First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade \u3e 1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (\u3e 9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks

Simple electric powered plankton wheel for the production of aggregates in seawater on-board ship

37-41A new handy plankton wheel was devised for use on-board a ship. Its efficacy to generate aggregates was tested on land using coastal waters. The device successfully generated aggregates of sizes varying up to 11.3 mm2 within eleven days. During an on-board experiment with oceanic water within approximately the same time period, no visible aggregates were observed but the concentration of transparent exopolymeric particles (TEPs) increased from 14.4 to 547.8 mg eq Alginic Acid L-1 indicating successful production of aggregate precursors and requirement of longer incubation periods for the production of visible aggregates with oceanic waters

Disruption of Microbial Biofilms by an Extracellular Protein Isolated from Epibiotic Tropical Marine Strain of <i>Bacillus licheniformis</i>

<div><p>Background</p><p>Marine epibiotic bacteria produce bioactive compounds effective against microbial biofilms. The study examines antibiofilm ability of a protein obtained from a tropical marine strain of <i>Bacillus licheniformis</i> D1.</p><p>Methodology/Principal Findings</p><p><i>B. licheniformis</i> strain D1 isolated from the surface of green mussel, <i>Perna viridis</i> showed antimicrobial activity against pathogenic <i>Candida albicans</i> BH, <i>Pseudomonas aeruginosa</i> PAO1 and biofouling <i>Bacillus pumilus</i> TiO1 cultures. The antimicrobial activity was lost after treatment with trypsin and proteinase K. The protein was purified by ultrafiltration and size-exclusion chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) analysis revealed the antimicrobial agent to be a 14 kDa protein designated as BL-DZ1. The protein was stable at 75°C for 30 min and over a pH range of 3.0 to 11.0. The sequence alignment of the MALDI-fingerprint showed homology with the NCBI entry for a hypothetical protein (BL00275) derived from <i>B. licheniformis</i> ATCC 14580 with the accession number gi52082584. The protein showed minimum inhibitory concentration (MIC) value of 1.6 µg/ml against <i>C. albicans</i>. Against both <i>P. aeruginosa</i> and <i>B. pumilus</i> the MIC was 3.12 µg/ml. The protein inhibited microbial growth, decreased biofilm formation and dispersed pre-formed biofilms of the representative cultures in polystyrene microtiter plates and on glass surfaces.</p><p>Conclusion/Significance</p><p>We isolated a protein from a tropical marine strain of <i>B. licheniformis</i>, assigned a function to the hypothetical protein entry in the NCBI database and described its application as a potential antibiofilm agent.</p></div

Methane stimulates massive nitrogen loss from freshwater reservoirs in India

The fate of the enormous amount of reactive nitrogen released to the environment by human activities in India is unknown. Here we show occurrence of seasonal stratification and generally low concentrations of dissolved inorganic combined nitrogen, and high molecular nitrogen (N2) to argon ratio, thus suggesting seasonal loss to N2 in anoxic hypolimnia of several dam-reservoirs. However, 15N-experiments yielded low rates of denitrification, anaerobic ammonium oxidation and dissimilatory nitrate reduction to ammonium—except in the presence of methane (CH4) that caused ~12-fold increase in denitrification. While nitrite-dependent anaerobic methanotrophs belonging to the NC10 phylum were present, previously considered aerobic methanotrophs were far more abundant (up to 13.9%) in anoxic hypolimnion. Methane accumulation in anoxic freshwater systems seems to facilitate rapid loss of reactive nitrogen, with generally low production of nitrous oxide (N2O), through widespread coupling between methanotrophy and denitrification, potentially mitigating eutrophication and emissions of CH4 and N2O to the atmosphere

Relationship between maternal periodontal disease and birth of preterm low weight babies Associação entre doença periodontal materna e nascimento de bebês prematuros e de baixo peso

It has been recently suggested that periodontal disease is an associated factor for prematurity and low birth weight. The aim of this work was to assess the periodontal status of puerperae and determine its possible relationship with preterm low birth weight (PLBW) delivery. The sample included 59 women seen at two maternity hospitals in Juiz de Fora, MG, Brazil. Nineteen mothers had premature and low birth weight babies (gestational age below 37 weeks and birth weight below 2,500 g - group I), and 40 had mature, normal weight babies (gestational age over 37 weeks and birth weight over 2,500 g - group II). The mothers' data were obtained from medical files, interview, and periodontal clinical examination carried out up to 48 hours after delivery. The Periodontal Screening and Recording (PSR) was used for periodontal assessment. The association between periodontal disease and PLBW was expressed as odds ratio (OR). There was a higher rate of periodontal disease in group I (84.21% - 16/19) as compared with group II (37.5% - 15/40). The data also showed a significant association between periodontal disease and PLBW (OR = 8.9 - 95% CI: 2.22-35.65 - p = 0.001). It was concluded that maternal periodontal disease was an associated factor for prematurity and low birth weight in this sample.<br>Estudos recentes sugerem que a doença periodontal é um fator associado para prematuridade e baixo peso ao nascimento. O objetivo deste trabalho foi avaliar a condição periodontal de puérperas e determinar sua possível associação com nascimentos prematuros e de baixo peso (NPBP). A amostra incluiu 59 mães atendidas em duas maternidades de Juiz de Fora, MG. Dentre essas, 19 tiveram bebês prematuros e de baixo peso (idade gestacional menor que 37 semanas e peso ao nascimento menor que 2.500 g - grupo I) e 40 tiveram bebês a termo e de peso normal (idade gestacional maior que 37 semanas e peso ao nascimento maior que 2.500 g - grupo II). Os dados das mães foram obtidos através de prontuário médico, entrevista e exame clínico periodontal, realizado até 48 horas após o parto. O Registro Periodontal Simplificado (RPS) foi utilizado para avaliar a condição periodontal. A associação entre doença periodontal e NPBP foi expressa em "odds ratio" (OR). Os resultados demonstraram uma freqüência maior de doença periodontal no grupo I (84,21% - 16/19) em comparação ao grupo II (37,5% - 15/40). Os dados demonstraram ainda uma associação significante entre a presença de doença periodontal e NPBP (OR = 8,9 - IC de 95%: 2,22-35,65 - p = 0,001). Concluiu-se que a doença periodontal materna atuou como fator associado para a prematuridade e o baixo peso ao nascimento nesta amostra