Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

Background: A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. <p/>Methods: Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). <p/>Results: 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1--10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. <p/>Conclusions: TP300 had predictable hematologic toxicity, and diarrhea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage

Radial shortening following a fracture of the proximal radius: Degree of shortening and short-term outcome in 22 proximal radial fractures

Background and purpose: The Essex-Lopresti lesion is thought to be rare, with a varying degree of disruption to forearm stability probable. We describe the range of radial shortening that occurs following a fracture of the proximal radius, as well as the short-term outcome in these patients. Patients and methods Over an 18-month period, we prospectively assessed all patients with a radiographically confirmed proximal radial fracture. Patients noted to have ipsilateral wrist pain at initial presentation underwent bilateral radiography to determine whether there was disruption of the distal radio-ulnar joint suggestive of an Essex-Lopresti lesion. Outcome was assessed after a mean of 6 (1.5-12) months using clinical and radiographic results, including the Mayo elbow score (MES) and the short musculoskeletal function assessment (SMFA) questionnaire. One patient with a Mason type-I fracture was lost to follow-up after initial presentation. Results 60 patients had ipsilateral wrist pain at the initial assessment of 237 proximal radial fractures. Radial shortening of ≥ 2mm (range: 2-4mm) was seen in 22 patients (mean age 48 (19-79) years, 16 females). The most frequent mechanism of injury was a fall from standing height (10/22). 21 fractures were classified as being Mason type-I or type-II, all of which were managed nonoperatively. One Mason type-III fracture underwent acute radial head replacement. Functional outcome was assessed in 21 patients. We found an excellent or good MES in 18 of the 20 patients with a Mason type-I or type-II injury. Interpretation The incidence of the Essex-Lopresti lesion type is possibly under-reported as there is a spectrum of injuries, and subtle disruptions often go unidentified. A full assessment of all patients with a proximal radial fracture is required in order to identify these injuries, and the index of suspicion is raised as the complexity of the fracture increases.</p

Transcriptomes and expression profiling of deep-sea corals from the Red Sea provide insight into the biology of azooxanthellate corals

Despite the importance of deep-sea corals, our current understanding of their ecology and evolutionis limited due to difficulties in sampling and studying deep-sea environments. Moreover, a recent reevaluation of habitat limitations has been suggested after characterization of deep-sea corals in the Red Sea, where they live at temperatures of above 20 °C at low oxygen concentrations. To gain further insight into the biology of deep-sea corals, we produced reference transcriptomes and studied gene expression of three deep-sea coral species from the Red Sea, i.e. Dendrophyllia sp., Eguchipsammia fistula, and Rhizotrochus typus. Our analyses suggest that deep-sea coral employ mitochondrial hypometabolism and anaerobic glycolysis to manage low oxygen conditions present in the Red Sea. Notably, we found expression of genes related to surface cilia motion that presumably enhance small particle transport rates in the oligotrophic deep-sea environment. This is the first study to characterize transcriptomes and in situ gene expression for deep-sea corals. Our work offers several mechanisms by which deep-sea corals might cope with the distinct environmental conditions present in the Red Sea. As such, our data provides direction for future research and further insight to organismal response of deep sea coral to environmental change and ocean warming.Tis work was supported by King Abdullah University of Science and Technology (KAUST), baseline funds to CRV and Center Competitive Funding (CCF) Program FCC/1/1973-18-01

Airborne Signals from a Wounded Leaf Facilitate Viral Spreading and Induce Antibacterial Resistance in Neighboring Plants

Many plants release airborne volatile compounds in response to wounding due to pathogenic assault. These compounds serve as plant defenses and are involved in plant signaling. Here, we study the effects of pectin methylesterase (PME)-generated methanol release from wounded plants (“emitters”) on the defensive reactions of neighboring “receiver” plants. Plant leaf wounding resulted in the synthesis of PME and a spike in methanol released into the air. Gaseous methanol or vapors from wounded PME-transgenic plants induced resistance to the bacterial pathogen Ralstonia solanacearum in the leaves of non-wounded neighboring “receiver” plants. In experiments with different volatile organic compounds, gaseous methanol was the only airborne factor that could induce antibacterial resistance in neighboring plants. In an effort to understand the mechanisms by which methanol stimulates the antibacterial resistance of “receiver” plants, we constructed forward and reverse suppression subtractive hybridization cDNA libraries from Nicotiana benthamiana plants exposed to methanol. We identified multiple methanol-inducible genes (MIGs), most of which are involved in defense or cell-to-cell trafficking. We then isolated the most affected genes for further analysis: β-1,3-glucanase (BG), a previously unidentified gene (MIG-21), and non-cell-autonomous pathway protein (NCAPP). Experiments with Tobacco mosaic virus (TMV) and a vector encoding two tandem copies of green fluorescent protein as a tracer of cell-to-cell movement showed the increased gating capacity of plasmodesmata in the presence of BG, MIG-21, and NCAPP. The increased gating capacity is accompanied by enhanced TMV reproduction in the “receivers”. Overall, our data indicate that methanol emitted by a wounded plant acts as a signal that enhances antibacterial resistance and facilitates viral spread in neighboring plants

Valid and reliable instruments for arm-hand assessment at ICF activity level in persons with hemiplegia: a systematic review

Contains fulltext : 110141.pdf (publisher's version ) (Open Access)BACKGROUND: Loss of arm-hand performance due to a hemiparesis as a result of stroke or cerebral palsy (CP), leads to large problems in daily life of these patients. Assessment of arm-hand performance is important in both clinical practice and research. To gain more insight in e.g. effectiveness of common therapies for different patient populations with similar clinical characteristics, consensus regarding the choice and use of outcome measures is paramount. To guide this choice, an overview of available instruments is necessary. The aim of this systematic review is to identify, evaluate and categorize instruments, reported to be valid and reliable, assessing arm-hand performance at the ICF activity level in patients with stroke or cerebral palsy. METHODS: A systematic literature search was performed to identify articles containing instruments assessing arm-hand skilled performance in patients with stroke or cerebral palsy. Instruments were identified and divided into the categories capacity, perceived performance and actual performance. A second search was performed to obtain information on their content and psychometrics. RESULTS: Regarding capacity, perceived performance and actual performance, 18, 9 and 3 instruments were included respectively. Only 3 of all included instruments were used and tested in both patient populations. The content of the instruments differed widely regarding the ICF levels measured, assessment of the amount of use versus the quality of use, the inclusion of unimanual and/or bimanual tasks and the inclusion of basic and/or extended tasks. CONCLUSIONS: Although many instruments assess capacity and perceived performance, a dearth exists of instruments assessing actual performance. In addition, instruments appropriate for more than one patient population are sparse. For actual performance, new instruments have to be developed, with specific focus on the usability in different patient populations and the assessment of quality of use as well as amount of use. Also, consensus about the choice and use of instruments within and across populations is needed

Meropenem vs standard of care for treatment of late onset sepsis in children of less than 90 days of age: study protocol for a randomised controlled trial

Background: Late onset neonatal sepsis (LOS) with the mortality of 17 to 27% is still a serious disease. Meropenem is an antibiotic with wide antibacterial coverage. The advantage of it over standard of care could be its wider antibacterial coverage and thus the use of mono-instead of combination therapy.Methods: NeoMero-1, an open label, randomised, comparator controlled, superiority trial aims to compare the efficacy of meropenem with a predefined standard of care (ampicillin + gentamicin or cefotaxime + gentamicin) in the treatment of LOS in neonates and infants aged less than 90 days admitted to a neonatal intensive care unit. A total of 550 subjects will be recruited following a 1:1 randomisation scheme. The trial includes patients with culture confirmed (at least one positive culture from normally sterile site except coagulase negative staphylococci in addition to one clinical or laboratory criterion) or clinical sepsis (at least two laboratory and two clinical criteria suggestive of LOS in subjects with postmenstrual age = 44 weeks). Meropenem will be given at a dose of 20 mg/kg q12h or q8h depending on the gestational- and postnatal age. Comparator agents are administered as indicated in British National Formulary for Children. The primary endpoint measured at the test of cure visit (2 days after end of study therapy) is graded to success (all baseline symptoms and laboratory parameters are resolved or improved with no need to continue antibiotics and the baseline microorganisms are eradicated and no new microorganisms are identified and the patient has received allocated treatment for 11 +/- 3 days with no modification) or a failure (all remaining cases). Secondary outcome measures include comparison of survival, relapse rates or new infections by Day 28, clinical response at Day 3 and end of therapy, duration of hospitalisation, population pharmacokinetic analysis of meropenem and effect of antibiotics on mucosal colonisation and development of antibacterial resistance. The study will start recruitment in September 2011; the total duration is of 24 months

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402