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Recurrent problems of patients with myelofibrosis (MF) are cytopenias, debiliating disease-related symptoms and splenomegaly. Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. Momelotinib, a JAK1/2 inhibitor recently approved for the treatment of anemic MF patients, was shown to improve anemia via a direct inhibition of activin A receptor type I. In this German-wide, multicenter, retrospective analysis the safety and efficacy profile of momelotinib was evaluated in a real world setting within a cohort of 60 MF patients independent of pre-treatment. The median duration of treatment was 12 weeks. As a new, but manageable safety finding, creatinine increase (CTC°1–2) was detected in 10/60 patients (17%). Interestingly, not only hemoglobin levels increased in 84% of patients, but also platelet values (67%). In the cohort of transfusion-dependent individuals (n = 38), transfusion requirement improved in 15 patients (39%) with 8 reaching transfusion independency (21%). Transfusion independency was achieved within a median of 4 weeks (range 2–12). Spleen size decreased in 13/53 individuals (25%) with a median response time of 6 weeks. Thereof, 11 patients had been pre-treated with JAK inhibitor(s) (85%). Clinical improvement was detected in 24/51 symptomatic individuals (47%) with a median response time of 4 weeks. 5 patients stopped treatment due to side effects (8%), 6 patients due to a worsening of clinical symptoms (10%). Taken together, the MoReLife analysis identifies momelotinib as potent and safe therapeutic option also for heavily pre-treated cytopenic MF patients under real world conditions. [ABSTRACT FROM AUTHOR]

A comparative study of the processes of metal-stimulated formation of silicon nanocrystals in SiOx–Sm structures was carried out. Samples with identical oxide matrix stoichiometry and Sm impurity content were formed using two methods: layer-by-layer deposition and coevaporation of SiO and Sm. Studies of PL and IR absorption spectra found that the admixture of samarium in samples of both types accelerates the thermally stimulated decomposition of samarium-doped SiOx films into Si and SiO2 and reduces the transition temperature of silicon nanoparticles from an amorphous state to a crystalline state. However, in (SiOx/Sm)10 multilayers, this effect is more pronounced than in single-layer films obtained using the co-evaporation method. Studying the Raman spectra of (SiOx/Sm)10 multilayers annealed at 750 °C determined that the relative volume fraction of nanocrystals in the silicon phase of the sample is ~ 38%. No line corresponding to the crystalline nc-Si was observed in the Raman spectra of samples deposited by co-evaporation and annealed under the same conditions. For these samples, a narrow line in the Raman spectrum corresponding to crystalline nc-Si appears only after annealing at 970 °C. In this case, the relative fraction of Si nanocrystals in the silicon phase of the sample was ~ 17%, 2.2 times less than for a similar multilayer annealed at 750 °C. This also indicates that, in multilayer (SiOx/Sm)10 samples, the thermally stimulated decomposition of SiOx, as well as the formation and crystallization of silicon nanoparticles, occurs at lower temperatures than in similar samples obtained by coevaporation. A possible mechanism for lowering the crystallization temperature of nc-Si in (SiOx/Sm)10 multilayers is discussed. [ABSTRACT FROM AUTHOR]

The effect of Sm on thermally stimulated decomposition of SiOx and the formation of silicon nanocrystals during high-temperature air annealing was studied by measuring the spectra of photoluminescence (PL), infrared (IR) reflection and transmission and Micro-Raman scattering (RS). The SiOx: Sm films were produced by thermal co-evaporation of silicon monoxide and metallic samarium powders in a vacuum onto polished c-Si and silica substrates. The Sm concentration varied from 0.8 to 2.0 wt. %. In the SiOx: Sm films annealed at 970 ºC, an intense PL band of silicon nanocrystals was found in the 850–900 nm region, the position and intensity of which depend on the samarium concentration. The formation of Si nanocrystals in those films is also confirmed by studying their Raman spectra. At the same time, no Si nanocrystals were found in undoped SiOx films annealed under similar conditions. The analysis of these spectra made it possible to determine the sizes of silicon nanocrystals: 3.7 nm from the PL spectra and 3.6 nm from the Raman spectra. A possible mechanism of thermally stimulated interaction of Sm atoms with the SiOx matrix is discussed. [ABSTRACT FROM AUTHOR]

Introduction: Acute intermittent porphyria (AIP) is a very rare (orphan) metabolic disorder of porphyrin biosynthesis which is characterized by elevated plasma and urine levels of 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG). Patients with this disorder which is caused by a germline mutation of the hydroxymethylbilan-synthase (HMBS)-gene have a high risk of primary liver cancer which may be determined by disease activity. The exact mechanism of carcinogenesis of this rare tumor is unknown, however. Materials and methods: We analyzed paraffin-embedded formalin-fixed liver tumor and normal liver specimens of two female AIP patients treated at the Munich EPNET center. One patient had developed hepatocellular carcinoma (HCC), the other intrahepatic cholangiocarcinoma (CCA). Since biallelic inactivation of HMBS had been observed in one study, we used Sanger and next-generation sequencing with a 8 gene porphyria panel plus 6 potential modifier loci to search for mutations in DNA extractions. Results: In the patient with the HCC, we found a second inactivating mutation in the HMBS gene in the tumor but not in the adjacent normal liver tissue. No mutation could be found in the liver tissues of the patient with CCA, however. Conclusions: Biallelic inactivation of HMBS or protoporphyrinogen-oxidase (PPOX), another enzyme of porphyrin biosynthesis, has been observed in patients with acute porphyrias and liver tumors. We could confirm this in our patient with HCC with a mutation in HMBS but not in the one with CCA. Since 5-ALA can be converted into carcinogenic substances such as 4,5-dioxovaleric acid (DOVA) or 3,6-dihydropyrazine-2,5-dipropanoic acid (= cyclic dimerization product of 5-ALA), local production of these metabolites in hepatic areas with complete loss of HMBS activity may contribute to liver carcinogenesis. [ABSTRACT FROM AUTHOR]

Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC-MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 μmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation. [ABSTRACT FROM AUTHOR]

This paper presents a high-throughput method for Above Ground Estimation of Biomass (AGBE) in rice using multispectral near-infrared (NIR) imagery captured at different scales of the crop. By developing an integrated aerial crop monitoring solution using an Unmanned Aerial Vehicle (UAV), our approach calculates 7 vegetation indices that are combined in the form of multivariable regressions depending on the stage of rice growth: vegetative, reproductive or ripening. We model the relationship of these vegetation indices to estimate the biomass of a certain crop area. The methods are calibrated by using a minimum sampling area of 1 linear meter of the crop. Comprehensive experimental tests have been carried out over two different rice varieties under upland and lowland rice production systems. Results show that the proposed approach is able to estimate the biomass of large areas of the crop with an average correlation of 0.76 compared with the traditional manual destructive method. To our knowledge, this is the first work that uses a small sampling area of 1 linear meter to calibrate and validate NIR image-based estimations of biomass in rice crops. [ABSTRACT FROM AUTHOR]

In Germany, analyses of clinical and laboratory features of patients with acute porphyrias are only available for hereditary coproporphyria (HCP) but not with other acute porphyrias, acute intermittent porphyria (AIP) and variegate porphyria (VP). The aim of the study was to analyze a large cohort of patients with particular focus upon quality of life aspects. Sixty-two individuals from separate families with acute porphyrias (57 AIP, 5 VP) were included into an observational study collecting biochemical, genetic, and clinical data. A questionnaire was designed to complete anamnestic information and to assess the influence on quality of life. Most frequent signs and symptoms or laboratory abnormalities were abdominal colicky pain, red coloration of urine, and hyponatremia. Depression or anxiety was reported by 61% or 52% individuals, respectively. Fatigue was mentioned as the most quality of life-limiting symptom. In 59/61 patients, mutations could be identified. 44% (20/45) had to be admitted to an intensive care unit. Heme arginate was used in 64% (29/45) of patients for treatment of acute attacks at least once and in 33% for long-term treatment with high frequency of administration. Serum creatinine values increased in 47% (7/17) of the patients with recurrent attacks. Our analysis confirms a substantial influence of the diseases on the quality of life on patients. Percentages of urine discoloration and intensive care unit admissions were much higher than in other reports. Long-term treatment with heme arginate requires careful monitoring of iron status and renal values. [ABSTRACT FROM AUTHOR]

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations. [ABSTRACT FROM AUTHOR]