Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and ...dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.
Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.
Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).
Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.
•Relation between workability and setting adjustment and admixture dosage is derived.•Compressive strength is significantly enhanced by the plasticizing admixture.•Microstructure refinement by the ...plasticizing admixture is observed by SEM analysis.•Pore structure and porosity are investigated by mercury intrusion porosimetry.•Chloride migration resistance is affected by the admixture at different ages.
This paper investigates the influence of a plasticizing admixture on the pore structure refinement of alkali-activated concrete and paste mixtures and the consequently enhanced performance. Alkali-activated fly ash-slag concrete and paste are designed using a polycarboxylate-based admixture with different dosages. The pore structure and porosity are analyzed using mercury intrusion porosimetry (MIP). The workability, compressive strength, chloride migration resistance and electrical resistivity of alkali-activated fly ash-slag concrete and paste are determined. The results show that significantly improved workability and strength development are obtained at an increased admixture content. The admixture improves the gel polymerization product layer most likely around the GGBS particles, densifying the matrix. The 28-day Cl-migration coefficient of admixture (1–2 kg/m3) modified concrete is equal to the reference mixture, while at the highest admixture content the Cl-ingress is increased. At the later ages (91-days), the Cl-migration coefficients of all concretes, non- and admixture-containing samples, are comparable and low (about 2.6 × 10−12 m2/s). The MIP analyses show a significant decrease of the total and effective capillary porosity over time at an increased admixture content. The relationships between the porosity and other properties are discussed, at varying admixture contents.
Recently, GBR1, a seven-transmembrane domain protein with high affinity for gamma-aminobutyric acid (GABA)B receptor antagonists, was identified. Here, a GBR1-related protein, GBR2, was shown to be ...coexpressed with GBR1 in many brain regions and to interact with it through a short domain in the carboxyl-terminal cytoplasmic tail. Heterologously expressed GBR2 mediated inhibition of adenylyl cyclase; however, inwardly rectifying potassium channels were activated by GABAB receptor agonists only upon coexpression with GBR1 and GBR2. Thus, the interaction of these receptors appears to be crucial for important physiological effects of GABA and provides a mechanism in receptor signaling pathways that involve a heterotrimeric GTP-binding protein.
Summary
Very recently, Haeuptle and colleagues described a new glycosylation defect due to RFT1 deficiency (CDG In). Accumulation of intracellular DolPP-GlcNAc
2
Man
5
with absence of cytosolic ...GlcNAc
2
Man
5
resembled the profile of a yeast mutant deficient in RFT1, a protein that is thought to have a role as a flippase. This is the first detailed description of the clinical phenotype of this patient. It was a severe disorder affecting intrauterine development and movement, and leading to intrauterine growth retardation. The child was born with several musculoskeletal abnormalities including arthrogryposis. Postnatally, severe reflux and irregular bowl movements contributed to failure to thrive. The patient showed very little development and no vision and suffered from drug-resistant epilepsy. Abnormal coagulation resulted in thrombosis and the patient died at the age of 4 years from a pulmonary embolus.
BackgroundPrimary carnitine deficiency (PCD) is an autosomal recessive disorder of fatty acid oxidation, caused by mutations in the SLC22A5 gene encoding for the carnitine transporter OCTN2. ...Carnitine uptake deficiency prevents the body from using certain fats for energy, particularly during periods of fasting or illness. The first manifestation of PCD can be at any age, where patients can present with hypoglycemia, hyperammonaemia, encephalopathy, skeletal myopathy and cardiomyopathy.Case ReviewWe report on a previously well 15 year old boy who participated in a challenging Duke of Edinburgh expedition. The following morning he was found drowsy and subsequently admitted to hospital with worsening encephalopathy, hypoglycaemia and hyperammonaemia. This, along with rising CK and troponin levels meant PCD was included in the early differential and carnitine supplementation was commenced. Unfortunately his cardiac failure was too advanced and he had a cardiac arrest, dying after an hour of CPR. Genetic testing confirmed the diagnosis of PCD. On family cascade screening his asymptomatic sister was also diagnosed with PCD, started on oral carnitine supplements and continues to be well.A retrospective analysis of a total of thirteen diagnosed patients from one centre illustrates the variability of first presentation of PCD. Five children (ranging between 2 months and 7 years) presented with cardiac symptoms; four with cardiomyopathy, one with a cardiac arrest. Two children presented between 1 year and 3 years with hypoketotic hypoglycaemia. Two children presented with muscle fatigability at 7 months and 7 years of age. Another presented at 10 months old with motor regression, failure to thrive and an abnormal ECG. Two children were diagnosed at birth, either by newborn or sibling screening.ConclusionThis case series illustrates that PCD can present at any age with variable symptoms. Although rare, PCD should always be considered in patients with unexplained symptoms including encephalopathy. It is potentially lethal, but also extremely treatable, as early carnitine supplementation equates to excellent prognosis. Lastly, our case highlights the importance of family screening in preventing potential fatalities.
BACKGROUND Capacitation of sperm is a prerequisite for successful fertilization, determined by hyperactivated motility, increased tyrosine phosphorylation (TyrP) and membrane changes. However, the ...exact molecular mechanism is not fully clarified. The calpain–calmodulin-system is essential for membrane fusion during capacitation. Recently, interactions with caspase (CP) activation, a main feature of apoptotic cells, were postulated. The objective of our study was to examine interactions between apoptosis signalling and the calpain–calmodulin-system during capacitation. METHODS Semen samples from 20 healthy donors were incubated in human tubal fluid at 37°C, 5% CO2 for 3 h without additives (control), with 3% BSA (capacitation), 10 µM calpain-inhibitor III, 20 µM CP-1 inhibitor or 20 µM calmodulin-antagonist. Capacitation was monitored by computer assisted sperm motion analyzer, chlortetracycline (CTC)-assay and western blot (TyrP). Activation of caspases and integrity of transmembrane mitochondrial potential (TMP) were evaluated by flow cytometry. RESULTS Capacitation, as measured by CTC assay, increased TyrP levels and hyperactivation, resulted in inactivation of CP-9, CP-3 and improved integrity of the TMP. Inhibition of calpain and CP-1 during capacitation reduced the capacitation-related parameters, but did not lead to apoptosis. Inhibition of calmodulin resulted in blocking of capacitation and stimulation of apoptosis. CONCLUSION Interaction of the capacitation and apoptosis signalling systems seems to enable the capacitation process by prevention of apoptosis.
Summary
High amounts of nicotinamide phosphoribosyltransferase (NAMPT) were found in human seminal plasma. This enzyme influences energy metabolism and apoptosis and is essential for the regulation ...of cellular nicotinamide adenine dinucleotide (NAD)+ levels in somatic cells. NAD+ is required as a co‐substrate for dehydrogenases, which are potentially important for spermatogenesis. The functional significance of intra‐ and extracellular NAMPT in human reproduction, however, has not been defined yet. The objectives of the study were therefore to determine NAMPT protein expression in human spermatozoa and testes, the secretion of NAMPT by spermatozoa depending on their maturation stage and the impact of NAMPT enzymatic function on sperm viability, motility, fertilisation capacity and induction of apoptosis. Firstly, we detected NAMPT protein in different cell types of human testes. NAMPT protein was also detected in spermatozoa, with significantly higher amounts in immature than in mature ejaculated spermatozoa. Additionally, NAD+ levels were significantly higher in immature than in mature spermatozoa. Secondly, NAMPT was released into the supernatant of human spermatozoa, with significantly higher NAMPT levels in supernatant of immature spermatozoa compared with mature cells. Finally, the specific inhibition of the enzyme by FK866 did not influence motility, capacitation or apoptosis signalling. In summary, NAMPT is produced in human spermatozoa in a maturation‐dependent manner.
We present QNet, a method for constructing split networks from weighted quartet trees. QNet can be viewed as a quartet analogue of the distance-based Neighbor-Net (NNet) method for network ...construction. Just as NNet, QNet works by agglomeratively computing a collection of circular weighted splits of the taxa set which is subsequently represented by a planar split network. To illustrate the applicability of QNet, we apply it to a previously published Salmonella data set. We conclude that QNet can provide a useful alternative to NNet if distance data are not available or a character-based approach is preferred. Moreover, it can be used as an aid for determining when a quartet-based tree-building method may or may not be appropriate for a given data set. QNet is freely available for download.
Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced ...mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death. Triheptanoin is a medium odd-chain fatty acid. Anaplerotic metabolites of triheptanoin have the potential to replace deficient tricarboxylic acid (TCA) cycle intermediates, resulting in net glucose production as a novel energy source for the treatment of LC-FAOD.
A single-arm, open-label, multicenter Phase 2 safety and efficacy study evaluated patients with severe LC-FAOD evidenced by ongoing related musculoskeletal, cardiac, and/or hepatic events despite treatment. After a four-week run-in on current regimen, investigational triheptanoin (UX007) was titrated to a target dose of 25–35% of total daily caloric intake. Patients were evaluated on several age/condition-eligible endpoints, including submaximal exercise tests to assess muscle function/endurance (12-minute walk test; 12MWT) and exercise tolerance (cycle ergometry), and health related quality of life (HR-QoL). Results through 24weeks of treatment are presented; total study duration is 78weeks.
Twenty-nine patients (0.8 to 58years) were enrolled; most qualified based on severe musculoskeletal disease. Twenty-five patients (86%) completed the 24-week treatment period. At Week 18, eligible patients (n=8) demonstrated a 28% increase (LS mean=+181.9 meters; p=0.087) from baseline (673.4meters) in 12MWT distance. At Week 24, eligible patients (n=7) showed a 60% increase in watts generated (LS mean=+409.3W; p=0.149) over baseline (744.6W) for the exercise tolerance test. Improvements in exercise tests were supported by significant improvements from baseline in the adult (n=5) self-reported SF-12v2 physical component summary score (LS mean=+8.9; p<0.001). No difference from baseline was seen in pediatric parent-reported (n=5) scores (SF-10) at Week 24. Eighteen patients (62%) had treatment-related adverse events, predominantly gastrointestinal (55%), mild-to-moderate in severity, similar to that seen with prior treatment with medium chain triglyceride (MCT) oil. One patient experienced a treatment-related serious adverse event of gastroenteritis. One patient discontinued from study due to diarrhea of moderate severity; the majority of patients (25/29; 86%) elected to continue treatment in the extension period.
In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.
•Fatty acid oxidations (FAODs) are serious inborn errors of metabolism that are significant causes of morbidity and mortality.•Dietary therapy has been only partially successful in preventing symptoms.•We present 24week results of a Phase 2 clinical trial of the use of a novel therapy for FAODs, UX007.•This medication improved exercise tolerance and wellbeing in patients.
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