Search

Abstract: The growth rates and aluminium contents of Al x Ga1−x N layers grown in a close-coupled showerhead reactor were investigated as a function of growth pressure and chamber height during metal-organic vapour phase epitaxy. The data show strong non-linear dependencies due to nanoparticle formation in the gas-phase. Good agreement between the experimental data and modeling results is obtained when the contribution of both Ga- and Al-containing species to the gas-phase particle formation is considered. [Copyright &y& Elsevier] more...

Abstract: Maskless epitaxial overgrowth of AlGaN on structured AlN templates was performed and the impact of stripe orientation on the lateral growth of AlGaN was studied. AlN/sapphire templates were patterned into stripes with wide bars and a period of . AlGaN and AlN growths were performed on the patterned templates. Two stripe orientations were investigated: stripes parallel to the and parallel to the directions. Coalescence was achieved for both stripe orientations. AlGaN layers grown on stripes oriented along the direction show a flat and closed surface in contrast to overgrown stripes oriented along the direction where the surface is facetted and rough. The Al content is strongly dependent on the growth facet and varies between 25% at the sidewalls and 50% on the c-facet. The overgrowth of stripes parallel to the direction with AlN shows coalescence and flat surfaces. The X-ray rocking curve full width at half-maximum of the reflection is reduced from 1000arcsec to 500arcsec for the overgrown AlN. Temperature dependent photoluminescence measurements of AlGaN:Si grown on these coalesced AlN templates also indicate a dislocation density reduction via this method. [Copyright &y& Elsevier] more...

Abstract: InGaN/GaN multiple quantum well structures emitting in the blue/green wavelength region were grown by metal organic vapor phase epitaxy. By reducing the quantum well growth time the influence of the quantum well thicknesses between 3.8 and 1.1nm on the indium incorporation and the distribution of indium in the quantum wells in growth direction were investigated. X-ray diffraction measurements show that the average indium mole fraction in the quantum wells decreases with reducing quantum well width due to a delay in the indium incorporation at the barrier/well interface. Quantitative analysis reveals a segregation length of about 2nm as a measure of the graded region in growth direction. Cathodoluminescence imaging reveals that the spatial variation of the wavelength is reduced with decreasing quantum well thickness down to 1.7nm. Reducing the width of the quantum well further results in an increase of the spatial wavelength variation. [ABSTRACT FROM AUTHOR] more...

The microstructure of nonpolar m-plane oriented GaN layers deposited on (100)γ-LiAlO2 was analysed by transmission electron microscopy. This study shows that the films contain a large number of defects. The most dominant defects in the m-plane GaN are intrinsic I1 basal plane stacking faults (∼104 cm−1), threading dislocations (∼109 cm−2) as well as a complex defect network consisting of planar defects located on prismatic GaN and differently inclined pyramidal planes. A large number of the stacking faults nucleate at the GaN/LiAlO2 interface. Furthermore, the inclined planar defects act as additional nucleation sites for the basal plane stacking faults. A decreasing crystal quality with an increasing layer thickness can be explained by this defect formation mechanism. [ABSTRACT FROM AUTHOR] more...

Abstract: The morphological and optical properties of InGaN multiple quantum wells (MQWs) emitting at 405nm are studied with respect to the MQW growth temperature. The latter was varied between 760 and 840°C in structures grown on c-plane sapphire substrates by metal-organic vapor-phase epitaxy (MOVPE). The indium content in the quantum well was kept constant for all temperatures by adjusting the trimethylindium supply. The MQWs were inserted as active region in both optically pumped laser heterostructures and laser diodes (LDs). We found that low growth temperatures result in a reduced spatial uniformity of the luminescence emission wavelength due to well thickness variations, whereas at higher temperatures it is difficult to obtain a spatially homogeneous indium concentration. A minimum threshold power density for optically pumped lasing was found for growth temperatures of the active region between 780 and 820°C. LDs with an MQW grown at these conditions showed an onset of lasing at a current density of 6.5kA/cm2 with output powers of more than 350mW. [Copyright &y& Elsevier] more...

Abstract: Epitaxial lateral overgrowth (ELOG) of a-plane GaN on r-plane sapphire with stripe orientations parallel to [0001], [], and [] has been investigated. The emission from ELOG stripes with different orientations and from different growth facets has been compared by spectrally and spatially resolved cathodoluminescence and by temperature-dependent photoluminescence measurements. A reduction in the nonradiative recombination rate by the ELOG process is clearly observed. For all stripe orientations the ELOG wing regions exhibit increased radiative emission intensities compared to the window areas, indicating a reduced dislocation density in the overgrown areas. The highest increase of the near band edge (NBE) emission is observed in the wing regions for stripes parallel to []. In this region, the density of basal plane stacking faults (BSFs) is also reduced. NBE emission is detected up to temperatures of 250K. [Copyright &y& Elsevier] more...

Abstract: In the present work we will report on the optical properties of an AlN film homoepitaxially grown on a high-quality large bulk AlN single crystal. The latter was grown by a sublimation-recondensation technique, while the film was grown by organometallic vapor-phase epitaxy. Cathodoluminescence measurements were performed using electron beam energies between 2 and 10keV in order to excite the sample and so to probe different sample depths, making it possible to differentiate between different features which originate in the AlN homoepitaxial film. The penetration depth has been determined through the calculation of the Bohr–Bethe maximum range of excitation using the approximation to the Everhart–Hoff expression for the energy loss within a solid. [Copyright &y& Elsevier] more...

Abstract: The critical thickness for the relaxation of InGaN layers grown on (0001)GaN on sapphire for an indium content between 10% and 20% has been determined experimentally. The layers were grown by metal-organic vapour phase epitaxy (MOVPE). The indium content was varied by changing growth temperature between 700 and 750°C. In-situ ellipsometry could identify a growth mode transition during layer growth, from relatively smooth InGaN layer to a rougher layer with higher indium content. X-ray diffraction found a completely strained layer with lower indium content and a completely relaxed layer with higher indium content. These findings were consistent with absorption and photoluminescence measurements. [Copyright &y& Elsevier] more...

Abstract: AlN layers were grown by metalorganic vapor-phase epitaxy at high temperatures up to 1500°C. Nucleation layer growth parameters and flow conditions before nucleation were changed and the effect on the AlN layer grown on top was studied. Structural analysis performed by high-resolution X-ray diffractometry and transmission electron microscopy showed that pregrowth conditions affect the material quality drastically. The best structural quality as indicated by a screw (including mixed) dislocation density of 8×108 cm−2, together with smooth surface morphology was found to result from simultaneous switching on of ammonia and TMAl at the beginning of nucleation layer growth. [Copyright &y& Elsevier] more...

• Fabrication of nano-pillars on sapphire using Displacement Talbot Lithography. • AlN overgrowth shows smooth surface by changing offcut from 0.2° to 0.1°. • Extended defect characterization comparing XRD, ECCI and defect etching. • Improved luminescence of AlGaN multi-quantum-wells (265 nm) on 0.1° offcut sample. • Realized UVC LED (265 nm) on 0.1° offcut sample (0.81 mW @ 20 mA, EQE = 0.86%). We present overgrowth of nano-patterned sapphire with different offcut angles by metalorganic vapor phase epitaxy. Hexagonal arrays of nano-pillars were prepared via Displacement Talbot Lithography and dry-etching. 6.6 µm crack-free and fully coalesced AlN was grown on such substrates. Extended defect analysis comparing X-ray diffraction, electron channeling contrast imaging and selective defect etching revealed a threading dislocation density of about 109 cm−2. However, for c-plane sapphire offcut of 0.2° towards m direction the AlN surface shows step bunches with a height of 10 nm. The detrimental impact of these step bunches on subsequently grown AlGaN multi-quantum-wells is investigated by cathodoluminescence and transmission electron microscopy. By reducing the sapphire offcut to 0.1° the formation of step bunches is successfully suppressed. On top of such a sample an AlGaN-based UVC LED heterostructure is realized emitting at 265 nm and showing an emission power of 0.81 mW at 20 mA (corresponds to an external quantum efficiency of 0.86%). [ABSTRACT FROM AUTHOR] more...

We demonstrate the first electrically injected AlGaN-based ultraviolet-B resonant-cavity light-emitting diode (RCLED). The devices feature dielectric SiO 2 /HfO 2subscript> distributed Bragg reflectors enabled by tunnel junctions (TJs) for lateral current spreading. A highly doped n ++ -AlGaN/n ++ -GaN/p ++ -AlGaN TJ and a top n-AlGaN current spreading layer are used as transparent contacts, resulting in a good current spreading up to an active region mesa diameter of 120 μm. To access the N-face side of the device, the substrate is removed by electrochemically etching a sacrificial n-AlGaN layer, leading to a smooth underetched surface without evident parasitic etching in the n- and n ++ -doped layers of the device. The RCLEDs show a narrow emission spectrum with a full width at half-maximum (FWHM) of 4.3 nm compared to 9.4 nm for an ordinary LED and a more directional emission pattern with an angular FWHM of 52° for the resonance at 310 nm in comparison to ∼126° for an LED. Additionally, the RCLEDs show a much more stable emission spectrum with temperature with a red-shift of the electroluminescence peak of about ∼18 pm/K and a negligible change of the FWHM compared to LEDs, which shift ∼30 pm/K and show spectrum broadening with temperature. The demonstration of those devices, where a highly reflective mirror is spatially separated from an ohmic metal contact, opens up a new design space to potentially increase the poor light extraction efficiency in UV LEDs and is an important step toward electrically injected UV vertical-cavity surface-emitting lasers., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.) more...

Introduction: Healthcare-acquired infections and overuse of antibiotics are a common problem. Rising emergence of antibiotic and antiseptic resistances requires new methods of microbial decontamination or decolonization as the use of far-UV-C radiation., Methods: The microbicidal efficacy of UV-C radiation (222 nm, 233 nm, 254 nm) was determined in a quantitative carrier test and on 3D-epidermis models against Staphylococcus (S.) aureus, S.epidermidis, S.haemolyticus, S.lugdunensis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. To mimic realistic conditions, sodium chloride solution, mucin, albumin, artificial saliva, artificial wound exudate and artificial sweat were used., Results: In sodium chloride solution, irradiation with a dose of 40 mJ/cm 2 (233 nm) was sufficient to achieve 5 lg reduction independent of bacteria genus or species. In artificial sweat, albumin and artificial wound exudate, a reduction >3 lg was reached for most of the bacteria. Mucin and artificial saliva decreased the reduction to <2 lg. On 3D epidermis models, reduction was lower than in the carrier test., Conclusion: UV-C radiation at 233 nm was proven to be efficient in bacteria inactivation independent of genus or species thus being a promising candidate for clinical use in the presence of humans and on skin/mucosa., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.) more...

Purpose: Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib., Methods: This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics., Results: Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg., Conclusions: The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings., Gov Identifier: NCT01425008., (© 2023. The Author(s).) more...

Existing barriers to efficient deep ultraviolet (UV) light-emitting diodes (LEDs) may be reduced or overcome by moving away from conventional planar growth and toward three-dimensional nanostructuring. Nanorods have the potential for enhanced doping, reduced dislocation densities, improved light extraction efficiency, and quantum wells free from the quantum-confined Stark effect. Here, we demonstrate a hybrid top-down/bottom-up approach to creating highly uniform AlGaN core-shell nanorods on sapphire repeatable on wafer scales. Our GaN-free design avoids self-absorption of the quantum well emission while preserving electrical functionality. The effective junctions formed by doping of both the n-type cores and p-type caps were studied using nanoprobing experiments, where we find low turn-on voltages, strongly rectifying behaviors and significant electron-beam-induced currents. Time-resolved cathodoluminescence measurements find short carrier liftetimes consistent with reduced polarization fields. Our results show nanostructuring to be a promising route to deep-UV-emitting LEDs, achievable using commercially compatible methods. more...

Ultraviolet light-emitting diodes (LEDs) suffer from a low wall-plug efficiency, which is to a large extent limited by the poor light extraction efficiency (LEE). A thin-film flip-chip (TFFC) design with a roughened N-polar AlGaN surface can substantially improve this. We here demonstrate an enabling technology to realize TFFC LEDs emitting in the UVB range (280-320 nm), which includes standard LED processing in combination with electrochemical etching to remove the substrate. The integration of the electrochemical etching is achieved by epitaxial sacrificial and etch block layers in combination with encapsulation of the LED. The LEE was enhanced by around 25% when the N-polar AlGaN side of the TFFC LEDs was chemically roughened, reaching an external quantum efficiency of 2.25%. By further optimizing the surface structure, our ray-tracing simulations predict a higher LEE from the TFFC LEDs than flip-chip LEDs and a resulting higher wall-plug efficiency., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.) more...

A newly developed UVC LED source with an emission wavelength of 233 nm was proved on bactericidal efficacy and skin tolerability. The bactericidal efficacy was qualitatively analysed using blood agar test. Subsequently, quantitative analyses were performed on germ carrier tests using the MRSA strain DSM11822, the MSSA strain DSM799, S. epidermidis DSM1798 with various soil loads. Additionally, the compatibility of the germicidal radiation doses on excised human skin and reconstructed human epidermis was proved. Cell viability, DNA damage and production of radicals were assessed in comparison to typical UVC radiation from discharge lamps (222 nm, 254 nm) and UVB (280-380 nm) radiation for clinical assessment. At a dose of 40 mJ/cm 2 , the 233 nm light source reduced the viable microorganisms by a log 10 reduction (LR) of 5 log 10 levels if no soil load was present. Mucin and protein containing soil loads diminished the effect to an LR of 1.5-3.3. A salt solution representing artificial sweat (pH 8.4) had only minor effects on the reduction. The viability of the skin models was not reduced and the DNA damage was far below the damage evoked by 0.1 UVB minimal erythema dose, which can be regarded as safe. Furthermore, the induced damage vanished after 24 h. Irradiation on four consecutive days also did not evoke DNA damage. The radical formation was far lower than 20 min outdoor visible light would cause, which is classified as low radical load and can be compensated by the antioxidant defence system., (© 2022. The Author(s).) more...

In the past years, light-emitting diodes (LED) made of GaN and its related ternary compounds with indium and aluminium have become an enabling technology in all areas of lighting. Visible LEDs have yet matured, but research on deep ultraviolet (UV) LEDs is still in progress. The polarisation in the anisotropic wurtzite lattice and the low free hole density in p-doped III-nitride compounds with high aluminium content make the design for high efficiency a critical step. The growth kinetics of the rather thin active quantum wells in III-nitride LEDs makes them prone to inhomogeneous broadening (IHB). Physical modelling of the active region of III-nitride LEDs supports the optimisation by revealing the opaque active region physics. In this work, we analyse the impact of the IHB on the luminescence and carrier transport III-nitride LEDs with multi-quantum well (MQW) active regions by numerical simulations comparing them to experimental results. The IHB is modelled with a statistical model that enables efficient and deterministic simulations. We analyse how the lumped electronic characteristics including the quantum efficiency and the diode ideality factor are related to the IHB and discuss how they can be used in the optimisation process. more...

Wavelength-dispersive X-ray (WDX) spectroscopy was used to measure silicon atom concentrations in the range 35-100 ppm [corresponding to (3-9) × 1018 cm-3] in doped AlxGa1-xN films using an electron probe microanalyser also equipped with a cathodoluminescence (CL) spectrometer. Doping with Si is the usual way to produce the n-type conducting layers that are critical in GaN- and AlxGa1-xN-based devices such as LEDs and laser diodes. Previously, we have shown excellent agreement for Mg dopant concentrations in p-GaN measured by WDX with values from the more widely used technique of secondary ion mass spectrometry (SIMS). However, a discrepancy between these methods has been reported when quantifying the n-type dopant, silicon. We identify the cause of discrepancy as inherent sample contamination and propose a way to correct this using a calibration relation. This new approach, using a method combining data derived from SIMS measurements on both GaN and AlxGa1-xN samples, provides the means to measure the Si content in these samples with account taken of variations in the ZAF corrections. This method presents a cost-effective and time-saving way to measure the Si doping and can also benefit from simultaneously measuring other signals, such as CL and electron channeling contrast imaging. more...

Multiresistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) cause serious postoperative infections. A skin tolerant far-UVC (< 240 nm) irradiation system for their inactivation is presented here. It uses UVC LEDs in combination with a spectral filter and provides a peak wavelength of 233 nm, with a full width at half maximum of 12 nm, and an irradiance of 44 µW/cm 2 . MRSA bacteria in different concentrations on blood agar plates were inactivated with irradiation doses in the range of 15-40 mJ/cm 2 . Porcine skin irradiated with a dose of 40 mJ/cm 2 at 233 nm showed only 3.7% CPD and 2.3% 6-4PP DNA damage. Corresponding irradiation at 254 nm caused 15-30 times higher damage. Thus, the skin damage caused by the disinfectant doses is so small that it can be expected to be compensated by the skin's natural repair mechanisms. LED-based far-UVC lamps could therefore soon be used in everyday clinical practice to eradicate multiresistant pathogens directly on humans., (© 2021. The Author(s).) more...

Ultraviolet light is essential for disinfection, fluorescence excitation, curing, and medical treatment. An ultraviolet light source with the small footprint and excellent optical characteristics of vertical-cavity surface-emitting lasers (VCSELs) may enable new applications in all these areas. Until now, there have only been a few demonstrations of ultraviolet-emitting VCSELs, mainly optically pumped, and all with low Al-content AlGaN cavities and emission near the bandgap of GaN (360 nm). Here, we demonstrate an optically pumped VCSEL emitting in the UVB spectrum (280-320 nm) at room temperature, having an Al 0.60 Ga 0.40 N cavity between two dielectric distributed Bragg reflectors. The double dielectric distributed Bragg reflector design was realized by substrate removal using electrochemical etching. Our method is further extendable to even shorter wavelengths, which would establish a technology that enables VCSEL emission from UVA (320-400 nm) to UVC (<280 nm)., Competing Interests: The authors declare no competing financial interest., (© 2020 American Chemical Society.) more...

Single longitudinal mode continuous-wave operation of distributed-feedback (DFB) laser diodes based on GaN is demonstrated using laterally coupled 10th-order surface Bragg gratings. The gratings consist of V-shaped grooves alongside a 1.5 µm wide p-contact stripe fabricated by using electron-beam lithography and plasma etching. By varying the period of the Bragg grating, the lasing wavelength could be adjusted between 404.8 and 408.5 nm. The feasibility of this device concept was confirmed by mode-hop-free operation up to an optical output power of 90 mW, a low temperature sensitivity of the lasing wavelength, and a Gaussian lateral far-field distribution. more...

Nano-engineering III-nitride semiconductors offers a route to further control the optoelectronic properties, enabling novel functionalities and applications. Although a variety of lithography techniques are currently employed to nano-engineer these materials, the scalability and cost of the fabrication process can be an obstacle for large-scale manufacturing. In this paper, we report on the use of a fast, robust and flexible emerging patterning technique called Displacement Talbot lithography (DTL), to successfully nano-engineer III-nitride materials. DTL, along with its novel and unique combination with a lateral planar displacement (D 2 TL), allow the fabrication of a variety of periodic nanopatterns with a broad range of filling factors such as nanoholes, nanodots, nanorings and nanolines; all these features being achievable from one single mask. To illustrate the enormous possibilities opened by DTL/D 2 TL, dielectric and metal masks with a number of nanopatterns have been generated, allowing for the selective area growth of InGaN/GaN core-shell nanorods, the top-down plasma etching of III-nitride nanostructures, the top-down sublimation of GaN nanostructures, the hybrid top-down/bottom-up growth of AlN nanorods and GaN nanotubes, and the fabrication of nanopatterned sapphire substrates for AlN growth. Compared with their planar counterparts, these 3D nanostructures enable the reduction or filtering of structural defects and/or the enhancement of the light extraction, therefore improving the efficiency of the final device. These results, achieved on a wafer scale via DTL and upscalable to larger surfaces, have the potential to unlock the manufacturing of nano-engineered III-nitride materials., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2019.) more...

The effects of composition and p-doping profile of the AlGaN:Mg electron blocking layer (EBL) in 310 nm ultraviolet B (UV-B) light emitting diodes (LEDs) have been investigated. The carrier injection and internal quantum efficiency of the LEDs were simulated and compared to electroluminescence measurements. The light output power depends strongly on the temporal biscyclopentadienylmagnesium (Cp 2 Mg) carrier gas flow profile during growth as well as on the aluminum profile of the AlGaN:Mg EBL. The highest emission power has been found for an EBL with the highest Cp 2 Mg carrier gas flow and a gradually decreasing aluminum content in direction to the p-side of the LED. This effect is attributed to an improved carrier injection and confinement that prevents electron leakage into the p-doped region of the LED with a simultaneously enhanced carrier injection into the active region., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. more...

Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median T max was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned., Competing Interests: Compliance with ethical standards Conflicts of interest AR has acted as a consultant for and has received honoraria from Amgen, Compugen, Flexus, GSK, Genentech, and Merck, and holds stock in Novartis and Kite Pharma. JAS has acted as a consultant for Millennium Pharmaceuticals, Inc., Merck, and Amgen, and has received honorarium from Millennium Pharmaceuticals, Inc. The institution of JAS has also received grants from Bristol-Myers Squibb, GSK, and Millennium Pharmaceuticals, Inc. XZ, SF, RN, MK, EG and VB were employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. AAA, PL, AP, and GKD have no conflicts of interest to disclose. Funding The work was supported by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. more...

Purpose: Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20(+)/CD22(+) B-cell non-Hodgkin lymphoma (NHL)., Patients and Methods: A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles., Results: In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m(2)) was confirmed to be the same as that for single-agent INO (1.8 mg/m(2)). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL., Conclusion: R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20(+)/CD22(+) B-cell NHL. more...

We demonstrate output wavelength and intensity switching in a three-element directly coupled microdisk device consisting of one spiral microdisk coupled to two semicircle microdisks. The gapless coupling mechanism used allows individual elements to achieve lasing while achieving optimal transfer of optical power between adjacent microdisks. By controlling the transparency of the center element via injection current, the edge elements can be allowed to exchange their amplified spontaneous emission. In this manner, on-off-on switching of the output intensity, as well as discontinuous shifts in the output wavelength, can be achieved as a function of increasing injection current. more...

We present an efficient design for direct coupling between a spiral-shaped and a semicircle-shaped microcavity (micro-cavity) as an alternative to traditional evanescent wave coupling for planar integrated photonic technology. We observe the preservation of the high Q-value of the spiral oscillator when coupled to a semicircle under current injection using an AlGaAs single-quantum-well heterostructure. With slight alterations to the directly coupled micro-cavity configuration, such as coupling shape and overlap distance, the number of observed modes and output intensity are changed. AlGaAs and InGaN spiral-shaped microcavities have unidirectional emission normal to the spiral notch. more...

Initiation of eukaryotic DNA replication is achieved by the sequential binding of different proteins to origins of DNA replication. Using EGFP-tagged initiator proteins and immunofluorescence techniques we found that most of the ORC and the MCM subunits are localised at centrosomes and are colocalised with the polo-like protein kinase, Plk1. Yeast two-hybrid studies revealed interactions of Plk1 with the Mcm2 as well as the Orc2 protein. Co-immunoprecipitations showed an interaction of Plk1 with Mcm2 as well as interactions of gamma-tubulin with Mcm3 and Orc2, respectively. An in vitro phosphorylation assay showed that the Orc2 protein is a substrate of Plk1. Depletion of Orc2 and Mcm3 by siRNA leads to an inhibition of cell proliferation, an altered cell cycle distribution as well as to multinucleated cells with insufficiently organised microtubules. These results indicate an important role of the MCM and ORC proteins in mitosis besides their described role in the establishment of the pre-replicative complex. more...

Recent in vitro studies suggest that the alpha chemokine stromal-derived factor-1alpha (SDF-1alpha) and its receptor CXCR-4 may contribute to neuronal apoptosis in HIV infection of the brain. The cellular and regional expression of this chemokine and its relationship to the AIDS dementia complex (ADC), however, have remained undetermined. Using immunohistochemistry and semiquantitative RT-PCR, we examined the expression of SDF-1alpha in the frontal cortex (FC), the adjacent deep white matter (DWM). and the basal ganglia (BG) of 17 patients with ADC and 5 normal controls, and the FC and temporal cortex of 6 patients with Alzheimer disease (AD). Additionally, SDF-1alpha expression was studied in 3 different neuronal cultures: differentiated SK-N-MC cells, primary human fetal neuronal, and mouse hippocampal cultures. SDF-1alpha staining was predominantly localized to astrocytes in all 3 groups in the gray matter of the FC and the BG, often in the vicinity of cortical and basal ganglia neurons, but was generally absent in the DWM. Further, the number of positive neurons was significantly greater in the BG of AIDS subjects with advanced brain disease compared to subjects with lesser disease (p = 0.029). All cultures showed prominent SDF-1alpha staining of neurons within the cytoplasm and in neurites, whereas preferential expression in GABA-ergic neurons was found in hippocampal cultures. This is the first study to show that SDF-1alpha is constitutively expressed in astrocytes of the deep and cortical gray matter as well as in neurons of the human brain. Its increased expression in basal ganglia neurons of patients with advanced HIV CNS disease suggests it may also contribute to pathogenesis. more...

Eukaryotic cells coordinate chromosome duplication by the assembly of protein complexes at origins of DNA replication by sequential binding of member proteins of the origin recognition complex (ORC), CDC6, and minichromosome maintenance (MCM) proteins. These pre-replicative complexes (pre-RCs) are activated by cyclin-dependent kinases and DBF4/CDC7 kinase. Here, we carried out a comprehensive yeast two-hybrid screen to establish sequential interactions between two individual proteins of the mouse pre-RC that are probably required for the initiation of DNA replication. The studies revealed multiple interactions among ORC subunits and MCM proteins as well as interactions between individual ORC and MCM proteins. In particular CDC6 was found to bind strongly to ORC1 and ORC2, and to MCM7 proteins. DBF4 interacts with the subunits of ORC as well as with MCM proteins. It was also demonstrated that CDC7 binds to different ORC and MCM proteins. CDC45 interacts with ORC1 and ORC6, and weakly with MCM3, -6, and -7. The three subunits of the single-stranded DNA binding protein RPA show interactions with various ORC subunits as well as with several MCM proteins. The data obtained by yeast two-hybrid analysis were paradigmatically confirmed in synchronized murine FM3A cells by immunoprecipitation of the interacting partners. Some of the interactions were found to be cell-cycle-dependent; however, most of them were cell-cycle-independent. Altogether, 90 protein-protein interactions were detected in this study, 52 of them were found for the first time in any eukaryotic pre-RC. These data may help to understand the complex interplay of the components of the mouse pre-RC and should allow us to refine its structural architecture as well as its assembly in real time. more...

Mutations in CCR5 and CCR2b have been recently shown to affect disease progression towards AIDS. A role for these host genotypes in AIDS dementia complex (ADC) has also been postulated but remains unclear. Additionally, brain-derived envelope sequences from HIV-1 have been associated with ADC but their specific contribution to pathogenesis remains uncertain. This study demonstrates the successful use of PCR techniques to isolate host CCR5 and CCR2b, and HIV-1 V3 sequences from paraffin embedded tissues from patients with and without ADC. PCR amplification from archival tissue offers a novel approach for studying the interactions between potential neuroprotective elements in the host and virulence determinants in HIV that may contribute to differences in susceptibility to ADC. more...

The kinase Dbf4p/Cdc7p is required for the G1/S phase transition during the cell cycle and plays a direct role in the activation of individual origins of replication in Saccharomyces cerevisiae. Here, we report the identification and characterization of mouse and human cDNAs whose products are related in sequence to Saccharomyces cerevisiae DBF4 cDNA. Both mammalian Dbf4 proteins contain a putative site for phosphorylation by CDK, PEST protease cleavage sites, nuclear localization signals and a short-looped zinc finger-like domain. Transcription of MmDBF4 is suppressed in mouse NIH3T3 fibroblasts made quiescent by serum starvation. Upon replenishment of the medium, transcript levels increase during progression through G1, peaking as cells enter S phase. MmDbf4p interacts physically with Cdc7p and Mcm2p in vivo. Using fluorescence in situ hybridization (FISH), the human DBF4 gene was localized to chromosome 7 (q21.3), whereas FISH mapped the murine counterpart to band A2 on chromosome 5. The results of chromosome mapping indicate that in both mouse and human the gene is present as a single copy. The structural conservation between Dbf4-related proteins suggests that these proteins play a key role in the regulation of DNA replication during the cell cycle in all eukaryotes. more...

The regional expression of immune-mediated and neurotoxic events in the human immunodeficiency virus (HIV)-infected brain in relationship to the acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) and brain pathology remains uncertain. The extent of gp41, inducible nitric oxide synthase (iNOS), and HLA-DR expression was examined in the frontal lobe and basal ganglia of 25 patients at varying stages of ADC. The expression of gp41 and iNOS was present predominantly in perivascular cells and most often in the basal ganglia. Staining for gp41 correlated significantly with iNOS in the basal ganglia, whereas the severity of staining for gp41 and iNOS in the basal ganglia and white matter was significantly greater in subjects with moderate to severe dementia compared with those with milder impairment. The degree of macrophage staining in the white matter and basal ganglia also correlated significantly with ADC severity and was more abundant than gp41 or iNOS staining, particularly in the white matter. Logistic regression analysis revealed that staining for iNOS and gp41 increased linearly with ADC severity and was significantly more abundant in the basal ganglia compared with the white matter. Double-immunolabeling studies colocalized iNOS predominantly to macrophage/microglia and to gp41-positive cells. The expression of iNOS and gp41 in the basal ganglia combined with immune activation contributes to the development and progression of the clinical syndrome. more...

Two new members of the mouse origin recognition complex (ORC) have been cloned that are closely related to Saccharomyces cerevisiae ORC4 and ORC5 as well as to their human homolog. Both MmORC4p and MmORC5p have a putative nucleotide triphosphate binding motif. Transcription of MmORC4 and MmORC5 is not suppressed in mouse NIH3T3 fibroblasts made quiescent by serum starvation. The transcription levels of both ORC genes are constantly high in all phases of the cell cycle. A screen based on the two-hybrid approach suggests that the product of the ORC4 gene interacts with the ORC2, but not with the ORC1 protein. The conservation of structure among members of the ORC4- and ORC5-related family of proteins suggests that these proteins play a key role in the initiation of DNA replication in all eukaryotes. more...

The E8 gene is expressed at a high level during fruit ripening, and is transcriptionally activated by ethylene. We have identified a 428 bp fragment of the E8 5'-flanking region, from -1528 to -1100, that makes a minimal 35S promoter responsive to ethylene. This fragment confers ethylene-responsiveness only in the 5'-to-3' orientation; in the reverse orientation it results in increased expression in unripe fruit. Interestingly, this ethylene-responsive construct does not have high levels of expression during fruit ripening, indicating that sequences required for high level expression during fruit ripening are separate from sequences required for ethylene response. The ethylene-responsive sequences of the E8 5'-flanking region interact with the same DNA-binding protein that interacts with sequences required for ethylene responsiveness of the coordinately regulated E4 gene. We also conducted experiments to test the function of a second DNA-binding protein that interacts with both E4 and E8 5'-flanking sequences, the E4/E8-binding protein (E4/E8BP). We examined the effect of an internal deletion from -1088 to -863, which includes the binding site for E4/E8BP, on gene expression. This deletion did not affect expression in ripening fruit, and did not impair ethylene responsiveness. The deletion had a negative effect on expression in unripe fruit, but resulted in increased expression in leaves. These results suggest that the E4/E8BP is not critical for high levels of expression during fruit ripening or for ethylene response, but may play a role in organ-specific gene transcription. more...

Obliterative processes of the carotid bifurcation can be a starting point for cerebral and especially retinal microemboli. Early diagnosis is essential in protecting such patients from a definitive insult, or a reduction of sight which can go as far as permanent blindness, whereas the amaurosis fugax being the most common ocular symptom of the internal carotid insufficiency. Due to the fact ca. 65%--75% of the patients with ocular symptoms of a carotid insufficiency show forms of amaurosis fugax or photopical sensations, this symptom complex, especially in combination with temporary contralateral hemiparalysis, has to be evaluated as a classical symptom of carotid stenosis until the contrary can be angiographically proven. Only during the last few years has it become apparent that these microemboli originate from ulcerous or verrucous beds of the carotid bifurcation. The discovery of the above connections was only made possible through the improvements in carotid angiography technique. more...