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Background: The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes are still missing. Methods: Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice. Results: Here, we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5 p was the most associated with whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5 p overexpression. Weight loss in obese mice decreased hepatic miR-182-5 p and restored Lrp6 expression and other miR-182-5 p target genes. Hepatic overexpression of miR-182-5 p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days. Conclusions: By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182-5 p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5 p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis. Funding: This work was supported by research funding from the Deutsche Forschungsgemeinschaft (KI 1887/2-1, KI 1887/2-2, KI 1887/3-1 and CRC-TR296), the European Research Council (ERC, CoG Yoyo LepReSens no. 101002247; PTP), the Helmholtz Association (Initiative and Networking Fund International Helmholtz Research School for Diabetes; MB) and the German Center for Diabetes Research (DZD Next Grant 82DZD09D1G).
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Diabetes Mellitus Tipo 2 , Fígado , MicroRNAs , Obesidade , Transcriptoma , MicroRNAs/metabolismo , MicroRNAs/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Animais , Humanos , Obesidade/genética , Obesidade/metabolismo , Fígado/metabolismo , Camundongos , Masculino , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Perfilação da Expressão GênicaRESUMO
Background: It remains unknown whether there is a causal relationship between intraoperative hypotension and postoperative neurocognitive disorders. We tested the hypothesis that personalised-compared to routine-intraoperative blood pressure management reduces the incidence of postoperative neurocognitive disorders in patients having major noncardiac surgery. Methods: In this single-centre trial, 328 elective major noncardiac surgery patients were randomly allocated to receive personalised blood pressure management (i.e. maintaining intraoperative mean arterial pressure [MAP] above preoperative baseline MAP from automated 24-h blood pressure monitoring) or routine blood pressure management (i.e. maintaining MAP above 65 mm Hg). The primary outcome was the incidence of neurocognitive disorders (composite of delayed neurocognitive recovery and delirium) between postoperative days 3 and 7. Results: The primary outcome, neurocognitive disorders, occurred in 18 of 147 patients (12%) assigned to personalised and 21 of 148 patients (14%) assigned to routine blood pressure management (odds ratio [OR]=0.84, 95% confidence interval [CI]: 0.40-1.75, P=0.622). Delayed neurocognitive recovery occurred in 17 of 146 patients (12%) assigned to personalised and 17 of 145 patients (12%) assigned to routine blood pressure management (OR=0.99, 95% CI: 0.45-2.17, P=0.983). Delirium occurred in 2 of 157 patients (1%) assigned to personalised and 4 of 158 patients (3%) assigned to routine blood pressure management (OR=0.50, 95% CI: 0.04-3.53, P=0.684). Conclusions: Personalised intraoperative blood pressure management maintaining preoperative baseline MAP neither reduced the incidence of the composite primary outcome neurocognitive disorders between postoperative days 3 and 7 nor the incidences of the components of the composite primary outcome-delayed neurocognitive recovery and delirium-compared to routine blood pressure management in patients having major noncardiac surgery. Clinical trial registration: ClinicalTrials.gov (NCT03442907).
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Background: Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL. Methods: Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used. Results: The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes. Conclusion: IL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is responsible for eliciting Coronavirus disease 2019 (COVID-19) still challenges healthcare services worldwide. While many patients only suffer from mild symptoms, patients with some pre-existing medical conditions are at a higher risk for a detrimental course of disease. However, the underlying mechanisms determining disease course are only partially understood. One key factor influencing disease severity is described to be immune-mediated. In this report, we describe a post-mortem analysis of 45 individuals who died from SARS-CoV-2 infection. We could show that although sociodemographic factors and premedical conditions such as obesity and diabetes mellitus reduced survival time in our cohort, they were not associated with changes in the expression of immune-related signature genes at the RNA level in the blood, the gut, or the liver between these different groups. Our data indicate that obesity and diabetes mellitus influence SARS-CoV-2-related mortality, without influencing the extrapulmonary gene expression of immunity-related signature genes at the RNA level.
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To investigate underlying mechanisms for cancer metastasis and promising therapies in animal models, spontaneous metastasis models can be used to recreate metastasis development. Here, we present three mouse models of spontaneous lung and/or liver metastasis induction. We describe steps for cancer cell preparation, mouse analgesia, and three injection techniques (subcutaneous, intracecal, and intramucosal). We then detail procedures for evaluating metastasis. Most of these models generate metastasis in a time span of 4 weeks in the majority of injected mice. For complete details on the use and execution of this protocol, please refer to Giannou et al.1.
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Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Pulmonares , Animais , Camundongos , Modelos Animais de DoençasRESUMO
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.
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Neoplasias Colorretais , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Interleucina-10 , Neoplasias Hepáticas/patologia , Receptores de Interleucina-10 , Microambiente TumoralRESUMO
BACKGROUND: Symptomatic and large hiatal hernia (HH) is a common disorder requiring surgical management. However, there is a lack of systematic, evidence-based recommendations summarizing recent reviews on surgical treatment of symptomatic HH. Therefore, this systematic review aimed to create evidence mapping on the key technical issues of HH repair based on the highest available evidence. METHODS: A systematic review identified studies on eight key issues of large symptomatic HH repair. The literature was screened for the highest level of evidence (LE from level 1 to 5) according to the Oxford Center for evidence-based medicine's scale. For each topic, only studies of the highest available level of evidence were considered. RESULTS: Out of the 28.783 studies matching the keyword algorithm, 47 were considered. The following recommendations could be deduced: minimally invasive surgery is the recommended approach (LE 1a); a complete hernia sac dissection should be considered (LE 3b); extensive division of short gastric vessels cannot be recommended; however, limited dissection of the most upper vessels may be helpful for a floppy fundoplication (LE 1a); vagus nerve should be preserved (LE 3b); a dorso-ventral cruroplasty is recommended (LE 1b); routine fundoplication should be considered to prevent postoperative gastroesophageal reflux (LE 2b); posterior partial fundoplication should be favored over other forms of fundoplication (LE 1a); mesh augmentation is indicated in large HH with paraesophageal involvement (LE 1a). CONCLUSION: The current evidence mapping is a reasonable instrument based on the best evidence available to guide surgeons in determining optimal symptomatic and large HH repair.
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Refluxo Gastroesofágico , Hérnia Hiatal , Laparoscopia , Humanos , Hérnia Hiatal/cirurgia , Refluxo Gastroesofágico/cirurgia , Fundoplicatura , ReoperaçãoRESUMO
The transplantation model provides the opportunity to assess the relevance of a molecule of interest for tumor cell extravasation by using a respective genetically modified donor animal. Here, we present a protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies. We describe steps for animal preparation, lung transplantation, and tumor cell injection. We then detail procedures for the direct comparison of tumor cell spreading between the genetically modified left lung and the naive right lung parenchyma. For complete details on the use and execution of this protocol, please refer to Giannou et al. (2023).1.
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Neoplasias Pulmonares , Transplante de Pulmão , Transplantes , Animais , CamundongosRESUMO
Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.
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Linfócitos T CD4-Positivos , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Interleucinas , Interleucina 22RESUMO
BACKGROUND: Patients undergoing bariatric surgery have a high incidence of non-alcoholic fatty liver disease (NAFLD). However, the effect of NAFLD or non-alcoholic steatohepatitis (NASH) on the weight loss and resolution of obesity-related disorders is a matter of debate. METHODS: In this study, we compare the long-term outcomes after bariatric with the presence of NAFLD in the liver biopsy at the time of surgery. RESULTS: The follow-up was available for 226 out of 288 patients. The mean follow-up time was 24.9 (± 13.6) months. The baseline histology showed that 112 patients (38.9%) had no NASH, 70 (24.3%) were borderline, and 106 (36.8%) had NASH. At follow-up, the mean BMI dropped from (52 ± 10.2) to (36.6 ± 8) kg/m 2. Excess weight loss (EWL) was similar in all NAFLD groups. Type 2 diabetes mellitus dropped from 35.7 to 11.4%, hypertension from 65.6 to 36.7%, hyperlipidemia from 62.3 to 33%, and obstructive sleep apnea from 37.5 to 14.9%. Only hyperlipidemia was significantly associated with NASH compared to the groups with no NASH or borderline NASH (p value = 0.002 and p value = 0.04, respectively) during the first two years of follow-up. CONCLUSION: The beneficial effects of bariatric surgery are evident across all patients with NAFLD. Patients with NASH have comparable outcomes regarding weight loss and resolution of obesity-related comorbidities.
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Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Hiperlipidemias , Hepatopatia Gordurosa não Alcoólica , Obesidade Mórbida , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/cirurgia , Diabetes Mellitus Tipo 2/complicações , Obesidade Mórbida/complicações , Obesidade Mórbida/cirurgia , Obesidade Mórbida/epidemiologia , Obesidade/complicações , Obesidade/cirurgia , Cirurgia Bariátrica/efeitos adversos , Redução de Peso , Fígado/patologiaRESUMO
The intestine is constantly balancing the maintenance of a homeostatic microbiome and the protection of the host against pathogens such as viruses. Many cytokines mediate protective inflammatory responses in the intestine, among them IL-1ß. IL-1ß is a proinflammatory cytokine typically activated upon specific danger signals sensed by the inflammasome. SARS-CoV-2 is capable of infecting multiple organs, including the intestinal tract. Severe cases of COVID-19 were shown to be associated with a dysregulated immune response, and blocking of proinflammatory pathways was demonstrated to improve patient survival. Indeed, anakinra, an Ab against the receptor of IL-1ß, has recently been approved to treat patients with severe COVID-19. However, the role of IL-1ß during intestinal SARS-CoV-2 infection has not yet been investigated. Here, we analyzed postmortem intestinal and blood samples from patients who died of COVID-19. We demonstrated that high levels of intestinal IL-1ß were associated with longer survival time and lower intestinal SARS-CoV-2 RNA loads. Concurrently, type I IFN expression positively correlated with IL-1ß levels in the intestine. Using human intestinal organoids, we showed that autocrine IL-1ß sustains RNA expression of IFN type I by the intestinal epithelial layer. These results outline a previously unrecognized key role of intestinal IL-1ß during SARS-CoV-2 infection.
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COVID-19 , Interferon Tipo I , Humanos , Citocinas , Intestinos , RNA Viral , SARS-CoV-2RESUMO
BACKGROUND: The Quality Outcomes Framework (QOF) is a pay incentive scheme in England designed to improve and standardise general practice. QOF attainment has been used as a proxy for primary care quality in previous research. AIM: To investigate whether there is a relationship between socioeconomic deprivation and QOF attainment in primary care in England. DESIGN & SETTING: Retrospective longitudinal study of primary care providers in England. METHOD: QOF scores were obtained for individual general practices in England from between 2007-2019 and linked to practice-level Indices of Multiple Deprivation (IMD) scores derived from census data. Beta regression analyses were used to analyse the relationship with either percentage of total QOF attainment or of domain-specific attainment with multivariate analyses, adjusting for additional practice-level demographics. QOF attainment in the most affluent quintile was used as the reference group. RESULTS: General practices in less deprived areas have consistently outperformed those in more deprived areas in terms of QOF achievement. Initially, the gap between least and most deprived practices decreased, however since 2015 there has been relatively little change in comparative performance. The magnitude of inequality was reduced after adjusting for demographic factors. Of the independent variables analysed, the proportion of patients aged >65 years ('over 65s') had the strongest relationship with QOF attainment. CONCLUSION: There remains an inequality in primary care quality by socioeconomic deprivation in England, even after accounting for demographic differences.
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OBJECTIVES: Better disease management can be achieved with earlier detection through robust, sensitive, and easily accessible biomarkers. The aim of the current study was to identify novel epigenetic biomarkers determining the risk of type 2 diabetes (T2D). METHODS: Livers of 10-week-old female New Zealand Obese (NZO) mice, slightly differing in their degree of hyperglycemia and liver fat content and thereby in their diabetes susceptibility were used for expression and methylation profiling. We screened for differences in hepatic expression and DNA methylation in diabetes-prone and -resistant mice, and verified a candidate (HAMP) in human livers and blood cells. Hamp expression was manipulated in primary hepatocytes and insulin-stimulated pAKT was detected. Luciferase reporter assays were conducted in a murine liver cell line to test the impact of DNA methylation on promoter activity. RESULTS: In livers of NZO mice, the overlap of methylome and transcriptome analyses revealed a potential transcriptional dysregulation of 12 hepatokines. The strongest effect with a 52% decreased expression in livers of diabetes-prone mice was detected for the Hamp gene, mediated by elevated DNA methylation of two CpG sites located in the promoter. Hamp encodes the iron-regulatory hormone hepcidin, which had a lower abundance in the livers of mice prone to developing diabetes. Suppression of Hamp reduces the levels of pAKT in insulin-treated hepatocytes. In liver biopsies of obese insulin-resistant women, HAMP expression was significantly downregulated along with increased DNA methylation of a homologous CpG site. In blood cells of incident T2D cases from the prospective EPIC-Potsdam cohort, higher DNA methylation of two CpG sites was related to increased risk of incident diabetes. CONCLUSIONS: We identified epigenetic changes in the HAMP gene which may be used as an early marker preceding T2D.
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Diabetes Mellitus Tipo 2 , Hepcidinas , Humanos , Feminino , Camundongos , Animais , Hepcidinas/genética , Hepcidinas/metabolismo , Metilação de DNA , Diabetes Mellitus Tipo 2/metabolismo , Estudos Prospectivos , Insulina/metabolismo , Obesidade/genética , Biomarcadores/metabolismo , Células Sanguíneas/metabolismoRESUMO
Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.
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About 20%-25% of patients experience weight regain (WR) or insufficient weight loss (IWL) following bariatric surgery (BS). Therefore, we aimed to retrospectively assess the effectiveness of adjunct treatment with semaglutide in patients without type 2 diabetes (T2D) with post-bariatric treatment failure over a 12 months period. Post-bariatric patients without T2D with WR or IWL (n = 29) were included in the analysis. The primary endpoint was weight loss 12 months after initiation of adjunct treatment. Secondary endpoints included change in body mass index, HbA1c, lipid profile, high sensitive C-reactive protein and liver enzymes. Total weight loss during semaglutide treatment added up to 14.7% ± 8.9% (mean ± SD, p < .001) after 12 months. Categorical weight loss was >5% in 89.7% of patients, >10% in 62.1% of patients, >15% in 34.5% of patients, >20% in 24.1% of patients and > 25% in 17.2% of patients. Adjunct treatment with semaglutide resulted in sustained weight loss regardless of sex, WR or IWL and type of surgery. Among patients with prediabetes (n = 6), 12 months treatment led to normoglycemia in all patients (p < .05). Treatment options to manage post-bariatric treatment failure are scarce. Our results imply a clear benefit of adjunct treatment with semaglutide in post-bariatric patients over a 12 months follow-up period.
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Bariatria , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Estudos Retrospectivos , Redução de Peso , Falha de TratamentoRESUMO
An optimized lymph node yield leads to better survival in colon cancer, but extended lymphadenectomy is not associated with survival benefits. Lymphatic mapping shows several colon cancers feature aberrant drainage pathways inducing local recurrence when not resected. Currently, different protocols exist for lymphatic mapping procedures. This meta-analysis assessed which protocol has the best capacity to detect tumor-draining and possibly metastatic lymph nodes. A systematic review was conducted according to PRISMA guidelines, including prospective trials with in vivo tracer application. The risk of bias was evaluated using the QUADAS-2 tool. Traced lymph nodes, total resected lymph nodes, and aberrant drainage detection rate were analyzed. Fifty-eight studies met the inclusion criteria, of which 42 searched for aberrant drainage. While a preoperative tracer injection significantly increased the traced lymph node rates compared to intraoperative tracing (30.1% (15.4, 47.3) vs. 14.1% (11.9, 16.5), p = 0.03), no effect was shown for the tracer used (p = 0.740) or the application sites comparing submucosal and subserosal injection (22.9% (14.1, 33.1) vs. 14.3% (12.1, 16.8), p = 0.07). Preoperative tracer injection resulted in a significantly higher rate of detected aberrant lymph nodes compared to intraoperative injection (26.3% [95% CI 11.5, 44.0] vs. 2.5% [95% CI 0.8, 4.7], p < 0.001). Analyzing 112 individual patient datasets from eight studies revealed a significant impact on aberrant drainage detection for injection timing, favoring preoperative over intraoperative injection (OR 0.050 [95% CI 0.010-0.176], p < 0.001) while indocyanine green presented itself as the superior tracer (OR 0.127 [95% CI 0.018-0.528], p = 0.012). Optimized lymphatic mapping techniques result in significantly higher detection of aberrant lymphatic drainage patterns and thus enable a personalized approach to reducing local recurrence.
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Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus does not only lead to pulmonary infection but can also infect other organs such as the gut, the kidney, or the liver. Recent studies confirmed that severe cases of COVID-19 are often associated with liver damage and liver failure, as well as the systemic upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα). However, the impact these immune mediators in the liver have on patient survival during SARS-CoV-2 infection is currently unknown. Here, by performing a post-mortem analysis of 45 patients that died from a SARS-CoV-2 infection, we find that an increased expression of TNFA in the liver is associated with elevated mortality. Using publicly available single-cell sequencing datasets, we determined that Kupffer cells and monocytes are the main sources of this TNFα production. Further analysis revealed that TNFα signaling led to the upregulation of pro-inflammatory genes that are associated with an unfavorable outcome. Moreover, high levels of TNFA in the liver were associated with lower levels of interferon alpha and interferon beta. Thus, TNFα signaling in the infected SARS-CoV-2 liver correlates with reduced interferon levels and overall survival time.
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COVID-19 , Fator de Necrose Tumoral alfa , Humanos , COVID-19/imunologia , Citocinas/imunologia , Fígado/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
De novo lipogenesis (DNL) in visceral adipose tissue (VAT) is associated with systemic insulin sensitivity. DNL in VAT is regulated through ChREBP activity and glucose uptake through Glut4 (encoded by Slc2a4). Slc2a4 expression, ChREBP activity, and DNL are decreased in obesity, the underlying cause however remains unidentified. We hypothesize that increased DNA methylation in an enhancer region of Slc2a4 decreases Slc2a4 expression in obesity and insulin resistance. We found that SLC2A4 expression in VAT of morbidly obese subjects with high HbA1c (>6.5%, n = 35) is decreased, whereas DNA methylation is concomitantly increased compared to morbidly obese subjects with low HbA1c (≤6.5%, n = 65). In diet-induced obese (DIO) mice, DNA methylation of Slc2a4 persistently increases with the onset of obesity and insulin resistance, while gene expression progressively decreases. The regulatory impact of DNA methylation in the investigated enhancer region on SLC2A4 gene expression was validated with a reporter gene assay. Additionally, treatment of 3T3 pre-adipocytes with palmitate/oleate during differentiation decreased DNA methylation and increased Slc2a4 expression. These findings highlight a potential regulation of Slc2a4 by DNA methylation in VAT, which is induced by fatty acids and may play a role in the progression of obesity and insulin resistance in humans.
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Resistência à Insulina , Insulinas , Obesidade Mórbida , Camundongos , Animais , Humanos , Resistência à Insulina/genética , Ácidos Graxos/metabolismo , Metilação de DNA , Obesidade Mórbida/metabolismo , Gordura Intra-Abdominal/metabolismo , Hemoglobinas Glicadas , Fatores de Transcrição/metabolismo , Insulinas/genética , Tecido Adiposo/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismoRESUMO
Remediation of residually contaminated soils remains a widespread problem. Biochar can immobilize polycyclic aromatic hydrocarbons (PAH). However, studies on its ability to immobilize PAH and N, S, and O substituted PAH (hetero-PAH) in real soils, and benchmarking with commercial activated carbon are missing. Here, we compared the ability of pristine biochar (BC), steam-activated biochar (SABC), and commercial activated carbon (AC) to immobilize PAH and hetero-PAH. The three carbons were tested on soils from four different contaminated sites in Austria. Different amendment rates (w/w) of the carbons were investigated (BC: 1.0, 2.5, and 5%; SABC: 0.5, 1.0, and 2.0%; AC: 1%) in batch experiments to cover meaningful ranges in relation to their performance. SABC performed better than AC, removing at least 80% PAH with the lowest application rate of 0.5%, and achieving a complete removal at an application rate of 1.0%. BC performed slightly worse but still acceptable in residually contaminated soils (40 and 100% removal at 1 and 5% amendment, respectively). The ability of BC and SABC to immobilize PAH decreased as the PAH-molar volume increased. PAH with three or more rings were preferentially removed by AC compared to SABC or BC. This can be explained by the difference in pore size distribution of the carbons which could limit the accessibility of PAH and hetero-PAH to reach sorption sites for π- π electron donor-acceptor interactions, which drive PAH and hetero-PAH sorption to carbons. Column percolation tests confirmed the results obtained in batch tests, indicating, that decisions for soil remediation can be derived from simpler batch experiments. In soil samples with 1% BC, a reduction of over 90% in the total concentration of PAH in the leached water was observed. Overall, BC and SABC were demonstrated to be valid substitutes for AC for stabilizing residually contaminated soils.
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Hidrocarbonetos Policíclicos Aromáticos , Poluentes do Solo , Hidrocarbonetos Policíclicos Aromáticos/análise , Carvão Vegetal , Benchmarking , Poluentes do Solo/análise , SoloRESUMO
BACKGROUND: Hematologic patients requiring abdominal emergency surgery are considered to be a high-risk population based on disease- and treatment-related immunosuppression. However, the optimal surgical therapy and perioperative management of patients with abdominal emergency surgery in patients with coexisting hematological malignancies remain unclear. METHODS: We here report a single-center retrospective analysis aimed to investigate the impact of abdominal emergency surgery due to clinically suspected gastrointestinal perforation (group A), intestinal obstruction (group B), or acute cholecystitis (group C) on mortality and morbidity of patients with coexisting hematological malignancies. All patients included in this retrospective single-center study were identified by screening for the ICD 10 diagnostic codes for gastrointestinal perforation, intestinal obstruction, and ischemia and acute cholecystitis. In addition, a keyword search was performed in the database of all pathology reports in the given time frame. RESULTS: A total of 56 patients were included in this study. Gastrointestinal perforation and intestinal obstruction occurred in 26 and 13 patients, respectively. Of those, 21 patients received a primary gastrointestinal anastomosis, and anastomotic leakage (AL) occurred in 33.3% and resulted in an AL-related 30-day mortality rate of 80%. The only factor associated with higher rates of AL was sepsis before surgery. In patients with suspected acute cholecystitis, postoperative bleeding events requiring abdominal packing occurred in three patients and lead to overall perioperative morbidity of 17.6% and surgery-related 30-day mortality of 5.9%. CONCLUSION: In patients with known or suspected hematologic malignancies who require emergency abdominal surgery due to gastrointestinal perforation or intestinal obstruction, a temporary or permanent stoma might be preferred to a primary intestinal anastomosis.