Clinical management of liver cyst infections: an international, modified Delphi-based clinical decision framework.

Liver cyst infections often necessitate long-term hospital admission and are associated with considerable morbidity and mortality. We conducted a modified Delphi study to reach expert consensus for a clinical decision framework. The expert panel consisted of 24 medical specialists, including 12 hepatologists, from nine countries across Europe, North America, and Asia. The Delphi had three rounds. The first round (response rate 21/24 [88%]) was an online survey with questions constructed from literature review and expert opinion, in which experts were asked about their management preferences and rated possible management strategies for seven clinical scenarios. Experts also rated 14 clinical decision-making items for relevancy and defined treatment outcomes. During the second round (response rate 13/24 [54%]), items that did not reach consensus and newly suggested themes were discussed in an online panel meeting. In the third round (response rate 16/24 [67%]), experts voted on definitions and management strategies using an online survey based on previous answers. Consensus was predefined as a vote threshold of at least 75%. We identified five subclassifications of liver cyst infection according to cyst phenotypes and patient immune status and consensus on episode definitions (new, persistent, and recurrent) and criteria for treatment success or failure was reached. The experts agreed that fever and elevated C-reactive protein are pivotal decision-making items for initiating and evaluating the management of liver cyst infections. Consensus was reached on 26 management statements for patients with liver cyst infections across multiple clinical scenarios, including two treatment algorithms, which were merged into one after comments. We provide a clinical decision framework for physicians managing patients with liver cyst infections. This framework will facilitate uniformity in the management of liver cyst infections and can constitute the basis for the development of future guidelines.

Unraveling factors associated with textbook outcome after cholecystectomy in patients with uncomplicated cholecystolithiasis: A posthoc analysis of individual data of 1,124 patients.

BACKGROUND: A textbook outcome for the management of uncomplicated cholecystolithiasis is the targeted clinical scenario and is characterized by no recurrent biliary colic, absence of surgical and biliary complications, and absence or relief of abdominal pain. The aim of this study was to assess the incidence of textbook outcomes after cholecystectomy and identify associated baseline factors. METHODS: Patients from 2 Dutch multicenter prospective trials between 2014 and 2019 (SECURE and SUCCESS trial) were included. The primary outcome was the proportion of patients with textbook outcomes after cholecystectomy at 6-month follow-up. Regression analysis was used to identify which factors before surgery were associated with textbook outcomes. RESULTS: A total of 1,124 patients underwent cholecystectomy. A textbook outcome at 6-month follow-up was reached in 67.9% of patients. Persistent abdominal pain was the main reason for the failure to achieve textbook outcome. Patients who did achieve textbook outcomes more often reported severe pain attacks (89.4% vs 81.7%, P < .001) and/or biliary colic (78.6% vs 68.4%, P < .001) at baseline compared with patients without textbook outcomes. The presence of biliary colic at baseline (odds ratio = 1.56, 95% confidence interval: 1.16-2.09, P = .003) and nausea/vomiting at baseline (odds ratio = 1.33, 95% confidence interval: 1.01-1.74, P = .039) were associated with textbook outcome. The use of non-opioid analgesics (odds ratio = 0.76, 95% confidence interval: 0.58-0.99, P = .043) and pain frequency ≥1/month (odds ratio = 0.56, 95% confidence interval: 0.43-0.73, P < .001) were negatively associated with textbook outcome. CONCLUSION: Textbook outcome is achieved in two-thirds of patients who undergo cholecystectomy for uncomplicated cholecystolithiasis. Intensity and frequency of pain, presence of biliary colic, and nausea/vomiting at baseline are independently associated with achieving textbook outcomes. A more stringent selection of patients may optimize the textbook outcome rate in patients with uncomplicated cholecystolithiasis.

Sialic Acid-Siglec-E Interactions Regulate the Response of Neonatal Macrophages to Group B Streptococcus.

The mammalian Siglec receptor sialoadhesin (Siglec1, CD169) confers innate immunity against the encapsulated pathogen group B Streptococcus (GBS). Newborn lung macrophages have lower expression levels of sialoadhesin at birth compared with the postnatal period, increasing their susceptibility to GBS infection. In this study, we investigate the mechanisms regulating sialoadhesin expression in the newborn mouse lung. In both neonatal and adult mice, GBS lung infection reduced Siglec1 expression, potentially delaying acquisition of immunity in neonates. Suppression of Siglec1 expression required interactions between sialic acid on the GBS capsule and the inhibitory host receptor Siglec-E. The Siglec1 gene contains multiple STAT binding motifs, which could regulate expression of sialoadhesin downstream of innate immune signals. Although GBS infection reduced STAT1 expression in the lungs of wild-type newborn mice, we observed increased numbers of STAT1+ cells in Siglece-/- lungs. To test if innate immune activation could increase sialoadhesin at birth, we first demonstrated that treatment of neonatal lung macrophages ex vivo with inflammatory activators increased sialoadhesin expression. However, overcoming the low sialoadhesin expression at birth using in vivo prenatal exposures or treatments with inflammatory stimuli were not successful. The suppression of sialoadhesin expression by GBS-Siglec-E engagement may therefore contribute to disease pathogenesis in newborns and represent a challenging but potentially appealing therapeutic opportunity to augment immunity at birth.

Multisegmented esophageal fully covered self-expandable metal stent for palliation of malignant dysphagia: a prospective, multicenter feasibility and safety study.

BACKGROUND AND AIMS: A novel multisegmented esophageal fully covered self-expandable metal stent (FCSEMS) was designed to reduce stent migration, which is seen in up to 30% of patients. The goal of this study was to evaluate the safety and efficacy of the multisegmented FCSEMS. METHODS: This multicenter prospective study aimed to include 30 patients undergoing palliative stent placement. Efficacy, defined as technically successful stent placement and dysphagia scores, and safety, defined as the number of adverse events (AEs) and serious AEs (SAEs), were measured. RESULTS: The study was prematurely terminated due to safety concerns after including 23 patients (mean ± standard deviation age, 72 ± 10 years; 78% male). Stent placement was technically successful in 21 patients (91%), and dysphagia scores had improved in all patients with successful stent placement. SAEs were reported in 16 (70%) patients. Stent-related mortality occurred in 3 patients (13%). CONCLUSIONS: The multisegmented FCSEMS successfully treated malignant dysphagia. The study was prematurely terminated, however, because stent placement was associated with a relatively high SAE rate. (Clinical trial registration number: NCT04415463.).

Cashmeran as a potential endocrine disrupting chemical: What does the weight-of-the-evidence indicate?

Cashmeran is a fragrance ingredient. Risk assessments are available but have not focused on its endocrine disruptor potential. The objective was to evaluate Cashmeran as a potential endocrine-disrupting chemical (EDC). The assessment was based on data from US EPA's CompTox Chemicals Dashboard, the Danish (Q)SAR Database, in vitro assays, and in vivo studies. ToxCast assays related to estrogen, androgen, thyroid, and steroidogenesis modalities were Inactive at non-cytotoxic concentrations. In vitro assays demonstrated no estrogenic activity in a human cervical epithelioid carcinoma HeLa cell line and indicated only weak agonist estrogenic activity in Chinese Hamster Ovary (CHO)-K1 cells. In the same test, no agonist or antagonist activity was detected for human androgen receptor (hAR) and thyroid hormone receptor ß (hTHRß) binding. The Danish QSAR database didn't indicate any ED potential. There were no adverse endocrine related effects in either a 90-day repeated gavage dosing study or a reproductive and developmental screening study. Regarding ED potential for environment, the data from two limited environmental ED related studies on Cashmeran did not raise any concern. Data from in vitro and in vivo studies were considered for environmental ED concern. Based on the weight-of-the-evidence, Cashmeran is not expected to cause endocrine effects.

Clinical trials on curcumin in relation to its bioavailability and effect on malignant diseases: critical analysis.

Curcumin is an ingredient of the root Curcuma longa, which is responsible for the characteristic yellow color of curcuma. Curcumin is said to have the potential ability to fight malignant diseases and to have an anti-inflammatory effect. In addition, it is used as a dietary supplement. However, one problem with the use of curcumin is its extremely low bioavailability. The aim of this study is to systematically review and critically analyze clinical studies related to the pharmacokinetics (or bioavailability) and to the use of curcumin in the treatment of malignant diseases. The platforms clinicaltrials.gov and PubMed served as the database for the literature research. A total of 293 available studies on curcumin were filtered according to their focus (bioavailability, therapy of malignant diseases) and other criteria (study results, main substance, topic reference, existing disease/other research purpose, reference to malignant diseases). The studies were further analyzed regarding their outcome measures, their design (number of participants, randomization, placebo group, masking, ethical standards, sponsor, primary outcome measures, secondary outcome measures, study bias) and their findings. The analysis failed to convincingly demonstrate that curcumin has a significant, positive effect on the therapy of malignant diseases. Regarding the increase in bioavailability, positive results have been obtained, which are in proximity to the pharmaceutical industry. Independent studies could not achieve increased bioavailability of curcumin. The available reviews in the literature also do not provide convincing evidence for the efficacy of curcumin. Thus, at the time being, the use of curcumin in malignant diseases is not justified scientifically.

CD40L modulates CD4+ T-cell activation through receptor for activated C kinase 1.

Inhibition of the co-stimulatory ligand CD40L has shown beneficial effects in many experimental models of autoimmune disease and inflammation. Here, we show that CD40L deficiency in T cells in mice causes a reduction of CD4+ T-cell activation and specifically a strong reduction in IFN-γ-producing Th1 cells. In vitro, we could not reproduce this antigen presenting cell-dependent effects, but found that T-cell CD40L affects cell death and proliferation. We identified receptor of activated C kinase, the canonical PKC binding partner and known to drive proliferation and apoptosis, as a mediator of CD40L reverse signaling. Furthermore, we found that CD40L clustering stabilizes IFN-γ mediated Th1 polarization through STAT1, a known binding partner of receptor of activated C kinase. Together this highlights the importance of both CD40L forward and reverse signaling.

Persistent and new-onset symptoms after cholecystectomy in patients with uncomplicated symptomatic cholecystolithiasis: A post hoc analysis of 2 prospective clinical trials.

BACKGROUND: Laparoscopic cholecystectomy is the gold standard for treating biliary colic in patients with gallstones, but post-cholecystectomy abdominal pain is commonly reported. This study investigates which symptoms are likely to persist and which may develop after a cholecystectomy. METHODS: Patients from 2 previous prospective trials who underwent laparoscopic cholecystectomy for symptomatic cholecystolithiasis were included. Patients completed questionnaires on pain and gastrointestinal symptoms before surgery and at 6 months follow-up. The prevalence of persistent and new-onset abdominal symptoms was evaluated. RESULTS: A total of 820 patients received cholecystectomy and were included, 75.4% female (n = 616/820) mean age 49.4 years (standard deviation 13.7). At baseline, 74.1% (n = 608/820) of patients met all criteria for biliary colic. Cholecystectomy successfully resolved biliary colic in 94.8% (n = 327/345) of patients, but 36.5% (n = 299/820) of patients reported persistent abdominal pain after 6 months of follow-up. The prevalence of most abdominal symptoms reduced significantly. Symptoms such as flatulence (17.8%, n = 146/820) or restricted eating (14.5%, n = 119/820) persisted most often. New-onset symptoms were frequent bowel movements (9.6%, n = 79/820), bowel urgency (8.5%, n = 70/820), and new-onset diarrhea (8.4%, 69/820). CONCLUSION: Postcholecystectomy symptoms are mainly flatulence, frequent bowel movements, and restricted eating. Newly reported symptoms are mainly frequent bowel movements, bowel urgency, and diarrhea. The present findings give clinical guidance in informing, managing, and treating patients with symptoms after cholecystectomy.

Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells.

INTRODUCTION: Posttranslational modification of proteins by reversible acetylation regulates key biological processes. Histone deacetylases (HDACs) catalyze protein deacetylation and are frequently dysregulated in tumors. This has spurred the development of HDAC inhibitors (HDACi). Such epigenetic drugs modulate protein acetylation, eliminate tumor cells, and are approved for the treatment of blood cancers. OBJECTIVES: We aimed to identify novel, nanomolar HDACi with increased potency over existing agents and selectivity for the cancer-relevant class I HDACs (HDAC1,-2,-3,-8). Moreover, we wanted to define how such drugs control the apoptosis-autophagy interplay. As test systems, we used human leukemic cells and embryonic kidney-derived cells. METHODS: We synthesized novel pyrimidine-hydroxamic acid HDACi (KH9/KH16/KH29) and performed in vitro activity assays and molecular modeling of their direct binding to HDACs. We analyzed how these HDACi affect leukemic cell fate, acetylation, and protein expression with flow cytometry and immunoblot. The publicly available DepMap database of CRISPR-Cas9 screenings was used to determine sensitivity factors across human leukemic cells. RESULTS: Novel HDACi show nanomolar activity against class I HDACs. These agents are superior to the clinically used hydroxamic acid HDACi SAHA (vorinostat). Within the KH-series of compounds, KH16 (yanostat) is the most effective inhibitor of HDAC3 (IC50 = 6 nM) and the most potent inducer of apoptosis (IC50 = 110 nM; p < 0.0001) in leukemic cells. KH16 though spares embryonic kidney-derived cells. Global data analyses of knockout screenings verify that HDAC3 is a dependency factor in 115 human blood cancer cells of different lineages, independent of mutations in the tumor suppressor p53. KH16 alters pro- and anti-apoptotic protein expression, stalls cell cycle progression, and induces caspase-dependent processing of the autophagy proteins ULK1 and p62. CONCLUSION: These data reveal that HDACs are required to stabilize autophagy proteins through suppression of apoptosis in leukemic cells. HDAC3 appears as a valid anti-cancer target for pharmacological intervention.

The regulatory landscape of macrophage interferon signaling in inflammation.

The pervasive role of the innate immune system is established by interferons. Emerging research shows an underappreciated ability of macrophages to regulate and propagate interferon responses in infectious and autoinflammatory disease states. In this review, we will discuss recent findings demonstrating the immunomodulating effects of macrophage interferon signaling. Apart from provoking cellular antimicrobial defenses, interferons augment the inflammatory activity of macrophages. These immunologic adaptations place the macrophage in the center of the interferon system and at the forefront of immunity. Consequently, macrophages are implicated in the pathogenesis of interferon-driven autoinflammatory disorders, such as SLE. In these disease states, the recognition of immunogenic ligands triggers macrophages to adopt an inflammatory phenotype through interferon signaling. This will amplify immune responses, eventually leading to autoinflammation. A better understanding of the macrophage's role in interferon signaling will support the future elucidation of novel targets amendable for clinical treatment.

Sterol-regulated transmembrane protein TMEM86a couples LXR signaling to regulation of lysoplasmalogens in macrophages.

Lysoplasmalogens are a class of vinyl ether bioactive lipids that have a central role in plasmalogen metabolism and membrane fluidity. The liver X receptor (LXR) transcription factors are important determinants of cellular lipid homeostasis owing to their ability to regulate cholesterol and fatty acid metabolism. However, their role in governing the composition of lipid species such as lysoplasmalogens in cellular membranes is less well studied. Here, we mapped the lipidome of bone marrow-derived macrophages (BMDMs) following LXR activation. We found a marked reduction in the levels of lysoplasmalogen species in the absence of changes in the levels of plasmalogens themselves. Transcriptional profiling of LXR-activated macrophages identified the gene encoding transmembrane protein 86a (TMEM86a), an integral endoplasmic reticulum protein, as a previously uncharacterized sterol-regulated gene. We demonstrate that TMEM86a is a direct transcriptional target of LXR in macrophages and microglia and that it is highly expressed in TREM2+/lipid-associated macrophages in human atherosclerotic plaques, where its expression positively correlates with other LXR-regulated genes. We further show that both murine and human TMEM86a display active lysoplasmalogenase activity that can be abrogated by inactivating mutations in the predicted catalytic site. Consequently, we demonstrate that overexpression of Tmem86a in BMDM markedly reduces lysoplasmalogen abundance and membrane fluidity, while reciprocally, silencing of Tmem86a increases basal lysoplasmalogen levels and abrogates the LXR-dependent reduction of this lipid species. Collectively, our findings implicate TMEM86a as a sterol-regulated lysoplasmalogenase in macrophages that contributes to sterol-dependent membrane remodeling.

Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs.

Regulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of TF spacing alterations resulting from naturally occurring insertions and deletions (InDels) has not been systematically analyzed. To address this question, we first characterized the genome-wide spacing relationships of 73 TFs in human K562 cells as determined by ChIP-seq (chromatin immunoprecipitation sequencing). We found a dominant pattern of a relaxed range of spacing between collaborative factors, including 45 TFs exclusively exhibiting relaxed spacing with their binding partners. Next, we exploited millions of InDels provided by genetically diverse mouse strains and human individuals to investigate the effects of altered spacing on TF binding and local histone acetylation. These analyses suggested that spacing alterations resulting from naturally occurring InDels are generally tolerated in comparison to genetic variants directly affecting TF binding sites. To experimentally validate this prediction, we introduced synthetic spacing alterations between PU.1 and C/EBPß binding sites at six endogenous genomic loci in a macrophage cell line. Remarkably, collaborative binding of PU.1 and C/EBPß at these locations tolerated changes in spacing ranging from 5 bp increase to >30 bp decrease. Collectively, these findings have implications for understanding mechanisms underlying enhancer selection and for the interpretation of non-coding genetic variation.

Functional Dyspepsia and Irritable Bowel Syndrome are Highly Prevalent in Patients With Gallstones and Are Negatively Associated With Outcomes After Cholecystectomy: A Prospective, Multicenter, Observational Study (PERFECT - Trial).

OBJECTIVE: To determine the prevalence of FD and IBS in patients eligible for cholecystectomy and to investigate the association between presence of FD/ IBS and resolution of biliary colic and a pain-free state. SUMMARY BACKGROUND DATA: More than 30% of patients with symptomatic cholecystolithiasis reports persisting pain postcholecystectomy. Coexistence of FD/IBS may contribute to this unsatisfactory outcome. METHODS: We conducted a multicenter, prospective, observational study (PERFECT-trial). Patients ≥18 years with abdominal pain and gallstones were included at 5 surgical outpatient clinics between 01/2018 and 04/2019. Follow-up was 6 months. Primary outcomes were prevalence of FD/IBS, and the difference between resolution of biliary colic and pain-free state in patients with and without FD/IBS. FD/IBS was defined by the Rome IV criteria, biliary colic by the Rome III criteria, and pain-free by an Izbicki Pain Score ≤10 and visual analogue scale ≤4. RESULTS: We included 401 patients with abdominal pain and gallstones (assumed eligible for cholecystectomy), mean age 52 years, 76% females. Of these, 34.9% fulfilled criteria for FD/IBS. 64.1% fulfilled criteria for biliary colic and 74.9% underwent cholecystectomy, with similar operation rates in patients with and without FD/IBS. Postcholecystectomy, 6.1% of patients fulfilled criteria for biliary colic, with no significant difference between those with and without FD/IBS at baseline (4.9% vs 8.6%, P = 0.22). Of all patients, 56.8% was pain-free after cholecystectomy, 40.7% of FD/IBS-group vs 64.4% of no FD/IBS-group, P < 0.001. CONCLUSIONS: One third of patients eligible for cholecystectomy fulfil criteria for FD/IBS. Biliary colic is reported by only a few patients postcholecys-tectomy, whereas nonbiliary abdominal pain persists in >40%, particularly in those with FD/IBS precholecystectomy. Clinicians should take these symptom-dependent outcomes into account in their shared decision-making process. TRIAL REGISTRATION: The Netherlands Trial Register NTR-7307. Registered on 18 June 2018.

Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4.

Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletions provided by five inbred strains of mice on the responses of macrophages to interleukin-4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage-determining and signal-dependent transcription factors driving IL-4 enhancer activation. These studies further revealed mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.

Web-Based Educational Intervention for Patients With Uninvestigated Dyspepsia Referred for Upper Gastrointestinal Tract Endoscopy: A Randomized Clinical Trial.

Importance: Diagnostic yield of upper gastrointestinal (GI) tract endoscopy for uninvestigated dyspepsia is low, and its clinical implications are limited. There is an unmet need for better strategies to reduce the volume of upper GI tract endoscopic procedures for dyspepsia. Objective: To study the effectiveness of a web-based educational intervention as a tool to reduce upper GI tract endoscopy in uninvestigated dyspepsia. Design, Setting, and Participants: This open-label, multicenter, randomized clinical trial enrolled participants between November 1, 2017, and March 31, 2019, with follow-up 52 weeks after randomization, at 4 teaching hospitals in the Netherlands. Participants included patients with uninvestigated dyspeptic symptoms who were referred for upper GI tract endoscopy by their general health care clinician without prior consultation of a gastroenterologist. A total of 119 patients, aged 18 to 69 years, were included. Patients were excluded if any of the following red flag symptoms were present: (indirect) signs of upper GI tract hemorrhage (hematemesis, melena, hematochezia, or anemia), unintentional weight loss of 5% or higher of normal body weight during a period of 6 to 12 months, persistent vomiting, dysphagia, or jaundice. Interventions: Patients were randomly assigned (1:1) to education (intervention) or upper GI tract endoscopy (control). Education consisted of a self-managed web-based educational intervention, containing information on gastric function, dyspepsia, and upper GI tract endoscopy. Main Outcomes and Measures: Difference in the proportion of upper GI tract endoscopy procedures between those who received access to the web-based educational intervention and those who did not at 12 weeks and 52 weeks after randomization, analyzed in the intention-to-treat population. Secondary outcomes included quality of life (Nepean Dyspepsia Index) and symptom severity (Patient Assessment of Gastrointestinal Disorders Symptom Severity Index) measured at baseline and 12 weeks. Results: Of 119 patients included (median age, 48 years [interquartile range, 37-56 years]; 48 men [40%]), 62 were randomized to web-based education (intervention) and 57 to upper GI tract endoscopy (control). Significantly fewer patients compared with controls underwent upper GI tract endoscopy after using the web-based educational intervention: 24 (39%) vs 47 (82%) (relative risk, 0.46; 95% CI, 0.33-0.64; P < .001). Symptom severity and quality of life improved equivalently in both groups. One additional patient in the intervention group required upper GI tract endoscopy during follow-up. Conclusions and Relevance: Findings of this study indicate that web-based patient education is an effective tool to decrease the need for upper GI tract endoscopy in uninvestigated dyspepsia. Trial Registration: ClinicalTrials.gov Identifier: NCT03205319.

The yield of upper gastrointestinal endoscopy in patients below 60 years and without alarm symptoms presenting with dyspepsia.

BACKGROUND AND AIMS: Upper gastrointestinal (GI) endoscopy is frequently performed in patients with upper abdominal symptoms. Although guidelines recommend withholding an endoscopy in the absence of alarm symptoms, dyspeptic symptoms remain a predominant indication for endoscopy. We aimed to investigate the yield of upper GI endoscopy in patients with low-risk dyspeptic symptoms. METHODS: We conducted an analysis in a prospectively maintained endoscopy reporting database. We collected the results of all upper GI endoscopy procedures between 2015 and 2019 that was performed in adult patients aged <60 years with dyspeptic symptoms. Patients with documented alarm symptoms were excluded. We categorized endoscopic findings into major and minor endoscopic findings. RESULTS: We identified 26,440 patients with dyspeptic symptoms who underwent upper GI endoscopy. A total of 13,978 patients were considered low-risk and included for analysis (median age 46 years, interquartile range (IQR) [36-53], 62% female). In 11,353 patients (81.2%), no endoscopic abnormalities were detected. Major endoscopic findings were seen in 513 patients (3.7%) and minor endoscopic findings in 2178 patients (15.6%). Endoscopic findings indicative of upper GI cancer were reported in 47 patients (0.3%), including 16 (0.1%) oesophageal, 28 (0.2%) gastric and 5 (0.04%) duodenal lesions. Despite an initial unremarkable endoscopy result, 1015 of 11,353 patients (8.9%) underwent a follow-up endoscopy after a median of 428 days [IQR 158-819]. This did not lead to the additional identification of malignancy. CONCLUSIONS: The yield of upper GI endoscopy in low-risk (<60 years, no alarm symptoms) patients with dyspepsia is very limited. This study further supports a restrictive use of upper GI endoscopy in these patients.

Genome-wide screens uncover KDM2B as a modifier of protein binding to heparan sulfate.

Heparan sulfate (HS) proteoglycans bind extracellular proteins that participate in cell signaling, attachment and endocytosis. These interactions depend on the arrangement of sulfated sugars in the HS chains generated by well-characterized biosynthetic enzymes; however, the regulation of these enzymes is largely unknown. We conducted genome-wide CRISPR-Cas9 screens with a small-molecule ligand that binds to HS. Screening of A375 melanoma cells uncovered additional genes and pathways impacting HS formation. The top hit was the epigenetic factor KDM2B, a histone demethylase. KDM2B inactivation suppressed multiple HS sulfotransferases and upregulated the sulfatase SULF1. These changes differentially affected the interaction of HS-binding proteins. KDM2B-deficient cells displayed decreased growth rates, which was rescued by SULF1 inactivation. In addition, KDM2B deficiency altered the expression of many extracellular matrix genes. Thus, KDM2B controls proliferation of A375 cells through the regulation of HS structure and serves as a master regulator of the extracellular matrix.

Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity.

Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.