Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin

Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD + bortezomib. Its presence was associated with a longer time to progression (TTP; median 330 vs. 129 days; p = 0.0008), progression-free survival (PFS; median 338 vs. 129 days; p = 0.0006), and overall survival (p = 0.0045). MDR1/3435(C > T), which was in Hardy–Weinberg equilibrium, showed a trend of association with PFS (p = 0.0578), response rate (p = 0.0782) and TTP (p = 0.0923) in PLD + bortezomib patients, though no correlation was found in the bortezomib arm. In a recessive genetic model, MDR1/3435 T was significantly associated with a better TTP (p = 0.0405) and PFS (p = 0.0186) in PLD + bortezomib patients. These findings suggest a potential role for MRP1 and MDR1 SNPs in modulating the long-term outcome of relapsed and/or refractory myeloma patients treated with PLD + bortezomib. Moreover, they support prospective studies to determine if such data could be used to tailor therapy to the genetic makeup of individual patients

Investigating Bacterial Sources of Toxicity as an Environmental Contributor to Dopaminergic Neurodegeneration

Parkinson disease (PD) involves progressive neurodegeneration, including loss of dopamine (DA) neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS), involved in protein degradation. The misfolding and accumulation of proteins, such as α-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH), the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent with the etiology of age-associated neurodegenerative diseases. Collectively, these data suggest the potential for exposures to the metabolites of specific common soil bacteria to possibly represent a contributory environmental component to PD

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Metal-organic frameworks as kinetic modulators for branched selectivity in hydroformylation.

Finding heterogeneous catalysts that are superior to homogeneous ones for selective catalytic transformations is a major challenge in catalysis. Here, we show how micropores in metal-organic frameworks (MOFs) push homogeneous catalytic reactions into kinetic regimes inaccessible under standard conditions. Such property allows branched selectivity up to 90% in the Co-catalysed hydroformylation of olefins without directing groups, not achievable with existing catalysts. This finding has a big potential in the production of aldehydes for the fine chemical industry. Monte Carlo and density functional theory simulations combined with kinetic models show that the micropores of MOFs with UMCM-1 and MOF-74 topologies increase the olefins density beyond neat conditions while partially preventing the adsorption of syngas leading to high branched selectivity. The easy experimental protocol and the chemical and structural flexibility of MOFs will attract the interest of the fine chemical industries towards the design of heterogeneous processes with exceptional selectivity

Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila

Kohlschutter-Tonz syndrome (KTS) is a rare genetic disorder with neurological dysfunctions including seizure and intellectual impairment. Mutations at the Rogdi locus have been linked to development of KTS, yet the underlying mechanisms remain elusive. Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission. Rogdi mutant flies displayed insomnia-like behaviors accompanied by sleep fragmentation and delay in sleep initiation. The sleep suppression phenotypes were rescued by sustaining GABAergic transmission primarily via metabotropic GABA receptors or by blocking wake-promoting dopaminergic pathways. Transgenic rescue further mapped GABAergic neurons as a cell-autonomous locus important for Rogdi-dependent sleep, implying metabotropic GABA transmission upstream of the dopaminergic inhibition of sleep. Consistently, an agonist specific to metabotropic but not ionotropic GABA receptors titrated the wake-promoting effects of dopaminergic neuron excitation. Taken together, these data provide the first genetic evidence that implicates Rogdi in sleep regulation via GABAergic control of dopaminergic signaling. Given the strong relevance of GABA to epilepsy, we propose that similar mechanisms might underlie the neural pathogenesis of Rogdi-associated KTS

Analysis of the use of fenthion via epicutaneous in dogs for Rhipicephalus sanguineus control Análise do uso de fenthion via epicutânea em cães para o controle de Rhipicephalus sanguineus

The action of fenthion was studied in a 15% epicutaneous formulation upon Rhipicephalus sanguineus, which may transmit pathogens to men and other animals, such as Ehrlichia, Babesia and Ricketsia. Dogs were artificially infected for the trial. The fenthion bioassays were begun four months after artificial infestation. The test group, having a mean of 186 ticks per dog, received the formulation dosage according to body weight on the neck region. Tick counts were performed, considering diameters > or = 2mm, during 11 days of treatment, in the most affected body areas: back, ears and paws. Before the application of fenthion in the dogs, it were observed an average 43.3% ticks in the ears, 38.1% in the back area and 17.6% in the paws. The number of ticks in dogs decreased by 36.2%, 63.8%, 82.7%, 67%, 40% and 4.9%, respectively on days 1, 2, 3, 5, 7, 9 and 11 after treatment. R. sanguineus anti-tick activity, lower than that officially recommended, was verified. The number of ticks increased progressively after the 5th day, demonstrating residual insecticide inefficacy. The results obtained did not indicate the use of this formulation, at the tested dosage, as an elective measure for R. sanguineus control.<br>Investigou-se a atividade de fenthion em formulação epicutânea a 15% sobre Rhipicephalus sanguineus, transmissor de patógenos ao homem e animais, tais como Ehrlichia, Babesia e Ricketsia. Infestou-se artificialmente cães com larvas deste carrapato. Os bioensaios com o fenthion iniciaram-se 4 meses após a infestação artificial. Constatada a média de 186 ixodídeos/cão, cães do grupo teste receberam na região da nuca a dosagem correspondente ao seu peso. Avaliaram-se a eficiência e a atividade residual através de contagens dos carrapatos com diâmetro > ou = 2mm, durante 11 dias, nas áreas corpóreas mais parasitadas: dorso, orelhas e patas. Anteriormente, à aplicação do fenthion, 44,3% dos carrapatos format observados nas orelhas, 38,1% na área estudada do dorso e 17,6% nas patas. Revelou-se uma redução do número de carrapatos nos cães de 36,2%, 63,8%, 82,7%, 67%, 40% e 4,9%, respectivamente, nos dias 1, 2, 3, 5, 7, 9 e 11. Atividade carrapaticida menor do que a recomendada oficialmente foi constatada. O número de carrapatos aumentou progressivamente após o 5° dia, denotando ineficácia carrapaticida residual. Os resultados obtidos impedem a indicação da formulação na dosagem testada como medida eletiva para controle de R. sanguineus