PARP1 Trapping by PARP Inhibitors Drives Cytotoxicity in Both Cancer Cells and Healthy Bone Marrow.

PARP inhibitors have recently been approved as monotherapies for the treatment of recurrent ovarian cancer and metastatic -associated breast cancer, and ongoing studies are exploring additional indications and combinations with other agents. PARP inhibitors trap PARP onto damaged chromatin when combined with temozolomide and methyl methanesulfonate, but the clinical relevance of these findings remains unknown. PARP trapping has thus far been undetectable in cancer cells treated with PARP inhibitors alone.

Cytoplasmic localization of Hug1p, a negative regulator of the MEC1 pathway, coincides with the compartmentalization of Rnr2p-Rnr4p.

The evolutionarily conserved MEC1 checkpoint pathway mediates cell cycle arrest and induction of genes including the RNR (Ribonucleotide reductase) genes and HUG1 (Hydroxyurea, ultraviolet, and gamma radiation) in response to DNA damage and replication arrest. Rnr complex activity is in part controlled by cytoplasmic localization of the Rnr2p-Rnr4p subunits and inactivation of negative regulators Sml1p and Dif1p upon DNA damage and hydroxyurea (HU) treatment. We previously showed that a deletion of HUG1 rescues lethality of mec1Δ and suppresses dun1Δ strains.

Construction of a cytosolic firefly luciferase reporter cassette for use in PCR-mediated gene deletion and fusion in Saccharomyces cerevisiae.

Monitoring promoter response to environmental changes using reporter systems has provided invaluable information regarding cellular state. With the development of in vivo luciferase reporter systems, inexpensive, sensitive and accurate promoter assays have been developed without the variability reported between in vitro samplings. Current luciferase reporter systems, however, are largely inflexible to modifications to the promoter of interest.

Perception of vowel-to-vowel transitions with different formant trajectories.

In this paper, the perceptual effects of vowel-to-vowel transitions determined by different temporal variations of model parameters which specify the shapes of the vocal tract area function are investigated. It is shown that, (a) the method of deformation of the vocal tract area function between two targets can be perceptually important and (b) conversely, within certain limits, the time course of parameters from one state to another, and the precise synchronization of two parameters is not important for the correct identification of a vowel series. These characteristics are necessary but not sufficient to prove the existence of a phonetic gesture percept.

Prolonged use of pancuronium bromide and sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia.

Sensorineural hearing loss (SNHL) is a significant neurologic morbidity in survivors of neonatal congenital diaphragmatic hernia (CDH), with a reported incidence of up to 60%. In a historical cohort study of 37 neonates with CDH, we investigated the use of pancuronium bromide (PB) and common ototoxic drugs during the neonatal period and their relationship to SNHL in childhood survivors. Survivors with SNHL (n = 23) had significantly higher cumulative dose of PB administered during the neonatal illness than survivors without SNHL (n = 14).

The Edmonton experience with venovenous extracorporeal membrane oxygenation.

Background/purpose: Despite the proven effectiveness of venovenous extracorporeal membrane oxygenation (VV ECMO) in the treatment of neonates with severe respiratory failure, this technique is not widely used. The purpose of this study was to assess the authors' policy of preferred use of VV ECMO with a cephalad catheter and to compare the results with those of the Extracorporeal Life Support Organization (ELSO) Registry.

Methods: Charts of neonatal ECMO candidates were reviewed retrospectively.

Congenital diaphragmatic hernia: developing a protocolized approach.

Background/purpose: The purpose of this study was to evaluate the evolving outcome of newborns who have congenital diaphragmatic hernia (CDH) using a protocolized approach to management, which includes extracorporeal membrane oxygenation (ECMO) and to present the details of such a management protocol.

Methods: A retrospective chart review was conducted of the neonatal outcome of near-term (>34 weeks' gestation) newborns with CDH all referred to the Royal Alexandra Hospital either before or after delivery. A protocol was developed that included antenatal assessment, the use of antenatal steroids, planned delivery, use of prophylactic surfactant, pressure limited gentle ventilation, permissive hypercarbia and hypoxia, and venovenous ECMO, if indicated.

Venovenous extracorporeal membrane oxygenation: the effects of proximal internal jugular cannulation.

Venovenous (VV) extracorporeal membrane oxygenation (ECMO) using a double lumen catheter has become an accepted method of providing ECMO support for critically ill newborn infants. In addition, use of the cephalic jugular catheter can provide augmented venous blood flow, potentially prevent increased cerebral venous pressure, maintain cerebral venous blood flow, and increase ECMO oxygen delivery. The authors compared their experience using VV double-lumen (VVDL) ECMO with a cephalic jugular catheter with their previous experience using venoarterial (VA) ECMO.

Radiological decompression of bowel gas and return of mediastinal shift in congenital diaphragmatic hernia: a signal for surgical repair?

The objective of this study was to document the pattern of bowel gas decompression and mediastinal shift in infants with congenital diaphragmatic hernia (CDH) before delayed surgical correction. The setting was the Neonatal Intensive Care Unit, Royal Alexandra Hospital, Edmonton. The design was a retrospective review of radiographs and charts of all infants with CDH between January 1990 and December 1993.

Recognition of plosive syllables in noise: comparison of an auditory model with human performance.

Some of the effects of noise on the perception of plosive-vowel syllables have been investigated. It was found that noise added to the syllables for the duration of the speech had a more deleterious effect on perception than noise of the same intensity played continuously. Physiological experiments have shown that the response thresholds of cochlear nerve fibers to tones are raised by continuous background noise but not by short bursts of noise.

Computerised measurement of fundamental frequency in Scottish neoglottal patients.

An electrolaryngograph has been used to investigate the fundamental frequency of neoglottal speech produced by patients who have undergone near-total (parsimonious) laryngectomy. The resulting estimates of fundamental frequency were compared with the fundamental frequency of normal and oesophageal speakers of a similar age and Scottish dialect. It was found that the average fundamental frequencies of neoglottal and oesophageal male speakers were higher than those in the normal group, though many fall into the normal range.

Perceptual comparison of neoglottal, oesophageal and normal speech.

The sex, normality, intelligibility, rate, rhythm and intonation of 44 neoglottal, oesophageal and normal speakers have been judged by a panel of 10 trained listeners. It was found that the sex of the alaryngeal speakers was perceived correctly much less reliably than that of the normal speakers. Neoglottal speakers were rated more normal and intelligible than oesophageal speakers.

Perception of pitch movement on tonic syllables in British English.

A set of intonation contours has been synthesized using "yes" as the carrier word. Discrimination and identification functions have been obtained for these intonation contours. It was found that the stimuli could be classified as "statement," "question," "emphatic statement," and, possibly, "hesitation" and "weak statement.

Perception of speech sounds with alternate formants presented to opposite ears.

The perception of speech syllables with alternate formants presented to opposite ears has been investigated. Using synthesized speech and normal-hearing subjects, it was found that this mode of presentation reduced the recognition scores with stop consonants by about 6%, semivowels by about 4%, and fricatives by about 5%, compared with binaural presentation. Vowel recognition, on the other hand, was not significantly reduced.

The perception of speech signals.

A brief outline of the mechanism of speech production is given. It is shown that the motion of the articulators is encoded in changes in the spectra of speech waveforms. Parameters derived from these spectra form the basis of a method of speech synthesis.

Electrolytic Growth of Silver Dendrites.

The growth rates of silver dendrites formed in narrow capillaries by electrodeposition under various physical conditions have been determined. Dissolution of such dendrites as well as their growth can be reliably controlled. This principle may be used in the design of components for adaptive electronic systems.