Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia.

We observed that high-dose methylprednisolone (HDMP) and rituximab was well tolerated and had promising activity when used in combination to treat patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). This prompted us to evaluate the use of these agents in frontline therapy. A total of 28 patients with a median age of 65 years enrolled in this study. Patients received HDMP at 1 g/m(2) each day for 3 days during each of the three 4-week cycles together with rituximab and prophylactic antimicrobial therapy. The treatment was well tolerated with few adverse events of grade III or higher. The overall response rate was 96% (N=27). Nine patients (32%) achieved a complete remission (CR), two of which were without detectable minimal residual disease (MRD). Six patients with MRD received consolidation with alemtuzumab; five of these patients achieved an MRD-negative CR. With over 3 years of follow-up median progression-free survival was 30.3 months with only 39% of patients requiring additional therapy, and an overall survival was 96%. This study demonstrates that HDMP and rituximab is an effective nonmyelosuppressive treatment combination for patients with CLL that warrants consideration particularly for patients with limited myeloid reserve that might not tolerate standard treatment regimens

CRAF phase 1, a framework to identify coastal hotspots to storm impacts

Low-frequency high-impact storms can cause flood and erosion over large coastal areas, which in turn can lead to a significant risk to coastal occupation, producing devastation and immobilising cities and even countries. It is therefore paramount to evaluate risk along the coast at a regional scale through the identification of storm impact hotspots. The Coastal Risk Assessment Framework Phase 1 (CRAF1) is a screening process based on a coastal-index approach that assesses the potential exposure of every kilometre along the coast to previously identified hazards. CRAF1 integrates both hazard (e.g. overwash, erosion) and exposure indicators to create a final Coastal Index (CI). The application of CRAF1 at two contrasting case studies (Ria Formosa, Portugal and the Belgian coast), validated against existing information, demonstrates the utility and reliability of this framework on the identification of hotspots. CRAF1 represents a powerful and useful instrument for coastal managers and/or end-users to identify and rank potential hotspot areas in order to define priorities and support disaster reduction plans

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance

Final Assembly of the Helmholtz Zentrum Berlin Series Connected Hybrid Magnet System

The final assembly of the Series Connected Hybrid magnet system for the Helmholtz Zentrum Berlin for Materials and Energy HZB has occurred with the integration of the superconducting cold mass, cryostat, resistive Florida Bitter coils, and the cryogenic, chilled water, power, and control subsystems. The hybrid magnet consists of a 13 T superconducting Nb3Sn CICC coil and a set of 12 T resistive, water cooled coils at 4.4 MW. Much of the cryostat and cold mass functional requirements were dictated by the electromagnetic interactions between the superconducting and resistive coils. This includes the radial decentering and axial aligning forces from normal operations and a 1.1 MN fault load. The system assembly was an international achievement with the cold mass being completed at the NHMFL in the USA, cryostat to cold mass interfaces made at Criotec Impianti in Italy, and final assembly at the HZB in German

Preparation of polyfunctional arylzinc organometallics in toluene by halogen/zinc exchange reactions

A wide range of polyfunctional diaryl-and diheteroarylzinc species were prepared in toluene within 10 min to 5 h through an I/Zn or Br/Zn exchange reaction using bimetallic reagents of the general formula R’2Zn·2LiOR (R’=sBu, tBu, pTol). Highly sensitive functional groups, such as a triazine, a ketone, an aldehyde, or a nitro group, were tolerated in these exchange reactions, enabling the synthesis of a plethora of functionalized (hetero)arenes after quenching with various electrophiles. Insight into the constitution and reactivity of these bimetallic mixtures revealed the formation of highly active lithium diorganodialkoxyzincates of type[R’2Zn-(OR)2Li2]

First Hybrid Magnet for Neutron Scattering at Helmholtz Zentrum Berlin

Helmholtz Zentrum Berlin HZB operates two large scale facilities the research reactor BER 2 and the syn chrotron source for soft X rays BESSY 2. This year HZB s neu tron instrument suite around BER 2 has been strengthened by a unique high magnetic field facility for neutron scattering. Its main components are the High Field Magnet HFM , which is the most powerful dc magnet for neutron scattering worldwide, and the Extreme Environment Di ffractometer EXED , which is a dedicated neutron instrument for time of flight technique. The hybrid magnet system is projected according to the special geo metric constraints of analyzing samples by neutron scattering in a high field magnet. Following our past experience, only steady state fields are adequate to achieve the goals of the project. In particular, inelastic scattering studies would virtually be excluded when using pulsed magnets. The new series connected hybrid magnet with a horizontal field orientation was designed and constructed in collaboration with the National High Magnetic Field Laboratory NHMFL , Tallahassee, FL, USA. With a set consisting of a su perconducting cable in conduit coil and different resistive coils of conical shape, maximum fields between 26 31 T are possible with cooling power between 4 and 8 MW for the resistive part. A series of commissioning activities of the magnet components and the technical infrastructure systems 20 kA power supply, water cooling, and 4 K Helium refrigerator was completed at HZB. The maximum field achieved with a 4 MW resistive coil was 26

Salvage Brachytherapy for Biochemically Recurrent Prostate Cancer Following Primary Brachytherapy

Purpose. In this study, we evaluated our experience with salvage brachytherapy after discovery of biochemical recurrence after a prior brachytherapy procedure. Methods and Materials. From 2001 through 2012 twenty-one patients treated by brachytherapy within University of Kentucky or from outside centers developed biochemical failure and had no evidence of metastases. Computed tomography (CT) scans were evaluated; patients who had an underseeded portion of their prostate were considered for reimplantation. Results. The majority of the patients in this study (61.9%) were low risk and median presalvage PSA was 3.49 (range 17.41–1.68). Mean follow-up was 61 months. At last follow-up after reseeding, 11/21 (52.4%) were free of biochemical recurrence. There was a trend towards decreased freedom from biochemical recurrence in low risk patients (p = 0.12). International Prostate Symptom Scores (IPSS) increased at 3-month follow-up visits but decreased and were equivalent to baseline scores at 18 months. Conclusions. Salvage brachytherapy after primary brachytherapy is possible; however, in our experience the side-effect profile after the second brachytherapy procedure was higher than after the first brachytherapy procedure. In this cohort of patients we demonstrate that approximately 50% oncologic control, low risk patients appear to have better outcomes than others

Exploiting Coordination Effects for the Regioselective Zincation of Diazines Using TMPZnX⋅LiX (X=Cl, Br)

A new method for regioselective zincations of challenging N-heterocyclic substrates such as pyrimidines and pyridazine was reported using bimetallic bases TMPZnX⋅LiX (TMP=2,2,6,6-tetramethylpiperidyl; X=Cl, Br). Reactions occurred under mild conditions (25-70 °C, using 1.75 equivalents of base without additives), furnishing 2-zincated pyrimidines and 3-zincated pyridazine, which were then trapped with a variety of electrophiles. Contrasting with other s-block metalating systems, which lack selectivity in their reactions even when operating at low temperatures, these mixed Li/Zn bases enabled unprecedented regioselectivities that cannot be replicated by either LiTMP nor Zn(TMP)2 on their own. Spectroscopic and structural interrogations of organometallic intermediates involved in these reactions have shed light on the complex constitution of reaction mixtures and the origins of their special reactivities

Understanding the Sustainable Aviation Biofuel Feedstock Potential in sub-Saharan Africa

The WWF-SA and the Roundtable on Sustainable Biomaterials (RSB) were collectively undertaking a project to support the development of sustainable aviation biofuels in South Africa and the sub-Saharan Africa region. The IIASA/FAO Global Agro-Ecological Zones (GAEZ) modelling system was applied for the estimation of the production potential of bio-energy feedstocks across Sub-Saharan Africa. GAEZ together with IIASA’s World Food System (WFS) are the main components of the ecological-economic modelling framework that connects biophysical and socio-economic processes on a global scale. It was used to analyze two development scenarios to estimate the sustainable biofuel potentials that are compatible with long-term food security and environmental integrity. The study applies sustainability criteria developed by the RSB. They include land use and conservation (no deforestation, preserve protected areas and areas of high environmental value), food security (retain adequate land for food production), greenhouse gas emission savings (minimum of 60% savings compared to fossil fuels when using a 20-year accounting period), and water security (only rain-fed biofuel production considered). Land reserves in sub-Saharan Africa compliant with the land-related RSB principles (termed REMAIN land) indicate the availability and productivity for biofuel feedstocks of some 1.9 million km2 grass- and shrubland. The greenhouse gas saving criteria set by the RSB implies that almost exclusively perennial biofuel feedstocks, requiring less frequent and less intensive cultivation of soils, can meet those criteria when conversion of natural grassland or shrub land is involved. Considering all 11 biofuel feedstocks evaluated in this study and selection of the best feedstock in energy terms when multiple feedstock production is agronomically viable, 0.8 million km2 are agro-ecologically very suitable (prime land) or suitable (good land) for biofuel feedstock production. The technical biofuel potential of these areas amount to 7.1 thousand PJ of biofuels (lower heating value equivalent). The majority of this biofuel ‘umbrella’ stems from miscanthus (52%), followed by oil-palm (18%), and sugarcane (13%). In the future, the estimated biofuel potentials of the available REMAIN land will likely be significantly reduced. Depending on scenario, by 2050, a reduction in the order of 20% is due to land conversion for food production needed in response to future demographic changes and improved diets due to the expected economic development process and income growth in sub-Saharan Africa. The land suitability and yield impacts of climate change will further reduce potential biofuel production by about 10-15%, especially when the potential is based only on perennial crops as a consequence of imposing a strict GHG criterion for soil carbon recuperation. The estimated biofuel potential on prime and good land compliant with the RSB sustainability criteria in 2050 amounts to 3.0– 4.0 thousand PJ. Results show a small but not insignificant potential for the production of sustainable biofuels in sub-Saharan Africa. It could be prioritized for the aviation industry, which has limited other options when it comes to reducing carbon emissions. This report represents a summary report that is based on the technical report titled “Sustainable aviation biofuel feedstock potential in sub-Saharan Africa: A systems analysis investigation into the current and future potential for biofuel feedstock production in sub-Saharan Africa.

Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110022/1/cptclpt1983136.pd