Positivity of hexagon perturbation theory

The hexagon-form-factor program was proposed as a way to compute three- and higher-point correlation functions in $\mathcal{N}=4$ super-symmetric Yang-Mills theory and in the dual AdS$_5\times$S$^5$ superstring theory, by exploiting the integrability of the theory in the 't Hooft limit. This approach is reminiscent of the asymptotic Bethe ansatz in that it applies to a large-volume expansion. Finite-volume corrections can be incorporated through L\"uscher-like formulae, though the systematics of this expansion is largely unexplored so far. Strikingly, finite-volume corrections may feature negative powers of the 't Hooft coupling $g$ in the small-$g$ expansion, potentially leading to a breakdown of the formalism. In this work we show that the finite-volume perturbation theory for the hexagon is positive and thereby compatible with the weak-coupling expansion for arbitrary $n$-point functions.Comment: v2: misprints corrected, further details on physical magnons adde

Association of homozygous variants of STING1 with outcome in human cervical cancer

DNA-sensing receptor Cyclic GMP-AMP Synthase (cGAS) and its downstream signaling effector STimulator of INterferon Genes (STING) have gained significant interest in the field of tumor immunology, as a dysfunctional cGAS-STING pathway is associated with poor prognosis and worse response to immunotherapy. However, studies so far have not taken into account the polymorphic nature of the STING-encoding STING1 gene. We hypothesized that the presence of allelic variance in STING1 would cause variation between individuals as to their susceptibility to cancer development, cancer progression, and potential response to (immuno)therapy. To start to address this, we defined the genetic landscapes of STING1 in cervical scrapings and investigated their corresponding clinical characteristics across a unique cohort of cervical cancer patients and compared them with independent control cohorts. Although we did not observe an enrichment of particular STING1 allelic variants in cervical cancer patients, we did find that the occurrence of homozygous variants HAQ/HAQ and R232H/R232H of STING1 were associated with both younger age of diagnosis and higher recurrence rate. These findings were accompanied by worse survival, despite comparable mRNA and protein levels of STING and numbers of infiltrated CD8(+) T cells. Our findings suggest that patients with HAQ/HAQ and R232H/R232H genotypes may have a dysfunctional cGAS-STING pathway that fails to promote efficient anticancer immunity. Interestingly, the occurrence of these genotypes coincided with homozygous presence of the V48V variant, which was found to be individually associated with worse outcome. Therefore, we propose V48V to be further evaluated as a novel prognostic marker for cervical cancer

The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice.

<p>BACKGROUND & AIMS: Non-alcoholic steatohepatitis is characterized by hepatic steatosis with inflammation. Although steatosis is benign and reversible, inflammation can increase liver damage. Hepatic inflammation has been associated with accumulation of cholesterol in lysosomes of Kupffer cells. 27-Hydroxycholesterol (27HC), a derivative of cholesterol formed by CYP27A1, can mobilize cholesterol from the lysosomes to the cytoplasm. We investigated whether 27HC can change the intracellular distribution cholesterol and reduce hepatic inflammation in mice. METHODS: We transplanted bone marrow from irradiated wild-type or Cyp27a1(-/-) mice to mice that do not express the low density lipoprotein receptor (Ldlr(-/-)), which are hyperlipidemic; 9 weeks later, mice were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 3 months. In a separate experiment, Ldlr(-/-) mice were given subcutaneous injections of 27HC and placed on regular chow or HFC diets for 3 weeks. Blood and liver tissues samples were collected and analyzed for intracellular cholesterol distribution and inflammation. RESULTS: In Ldlr(-/-) mice that received bone marrow transplants from Cyp27a1(-/-) mice, lysosomes of Kupfer cells had a greater accumulation of cholesterol than those of mice that received bone marrow from wild-type mice, after the HFC diet. Liver histology and gene expression analyses showed increased inflammation and liver damage in mice given bone marrow transplants from Cyp27a1(-/-) mice and placed on the HFC diet. Administration of 27HC to Ldlr(-/-) mice, following the HFC diet, reduced the accumulation of lysosomal cholesterol and hepatic inflammation, compared with mice that were not given 27HC. CONCLUSIONS: Accumulation of cholesterol in lysosomes of Kupfer cells promotes hepatic inflammation in mice. The cholesterol derivative 27HC reduces accumulation of cholesterol in lysosomes and might be used to treat non-alcoholic steatohepatitis.</p>

Protection of the Ovine Fetal Gut against Ureaplasma-Induced Chorioamnionitis: A Potential Role for Plant Sterols

Chorioamnionitis, clinically most frequently associated with Ureaplasma, is linked to intestinal inflammation and subsequent gut injury. No treatment is available to prevent chorioamnionitis-driven adverse intestinal outcomes. Evidence is increasing that plant sterols possess immune-modulatory properties. Therefore, we investigated the potential therapeutic effects of plant sterols in lambs intra-amniotically (IA) exposed to Ureaplasma. Fetal lambs were IA exposed to Ureaplasma parvum (U. parvum, UP) for six days from 127 d–133 d of gestational age (GA). The plant sterols β-sitosterol and campesterol, dissolved with β-cyclodextrin (carrier), were given IA every two days from 122 d–131 d GA. Fetal circulatory cytokine levels, gut inflammation, intestinal injury, enterocyte maturation, and mucosal phospholipid and bile acid profiles were measured at 133 d GA (term 150 d). IA plant sterol administration blocked a fetal inflammatory response syndrome. Plant sterols reduced intestinal accumulation of proinflammatory phospholipids and tended to prevent mucosal myeloperoxidase-positive (MPO) cell influx, indicating an inhibition of gut inflammation. IA administration of plant sterols and carrier diminished intestinal mucosal damage, stimulated maturation of the immature epithelium, and partially prevented U. parvum-driven reduction of mucosal bile acids. In conclusion, we show that β-sitosterol and campesterol administration protected the fetus against adverse gut outcomes following UP-driven chorioamnionitis by preventing intestinal and systemic inflammation

CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% +/- 1.2% for patients with deletions versus 83.5% +/- 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia

Somatostatin analogues for the prevention of pancreatic fistula after open pancreatoduodenectomy:A nationwide analysis

BACKGROUND: Somatostatin analogues (SA) are currently used to prevent postoperative pancreatic fistula (POPF) development. However, its use is controversial. This study investigated the effect of different SA protocols on the incidence of POPF after pancreatoduodenectomy in a nationwide population.METHODS: All patients undergoing elective open pancreatoduodenectomy were included from the Dutch Pancreatic Cancer Audit (2014-2017). Patients were divided into six groups: no SA, octreotide, lanreotide, pasireotide, octreotide only in high-risk (HR) patients and lanreotide only in HR patients. Primary endpoint was POPF grade B/C. The updated alternative Fistula Risk Score was used to compare POPF rates across various risk scenarios.RESULTS: 1992 patients were included. Overall POPF rate was 13.1%. Lanreotide (10.0%), octreotide-HR (9.4%) and no protocol (12.7%) POPF rates were lower compared to the other protocols (varying from 15.1 to 19.1%, p = 0.001) in crude analysis. Sub-analysis in patients with HR of POPF showed a significantly lower rate of POPF when treated with lanreotide (10.0%) compared to no protocol, octreotide and pasireotide protocol (21.6-26.9%, p = 0.006). Octreotide-HR and lanreotide-HR protocol POPF rates were comparable to lanreotide protocol, however not significantly different from the other protocols. Multivariable regression analysis demonstrated lanreotide protocol to be positively associated with a low odds-ratio (OR) for POPF (OR 0.387, 95% CI 0.180-0.834, p = 0.015). In-hospital mortality rates were not affected.CONCLUSION: Use of lanreotide in all patients undergoing pancreatoduodenectomy has a potential protective effect on POPF development. Protocols for HR patients only might be favorable too. However, future studies are warranted to confirm these findings.</p

Cerebral Accumulation of Dietary Derivable Plant Sterols does not Interfere with Memory and Anxiety Related Behavior in Abcg5−/− Mice

Plant sterols such as sitosterol and campesterol are frequently applied as functional food in the prevention of atherosclerosis. Recently, it became clear that plasma derived plant sterols accumulate in murine brains. We questioned whether plant sterols in the brain are associated with alterations in brain cholesterol homeostasis and subsequently with brain functions. ATP binding cassette (Abc)g5−/− mice, a phytosterolemia model, were compared to Abcg5+/+ mice for serum and brain plant sterol accumulation and behavioral and cognitive performance. Serum and brain plant sterol concentrations were respectively 35–70-fold and 5–12-fold increased in Abcg5−/− mice (P < 0.001). Plant sterol accumulation resulted in decreased levels of desmosterol (P < 0.01) and 24(S)-hydroxycholesterol (P < 0.01) in the hippocampus, the brain region important for learning and memory functions, and increased lanosterol levels (P < 0.01) in the cortex. However, Abcg5−/− and Abcg5+/+ displayed no differences in memory functions or in anxiety and mood related behavior. The swimming speed of the Abcg5−/− mice was slightly higher compared to Abcg5+/+ mice (P < 0.001). In conclusion, plant sterols in the brains of Abcg5−/− mice did have consequences for brain cholesterol metabolism, but did not lead to an overt phenotype of memory or anxiety related behavior. Thus, our data provide no contra-indication for nutritional intake of plant sterol enriched nutrition

Prophylactic Intra-Uterine β-Cyclodextrin Administration during Intra-Uterine Ureaplasma parvum Infection Partly Prevents Liver Inflammation without Interfering with the Enterohepatic Circulation of the Fetal Sheep

Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in β-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of β-sitosterol and campesterol dissolved in β-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + β-cyclodextrin, or β-cyclodextrin alone. In addition, IA administration of β-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier β-cyclodextrin did not have additional effects