ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.

OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. CONCLUSION: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Piezomagnetism and magnetoelastic memory in uranium dioxide.

The thermal and magnetic properties of uranium dioxide, a prime nuclear fuel and thoroughly studied actinide material, remain a long standing puzzle, a result of strong coupling between magnetism and lattice vibrations. The magnetic state of this cubic material is characterized by a 3-k non-collinear antiferromagnetic structure and multidomain Jahn-Teller distortions, likely related to its anisotropic thermal properties. Here we show that single crystals of uranium dioxide subjected to strong magnetic fields along threefold axes in the magnetic state exhibit the abrupt appearance of positive linear magnetostriction, leading to a trigonal distortion. Upon reversal of the field the linear term also reverses sign, a hallmark of piezomagnetism. A switching phenomenon occurs at ±18 T, which persists during subsequent field reversals, demonstrating a robust magneto-elastic memory that makes uranium dioxide the hardest piezomagnet known. A model including a strong magnetic anisotropy, elastic, Zeeman, Heisenberg exchange, and magnetoelastic contributions to the total energy is proposed.The nuclear fuel uranium dioxide is of intrinsic interest due to its industrial applications but it also exhibits intriguing electronic and magnetic properties. Here, the authors demonstrate how its complex magnetic structure and interactions give rise to a strong piezomagnetic effect.

Dichotomous ALK-IHC Is a Better Predictor for ALK Inhibition Outcome than Traditional ALK-FISH in Advanced Non-Small Cell Lung Cancer.

Purpose: ALK rearrangement detection using FISH is the standard test to identify patients with non-small cell lung carcinoma (NSCLC) eligible for treatment with ALK inhibitors. Recently, ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of patients with advanced NSCLC with ALK activation using both dichotomous immunohistochemical (IHC) staining and FISH.Experimental Design: Patients with stage IV NSCLC treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-break-apart FISH-Probe KIT) and IHC [Ventana ALK (D5F3) CDx assay]. Cohorts of patients with ALK-FISH-positive advanced NSCLC from four other hospitals were used for validation.Results: Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine-needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC-positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH-positive but ALK-IHC-negative patients. This was confirmed in an external cohort of 16 patients. Receiver operator characteristic (ROC) curves for ALK-IHC and ALK-FISH compared with treatment outcome showed that dichotomous ALK-IHC outperforms ALK-FISH [tumor response area under the curve: (AUC), 0.86 vs. 0.64, P = 0.03; progression-free survival (PFS): AUC 0.86 vs. 0.36, P = 0.005; overall survival (OS): AUC, 0.78 vs. 0.41, P = 0.01, respectively].Conclusions: Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC. Our data strongly suggest adapting the guidelines and using dichotomous ALK-IHC as standard companion diagnostic test to select patients with NSCLC who benefit from ALK-targeting therapy. Clin Cancer Res; 23(15); 4251-8. ©2017 AACR.

Superconductivity and spin-orbit coupling in non-centrosymmetric materials: a review.

In non-centrosymmetric superconductors, where the crystal structure lacks a centre of inversion, parity is no longer a good quantum number and an electronic antisymmetric spin-orbit coupling (ASOC) is allowed to exist by symmetry. If this ASOC is sufficiently large, it has profound consequences on the superconducting state. For example, it generally leads to a superconducting pairing state which is a mixture of spin-singlet and spin-triplet components. The possibility of such novel pairing states, as well as the potential for observing a variety of unusual behaviors, led to intensive theoretical and experimental investigations. Here we review the experimental and theoretical results for superconducting systems lacking inversion symmetry. Firstly we give a conceptual overview of the key theoretical results. We then review the experimental properties of both strongly and weakly correlated bulk materials, as well as two dimensional systems. Here the focus is on evaluating the effects of ASOC on the superconducting properties and the extent to which there is evidence for singlet-triplet mixing. This is followed by a more detailed overview of theoretical aspects of non-centrosymmetric superconductivity. This includes the effects of the ASOC on the pairing symmetry and the superconducting magnetic response, magneto-electric effects, superconducting finite momentum pairing states, and the potential for non-centrosymmetric superconductors to display topological superconductivity.

Flexible, ultralight, porous superconducting yarns containing shell-core magnesium diboride-carbon nanotube nanofibers.

Magnesium-diboride-coated carbon nanotube arrays are synthesized by templating carbon-nanotube aerogel sheets with boron and then converting the boron to MgB2. The resultant MgB2-CNT sheets are twisted into flexible, light-weight yarns that have a superconducting transition around 37.8 K and critical current and critical field comparable with those of existing MgB2 wires, but have about 20 times lower density than bulk MgB2.

Adverse circulatory effects of passive smoking during infancy: surprisingly strong, manifest early, easily avoided.

AIM: To compare blood pressure reactions (BPR) of infants to mild stress for evidence of adverse cardiovascular effects of passive exposure to tobacco smoke during pregnancy and early infancy. METHODS: An observational field study conducted in Crete. We compared 4- to 6-month olds of lifelong nonsmokers minimally (controls, n = 9) or frequently exposed to tobacco smoke (passive smokers; n = 10) with those born to habitual smokers (n = 6). Smoke exposure was verified biochemically (urine cotinine each trimester and at study). We recorded beat-to-beat blood pressure (BP) during brief repositioning manoeuvres performed during a daytime nap and analysed BPR (% change in BP during head-up tilt) for associations with maternal and infant cotinine. RESULTS: We observed a 20-fold difference between BPR of infants of controls versus passive smokers - exceptional given number of infants (α error/confidence level <10% i.e. power >90%). The BPR declined linearly as the infant's (but not mother's) cotinine level rose (p = 0.04), indicating abnormal BPR was caused mainly by postnatal smoke exposure. Infants of active smokers differed from those of passive smokers. CONCLUSION: Cardiovascular effects of passive smoking by a newborn infant manifest early on and are exceptionally strong. They can be largely avoided by keeping the home smoke rigorously free.

Influence of lung injury on cardiac output measurement using transpulmonary ultrasound dilution: a validation study in neonatal lambs.

BACKGROUND: Transpulmonary ultrasound dilution (TPUD) is a promising method for cardiac output (CO) measurement in severely ill neonates. The incidence of lung injury in this population is high, which might influence CO measurement using TPUD because of altered lung perfusion. We evaluated the influence of lung injury on the accuracy and precision of CO measurement using TPUD in an animal model. METHODS: In nine neonatal lambs, central venous and arterial catheters were inserted and connected to the TPUD monitor. Repeated lavages with warmed isotonic saline were performed to gradually induce lung injury. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe around the main pulmonary artery (COufp). An increase in oxygenation index was used as an indicator of induced lung injury during the experiment. Post-mortem lung injury was confirmed by histopathological examination. RESULTS: Fifty-five sessions of three paired CO measurements were analysed. The mean COufp was 1.53 litre min(-1) (range 0.66-2.35 litre min(-1)), and the mean COtpud was 1.65 litre min(-1) (range 0.78-2.91 litre min(-1)). The mean bias (standard deviation) between the two methods was 0.13 (0.15) litre min(-1) with limits of agreement of ±0.29 litre min(-1). The overall percentage error was 19.1%. The accuracy and precision did not change significantly during progressive lung injury. Histopathological severity scores were consistent with heterogeneous lung injury. The capability to track changes in CO using TPUD was moderate to good. CONCLUSIONS: The accuracy and precision of CO measurement using TPUD is not influenced in the presence of heterogeneous lung injury in an animal model.

Animal perception of seasonal thresholds: changes in elephant movement in relation to rainfall patterns.

BACKGROUND: The identification of temporal thresholds or shifts in animal movement informs ecologists of changes in an animal's behaviour, which contributes to an understanding of species' responses in different environments. In African savannas, rainfall, temperature and primary productivity influence the movements of large herbivores and drive changes at different scales. Here, we developed a novel approach to define seasonal shifts in movement behaviour by examining the movements of a highly mobile herbivore (elephant; Loxodonta africana), in relation to local and regional rainfall patterns. METHODOLOGY/PRINCIPAL FINDINGS: We used speed to determine movement changes of between 8 and 14 GPS-collared elephant cows, grouped into five spatial clusters, in Kruger National Park, South Africa. To detect broad-scale patterns of movement, we ran a three-year daily time-series model for each individual (2007-2009). Piecewise regression models provided the best fit for elephant movement, which exhibited a segmented, waveform pattern over time. Major breakpoints in speed occurred at the end of the dry and wet seasons of each year. During the dry season, female elephant are constrained by limited forage and thus the distances they cover are shorter and less variable. Despite the inter-annual variability of rainfall, speed breakpoints were strongly correlated with both local and regional rainfall breakpoints across all three years. Thus, at a multi-year scale, rainfall patterns significantly affect the movements of elephant. The variability of both speed and rainfall breakpoints across different years highlights the need for an objective definition of seasonal boundaries. CONCLUSIONS/SIGNIFICANCE: By using objective criteria to determine behavioural shifts, we identified a biologically meaningful indicator of major changes in animal behaviour in different years. We recommend the use of such criteria, from an animal's perspective, for delineating seasons or other extrinsic shifts in ecological studies, rather than arbitrarily fixed definitions based on convention or common practice.

The effect of growth hormone on sleep-related cardio-respiratory control in Prader-Willi syndrome.

AIM: To evaluate the effects of growth hormone (GH) treatment on control of breathing, heart rate and blood pressure during sleep in Prader-Willi Syndrome (PWS). STUDY DESIGN: In a prospective clinical case series study, sixteen consecutive PWS patients (median age 16 months at enrolment) were followed-up 6 months (2-32 months) after commencing GH treatment. We compared heart rate (HR), Pulse Transit Time (PTT; an index of blood pressure, BP) and ventilatory responses to standard chemostimuli (4% CO(2) and 100% O(2)) during quiet sleep prior to and after commencing GH treatment. RESULTS: Growth hormone treatment increased arterial oxygenation during sleep but did not significantly improve breathing stability (apnoea-hypopnoea index remained unchanged). GH treatment did not alter ventilatory, HR and PTT chemoreceptor-mediated responsiveness (p = 0.23-0.97) but did significantly improve the coupling between and HR and PTT, indicating that HR and BP rose (or fell) in parallel after but not before GH therapy (p = 0.01). CONCLUSION: Growth hormone treatment improves arterial oxygenation and cardiovascular function during sleep; these changes are not owing to improved (stronger) chemoreflex-mediated autonomic drive.

Direct imaging of nanoscale phase separation in La(0.55)Ca(0.45)MnO(3): relationship to colossal magnetoresistance.

A nanoscale phase is known to coincide with colossal magnetoresistance (CMR) in manganites, but its volume fraction is believed to be too small to affect CMR. Here we provide scanning-electron-nanodiffraction images of nanoclusters as they form and evolve with temperature in La(1-x)Ca(x)MnO(3), x = 0.45. They are not doping inhomogeneities, and their structure is that of the bulk compound at x = 0.60, which at low temperatures is insulating. Their volume fraction peaks at the CMR critical temperature and is estimated to be 22% at finite magnetic fields. In view of the known dependence of the nanoscale phase on magnetic fields, such a volume fraction can make a significant contribution to the CMR peak.

Mode of delivery modulates physiological and behavioral responses to neonatal pain.

OBJECTIVE: To study whether the mode of delivery alters pain expression. STUDY DESIGN: Full-term infants born by vaginal delivery or elective caesarean section were observed following high- and low-intensity pain stimuli, with recording of electrocardiogram, facial expression and vocalization. RESULT: Graded physiological and behavioral responses occurred, with greater responses to higher than lower intensity pain stimuli. Elevation in heart rate following both stimuli increased with time after vaginal delivery. Infants delivered by elective caesarean section showed stronger facial expressions and briefer time in vocalizations response to both interventions. CONCLUSION: Diminished responses following vaginal delivery suggest that physiological events associated with a normal delivery reduce the physiologic and sympathoadrenal activation by nociceptive mechanisms. Pain and stress reactivity appear to be inhibited during fetal life and sensory inputs during vaginal delivery may reverse this inhibition. To minimize neonatal pain, we recommend that postnatal invasive procedures to be performed shortly after vaginal birth.

Space and time-resolved gene expression experiments on cultured mammalian cells by a single-cell electroporation microarray.

Single-cell experiments represent the next frontier for biochemical and gene expression research. Although bulk-scale methods averaging populations of cells have been traditionally used to investigate cellular behavior, they mask individual cell features and can lead to misleading or insufficient biological results. We report on a single-cell electroporation microarray enabling the transfection of pre-selected individual cells at different sites within the same culture (space-resolved), at arbitrarily chosen time points and even sequentially to the same cells (time-resolved). Delivery of impermeant molecules by single-cell electroporation was first proven to be finely tunable by acting on the electroporation protocol and then optimized for transfection of nucleic acids into Chinese Hamster Ovary (CHO-K1) cells. We focused on DNA oligonucleotides (ODNs), short interfering RNAs (siRNAs), and DNA plasmid vectors, thus providing a versatile and easy-to-use platform for time-resolved gene expression experiments in single mammalian cells.

Cardiorespiratory development in extremely preterm infants: vulnerability to infection and persistence of events beyond term-equivalent age.

OBJECTIVE: Apnoea, bradycardia and hypoxemia occur frequently in extremely preterm infants, yet there is little longitudinal data describing cardiorespiratory development in these infants. This prospective study characterized early age-dependent changes in cardiorespiratory function and determined how activity is affected by factors such as underlying disease, postnatal insults and therapeutic interventions. PATIENTS AND METHODS: Thirty-three infants born between 23 and 28 weeks gestational age (GA) were monitored weekly from birth to beyond term-equivalent age (i.e. 25-45 weeks postconceptional age, PCA). Baseline cardiorespiratory activity as well as apnoea/hypopnoea, bradycardia and hypoxemia events were examined using impedance pneumography, electrocardiography (ECG) and pulse oximetry, respectively. RESULTS: Three hundred thirty-eight cardiorespiratory recordings lasting 3236 h were analysed. While the respiratory rate (RR) did not change during the early postnatal period, heart rate (HR) decreased and O2 saturation improved. There were 5973 total cardiorespiratory events, and their incidence decreased with advancing age. However, they still occurred frequently at term-equivalent age and after hospital discharge (mean PCA at discharge=38.3+/-0.5 weeks). Moreover, infection significantly increased apnoea/hypopnoea and hypoxemia incidence. CONCLUSION: The persistence of cardiorespiratory events beyond term-equivalent age as well as the marked impact of infection on cardiorespiratory function indicate that close surveillance after hospitalization is of crucial importance in extremely preterm infants.

Implementation of surfactant treatment during continuous positive airway pressure.

OBJECTIVE: To study the effects of implementing a method for surfactant administration by transient intubation, INSURE (i.e. INtubation SURfactant Extubation) during nasal continuous positive airway pressure (nCPAP) for moderately preterm infants with respiratory distress syndrome (RDS). STUDY DESIGN: A descriptive, retrospective, bi-center study in Stockholm, Sweden, comparing mechanical ventilation (MV) rates, surfactant use, treatment response and outcome of all inborn infants with gestational age 27 to 34 weeks and RDS, (n=420), during the 5-year periods before and after the introduction of the INSURE-strategy at one of the centers (Karolinska Huddinge) in 1998. The other center (Karolinska Solna) continued conventional surfactant therapy in conjunction with MV throughout the study. RESULTS: Implementation of INSURE at Karolinska Huddinge reduced the number of infants requiring MV by 50% (P<0.01), resulted in earlier surfactant administration and increased overall surfactant use. INSURE-treatment improved oxygenation and the treatment response was sustained over time with only 17% of the infants requiring >1 dose of surfactant. At Karolinska Solna, the MV rates were unaltered between the first and second 5-year period. CONCLUSION: Implementing a strategy of surfactant administration by transient intubation during nCPAP reduces the need for MV without adverse effects on outcome and may be an option to more effectively treat RDS, particularly in a care setting where transfer is necessary to provide MV.

The role of topological spin defects in magnetotransport of CrO(2).

We investigated the temperature dependence of the resistivity for a wide temperature range for CrO(2)(100) epitaxial films. The temperature derivative dρ/dT definitely shows the same character as the magnetic heat capacity anomaly in the critical regime even in a finite magnetic field and the critical exponents (α) deduced are consistent with those of 3D Heisenberg ferromagnets. In addition, we found that the spin dependent resistivity over a wide temperature range can be simply proportional to the density of diluted topological spin defects (Skyrmion strings) suggesting that those nontrivial topological defects scatter conduction electrons just like impurities. The excitation energy of such topological defects is quite comparable to that obtained by anomalous Hall effect analysis of the Ye et al model based on the Berry phase. The overall results give a simple picture wherein the density of the topological defects can be a dominant mechanism of resistivity, like the anomalous Hall effect. The results concerning the critical exponent analysis and intuition concerning scattering centres of magnetic disorder suggest a specific picture of the Fisher-Langer model.

Nanoscale magnetic structure of ferromagnet/antiferromagnet manganite multilayers.

We use polarized neutron reflectometry and dc magnetometry to obtain a comprehensive picture of the magnetic structure of a series of La(2/3)Sr(1/3)MnO3/Pr(2/3)Ca(1/3)MnO3 (LSMO/PCMO) superlattices, with varying thickness of the antiferromagnetic (AFM) PCMO layers (0

Eosinophil activation in preterm infants with lung disease.

AIM: We investigated the role of eosinophils in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: Fifteen preterm infants with BPD were compared to 13 preterms with respiratory distress syndrome (RDS) and to 16 healthy preterms. We assessed total eosinophil and neutrophil counts in venous blood samples and the levels of the eosinophilic activity markers eosinophilic cationic protein (ECP) and the cellular surface antigen (CD9). RESULTS: The eosinophil count was greater in BPD compared with RDS and healthy infants (1414 vs. 797 and 471 cells per microlitre, respectively, p = 0.03). ECP levels were elevated (34 vs. 12.8 and 9.8 microg/L, respectively, p = 0.002) and CD9 levels reduced (75 vs. 94 and 86 mean fluorescence intensity units, respectively, p = 0.01) in BPD compared with RDS and healthy infants, suggesting eosinophilic activation in BPD. These findings were not solely explained by differences between gestational age or birth weight of the different groups. ECP levels were positively correlated with the duration of oxygen supplementation in the BPD group. The eosinophil count fell promptly after steroid treatment was commenced in the BPD group. CONCLUSION: The findings suggest that BPD is linked to eosinophil activation, which might contribute to the pathogenesis.

S-wave spin-triplet order in superconductors without inversion symmetry: Li2Pd3B and Li2Pt3B.

We investigate the order parameter of noncentrosymmetric superconductors Li2Pd3B and Li2Pt3B via the behavior of the penetration depth lambda(T). The low-temperature penetration depth shows BCS-like behavior in Li2Pd3B, while in Li2Pt3B it follows a linear temperature dependence. We propose that broken inversion symmetry and the accompanying antisymmetric spin-orbit coupling, which admix spin-singlet and spin-triplet pairing, are responsible for this behavior. The triplet contribution is weak in Li2Pd3B, leading to a wholly open but anisotropic gap. The significantly larger spin-orbit coupling in Li2Pt3B allows the spin-triplet component to be larger in Li2Pt3B, producing line nodes in the energy gap as evidenced by the linear temperature dependence of lambda(T). The experimental data are in quantitative agreement with theory.

Hidden magnetism and quantum criticality in the heavy fermion superconductor CeRhIn5.

With only a few exceptions that are well understood, conventional superconductivity does not coexist with long-range magnetic order (for example, ref. 1). Unconventional superconductivity, on the other hand, develops near a phase boundary separating magnetically ordered and magnetically disordered phases. A maximum in the superconducting transition temperature T(c) develops where this boundary extrapolates to zero Kelvin, suggesting that fluctuations associated with this magnetic quantum-critical point are essential for unconventional superconductivity. Invariably, though, unconventional superconductivity masks the magnetic phase boundary when T < T(c), preventing proof of a magnetic quantum-critical point. Here we report specific-heat measurements of the pressure-tuned unconventional superconductor CeRhIn5 in which we find a line of quantum-phase transitions induced inside the superconducting state by an applied magnetic field. This quantum-critical line separates a phase of coexisting antiferromagnetism and superconductivity from a purely unconventional superconducting phase, and terminates at a quantum tetracritical point where the magnetic field completely suppresses superconductivity. The T --> 0 K magnetic field-pressure phase diagram of CeRhIn5 is well described with a theoretical model developed to explain field-induced magnetism in the high-T(c) copper oxides, but in which a clear delineation of quantum-phase boundaries has not been possible. These experiments establish a common relationship among hidden magnetism, quantum criticality and unconventional superconductivity in copper oxides and heavy-electron systems such as CeRhIn5.