Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides ...polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H. polygyrus TGF-β mimic (Hp-TGM) that replicates the biological and functional properties of TGF-β, including binding to mammalian TGF-β receptors and inducing mouse and human Foxp3
Treg cells. Hp-TGM has no homology with mammalian TGF-β or other members of the TGF-β family, but is a member of the complement control protein superfamily. Thus, our data indicate that through convergent evolution, the parasite has acquired a protein with cytokine-like function that is able to exploit an endogenous pathway of immunoregulation in the host.
Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of ...neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in human patients. Here, high-resolution morphological analyses were undertaken on NMJs of rectus abdominis obtained from patients undergoing upper GI cancer surgery compared with controls (N = 30; n = 1,165 NMJs). Cancer patients included those with cachexia and weight-stable disease. Despite the low skeletal muscle index and significant muscle fiber atrophy (P < 0.0001) in patients with cachexia, NMJ morphology was fully conserved. No significant differences were observed in any of the pre- and postsynaptic variables measured. We conclude that NMJs remain structurally intact in rectus abdominis in both cancer and cachexia, suggesting that denervation of skeletal muscle is not a major driver of pathogenesis. The absence of NMJ pathology is in stark contrast to what is found in related conditions, such as age-related sarcopenia, and supports the hypothesis that intrinsic changes within skeletal muscle, independent of any changes in motor neurons, represent the primary locus of neuromuscular pathology in cancer cachexia.
Linked ContentThis article is linked to Gonzalez‐Carmona et al papers. To view
these articles, visit https://doi.org/10.1111/apt.15050 and https://doi.org/10.1111/apt.15134.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Preeclampsia is characterized clinically by hypertension and proteinuria. Soluble Flt-1 (sFlt-1; also known as soluble vascular endothelial growth factor receptor-1 VEGFR-1) and soluble endoglin ...(sEng) are elevated in preeclampsia, and their administration to pregnant rats elicits preeclampsia-like symptoms. Heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) exert protective effects against oxidative stimuli. Thus, we hypothesized that HO-1 upregulation may offer protection against preeclampsia by inhibiting sFlt-1 and sEng release.
Preeclamptic villous explants secreted high levels of sFlt-1 and sEng. Adenoviral overexpression of HO-1 in endothelial cells inhibited VEGF-mediated sFlt-1 release and interferon-gamma- and tumor necrosis factor-alpha-induced sEng release, whereas HO-1 inhibition potentiated sFlt-1 and sEng production from endothelial cells and placental villous explants. Consistent with these findings, mice lacking HO-1 produced higher levels of sFlt-1 and sEng compared with wild-type mice. Using selective ligands (VEGF-E and placental growth factor) and a receptor-specific inhibitor (SU-1498), we demonstrated that VEGF-induced sFlt-1 release was VEGFR-2 dependent. Furthermore, CO-releasing molecule-2 (CORM-2) or CO decreased sFlt-1 release and inhibited VEGFR-2 phosphorylation. Treatment of endothelial cells with statins upregulated HO-1 and inhibited the release of sFlt-1, whereas vitamins C and E had no effect.
The present study demonstrates that the HO-1/CO pathway inhibits sFlt-1 and sEng release, providing compelling evidence for a protective role of HO-1 in pregnancy, and identifies HO-1 as a novel target for the treatment of preeclampsia.
Summary
Background
The importance of primary biliary cholangitis as an indication for liver transplantation has probably been influenced by the introduction of therapies, and changes in selection ...criteria and disease epidemiology.
Aims
To assess the time trends in liver transplantation for primary biliary cholangitis and to evaluate the characteristics of the patient population during the past three decades.
Methods
Patients undergoing liver transplantation from 1986 to 2015 in centres reporting to the European Liver Transplantation Registry were included. We excluded combined organ transplantations and patients <18 years. Trends were assessed using linear regression models.
Results
We included 112 874 patients, of whom 6029 (5.3%) had primary biliary cholangitis. After an initial increase in the first decade, the annual number of liver transplantation for primary biliary cholangitis remained stable at around 200. The proportion of liver transplantations for primary biliary cholangitis decreased from 20% in 1986 to 4% in 2015 (P < 0.001). Primary biliary cholangitis was the only indication showing a consistent proportional decrease throughout all decades. From the first to the third decade, the age at liver transplantation increased from 54 (IQR 47‐59) to 56 years (IQR 48‐62) and the proportion of males increased from 11% to 15% (both P < 0.001).
Conclusions
We have found a proportional decrease in primary biliary cholangitis as indication for liver transplantation. However, despite treatment with ursodeoxycholic acid and improved disease awareness, the absolute annual number of liver transplantations has stabilised.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, ...determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered, which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacologic coinhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC.
This work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow, suggesting common therapeutic vulnerabilities across patients.
Abstract Introduction The role of systemic chemotherapy in patients with resectable colorectal liver metastases (CRLM) is ambiguous. The aim of this review was to compare the outcomes of regimens ...using systemic neoadjuvant, adjuvant or perioperative (combination of pre and postoperative) chemotherapy, for the treatment of resectable CRLM. Methods MEDLINE was searched for articles investigating the use of chemotherapy for adults with resectable CRLM. Randomized controlled trials reporting overall survival (OS), disease-free survival (DFS) and grade 3–4 adverse events (AEs) were screened for inclusion. PROSPERO record: CRD42015020609. Results Four trials met the inclusion criteria (1098 patients). No significant improvement in median OS was achieved with chemotherapy/surgery compared with surgery-alone. Two trials demonstrated a significant improvement in DFS with chemotherapy/surgery compared to surgery-alone (Hazard ratio 0.78 (0.61–0.99) p = 0.04 and HR 0.66 (0.46–0.96) p = 0.03). Fluorouracil/folinic acid alone had a lower incidence of AEs than combination therapies, and the addition of cetuximab shortened DFS in one trial (HR 1.48 (1.04–2.12) p = 0.03). Conclusion There is a lack of adequately powered trials of chemotherapy in combination with liver resection for CRLM, partly due to difficulties in recruitment. In an unselected patient group, FOLFOX in combination with liver resection appears to improve DFS compared to surgery-alone, but trials are underpowered for OS. Future trials will require prospective stratification of patients based on biomarkers predictive of response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Curcumin is a naturally occurring compound which is known to induce heme
oxygenase 1 (HO-1), although the underlying mechanism has not been fully elucidated.
This study investigates in detail the ...mechanism of HO-1 induction by curcumin
in human hepatoma cells. There was increasing toxicity of curcumin at concentrations
higher than 10 µM. Curcumin was found to induce HO-1 at doses of 10 to 25 µM.
At both non-toxic and toxic doses, HO-1 induction was found to correlate with
production of reactive oxygen species (ROS), suggesting a causative relationship.
This was reinforced by the finding that pretreatment with the antioxidants N-acetylcysteine,
vitamin E and catalase prevented HO-1 induction by curcumin. ROS production appeared
to be mitochondrial in origin, and curcumin treatment resulted in depolarisation
of the mitochondrial membrane potential. Nrf2 was induced by curcumin treatment,
which was also partly ROS dependent. Using siRNA, Nrf2 was demonstrated to contribute
to HO-1 induction. A panel of kinase inhibitors was used to examine the contribution
of MAP kinases to the induction of HO-1 by curcumin. PKC and p38 MAPK activity
are required for full induction of HO-1. Furthermore, curcumin also inhibited
protein phosphatase activity. In conclusion, curcumin treatment results in ROS
generation, activation of Nrf2 and MAP kinases and the inhibition of phosphatase
activity in hepatocytes, and when curcumin is not administered in toxic doses,
these multiple pathways converge to induce HO-1.
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