We report a case of an 84-year-old male patient with primary small intestinal angiosarcoma.The patient initially presented with anemia and melena.Consecutive endoscopy revealed no signs of upper or ...lower active gastrointestinal bleeding.The patient had been diagnosed 3 years previously with an aortic dilation,which was treated with a stent.Computed tomography suggested an aorto-intestinal fistula as the cause of the intestinal bleeding,leading to operative stent explantation and aortic replacement.However,an aorto-intestinal fistula was not found,and the intestinal bleeding did not arrest postoperatively.The constant need for blood transfusions made an exploratory laparotomy imperative,which showed multiple bleeding sites,predominately in the jejunal wall.A distal loop jejunostomy was conducted to contain the small intestinal bleeding and a segmental resection for histological evaluation was performed.The histological analysis revealed a lessdifferentiated tumor with characteristic CD31,cytokeratin,and vimentin expression,which led to the diagnosis of small intestinal angiosarcoma.Consequently,the infiltrated part of the jejunum was successfully resected in a subsequent operation,and adjuvant chemotherapy with paclitaxel was planned.Angiosarcoma of the small intestine is an extremely rare malignant neoplasm that presents with bleeding and high mortality.Early diagnosis and treatment are essential to improve outcome.A small intestinal angiosarcoma is a challenging diagnosis to make because of its rarity,nonspecific symptoms of altered intestinal function,nonspecific abdominal pain,severe melena,and acute abdominal signs.Therefore,a quick clinical and histological diagnosis and decisive measures including surgery and adjuvant chemotherapy should be the aim.
Genetic, preclinical and clinical data link Parkinson's disease and Gaucher's disease and provide a rational entry point to disease modification therapy via enhancement of β‐Glucocerebrosidase ...(GCase) activity. We discovered a new class of pyrrolo2,3‐bpyrazine activators effecting both Vmax and Km. They bind to human GCase and increase substrate metabolism in the lysosome in a cellular assay. We obtained the first crystal structure for an activator and identified a novel non‐inhibitory binding mode at the interface of a dimer, rationalizing the observed structure–activity relationship (SAR). The compound binds GCase inducing formation of a dimeric state at both endoplasmic reticulum (ER) and lysosomal pHs, as confirmed by analytical ultracentrifugation. Importantly, the pyrrolo2,3‐bpyrazines have central nervous system (CNS) drug‐like properties. Our findings are important for future drug discovery efforts in the field of GCase activation and provide a deeper mechanistic understanding of the requirements for enzymatic activation, pointing to the relevance of dimerization.
A first crystal structure for a novel GCase activator is obtained and a novel non‐inhibitory binding mode at a dimer interface, rationalizing the observed structure–activity relationship, is identified. Mechanistic insights and key information for future drug discovery efforts towards GCase activation are provided.
This study aimed to evaluate (
)-
FYH134 as a novel PET tracer for imaging monoacylglycerol lipase (MAGL). Considering the ubiquitous expression of MAGL throughout the whole body, the impact of ...various MAGL inhibitors on (
)-
FYH134 brain uptake and its application in brain-periphery crosstalk were explored.
MAGL knockout and wild-type mice were used to evaluate (
)-
FYH134 in in vitro autoradiography and PET experiments. To explore the impact of peripheral MAGL occupancy on (
)-
FYH134 brain uptake, PET kinetics with an arterial input function were studied in male Wistar rats under baseline and blocking conditions.
In in vitro autoradiography, (
)-
FYH134 revealed a heterogeneous distribution pattern with high binding to MAGL-rich brain regions in wild-type mouse brain slices, whereas the radioactive signal was negligible in MAGL knockout mouse brain slices. The in vivo brain PET images of (
)-
FYH134 in wild-type and MAGL knockout mice demonstrated its high specificity and selectivity in mouse brain. A Logan plot with plasma input function was applied to estimate the distribution volume (
) of (
)-
FYH134.
was significantly reduced by a brain-penetrant MAGL inhibitor but was unchanged by a peripherally restricted MAGL inhibitor. The MAGL target occupancy in the periphery was estimated using (
)-
FYH134 PET imaging data from the brain.
(
)-
FYH134 is a highly specific and selective PET tracer with favorable kinetic properties for imaging MAGL in rodent brain. Our results showed that blocking of the peripheral target influences brain uptake but not the
of (
)-
FYH134. (
)-
FYH134 can be used for estimating the dose of MAGL inhibitor at half-maximal peripheral target occupancy.
In the field of Dirac materials, spin-orbit coupling (SOC) is usually considered disruptive, since it may lift degeneracies that are not protected by high-symmetry elements. Nonsymmorphic symmetries ...force degenerate points in the band structure at high-symmetry points that are not disrupted by SOC. The degeneracy is, however, often protected along whole high-symmetry lines or faces resulting in highly anisotropic crossings or nodal lines, which can considerably limit the region, in which the bands are linearly dispersed. It has been theoretically suggested that SOC could circumvent this problem. Here, we show experimentally that SOC can lift the extended protection in nonsymmorphic square-net compounds. We compare ZrSiS and CeSbTe, two materials with drastically different SOC, to show the effect of SOC on the band structure by means of angle-resolved photoemission spectroscopy and density functional theory calculations.
•The effect of spin-orbit coupling in nonsymmorphic square-net materials is investigated•We find that SOC can create more symmetric Dirac cones protected by nonsymmorphic symmetry•SOC does not gap Dirac cone in nonsymmorphic compounds•We conclude that in nonsymmorphic materials SOC can be a useful tuning parameter for creating Dirac Semimetals
The antioxidant xanthophylls lutein and zeaxanthin are absorbed from the diet in a process involving lipoprotein formation. Selective mechanisms exist for their intestinal uptake and tissue-selective ...distribution, but these are poorly understood. We investigated the role of high-density lipoprotein (HDL), apolipoprotein (apo) A1 and ATP-binding cassette transporter (ABC) A1 in intestinal uptake of lutein in a human polarized intestinal cell culture and a hamster model. Animals received dietary lutein and zeaxanthin and either a liver X receptor (LXR) agonist or statin, which up- or down-regulate intestinal ABCA1 expression, respectively. The role of HDL was studied following treatment with the cholesteryl ester transfer protein (CETP) modulator dalcetrapib or the CETP inhibitor anacetrapib. In vitro, intestinal ABCA1 at the basolateral surface of enterocytes transferred lutein and zeaxanthin to apoA1, not to mature HDL. In hamsters, plasma lutein and zeaxanthin levels were markedly increased with the LXR agonist and decreased with simvastatin. Dalcetrapib, but not anacetrapib, increased plasma and liver lutein and zeaxanthin levels. ABCA1 expression and apoA1 acceptor activity are important initial steps in intestinal uptake and maintenance of lutein and zeaxanthin levels by an HDL-dependent pathway. Their absorption may be improved by physiological and pharmacological interventions affecting HDL metabolism.
New developments in the field of topological matter are often driven by materials discovery, including novel topological insulators, Dirac semimetals and Weyl semimetals. In the last few years, large ...efforts have been performed to classify all known inorganic materials with respect to their topology. Unfortunately, a large number of topological materials suffer from non-ideal band structures. For example, topological bands are frequently convoluted with trivial ones, and band structure features of interest can appear far below the Fermi level. This leaves just a handful of materials that are intensively studied. Finding strategies to design new topological materials is a solution. Here we introduce a new mechanism that is based on charge density waves and non-symmorphic symmetry to design an idealized Dirac semimetal. We then show experimentally that the antiferromagnetic compound GdSb0.46Te1.48 is a nearly ideal Dirac semimetal based on the proposed mechanism, meaning that most interfering bands at the Fermi level are suppressed. Finally, its highly unusual transport behavior points to a thus far unknown regime, in which Dirac carriers with Fermi energy very close to the node seem to gradually localize in the presence of lattice and magnetic disorder.
Transition-metal chalcogenides are a promising family of materials for applications as photocathodes in photoelectrochemical (PEC) H2 generation. A long-standing challenge for chalcopyrite ...semiconductors is characterizing their electronic structure, both experimentally and theoretically, because of their relatively high-energy band gaps and spin–orbit coupling (SOC), respectively. In this work, we present single crystals of CuInTe2, whose relatively small optically measured band gap of 0.9 ± 0.03 eV enables electronic structure characterization by angle-resolved photoelectron spectroscopy (ARPES) in conjunction with first-principles calculations incorporating SOC. ARPES measurements reveal bands that are steeply dispersed in energy with a band velocity of 2.5–5.4 × 105 m/s, almost 50% of the extremely conductive material graphene. Additionally, CuInTe2 single crystals are fabricated into electrodes to experimentally determine the valence band edge energy and confirm the thermodynamic suitability of CuInTe2 for water redox chemistry. The electronic structure characterization and band edge position presented in this work provide kinetic and thermodynamic factors that support CuInTe2 as a strong candidate for water reduction.
Transition-metal chalcogenides are a promising family of materials for applications as photocathodes in photoelectrochemical (PEC) H
generation. A long-standing challenge for chalcopyrite ...semiconductors is characterizing their electronic structure, both experimentally and theoretically, because of their relatively high-energy band gaps and spin-orbit coupling (SOC), respectively. In this work, we present single crystals of CuInTe
, whose relatively small optically measured band gap of 0.9 ± 0.03 eV enables electronic structure characterization by angle-resolved photoelectron spectroscopy (ARPES) in conjunction with first-principles calculations incorporating SOC. ARPES measurements reveal bands that are steeply dispersed in energy with a band velocity of 2.5-5.4 × 10
m/s, almost 50% of the extremely conductive material graphene. Additionally, CuInTe
single crystals are fabricated into electrodes to experimentally determine the valence band edge energy and confirm the thermodynamic suitability of CuInTe
for water redox chemistry. The electronic structure characterization and band edge position presented in this work provide kinetic and thermodynamic factors that support CuInTe
as a strong candidate for water reduction.
Intrahepatic cholestasis without jaundice Namdar, Thomas; Raffel, Andreas; Topp, Stefan Andreas ...
Hepatobiliary & pancreatic diseases international,
02/2009, Letnik:
8, Številka:
1
Journal Article
Recenzirano
BACKGROUND:Cholangiocarcinoma(CC),the most common biliary tract malignancy,is frequently seen in advanced unresectable stages and is typically localized extrahepatically.Early diagnosis is unusual ...because of nonspecific symptoms.Painless jaundice is usually the first sign of tumor. METHOD:We present a patient with a CC(Klatskin tumor) with a complete biliary drainage by an aberrant bile duct without jaundice. RESULTS:A 67-year-old woman presented with persisting elevation of liver parameters.Diagnostic tests showed a Klatskin tumor typeⅡ.A curative right hepatic trisegmentectomy was performed after liver volume augmentation by preoperative vein embolization. CONCLUSIONS:A direct drainage of the right posterior bile duct into the common bile duct as an aberrant hepatic duct is a rare variation and is present in less than 5%of the population.In case of persistently perturbed liver function tests,an aberrant bile duct can cover up severe intrahepatic cholestasis and even obscure the diagnosis of a Klatskin tumor.Up to now it has not been described in the literature.
In the field of Dirac materials, spin-orbit coupling (SOC) is usually considered disruptive, since it may lift degeneracies that are not protected by high-symmetry elements. Nonsymmorphic symmetries ...force degenerate points in the band structure at high-symmetry points that are not disrupted by SOC. The degeneracy is, however, often protected along whole high-symmetry lines or faces resulting in highly anisotropic crossings or nodal lines, which can considerably limit the region, in which the bands are linearly dispersed. It has been theoretically suggested that SOC could circumvent this problem. Here, we show experimentally that SOC can lift the extended protection in nonsymmorphic square-net compounds. Here, we compare ZrSiS and CeSbTe, two materials with drastically different SOC, to show the effect of SOC on the band structure by means of angle-resolved photoemission spectroscopy and density functional theory calculations.
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