The enteric nervous system relays psychological stress to intestinal inflammation.

Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-ß2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

SeqCAT: Sequence Conversion and Analysis Toolbox.

Dealing with sequence coordinates in different formats and reference genomes is challenging in genetic research. This complexity arises from the need to convert and harmonize datasets of different sources using alternating nomenclatures. Since manual processing is time-consuming and requires specialized knowledge, the Sequence Conversion and Analysis Toolbox (SeqCAT) was developed for daily work with genetic datasets. Our tool provides a range of functions designed to standardize and convert gene variant coordinates based on various sequence types. Its user-friendly web interface provides easy access to all functionalities, while the Application Programming Interface (API) enables automation within pipelines. SeqCAT provides access to human genomic, protein and transcript data, utilizing various data resources and packages and extending them with its own unique features. The platform covers a wide range of genetic research needs with its 14 different applications and 3 info points, including search for transcript and gene information, transition between reference genomes, variant mapping, and genetic event review. Notable examples are 'Convert Protein to DNA Position' for translation of amino acid changes into genomic single nucleotide variants, or 'Fusion Check' for frameshift determination in gene fusions. SeqCAT is an excellent resource for converting sequence coordinate data into the required formats and is available at: https://mtb.bioinf.med.uni-goettingen.de/SeqCAT/.

An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.

Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression.

BACKGROUND AND AIMS: Genetic risk factors are major determinants of chronic liver disease (CLD) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin (AAT) E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD through increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown. Here, we aimed to test our working hypothesis that their combined incidence triggers CLD disease progression. APPROACH AND RESULTS: We showed that patients with PiZZ/PNPLA3 I148M from the European alpha-1-antitrypsin deficiency (AATD) liver consortium and the UK Biobank had a trend towards higher liver enzymes, but no increased liver fat accumulation was evident between subgroups. After generating transgenic mice that overexpress the PiZ variant and simultaneously harbor the PNPLA3 I148M knockin (designated as PiZ/PNPLA3 I148M ), we observed that animals with PiZ and PiZ/PNPLA3 I148M showed increased liver enzymes compared to controls during aging. However, no significant difference between PiZ and PiZ/PNPLA3 I148M groups was observed, with no increased liver fat accumulation over time. To further study the impact on CLD progression, a Western-styled diet was administered, which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3 I148M livers compared to controls, but the additional presence of PNPLA3 I148M had no impact on liver phenotype. Notably, the PiZ variant protected PNPLA3 I148M mice from liver damage and obesity after Western-styled diet feeding. CONCLUSION: Our results demonstrate that the PNPLA3 polymorphism in the absence of additional metabolic risk factors is insufficient to drive the development of advanced liver disease in severe AATD.

Cardiovascular and mortality outcomes with GLP-1 receptor agonists vs other glucose-lowering drugs in individuals with NAFLD and type 2 diabetes: a large population-based matched cohort study.

AIMS/HYPOTHESIS: We aimed to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1RA) in individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus decreases the risk of new-onset adverse cardiovascular events (CVEs) and mortality rate compared with other glucose-lowering drugs in a real setting at a population level. METHODS: We conducted a population-based propensity-matched retrospective cohort study using TriNetX. The cohort comprised patients over 20 years old who were newly treated with glucose-lowering drugs between 1 January 2013 and 31 December 2021, and followed until 30 September 2022. New users of GLP-1RAs were matched based on age, demographics, comorbidities and medication use by using 1:1 propensity matching with other glucose-lowering drugs. The primary outcome was the new onset of adverse CVEs, including heart failure, composite incidence of major adverse cardiovascular events (MACE; defined as unstable angina, myocardial infarction, or coronary artery procedures or surgeries) and composite cerebrovascular events (defined as the first occurrence of stroke, transient ischaemic attack, cerebral infarction, carotid intervention or surgery), and the secondary outcome was all-cause mortality. Cox proportional hazards models were used to estimate HRs. RESULTS: The study involved 2,835,398 patients with both NAFLD and type 2 diabetes. When compared with the sodium-glucose cotransporter 2 (SGLT2) inhibitors group, the GLP-1RAs group showed no evidence of a difference in terms of new-onset heart failure (HR 0.97; 95% CI 0.93, 1.01), MACE (HR 0.95; 95% CI 0.90, 1.01) and cerebrovascular events (HR 0.99; 95% CI 0.94, 1.03). Furthermore, the two groups had no evidence of a difference in mortality rate (HR 1.06; 95% CI 0.97, 1.15). Similar results were observed across sensitivity analyses. Compared with other second- or third-line glucose-lowering medications, the GLP-1RAs demonstrated a lower rate of adverse CVEs, including heart failure (HR 0.88; 95% CI 0.85, 0.92), MACE (HR 0.89; 95% CI 0.85, 0.94), cerebrovascular events (HR 0.93; 95% CI 0.89, 0.96) and all-cause mortality rate (HR 0.70; 95% CI 0.66, 0.75). CONCLUSIONS/INTERPRETATION: In individuals with NAFLD and type 2 diabetes, GLP-1RAs are associated with lower incidences of adverse CVEs and all-cause mortality compared with metformin or other second- and third-line glucose-lowering medications. However, there was no significant difference in adverse CVEs or all-cause mortality when compared with those taking SGLT2 inhibitors.

Epigenetic control of pancreatic cancer metastasis.

Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.

Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Comorbidities, mortality and metabolic profile in individuals with primary biliary cholangitis-A Phenome-Wide-Association-Study.

BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease that can lead to fibrosis and cirrhosis. In this cohort study, we aimed to investigate morbidity and mortality in conjunction with metabolomic changes of PBC in a UK population-based cohort. METHODS: 454 participants with PBC and 908 propensity score (age, sex, BMI, ethnicity) matched controls without liver disease were included in the study. A subset of participants with PBC and controls were analysed for their metabolomic profile. Further, PBC-associated comorbidities were investigated by PheWAS analysis. Lastly, we assessed causes of death in individuals with PBC using a Fine and Grey competing-risks regression model. RESULTS: Compared to the control group, various pathways associated with the metabolism of amino acids, lipids, and liver biochemistry were significantly enriched in individuals with PBC. We found reduced levels of S-HDL-cholesterol and Glycoprotein Acetyls in individuals with PBC as well as an association with diseases of the circulatory system. Notably, PBC individuals had a higher prevalence of digestive diseases, autoimmune diseases, cardiovascular diseases, anaemias, mental disorders, and urinary tract infections compared to the control group. Strikingly, the overall mortality was almost three times higher in the PBC group compared to the control group, with diseases of the digestive system accounting for a significant elevation of the death rate. A subsequent analysis, enhanced by propensity score matching that included the APRI score, demonstrated that the observed morbidity could not be exclusively attributed to advanced hepatic disease. CONCLUSIONS: Our study provides a detailed perspective on the morbidity of individuals with PBC. The exploration of potential effects of disease state on morbidity suggest that early detection and early treatment of PBC could enhance patient prognosis and prevent the onset of comorbid diseases. Finally, the metabolomic alterations could represent a link between the pathophysiological processes underlying PBC development, progression, and associated morbidity.

Soluble Neuropilin-1 Is Elevated in Sepsis and Correlates with Organ Dysfunction and Long-Term Mortality in Critical Illness.

Critical illness and sepsis may cause organ failure and are recognized as mortality drivers in hospitalized patients. Neuropilin-1 (NRP-1) is a multifaceted transmembrane protein involved in the primary immune response and is expressed in immune cells such as T and dendritic cells. The soluble form of NRP-1 (sNRP-1) acts as an antagonist to NRP-1 by scavenging its ligands. The aim of this study was to determine the value of sNRP-1 as a biomarker in critical illness and sepsis. We enrolled 180 critically ill patients admitted to a medical intensive care unit and measured serum sNRP-1 concentrations at admission, comparing them to 48 healthy individuals. Critically ill and septic patients showed higher levels of sNRP-1 compared to healthy controls (median of 2.47 vs. 1.70 nmol/L, p < 0.001). Moreover, sNRP-1 was also elevated in patients with sepsis compared to other critical illness (2.60 vs. 2.13 nmol/L, p = 0.01), irrespective of disease severity or organ failure. In critically ill patients, sNRP-1 is positively correlated with markers of kidney and hepatic dysfunction. Most notably, critically ill patients not surviving in the long term (one year after admission) showed higher concentrations of sNRP-1 at the time of ICU admission (p = 0.036), with this association being dependent on the presence of organ failure. Critically ill and septic patients exhibit higher serum concentrations of circulating sNRP-1, which correlates to organ failure, particularly hepatic and kidney dysfunction.

Risk of severe disease and mortality of COVID-19 in patients with Budd-Chiari syndrome: A population-based matched cohort study.

BACKGROUND & AIMS: Budd-Chiari syndrome (BCS) is a rare and potentially life-threatening disorder characterized by obstruction of the hepatic outflow tract. It is unknown whether patients with BCS represent a high risk for severe disease and mortality from coronavirus disease 2019 (COVID-19). Thus, we aimed to assess hospitalization rates, severe disease, all-cause mortality, intensive care unit (ICU) requirement and acute kidney injury (AKI) from COVID-19 diagnoses. METHODS & RESULTS: We identified 467 patients with BCS with COVID-19, 96 427 non-chronic liver disease (CLD) and 9652 non-BCS CLD. The BCS and non-CLD cohorts (n = 467 each) and BCS and non-BCS CLD (n = 440 each) were well balanced after propensity matching. When compared to the non-CLD cohort, the BCS group had a higher risk of all-cause mortality (5.1% vs. 2.4%, HR 2.18; 95% CI, 1.08-4.40), severe disease (6.0% vs. 2.4%, HR 2.20; 95% CI, 1.09-4.43), hospitalization (24.6% vs. 13.1%, HR 1.77; 95% CI, 1.30-2.42) and AKI (7.9% vs. 2.8%, HR 2.57; 95% CI, 1.37-4.85), but no significant differences in ICU requirements (2.4% vs. 2.1%, HR 0.75; 95% CI, 0.27-2.08) at 60-days time points. When compared to the non-BCS CLD cohort, the BCS group had a higher risk of all-cause mortality (3.6% vs. 2.5%, HR 3.94; 95% CI, 1.31-11.79), hospitalization (29.8% vs. 21.6%, HR 1.43; 95% CI, 1.09-1.86), but differences in ICU requirements (HR 0.90 (0.38-2.12)), AKI (HR 1.41 (0.86-2.30)) or severe disease (HR 1.92 (0.99-3.71)) did not reach statistical significance at 60-day follow up. CONCLUSION: In conclusion, COVID-19 infection in patients with BCS is associated with poor outcomes. Patients with BCS infected with COVID-19 carry a significantly higher risk of hospitalization and all-cause mortality and a possible effect on severe disease and AKI compared with COVID-19 patients without CLD or with non-BCS-CLD.

AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer.

Targeting KRAS downstream signaling remains an important therapeutic approach in pancreatic cancer. We used primary pancreatic ductal epithelial cells and mouse models allowing the conditional expression of oncogenic KrasG12D, to investigate KRAS signaling integrators. We observed that the AP1 family member FRA1 is tightly linked to the KRAS signal and expressed in pre-malignant lesions and the basal-like subtype of pancreatic cancer. However, genetic-loss-of-function experiments revealed that FRA1 is dispensable for KrasG12D-induced pancreatic cancer development in mice. Using FRA1 gain- and loss-of-function models in an unbiased drug screen, we observed that FRA1 is a modulator of the responsiveness of pancreatic cancer to inhibitors of the RAF-MEK-ERK cascade. Mechanistically, context-dependent FRA1-associated adaptive rewiring of oncogenic ERK signaling was observed and correlated with sensitivity to inhibitors of canonical KRAS signaling. Furthermore, pharmacological-induced degradation of FRA1 synergizes with MEK inhibitors. Our studies establish FRA1 as a part of the molecular machinery controlling sensitivity to MAPK cascade inhibition allowing the development of mechanism-based therapies.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder.

Alpha-1 antitrypsin deficiency (AATD) arises from mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT) that lead to AAT retention in the endoplasmic reticulum of hepatocytes, causing proteotoxic liver injury and loss-of-function lung disease. The homozygous Pi∗Z mutation (Pi∗ZZ genotype) is responsible for the majority of severe AATD cases and can precipitate both paediatric and adult liver diseases, while the heterozygous Pi∗Z mutation (Pi∗MZ genotype) is an established genetic modifier of liver disease. We review genotype-related hepatic phenotypes/disease predispositions. We also describe the mechanisms and factors promoting the development of liver disease, as well as approaches to evaluate the extent of liver fibrosis. Finally, we discuss emerging diagnostic and therapeutic approaches for the clinical management of this often neglected disorder.

Dietary Vitamin E Intake Is Associated With a Reduced Risk of Developing Digestive Diseases and Nonalcoholic Fatty Liver Disease.

INTRODUCTION: Vitamin E supplementation is recommended for the treatment of nonalcoholic fatty liver disease (NAFLD) for nondiabetic patients, but its preventative effects are unclear. METHODS: We assessed dietary vitamin E intake with disease phenotypes and evaluated vitamin E levels with the development of NAFLD. RESULTS: Data from >210,000 participants demonstrate that increased dietary vitamin E associates with reduced rates of several gastrointestinal diseases and reduced overall mortality. Diabetic and overweight subjects with increased vitamin E intake have fewer NAFLD diagnoses. DISCUSSION: Our findings reveal the relevance of vitamin E consumption for several gastrointestinal diseases and warrant further mechanistic and therapeutic investigations.

Comorbidities in lichen planus by phenome-wide association study in two biobank population cohorts.

BACKGROUND: Lichen planus (LP) is a relatively frequent mucocutaneous inflammatory disease affecting the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx. OBJECTIVES: To estimate the association of LP, with emphasis on dermatological and gastrointestinal conditions, in two large independent population cohorts. MATERIALS AND METHODS: We performed a phenome-wide association study (PheWAS) and examined conditions associated with LP in two unrelated cohorts, i.e. the multicentre, community-based UK Biobank (UKB: 501 381 controls; 1130 LP subjects) and the healthcare-associated Penn Medicine BioBank (PMBB; 42 702 controls; 764 LP subjects). The data were analysed in 2021. The 'PheWAS' R package was used to perform the PheWAS analyses and Bonferroni correction was used to adjust for multiple testing. Odds ratios (ORs) were adjusted for age, sex and body mass index. RESULTS: In the UKB, PheWAS revealed 133 phenome codes (PheCodes) significantly associated with LP and most of them were confirmed in PMBB. Dermatological and digestive PheCodes were the most abundant: 29 and 34 of these disorders, respectively, were significantly overrepresented in LP individuals from both cohorts. The 29 dermatological and 12 oral disorders were often highly enriched, whereas hepatic, gastric, oesophageal and intestinal PheCodes displayed ORs in the range of 1·6-4·5. Several autoimmune disorders also exhibited OR > 5 in both cohorts. CONCLUSIONS: PheWAS in two large unrelated cohorts identified previously unknown comorbidities and may support clinical counselling of patients with LP. What is already known about this topic? Lichen planus (LP) is known to affect the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx. What does this study add? Our data provide the most comprehensive collection of associated dermatological, digestive and autoimmune disorders to date. Our findings are expected to be useful for the evaluation and management of patients with LP.

Early prediction of decompensation (EPOD) score: Non-invasive determination of cirrhosis decompensation risk.

BACKGROUND & AIMS: Decompensation is a hallmark of disease progression in cirrhotic patients. Early detection of a phase transition from compensated cirrhosis to decompensation would enable targeted therapeutic interventions potentially extending life expectancy. This study aims to (a) identify the predictors of decompensation in a large, multicentric cohort of patients with compensated cirrhosis, (b) to build a reliable prognostic score for decompensation and (c) to evaluate the score in independent cohorts. METHODS: Decompensation was identified in electronic health records data from 6049 cirrhosis patients in the IBM Explorys database training cohort by diagnostic codes for variceal bleeding, encephalopathy, ascites, hepato-renal syndrome and/or jaundice. We identified predictors of clinical decompensation and developed a prognostic score using Cox regression analysis. The score was evaluated using the IBM Explorys database validation cohort (N = 17662), the Penn Medicine BioBank (N = 1326) and the UK Biobank (N = 317). RESULTS: The new Early Prediction of Decompensation (EPOD) score uses platelet count, albumin, and bilirubin concentration. It predicts decompensation during a 3-year follow-up in three validation cohorts with AUROCs of 0.69, 0.69 and 0.77, respectively, and outperforms the well-known MELD and Child-Pugh score in predicting decompensation. Furthermore, the EPOD score predicted the 3-year probability of decompensation. CONCLUSIONS: The EPOD score provides a prediction tool for the risk of decompensation in patients with cirrhosis that outperforms well-known cirrhosis scores. Since EPOD is based on three blood parameters, only, it provides maximal clinical feasibility at minimal costs.

A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer.

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

COVID-19: Challenges and solutions for the provision of care to seriously ill and dying people and their relatives during SARS-CoV-2 pandemic - perspectives of pandemic response team members: A qualitative study on the basis of expert interviews (part of PallPan).

BACKGROUND: During the SARS-CoV-2 pandemic's initial waves, bans on visiting and isolation measures placed limits on providing services for seriously ill and dying people and their relatives. Pandemic response teams at governmental level (macro), at federal state and municipal level (meso) and in healthcare facilities (micro) played their role in pandemic management procedures. AIM: To explore pandemic-related challenges and solutions of pandemic response teams regarding the provision of care to seriously ill and dying people and their relatives. Findings were to be integrated into a national strategy (PallPan). DESIGN: Semi-structured expert interviews (10/2020-2/2021) analysed via structured content analysis. SETTINGPARTICIPANTS: We interviewed 41 members, who discussed the work of 43 German pandemic response teams (micro n = 23; meso n = 20; no members were available at macro level) from 14 German federal states. RESULTS: Twenty-nine of 43 teams took account of the needs of seriously ill and dying. Their main challenges resulted from pandemic-related legal requirements in hospitals and long-term care facilities. The implementation of such was in the remits of the meso level. Dysfunctional or non-existent communication between the levels was reported to be challenging. To foster patient-related solutions the micro level pandemic response teams supported individual decisions to enable patient-relative contact for example, visiting and saying goodbye outside, meeting via digital solutions. CONCLUSIONS: Pandemic response teams evidently struggled to find appropriate solutions to ease pandemic-related impact on the care of seriously ill and dying patients and their relatives. We recommend bringing palliative care expertise on board.

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.

BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.

Mortality in Patients With Genetic and Environmental Risk of Liver Disease.

INTRODUCTION: The increasing liver-related mortality calls for hepatic surveillance programs. To design them, factors selectively increasing liver-related vs overall mortality need to be identified. METHODS: We analyzed mortality data from 467,558 individuals recruited by the community-based UK Biobank. The mean follow-up was 11.4 years. RESULTS: While all assessed genetic factors associated with increased liver-specific mortality, only homozygous TM6SF2 mutation and SERPINA1 mutation conferred elevated overall mortality. Among the environmental factors, obesity and metabolic syndrome disproportionately contributed to liver-related deaths. DISCUSSION: Our data demonstrate an interplay between genetics and environment and provide a basis for hepatic surveillance programs.