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.

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.

A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys.

The growing disparity between the demand for transplants and the available donor supply, coupled with an aging donor population and increasing prevalence of chronic diseases, highlights the urgent need for the development of platforms enabling reconditioning, repair, and regeneration of deceased donor organs. This necessitates the ability to preserve metabolically active kidneys ex vivo for days. However, current kidney normothermic machine perfusion (NMP) approaches allow metabolic preservation only for hours. Here we show that human kidneys discarded for transplantation can be preserved in a metabolically active state up to 4 days when perfused with a cell-free perfusate supplemented with TCA cycle intermediates at subnormothermia (25 °C). Using spatially resolved isotope tracing we demonstrate preserved metabolic fluxes in the kidney microenvironment up to Day 4 of perfusion. Beyond Day 4, significant changes were observed in renal cell populations through spatial lipidomics, and increases in injury markers such as LDH, NGAL and oxidized lipids. Finally, we demonstrate that perfused kidneys maintain functional parameters up to Day 4. Collectively, these findings provide evidence that this approach enables metabolic and functional preservation of human kidneys over multiple days, establishing a solid foundation for future clinical investigations.

Feasibility of implementing an integrated long-term database to advance ecosystem-based management in the Laurentian Great Lakes basin.

The North American Great Lakes have been experiencing dramatic change during the past half-century, highlighting the need for holistic, ecosystem-based approaches to management. To assess interest in ecosystem-based management (EBM), including the value of a comprehensive public database that could serve as a repository for the numerous physical, chemical, and biological monitoring Great Lakes datasets that exist, a two-day workshop was organized, which was attended by 40+ Great Lakes researchers, managers, and stakeholders. While we learned during the workshop that EBM is not an explicit mission of many of the participating research, monitoring, and management agencies, most have been conducting research or monitoring activities that can support EBM. These contributions have ranged from single-resource (-sector) management to considering the ecosystem holistically in a decision-making framework. Workshop participants also identified impediments to implementing EBM, including: 1) high anticipated costs; 2) a lack of EBM success stories to garner agency buy-in; and 3) difficulty in establishing common objectives among groups with different mandates (e.g., water quality vs. fisheries production). We discussed as a group solutions to overcome these impediments, including construction of a comprehensive, research-ready database, a prototype of which was presented at the workshop. We collectively felt that such a database would offer a cost-effective means to support EBM approaches by facilitating research that could help identify useful ecosystem indicators and management targets and allow for management strategy evaluations that account for risk and uncertainty when contemplating future decision-making.

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.

Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation.

T cells are the most common immune cells in atherosclerotic plaques, and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, upregulates core metabolic pathways and promotes differentiation into interleukin-9 (IL-9)-producing cells upon activation. RNA sequencing of non-activated T cells reveals that oleic acid upregulates genes encoding key enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis links these expression changes to the differentiation toward TH9 cells, a pro-atherogenic subset. Spectral flow cytometry shows that pre-exposure to oleic acid results in a skew toward IL-9+-producing T cells upon activation. Importantly, pharmacological inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, oleic acid may affect inflammatory diseases like atherosclerosis by rewiring T cell metabolism.

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.).

Red blood cells as oxygen carrier during normothermic machine perfusion of kidney grafts: Friend or foe?

Renal ex vivo normothermic machine perfusion (NMP) is under development as an assessment tool for high-risk kidney grafts and as a means of achieving more physiologically accurate organ preservation. On-going hemolysis has been reported during NMP, as this technique relies on red blood cells for oxygen delivery. In this study, we confirm the occurrence of progressive hemolysis during 6-hour kidney NMP. NMP-associated erythrostasis in the glomeruli and in peri-glomerular vascular networks points to an interaction between the red blood cells and the graft. Continuous hemolysis resulted in prooxidative changes in the perfusate, which could be quenched by addition of fresh frozen plasma. In a cell-based system, this hemolysis induced redox stress and exhibited toxic effects at high concentrations. These findings highlight the need for a more refined oxygen carrier in the context of renal NMP.

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.

Endothelial to mesenchymal transition in kidney fibrosis.

Fibrotic disease are characterized by the uncontrolled accumulation of extracellular matrix (ECM) components leading to disruption of tissue homeostasis. Myofibroblasts as main ECM-producing cells can originate from various differentiated cell types after injury. Particularly, the process of endothelial-to-mesenchymal transition (endMT), describing phenotypic shifts of endothelial cells (ECs) to adopt a fully mesenchymal identity, may contribute to the pool of myofibroblasts in fibrosis, while leading to capillary rarefaction and exacerbation of tissue hypoxia. In renal disease, incomplete recovery from acute kidney injury (AKI) and the ensuing fibrotic reaction stand out as major contributors to chronic kidney disease (CKD) development. While the focus has largely been on impaired tubular epithelial repair as a potential fibrosis-driving mechanism, alterations in the renal microcirculation post-AKI, and in particular endMT as a maladaptive response, could hold equal significance. Dysfunctional interplays among various cell types in the kidney microenvironment can instigate endMT. Transforming growth factor beta (TGF-ß) signaling, with its downstream activation of canonical/Smad-mediated and non-canonical pathways, has been identified as primary driver of this process. However, non-TGF-ß-mediated pathways involving inflammatory agents and metabolic shifts in intercellular communication within the tissue microenvironment can also trigger endMT. These harmful, maladaptive cell-cell interactions and signaling pathways offer potential targets for therapeutic intervention to impede endMT and decelerate fibrogenesis such as in AKI-CKD progression. Presently, partial reduction of TGF-ß signaling using anti-diabetic drugs or statins may hold therapeutic potential in renal context. Nevertheless, further investigation is warranted to validate underlying mechanisms and assess positive effects within a clinical framework.

The Relevance of Advanced Therapy Medicinal Products in the Field of Transplantation and the Need for Academic Research Access: Overcoming Bottlenecks and Claiming a New Time.

The field of transplantation has witnessed the emergence of Advanced Therapy Medicinal Products (ATMPs) as highly promising solutions to address the challenges associated with organ and tissue transplantation. ATMPs encompass gene therapy, cell therapy, and tissue-engineered products, hold immense potential for breakthroughs in overcoming the obstacles of rejection and the limited availability of donor organs. However, the development and academic research access to ATMPs face significant bottlenecks that hinder progress. This opinion paper emphasizes the importance of addressing bottlenecks in the development and academic research access to ATMPs by implementing several key strategies. These include the establishment of streamlined regulatory processes, securing increased funding for ATMP research, fostering collaborations and partnerships, setting up centralized ATMP facilities, and actively engaging with patient groups. Advocacy at the policy level is essential to provide support for the development and accessibility of ATMPs, thereby driving advancements in transplantation and enhancing patient outcomes. By adopting these strategies, the field of transplantation can pave the way for the introduction of innovative and efficacious ATMP therapies, while simultaneously fostering a nurturing environment for academic research.

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.

Chronic Pancreas Allograft Rejection Followed by Successful HLA-Incompatible Islet Alloautotransplantation: A Novel Strategy?

The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this "islet alloautotransplantation" consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.

European Society for Organ Transplantation (ESOT) Consensus Statement on the Role of Pancreas Machine Perfusion to Increase the Donor Pool for Beta Cell Replacement Therapy.

The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney's and the liver presents opportunities in the field of beta-cell replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the "Role of pancreas machine perfusion to increase the donor pool for beta cell replacement," the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.

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.