36 research outputs found
Pre-trained language models evaluating themselves - A comparative study
Evaluating generated text received new attention with the introduction of model-based metrics in recent years. These new metrics have a higher correlation with human judgments and seemingly overcome many issues of previous n-gram based metrics from the symbolic age. In this work, we examine the recently introduced metrics BERTScore, BLEURT, NUBIA, MoverScore, and Mark-Evaluate (Petersen). We investigate their sensitivity to different types of semantic deterioration (part of speech drop and negation), word order perturbations, word drop, and the common problem of repetition. No metric showed appropriate behaviour for negation, and further none of them was overall sensitive to the other issues mentioned above
Einfluss der sympathischen Innervation auf L-Typ-Ca2+-Kanal abhĂ€ngige Signalwege in renalen WiderstandsgefĂ€Ăen
Die neonatale sympathische Denervierung steigert die Agonist-induzierte GefĂ€Ăkontraktion. Dieser Effekt kommt möglicherweise durch modifizierte Signaltransduktionsmechanismen zustande. Dazu könnten VerĂ€nderungen in Rho-Kinase(ROCK)- und L-Typ-Ca2+-KanalabhĂ€ngigen Signalwegen gehören, welche den Rezeptoren der vasoaktiven Agonisten nachgeschaltet sind. In der vorliegenden Studie wurde untersucht, ob die verstĂ€rkte
Aktivierung der ROCK und/oder L-Typ-Ca2+-KanÀle zur gesteigerten
Noradrenalin(NA)-induzierten GefĂ€Ăkontraktion bei renalen WiderstandsgefĂ€Ăen neonatal sympathektomierter Ratten beitragen. FĂŒr die experimentellen Untersuchungen wurden normotensive mĂ€nnliche Wistar-Ratten (Crl:Wi) verwendet. Diese wurden neonatal sympathektomiert oder scheinsympathektomiert. Es folgte die Untersuchung isolierter renaler
Widerstandsarterien 9 bis 12 Wochen alter Tiere mittels Small-Vessel-Myographie. Die Expression der L-Typ-Ca2+-KanĂ€le isolierter renaler WiderstandsgefĂ€Ăe wurde mittels Western-Blot untersucht. ZusĂ€tzlich wurde das Ruhemembranpotential der glatten GefĂ€Ămuskelzellen mittels Mikroelektroden registriert. Die neonasale sympathische Denervierung fĂŒhrte im Vergleich zur Scheinsympathektomie zu einer gesteigerten NA-SensitivitĂ€t bei GefĂ€Ăen normotensiver Ratten. Sowohl die Inhibition der ROCK als auch die Blockade von L-Typ-Ca2+-KanĂ€len fĂŒhrte zur Rechtsverschiebung der NA-Konzentrations-Wirkungs-Kurve. Diese Effekte waren bei GefĂ€Ăen sympathektomierter Tiere im Vergleich zu scheinbehandelten Kontrollen deutlicher ausgeprĂ€gt. L-Typ-Ca2+-Kanalaktivierung mittels
S-(-)-BayK8644 löste bei Nierenarterien sympathektomierter Ratten starke
GefĂ€Ăkontraktionen aus. Die GefĂ€Ăe der Kontrollen reagierten hingegen nur schwach auf S-(-)-BayK8644. Der Proteingehalt der a1-Untereinheit der L-Typ-Ca2+-KanĂ€le glatter GefĂ€Ămuskelzellen unterschied sich nicht zwischen beiden Gruppen. Das Ruhemembranpotential glatter GefĂ€Ămuskelzellen unterschied sich statistisch signifikant zwischen beiden Gruppen (p < 0,05) und betrug â57,5 ± 2,2 mV bei renalen WiderstandsgefĂ€Ăen sympathektomierter Tiere und â64,3 ± 0,3 mV bei Kontrollen. Die Depolarisation der glattmuskulĂ€ren Zellmembran durch kaliumreiche Organbadlösung steigerte die S-(-)-BayK8644-induzierte Kontraktion der GefĂ€Ăe sympathektomierter Tiere und löste Kontraktionen bei GefĂ€Ăen der Kontrolltiere aus. Die Aktivierung von KATP-KanĂ€len fĂŒhrte zum vollstĂ€ndigen Verschwinden der S-(-)-BayK8644-induzierten Kontraktion bei GefĂ€Ăen
sympathektomierter Tiere. Diese Befunde zeigen, dass die sympathische Denervierung renaler GefĂ€Ăe zu einer Depolarisation des Membranpotentials der GefĂ€Ămuskelzellen fĂŒhrt, die zu einer gesteigerten Aktivierbarkeit L-Typ-Ca2+-Kanal-abhĂ€ngiger Signalwege beitrĂ€gt.Neonatal sympathectomy increases norepinephrine-sensitivity and maximum force-development in isolated renal resistance arteries. Our data suggest that enhanced L-type Ca2+ channel-dependent signaling contributes to denervation supersensitivity in small intrarenal arteries. This is not due to increased Cav1.2 protein abundance. Enhanced L-type Ca2+ channel-dependent signaling seem to be a consequence of a more depolarized vascular smooth muscle membrane potential after sympathetic denervation
Insights in Molecular Therapies for Hepatocellular Carcinoma
We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation
Unraveling the Role of Reactive Oxygen Species in T Lymphocyte Signaling
Reactive oxygen species (ROS) are central to inter- and intracellular signaling. Their localized and transient effects are due to their short half-life, especially when generated in controlled amounts. Upon T cell receptor (TCR) activation, regulated ROS signaling is primarily initiated by complexes I and III of the electron transport chain (ETC). Subsequent ROS production triggers the activation of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2), prolonging the oxidative signal. This signal then engages kinase signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway and increases the activity of REDOX-sensitive transcription factors such as nuclear factor-kappa B (NF-ÎșB) and activator protein-1 (AP-1). To limit ROS overproduction and prevent oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant proteins such as superoxide dismutases (SODs) finely regulate signal intensity and are capable of terminating the oxidative signal when needed. Thus, oxidative signals, such as T cell activation, are well-controlled and critical for cellular communication
Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-/and alcoholic fatty liver disease (N/AFLD), and tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, etc.), and dysregulation of key signaling pathways (Wnt/ÎČ-catenin, JAK/STAT, etc.) strongly contribute to the development of HCC. The multitude and complexity of different pathomechanisms also reflect the difficulties in tailored medical therapy of HCC. Treatment options for HCC are strictly dependent on tumor staging and liver function, which are structured by the updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, and liver transplantation are valid and curative therapeutic options for early tumor stages. For multifocal and metastatic diseases, systemic therapy is recommended. While Sorafenib had been the standalone HCC first-line therapy for decades, recent developments had led to the approval of new treatment options as first-line as well as second-line treatment. Anti-PD-L1 directed combination therapies either with anti-VEGF directed agents or with anti-CTLA-4 active substances have been implemented as the new treatment standard in the first-line setting. However, data from clinical trials indicate different responses on specific therapeutic regimens depending on the underlying pathogenesis of hepatocellular cancer. Therefore, histopathological examinations have been re-emphasized by current international clinical guidelines in addition to the standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. In this review, we emphasize the current knowledge on molecular pathogenesis of hepatocellular carcinoma. On this occasion, the treatment sequences for early and advanced tumor stages according to the recently updated Barcelona Clinic Liver Cancer classification system and the current algorithm of systemic therapy (first-, second-, and third-line treatment) are summarized. Furthermore, we discuss novel precautional and pre-therapeutic approaches including therapeutic vaccination, adoptive cell transfer, locoregional therapy enhancement, and non-coding RNA-based therapy as promising treatment options. These novel treatments may prolong overall survival rates in regard with quality of life and liver function as mainstay of HCC therapy
The p53 Family of Transcription Factors Represses the Alpha- fetoprotein Gene Expression in Hepatocellular Carcinoma
Background: p53 deletion and mutation as well as upregulation of alpha-fetoprotein (AFP) are hallmarks of hepatocarcinogenesis. p63 and p73 belong to the family of p53-related transcription factors expressing a variety of isoforms. The expression of dominant negative (ÎN) p73 is related to the reduced survival of patients with hepatocellular carcinoma (HCC). In this study, we characterized the interaction between p53 family-dependent signaling pathways and the regulation of AFP at the gene and protein levels as essential determinants of therapeutic response and prognosis in HCC.
Methods: Putative p53-, p63- and p73-binding sites within the AFP gene were identified in silico. Hep3B cells were transfected with plasmids encoding for p53, p63 and p73 to analyze the interplay of the p53 family with AFP. AFP transcription was determined by RT-qPCR. Protein levels of AFP, p53, p63 and p73 were analyzed by Western blot.
Results: Underlining the importance of the crosstalk between the p53 family-dependent pathways and AFP regulation we identified eight novel putative binding sites for the members of the p53 family within the introns 1, 2, 3, 4, 7, 8, 11, and 12 of the AFP gene. Accordingly, full-length isoforms of p53, p63 and p73 efficiently downregulated AFP both on mRNA and protein level. Thus, the p53 family members were identified to be major regulators of AFP repression. Of note, p63 was characterized as a novel and p73 as the most efficient repressor of AFP.
Conclusion: p53 mutation and upregulation of AFP are essential oncogenic events in the development of HCC. Here we show that AFP gene regulation occurs via a combined action of the p53 family members p53, p63 and p73. All three tumor suppressors reduce AFP gene and protein expression. Thus, our findings reveal a novel interaction of p53 family-dependent signaling pathways and AFP regulation at the gene and protein levels in HCC
Simultaneous Inhibition of Mcl-1 and Bcl-2 Induces Synergistic Cell Death in Hepatocellular Carcinoma
Despite the recent approval of new therapies, the prognosis for patients with hepatocellular carcinoma (HCC) remains poor. There is a clinical need for new highly effective therapeutic options. Here, we present a combined application of BH3-mimetics as a potential new treatment option for HCC. BH3-mimetics inhibit anti-apoptotic proteins of the BCL-2 family and, thus, trigger the intrinsic apoptosis pathway. Anti-apoptotic BCL-2 proteins such as Bcl-2 and Mcl-1 are frequently overexpressed in HCC. Therefore, we analyzed the efficacy of the two BH3-mimetics ABT-199 (Bcl-2 inhibitor) and MIK665 (Mcl-1 inhibitor) in HCC cell lines with differential expression levels of endogenous Bcl-2 and Mcl-1. While administration of one BH3-mimetic alone did not substantially trigger cell death, the combination of two inhibitors enhanced induction of the intrinsic apoptosis pathway. Both drugs acted synergistically, highlighting the effectivity of this specific BH3-mimetic combination, particularly in HCC cell lines. These results indicate the potential of combining inhibitors of the BCL-2 family as new therapeutic options in HCC
Case report: Predictability of clinical response and rejection risk after immune checkpoint inhibition in liver transplantation
BackgroundThe approval of Atezolizumab / Bevacizumab therapy (Atezo/Bev) in 2020 opened up a promising new treatment option for patients with end-stage hepatocellular carcinoma (HCC). However, liver transplant (LTx) patients with HCC are still denied this therapy owing to concerns about ICI-induced organ rejection and lack of regulatory approval.MethodsA prospective observational study at a tertiary liver transplant centre monitored the compassionate, off-label use of Atezo/Bev in a single, stable LTx recipient with non-resectable HCC recurrence. Close clinical, laboratory and immunological monitoring of the patient was performed throughout a four-cycle Atezo/Bev treatment. Measured parameters were selected after a systematic review of the literature on predictive markers for clinical response and risk of graft rejection caused by ICI therapy.Results19 articles describing 20 unique predictive biomarkers were identified. The most promising negative prognostic factors were the baseline values and dynamic course of IL-6, alpha-fetoprotein (AFP) and the AFP/CRP ratio. The frequency of regulatory T cells (Treg) reportedly correlates with the success of ICI therapy. PD-L1 and CD28 expression level with the allograft, peripheral blood CD4+ T cell numbers and Torque Teno Virus (TTV) titre may predict risk of LTx rejection following ICI therapy. No relevant side effects or acute rejection occurred during Atezo/Bev therapy; however, treatment did not prevent tumor progression. Absence of PD-L1 expression in pre-treatment liver biopsies, as well as a progressive downregulation of CD28 expression by CD4+ T cells during therapy, correctly predicted absence of rejection. Furthermore, increased IL-6 and AFP levels after starting therapy, as well as a reduction in blood Treg frequency, correctly anticipated a lack of therapeutic response.ConclusionAtezo/Bev therapy for unresectable HCC in stable LTx patients remains a controversial strategy because it carries a high-risk of rejection and therapeutic response rates are poorly defined. Although previously described biomarkers of rejection risk and therapeutic response agreed with clinical outcomes in the described case, these immunological parameters are difficult to reliably interpret. Clearly, there is an important unmet need for standardized assays and clinically validated cut-offs before we use these biomarkers to guide treatment decisions for our patients
IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction
Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. Results: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. Impact and implications: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.</p
IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction
Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. Results: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. Impact and implications: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.</p