction, and changes in molecular expression or post-translational modifications. This chapter will comprehensively review biological processes that regulate phagocytosis in macrophages, including; changes in metabolic processes, signal transduction, molecular expression, and post-translational modifications

    Neuroprotective Properties of Peptides

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    The development of a treatment strategy for neurodegenerative disorders is a serious issue for the healthcare world and a crucial subject of discussion. In the past two decades, a lot of focus has been placed on identifying the pathophysiological processes involved in neuronal death linked to neurodegenerative disorders and developing a variety of treatment options for neuroprotection. Numerous research teams have studied the use of peptides as neuroprotective treatments for different types of neurodegenerative disorders for a long time. The review aims to provide details about the roles of erythropoietin (EPO), glucagon-like peptide-1 (GLP-1), granulocyte colony-stimulating factor (G-CSF), and oxytocin (OXT) in neurodegenerative disorders as well as what cellular and molecular mechanisms they trigger to elicit the neuroprotective action, with a focus on neurodegenerative disorders

    Die akute Appendizitis im Kindes- und Jugendalter: neue diagnostische Verfahren f├╝r die pr├Ątherapeutische Differenzierung histopathologischer Entit├Ąten zur Unterst├╝tzung konservativer Therapiestrategien

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    Hintergrund der hier zusammengefassten Studien war die aktuelle Datenlage, die daf├╝r spricht, dass es sich bei der klinisch unkomplizierten, histopathologisch phlegmon├Âsen und der klinisch komplizierten, histopathologisch gangr├Ąn├Âsen Appendizitis um unabh├Ąngige Entit├Ąten handelt. Diese k├Ânnen unterschiedlichen Therapieoptionen (konservativ vs. operativ) zugef├╝hrt werden. Vor diesem Hintergrund war es ein Ziel der Arbeiten zu untersuchen, wie die Formen der akuten Appendizitis im Kindes- und Jugendalter bereits pr├Ątherapeutisch unterschieden werden k├Ânnen. Sowohl in der Labordiagnostik (P1 und P2) als auch im Ultraschall (P3) lassen sich Unterschiede zwischen Patient*innen mit unkomplizierter, phlegmon├Âser und komplizierter (gangr├Ąn├Âser und perforierender) Appendizitis aufzeigen. Hierdurch allein kann allerdings aufgrund unzureichender Trennsch├Ąrfe noch keine ausreichende Entscheidungssicherheit erreicht werden. Mit Verfahren der k├╝nstlichen Intelligenz auf Untersucher-unabh├Ąngige diagnostische Parameter (P4) konnte die Vorhersagegenauigkeit der akuten Appendizitis weiter gesteigert werden. Interessante Ergebnisse bez├╝glich der unterschiedlichen Pathomechanismen der beiden inflammatorischen Entit├Ąten ergaben sich durch eine differenzielle Genexpressionsanalyse (P5). In einer Proof-of-Concept-Studie wurden zuvor beschriebene Methoden der k├╝nstlichen Intelligenz auf die Genexpressionsdaten angewandt (P6). Hierdurch konnte im Modell eine grunds├Ątzliche Differenzierbarkeit der Entit├Ąten durch die Anwendung der neuen Methode aufgezeigt werden. Ein mittelfristiges Ziel ist es, eine Biomarkersignatur zu definieren, die ihre Aussagekraft durch einen Computeralgorithmus hat. Hierdurch soll eine schnelle Therapieentscheidung erm├Âglicht werden. Im Idealfall sollte diese Biomarkersignatur sicher, objektiv und einfach zu bestimmen sein sowie eine h├Âhere diagnostische Sicherheit als die bisherige Diagnostik mittels Anamnese, Untersuchung, Laboranalyse und Ultraschall bieten. Langfristiges Ziel von Folgestudien ist die Identifizierung einer Biomarkersignatur mit der bestm├Âglichen Vorhersagekraft. Hinsichtlich der routinem├Ą├čigen klinischen Diagnostik ist die Anwendung von Point-of-Care Devices auf PCR-Basis denkbar. Hier k├Ânnte eine limitierte Anzahl von Primern f├╝r eine Biomarkersignatur mit hoher Vorhersagekraft zum Einsatz kommen. Der dadurch ermittelte Biomarker w├╝rde seine Aussagekraft durch einen einfach anzuwendenden Computeralgorithmus erhalten. Die Kombination aus Genexpressionsanalyse mit Methoden der k├╝nstlichen Intelligenz kann somit die Grundlage f├╝r ein neues diagnostisches Instrument zur sicheren Unterscheidung unterschiedlicher Appendizitisentit├Ąten darstellen

    PENGARUH STRESOR FISIK AKUT TERHADAP KADAR TNF-╬▒ PADA TIKUS JANTAN PUTIH (Rattus norvegicus)

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    Stress is a state of the body's psycho-physiological reaction in the face of various emotional or physical stimuli that disturb homeostasis. As a result of stress, the body holds various adjustment processes to maintain the shape and function of the organs. Stressors are defined as changes in the external environment (changes in temperature or (pH) that cause a physiological response in the organism concerned to maintain homeostasis. Acute stressors cause a short-term physiological response that immediately returns to a state of homeostasis. An experimental laboratory study was conducted with a post-test only control group design. design which aims to determine the effect of acute physical stressors on TNF-╬▒ levels in white male rats (Rattus norvegicus).Male white rats were used as test animals using 34 rats.In the preliminary study 2 rats were used and 32 rats were divided into 2 groups namely the control group and the treatment group.The stressor used was a mosquito racket with a voltage of 3 Volts and 5 seconds for 1 time of the stressor.The variable examined was the level of TNF-╬▒ in the rat blood serum.Then the results were analyzed using the T test.The results were obtained that there is an increase n TNF ÔÇô╬▒ levels under stress conditions in the treatment group (p <0.05). There is a significant relationship to the increase in TNF-╬▒ levels in conditions of acute physical stressors. This study concluded that the influence of acute physical stressors can increase the immune system. It is recommended to carry out the influence of chronic physical stressors on TNF-╬▒ levels.Stres adalah keadaan reaksi psiko-fisiologis tubuh dalam menghadapi berbagai rangsangan emosional atau fisik yang mengganggu homeostasis. Akibat stres, tubuh mengadakan berbagai proses penyesuaian untuk mempertahankan bentuk dan fungsi alat tubuh. Stresor diartikan sebagai perubahan lingkungan eksternal (perubahan temperatur atau (pH) yang menimbulkan respon fisiologik pada organisme bersangkutan untuk mempertahankan homeostasis. Stresor akut menimbulkan respon fisiologik jangka pendek yang segera kembali ke keadaan homeostasis. Dilakukan penelitian experimental laboratoris dengan desain post-test only control group design yang bertujuan untuk mengetahui pengaruh stresor fisik akut terhadap kadar TNF-╬▒ pada tikus jantan putih (Rattus norvegicus).Tikus putih jantan sebagai hewan uji dengan menggunakan 34 ekor tikus. Pada penelitian pendahuluan digunakan 2 ekor tikus dan 32 ekor lagi dibagi 2 menjadi kelompok yaitu kelompok kontrol dan kelompok perlakuan. Stresor yang digunakan raket nyamuk dengan tegangan 3 Volt dan waktu 5 detik selama 1 kali stresor. Variabel yang diperiksa adalah kadar TNF-╬▒ pada serum darah tikus. Kemudian hasilnya dianalisa dengan menggunakan uji T test. Hasil penelitian diperoleh bahwa terjadinya peningkatan kadar TNF ÔÇô╬▒ pada kondisi stresor pada kelompok perlakuan (p < 0.05). Terdapat hubungan yang signifikan pada kenaikan kadar TNF-╬▒ pada kondisi stresor fisik akut. Penelitian ini disimpulkan bahwa pengaruh stresor fisik akut dapat menaikan sistem sistem imun. Disarankan untuk melakukan pengaruh stresor fisik kronis terhadap kadar TNF-╬▒

    Immunosuppressive drugs in renal transplantation

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    A kidney transplant, sometimes known as a renal transplant, is the treatment of choice for kidney failure at end stage renal disease (ESRD). The renal transplant surgery is followed by a lifetime course of immunosuppressive agents, divided into initial induction phase and later maintenance phase. It is seen that the risk of acute rejection is maximum in the initial months after transplantation (induction phase) and then reduces later (maintenance phase). In induction phase there is use of high-intensity immunosuppression immediately after transplantation, when the risk of rejection is maximum and then the dose reduced for long- term therapy. The main challenge in the renal transplantation community is long- term transplant survival. Long-term graft loss is mainly due to acute and chronic graft rejection, and also due to complications of immunosuppressive therapy. Currently, there is triple therapy as conventional immunosuppressive protocol: a calcineurin inhibitor, an antimetabolite agent, and a corticosteroid. The main aim of development of new immunosuppressive agents is not only improvement of short- term outcomes but also to increase the long- term graft survival by less nephrotoxicity, and minimal side-effects
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