The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Extragalactic Results from the Infrared Space Observatory

More than a decade ago the IRAS satellite opened the realm of external galaxies for studies in the 10 to 100 micron band and discovered emission from tens of thousands of normal and active galaxies. With the 1995-1998 mission of the Infrared Space Observatory the next major steps in extragalactic infrared astronomy became possible: detailed imaging, spectroscopy and spectro-photometry of many galaxies detected by IRAS, as well as deep surveys in the mid- and far- IR. The spectroscopic data reveal a wealth of detail about the nature of the energy source(s) and about the physical conditions in galaxies. ISO's surveys for the first time explore the infrared emission of distant, high-redshift galaxies. ISO's main theme in extragalactic astronomy is the role of star formation in the activity and evolution of galaxies.Comment: 106 pages, including 17 figures. Ann.Rev.Astron.Astrophys. (in press), a gzip'd pdf file (667kB) is also available at http://www.mpe.mpg.de/www_ir/preprint/annrev2000.pdf.g

The Global Diversity of Parasitic Isopods Associated with Crustacean Hosts (Isopoda: Bopyroidea and Cryptoniscoidea)

Parasitic isopods of Bopyroidea and Cryptoniscoidea (commonly referred to as epicarideans) are unique in using crustaceans as both intermediate and definitive hosts. In total, 795 epicarideans are known, representing ∼7.7% of described isopods. The rate of description of parasitic species has not matched that of free-living isopods and this disparity will likely continue due to the more cryptic nature of these parasites. Distribution patterns of epicarideans are influenced by a combination of their definitive (both benthic and pelagic species) and intermediate (pelagic copepod) host distributions, although host specificity is poorly known for most species. Among epicarideans, nearly all species in Bopyroidea are ectoparasitic on decapod hosts. Bopyrids are the most diverse taxon (605 species), with their highest diversity in the North West Pacific (139 species), East Asian Sea (120 species), and Central Indian Ocean (44 species). The diversity patterns of Cryptoniscoidea (99 species, endoparasites of a diverse assemblage of crustacean hosts) are distinct from bopyrids, with the greatest diversity of cryptoniscoids in the North East Atlantic (18 species) followed by the Antarctic, Mediterranean, and Arctic regions (13, 12, and 8 species, respectively). Dajidae (54 species, ectoparasites of shrimp, mysids, and euphausids) exhibits highest diversity in the Antarctic (7 species) with 14 species in the Arctic and North East Atlantic regions combined. Entoniscidae (37 species, endoparasites within anomuran, brachyuran and shrimp hosts) show highest diversity in the North West Pacific (10 species) and North East Atlantic (8 species). Most epicarideans are known from relatively shallow waters, although some bopyrids are known from depths below 4000 m. Lack of parasitic groups in certain geographic areas is likely a sampling artifact and we predict that the Central Indian Ocean and East Asian Sea (in particular, the Indo-Malay-Philippines Archipelago) hold a wealth of undescribed species, reflecting our knowledge of host diversity patterns

Atmospheric oxygen regulation at low Proterozoic levels by incomplete oxidative weathering of sedimentary organic carbon

It is unclear why atmospheric oxygen remained trapped at low levels for more than 1.5 billion years following the Paleoproterozoic Great Oxidation Event. Here, we use models for erosion, weathering and biogeochemical cycling to show that this can be explained by the tectonic recycling of previously accumulated sedimentary organic carbon, combined with the oxygen sensitivity of oxidative weathering. Our results indicate a strong negative feedback regime when atmospheric oxygen concentration is of order pO2∼0.1 PAL (present atmospheric level), but that stability is lost at pO2<0.01 PAL. Within these limits, the carbonate carbon isotope (δ13C) record becomes insensitive to changes in organic carbon burial rate, due to counterbalancing changes in the weathering of isotopically light organic carbon. This can explain the lack of secular trend in the Precambrian δ13C record, and reopens the possibility that increased biological productivity and resultant organic carbon burial drove the Great Oxidation Event

Recovery of visual fields in brain-lesioned patients by reaction perimetry treatment

<p>Abstract</p> <p>Background</p> <p>The efficacy of treatment in hemianopic patients to restore missing vision is controversial. So far, successful techniques require laborious stimulus presentation or restrict improvements to selected visual field areas. Due to the large number of brain-damaged patients suffering from visual field defects, there is a need for an efficient automated treatment of the total visual field.</p> <p>Methods</p> <p>A customized treatment was developed for the reaction perimeter, permitting a time-saving adaptive-stimulus presentation under conditions of maximum attention. Twenty hemianopic patients, without visual neglect, were treated twice weekly for an average of 8.2 months starting 24.2 months after the insult. Each treatment session averaged 45 min in duration.</p> <p>Results</p> <p>In 17 out of 20 patients a significant and stable increase of the visual field size (average 11.3° ± 8.1) was observed as well as improvement of the detection rate in the defective visual field (average 18.6% ± 13.5). A two-factor cluster analysis demonstrated that binocular treatment was in general more effective in augmenting the visual detection rate than monocular. Four out of five patients with a visual field increase larger than 10° suffered from hemorrhage, whereas all seven patients with an increase of 5° or less suffered from infarction. Most patients reported that visual field restoration correlated with improvement of visual-related activities of daily living.</p> <p>Conclusion</p> <p>Rehabilitation treatment with the Lubeck Reaction Perimeter is a new and efficient method to restore part of the visual field in hemianopia. Since successful transfer of treatment effects to the occluded eye is achieved under monocular treatment conditions, it is hypothesized that the damaged visual cortex itself is the structure in which recovery takes place.</p

Physical fitness, fatigue, and quality of life after liver transplantation

Fatigue is often experienced after liver transplantation. The aims of this cross-sectional study were to assess physical fitness (cardiorespiratory fitness, neuromuscular fitness, body composition) in liver transplant recipients and to explore whether physical fitness is related to severity of fatigue. In addition, we explored the relationship between physical fitness and health-related quality of life. Included were 18 patients 1–5 years after transplantation (aged 48.0 ± 11.8 years) with varying severity of fatigue. Peak oxygen uptake during cycle ergometry, 6-min walk distance, isokinetic muscle strength of the knee extensors, body mass index, waist circumference, skinfold thickness, severity of fatigue, and health-related quality of life were measured. Cardiorespiratory fitness in the liver transplant recipients was on average 16–34% lower than normative values (P ≤ 0.05). Furthermore, the prevalence of obesity seemed to be higher than in the general population (17 vs. 10%). We found no deficit in neuromuscular fitness. Cardiorespiratory fitness was the only fitness component that was related with severity of fatigue (rs = −0.61 to rs = -0.50, P ≤ 0.05). Particularly cardiorespiratory fitness was related with several aspects of health-related quality of life (rs = 0.48 to rs = 0.70, P ≤ 0.05). Results of our study imply that cardiorespiratory fitness and body composition are impaired in liver transplant recipients and that fitness is related with severity of fatigue (only cardiorespiratory fitness) and quality of life (particularly cardiorespiratory fitness) in this group. These findings have implications for the development of rehabilitation programs for liver transplant recipients

The flipflop orphan genes are required for limb bud eversion in the Tribolium embryo

Abstract Background Unlike Drosophila but similar to other arthropod and vertebrate embryos, the flour beetle Tribolium castaneum develops everted limb buds during embryogenesis. However, the molecular processes directing the evagination of epithelia are only poorly understood. Results Here we show that the newly discovered genes Tc-flipflop1 and Tc-flipflop2 are involved in regulating the directional budding of appendages. RNAi-knockdown of Tc-flipflop results in a variety of phenotypic traits. Most prominently, embryonic limb buds frequently grow inwards rather than out, leading to the development of inverted appendages inside the larval body. Moreover, affected embryos display dorsal closure defects. The Tc-flipflop genes are evolutionarily non-conserved, and their molecular function is not evident. We further found that Tc-RhoGEF2, a highly-conserved gene known to be involved in actomyosin-dependent cell movement and cell shape changes, shows a Tc-flipflop-like RNAi-phenotype. Conclusions The similarity of the inverted appendage phenotype in both the flipflop- and the RhoGEF2 RNAi gene knockdown led us to conclude that the Tc-flipflop orphan genes act in a Rho-dependent pathway that is essential for the early morphogenesis of polarised epithelial movements. Our work describes one of the few examples of an orphan gene playing a crucial role in an important developmental process

Rise to modern levels of ocean oxygenation coincided with the Cambrian radiation of animals.

The early diversification of animals (∼630 Ma), and their development into both motile and macroscopic forms (∼575-565 Ma), has been linked to stepwise increases in the oxygenation of Earth's surface environment. However, establishing such a linkage between oxygen and evolution for the later Cambrian 'explosion' (540-520 Ma) of new, energy-sapping body plans and behaviours has proved more elusive. Here we present new molybdenum isotope data, which demonstrate that the areal extent of oxygenated bottom waters increased in step with the early Cambrian bioradiation of animals and eukaryotic phytoplankton. Modern-like oxygen levels characterized the ocean at ∼521 Ma for the first time in Earth history. This marks the first establishment of a key environmental factor in modern-like ecosystems, where animals benefit from, and also contribute to, the 'homeostasis' of marine redox conditions