Fast dose fractionation using ultra-short laser accelerated proton pulses can increase cancer cell mortality, which relies on functional PARP1 protein.

Radiotherapy is a cornerstone of cancer management. The improvement of spatial dose distribution in the tumor volume by minimizing the dose deposited in the healthy tissues have been a major concern during the last decades. Temporal aspects of dose deposition are yet to be investigated. Laser-plasma-based particle accelerators are able to emit pulsed-proton beams at extremely high peak dose rates (~109 Gy/s) during several nanoseconds. The impact of such dose rates on resistant glioblastoma cell lines, SF763 and U87-MG, was compared to conventionally accelerated protons and X-rays. No difference was observed in DNA double-strand breaks generation and cells killing. The variation of the repetition rate of the proton bunches produced an oscillation of the radio-induced cell susceptibility in human colon carcinoma HCT116 cells, which appeared to be related to the presence of the PARP1 protein and an efficient parylation process. Interestingly, when laser-driven proton bunches were applied at 0.5 Hz, survival of the radioresistant HCT116 p53-/- cells equaled that of its radiosensitive counterpart, HCT116 WT, which was also similar to cells treated with the PARP1 inhibitor Olaparib. Altogether, these results suggest that the application modality of ultrashort bunches of particles could provide a great therapeutic potential in radiotherapy.

[Neurodevelopmental outcome at 3 years of age of infants born at less than 26 weeks]. / Devenir à l'âge de 3ans d'une cohorte d'enfants nés à moins de 26 semaines d'aménorrhée.

OBJECTIVE: To describe the neurodevelopmental outcome and perinatal factors associated with favorable outcome among extremely preterm children at 3 years of age. METHODS: All infants born before 26 weeks of gestation between 2007 and 2011, admitted to intensive care units participating in a French regional network (western PACA-southern Corsica) were included. Perinatal data were collected to assess the main neonatal morbidities. At 3 years of age, the children's neurodevelopment was assessed by trained physicians participating in the follow-up network. Children were classified according to their disability: none, moderate, or severe. Using logistic regression, we determined the perinatal factors associated with the absence of disability at 3 years of age. RESULTS: One hundred and sixty-two very preterm newborns were admitted to neonatal intensive care units. At discharge the survival rate was 62% (101). Rates of survival increased with gestational age (33% at 23 weeks, 57% at 24 weeks and 68% at 25 weeks). Among the 101 surviving extremely preterm children, 66 were evaluated at 3 years. The perinatal characteristics were not significantly different from those of the children lost to follow-up. Overall, 56% of extremely preterm children had no disability and 6% had severe disability. Cerebral palsy was diagnosed in 13% of children. At 3 years of age, the main perinatal factors associated with no disability were short duration of mechanical ventilation (OR=0.96 [0.93-0.99]; P=0.03) and complete course of prenatal corticosteroids (OR=4.7 [1.2-17.7]; P=0.02). CONCLUSION: As mortality rates continue to decrease for very preterm infants, concerns are rising about their long-term outcome. In this high-risk population, improving perinatal care remains a challenge to improve long-term outcome.

Gain dynamics in quickly ionized plasma for seeded operated soft x-ray lasers.

Harmonic seeded operation of a neon-like titanium plasma-based soft x-ray laser is described. The plasma amplifier is pumped with a variation of the grazing incidence technique involving a fast and localized ionization step. We discuss its effect on gain dynamics by measuring the amplifying factor as a function of the delay between pump pulse and harmonic seed. Two different regimes are pointed out, following the pumping scheme used. For one of them, a delay in the gain generation compared with the pumping laser pulse is observed.

[Uncommon neonatal case of hypoglycemia: ACTH resistance syndrome]. / Hypoglycémie néonatale sévère et récidivante sans perte de sel révélatrice d'un syndrome de résistance à l'ACTH.

Monitoring of blood glucose is usually reported to reduce the risk of hypoglycemia in term newborns with high risk factors and for prematurity in neonatal intensive care unit patients. Differential diagnosis has rarely been discussed. In the eutrophic term newborn, hypoglycemia remains rare and an etiological diagnosis must be made. Intensive management of neonatal hypoglycemia is required to prevent neurodevelopmental defects. Without evident cause or if hypoglycemia persists, a systematic review of possible causes should be made. We report isolated glucocorticoid deficiency diagnosed in an infant at 10 months of age. This boy had neonatal hypoglycemia and mild jaundice that had not been investigated. During his first 9 months of life, he presented frequent infections. At 10 months of age, febrile seizures occurred associated with shock, hypoglycemia, hyponatremia, mild hyperpigmentation, and coma. He was diagnosed with hypocortisolemia and elevated ACTH levels. Brain injury was revealed by MRI after resuscitation, with hypoxic-ischemic and hypoglycemic encephalopathy. The molecular studies demonstrated the presence of p.Asp107Asn and previously unreported frameshift p.Pro281GlnfsX9 MC2R gene mutations. A substitutive hormone therapy was provided and during a follow-up of 12 months no adrenal crisis was noted. We report an unusual case of familial glucocorticoid deficiency with severe neurological injury. This case demonstrates the importance of an appropriate etiological diagnosis in neonatal hypoglycemia.

Energy transport in short-pulse-laser-heated targets measured using extreme ultraviolet laser backlighting.

The accurate characterization of thermal electron transport and the determination of heating by suprathermal electrons in laser driven solid targets are both issues of great importance to the current experiments being performed at the National Ignition Facility, which aims to achieve thermonuclear fusion ignition using lasers. Ionization, induced by electronic heat conduction, can cause the opacity of a material to drop significantly once bound-free photoionization is no longer energetically possible. We show that this drop in opacity enables measurements of the transmission of extreme ultraviolet (EUV) laser pulses at 13.9 nm to act as a signature of the heating of thin (50 nm) iron layers with a 50-nm thick parylene-N (CH) overlay irradiated by 35-fs pulses at irradiance 3×10(16) Wcm(-2). Comparing EUV transmission measurements at different times after irradiation to fluid code simulations shows that the target is instantaneously heated by hot electrons (with approximately 10% of the laser energy), followed by thermal conduction with a flux limiter of ≈0.05.

Genomics and structure/function studies of Rhabdoviridae proteins involved in replication and transcription.

Some mammalian rhabdoviruses may infect humans, and also infect invertebrates, dogs, and bats, which may act as vectors transmitting viruses among different host species. The VIZIER programme, an EU-funded FP6 program, has characterized viruses that belong to the Vesiculovirus, Ephemerovirus and Lyssavirus genera of the Rhabdoviridae family to perform ground-breaking research on the identification of potential new drug targets against these RNA viruses through comprehensive structural characterization of the replicative machinery. The contribution of VIZIER programme was of several orders. First, it contributed substantially to research aimed at understanding the origin, evolution and diversity of rhabdoviruses. This diversity was then used to obtain further structural information on the proteins involved in replication. Two strategies were used to produce recombinant proteins by expression of both full length or domain constructs in either E. coli or insect cells, using the baculovirus system. In both cases, parallel cloning and expression screening at small-scale of multiple constructs based on different viruses including the addition of fusion tags, was key to the rapid generation of expression data. As a result, some progress has been made in the VIZIER programme towards dissecting the multi-functional L protein into components suitable for structural and functional studies. However, the phosphoprotein polymerase co-factor and the structural matrix protein, which play a number of roles during viral replication and drives viral assembly, have both proved much more amenable to structural biology. Applying the multi-construct/multi-virus approach central to protein production processes in VIZIER has yielded new structural information which may ultimately be exploitable in the derivation of novel ways of intervening in viral replication.

Clinical experience with technetium-99m teboroxime scintigraphy in patients referred for myocardial perfusion evaluation.

A series of 30 patients (25 males, 5 females, age = 28-73 years) with a clinical indication of thallium-201 stress/4 hours redistribution scintigraphy has been studied using stress/rest (n = 7) or rest/stress (n = 23) protocols with technetium-99m teboroxime (CARDIOTEC, Squibb Diagnostics) in order to assess the clinical usefulness of this new molecule and to compare it to thallium. In all cases coronary artery disease was known or highly suspected, with a history of myocardial infarction in 18 cases (subacute n = 6, remote n = 12) and/or previous by-pass surgery or PTCA in 5 cases. Medical treatment was not discontinued at the time of stress testing. Coronary angiography was available for 27 patients. Exercise tests for both tracers were carried out on an ergometric bicycle during the same day and the levels of exercise achieved for the thallium studies were very similar to those achieved for teboroxime. Imaging was performed in three planar projections and sudies were evaluated using a model with 4 territories: septal and anterior assumed to correspond to the LAD artery, lateral and latero-posterior (= LCX), inferior and posterior (= RCA) and apex. Classification of results was: normal, ischemic, infarcted and infarcted with ischemia. With reference to the thallium-201 results, agreement was found in 86% (37/43) of normal regions and in 82% (63/77) of abnormal regions. Relative to documented coronary artery lesions (27 patients) sensitivity and specificity of thallium and teboroxime for exact correspondence between arteries and territories were, respectively: thallium, se = 71%, sp = 64%, teboroxime, se = 67%, sp = 75%.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel secreted cyclophilin-like protein (SCYLP).

A novel cyclosporin A binding glycoprotein of 21 kDa was isolated from human milk by several steps of cation exchange chromatography. The corresponding gene was cloned from human T cells, expressed in Escherichia coli and the recombinant protein purified. The protein shares 58% amino acid identity with the cytosolic cyclophilin and is initially synthesized with a hydrophobic leader sequence. The cyclophilin-like protein has also peptidyl-prolyl cis/trans-isomerase activity, although less efficient, that is inhibited by cyclosporin A. The existence of a secreted form of cyclophilin-like protein in addition to the previously known cytosolic cyclophilin implies that these proteins act on different in vivo targets.

Technetium-99m teboroxime scintigraphy. Clinical experience in patients referred for myocardial perfusion evaluation.

In order to evaluate the clinical value of a new myocardial perfusion tracer, a series of 30 patients (25 male, 5 female, mean age 56 years) referred for thallium 201 stress/redistribution scintigraphy has been studied using stress/rest (n = 7) or rest/stress (n = 23) protocols with technetium 99m teboroxime (Cardiotec SQUIBB). In all cases coronary artery disease was known or highly probable, with a history of myocardial infarction in 18 cases. Medical treatment was not discontinued at the time of stress testing, and coronary angiography was available in 27 patients. Exercise tests for both tracers were carried out on a bicycle ergometer during the same day, and the levels of exercise achieved for the 201Tl study were very similar to those achieved for 99mTc-teboroxime. Studies performed in three planar projections were evaluated using a model with four territories: septal and anterior assumed to correspond to the left anterior descending artery, lateral and latero-posterior (left circonflex), inferior and posterior (right coronary artery) and apex. Classification of results was: normal, ischaemic, infarcted and infarcted with ischaemia. On comparison with the 201Tl results, agreement was found in 86% (37/43) of normal regions and in 82% (63/77) of abnormal regions. Relative to documented coronary artery lesions (27 patients), sensitivity and specificity of 201Tl and 99mTc-teboroxime for exact correspondence between arteries and territories were respectively: 201Tl: sensitivity 64%, specificity 60%; 99mTc-teboroxime: sensitivity 62%, specificity 77%.(ABSTRACT TRUNCATED AT 250 WORDS)