Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival

The aim of this study was to assess the side effects and the efficacy of thalidomide alone or in combination with dexamethasone in relapsed multiple myeloma (MM) and to evaluate possible predictive factors for response rate and survival. Twenty-nine pretreated patients were enrolled, including 13 patients with a relapse after high-dose chemotherapy. The median number of relapses was 3 (range: 1–7). Twenty-two patients received thalidomide in combination with dexamethasone and seven patients thalidomide alone. The dosage of thalidomide was 400 mg/day and the dosage of dexamethasone 20 mg/m² daily for 4 consecutive days every 3 weeks. Cycles of dexamethasone were given until maximal decline of myeloma protein was achieved, whereas therapy with thalidomide was maintained until disease progression. Responses occurred in 62% of patients, including 5 (17%) complete remissions and 13 (45%) partial remissions. The median event-free survival (EFS) was 7.2 months and the median overall survival (OS) 26.1 months. In multivariate analysis, pretreatment serum levels of soluble interleukin-2 receptor (sIL-2R) were a significant prognostic factor for EFS, and those of ₂-microglobulin (2M) and sIL-2R for OS. Serum levels of sIL-2R significantly increased after 3 weeks of treatment in 89% of patients, possibly representing lymphocyte activation induced by thalidomide. Two patients died of septic complications within 3 months after starting treatment with thalidomide and dexamethasone and one patient of herpes encephalitis after 26 months of treatment with thalidomide alone. Also, one case of pneumonia and one case of deep venous thrombosis of the lower limb occurred. Other side effects were somnolence, peripheral neuropathy, and bradycardia occurring in 35, 55, 38 and 55% of patients, respectively. The combination of thalidomide and dexamethasone is an effective therapy in heavily pretreated myeloma patients with a high response rate and acceptable toxicities. A powerful predictive factor both for EFS and OS was the pretreatment serum level of sIL-2R.     

Self-assembly of the general membrane-remodeling protein PVAP into sevenfold virus-associated pyramids

Viruses have developed a wide range of strategies to escape from the host cells in which they replicate. For egress some archaeal viruses use a pyramidal structure with sevenfold rotational symmetry. Virus-associated pyramids (VAPs) assemble in the host cell membrane from the virus-encoded protein PVAP and open at the end of the infection cycle. We characterize this unusual supramolecular assembly using a combination of genetic, biochemical, and electron microscopic techniques. By whole-cell electron cryotomography, we monitored morphological changes in virus-infected host cells. Subtomogram averaging reveals the VAP structure. By heterologous expression of PVAP in cells from all three domains of life, we demonstrate that the protein integrates indiscriminately into virtually any biological membrane, where it forms sevenfold pyramids. We identify the protein domains essential for VAP formation in PVAP truncation mutants by their ability to remodel the cell membrane. Self-assembly of PVAP into pyramids requires at least two different, in-plane and out-of-plane, protein interactions. Our findings allow us to propose a model describing how PVAP arranges to form sevenfold pyramids and suggest how this small, robust protein may be used as a general membrane-remodeling system.Release of virus particles from infected cells is the last essential step of the viral replication cycle. In the course of this process, virions face the challenging task of crossing the cell envelope. Viruses have developed an arsenal of diverse strategies to overcome this problem. Most bacterial viruses are lytic and induce lysis of the infected cell with help of the holin-endolysin system (1), whereas others disrupt the host cell envelope via inhibition of the murein biosynthesis pathway (2). The morphological and genomic properties of archaeal viruses (3) suggested that their egress from host cells may have unusual traits that are different from those of bacterial viruses. Indeed, although most archaeal viruses exit cells without lysis, some, in particular the Sulfolobus islandicus rod-shaped virus 2 (SIRV2) and Sulfolobus turreted icosahedral virus (STIV), are lytic and exploit a special mechanism of virion egress (4–8). During the infection cycle of these viruses, pyramidal protrusions with sevenfold rotational symmetry form in the host cell membrane. As the final step of the infection cycle the virus-associated pyramids (VAPs) open outwards along the seams of their seven facets, creating ∼100-nm apertures through which the newly formed virions escape from the host cell (4, 7). VAPs consist of multiple copies of an ∼10-kDa virus-encoded protein, which we term “PVAP” (Protein forming Virus-Associated Pyramids/SIRV2_P98) (7–9). Surprisingly, PVAP assembles into membrane pyramids even when expressed heterologously in archaeal and bacterial expression systems, demonstrating that no other viral proteins are required for VAP formation (7). The mechanism by which VAPs self-assembles in the membrane remains unknown.In the present study we used electron cryotomography to investigate morphological features of SIRV2 replication and the formation of VAPs at different time points after infection. By subtomogram averaging, we determined a 3D map of the VAP. This map, in combination with secondary structure predictions of PVAP and the expression of wild-type (WT) PVAP or a variety of truncation mutants in archaeal, bacterial and eukaryotic cells allows us to propose a model showing how PVAP arranges to form the sevenfold pyramids. These insights are fundamental for understanding how this mechanism can be exploited as a universal tool to engineer the formation and controlled opening of large pores in biological or artificial lipid bilayers.     

Tufted puffin reproduction reveals ocean climate variability

Anomalously warm sea-surface temperatures (SSTs) are associated with interannual and decadal variability as well as with long-term climate changes indicative of global warming. Such oscillations could precipitate changes in a variety of oceanic processes to affect marine species worldwide. As global temperatures continue to rise, it will be critically important to be able to predict the effects of such changes on species' abundance, distribution, and ecological relationships so as to identify vulnerable populations. Off the coast of British Columbia, warm SSTs have persisted through the last two decades. Based on 16 years of reproductive data collected between 1975 and 2002, we show that the extreme variation in reproductive performance exhibited by tufted puffins (Fratercula cirrhata) was related to changes in SST both within and among seasons. Especially warm SSTs corresponded with drastically decreased growth rates and fledging success of puffin nestlings. Puffins may partially compensate for within-season changes associated with SST by adjusting their breeding phenology, yet our data also suggest that they are highly vulnerable to the effects of climate change at this site and may serve as a valuable indicator of biological change in the North Pacific. Further and prolonged increases in ocean temperature could make Triangle Island, which contains the largest tufted puffin colony in Canada, unsuitable as a breeding site for this species.     

Erfahrungen von Tumorpatienten mit Durchbruchschmerzen und medikamentösen Behandlungen

Background

Of cancer patients receiving palliative care, 80% suffer from cancer pain, and again 80% of these patients report breakthrough pain. This study explores the patients’ perception of breakthrough pain, their experiences with existing therapeutic regimens and their expectations regarding an ideal breakthrough pain medication.

Method

From November 2008 to February 2010 two German palliative care units recruited 80 in- or outpatient cancer patients who completed a standardized questionnaire on breakthrough pain characteristics, analgesic medication, attitudes towards new treatment approaches for breakthrough pain, and experiences with alternative routes of drug administration as part of the “European Survey of Oncology Patients’ Experience of Breakthrough Pain”.

Results

The study participants suffered from 1–12 episodes of either incident (47.5%) or spontaneous pain (37.5%) per day which were perceived as “severe” in 71% of all cases. These exacerbations highly interfered with the patients’ general activity, mood, walking ability, and normal work. Overall, 64% of the patients reported alleviation from pharmacological (26%) and non-pharmacological (73%) interventions. Subcutaneous (40%) and oral (39%) routes were used frequently; intranasal (1.25%) and intrapulmonary (1.25%) routes were used rarely. Only 64% of all participants stated an overall satisfaction with their breakthrough analgesia.

Conclusion

The diagnosis and treatment of breakthrough pain seems to be conducted in a suboptimal manner, and standard recommendations on breakthrough pain relief are not implemented consistently. Possible causes of pain should be taken into account as well as multi-professional treatment interventions and alternative routes of administration of fast onset, effective drugs should be considered.     

The N-terminal domain of the vaccinia virus E3L-protein is required for neurovirulence, but not induction of a protective immune response

Encephalitis is a rare, but serious complication from vaccination against smallpox using replication competent strains of vaccinia virus. In this report we describe mutants of vaccinia virus, containing N-terminal deletions of the vaccinia virus interferon resistance gene, E3L, that are attenuated for neuropathogenesis in a mouse model system. These recombinant viruses replicated to high titers in the nasal mucosa after intra-nasal infection of C57BL/6 mice but failed to spread to the lungs or brain. These viruses demonstrated reduced pathogenicity after intra-cranial infection as well, indicating a decrease in neurovirulence. Intra-nasal inoculation or inoculation by scarification with a low dose of recombinant virus containing a deletion of the entire N-terminal domain of E3L protected against challenge with a high dose of wild-type vaccinia virus, suggesting that this replication competent, but attenuated strain of vaccinia virus may have promise as an improved vaccine for protecting against smallpox, and as a vector for inducing mucosal immunity to heterologous pathogenic organisms.     

Influences of disgust sensitivity on hemodynamic responses towards a disgust-inducing film clip.

The major goal of the present functional magnetic resonance imaging study was to investigate the influence of disgust sensitivity on hemodynamic responses during disgust induction. Fifteen subjects viewed three different film excerpts (duration: 135 s each) with disgust-evoking, threatening and neutral content. The films were presented in a block design with four repetitions of each condition. Afterwards, subjects gave affective ratings for the films and answered the questionnaire for the assessment of disgust sensitivity (QADS, []). The subjects' overall disgust sensitivity was positively related to their experienced disgust, as well as to their prefrontal cortex activation during the disgust condition. Further, there was a positive correlation between subjects' scores on the QADS subscale spoilage/decay and their amygdala activation (r=0.76). This was reasonable since the disgust film clip depicted a cockroach-invasion and the subscale spoilage/decay contains, among others, an item asking for disgust towards cockroaches. The study stresses, in accordance to previous studies, the importance of considering personality traits when studying affective responses in fMRI studies.     

Erotic and disgust-inducing pictures--differences in the hemodynamic responses of the brain

The aim of this fMRI study was to explore brain structures that are involved in the processing of erotic and disgust-inducing pictures. The stimuli were chosen to trigger approach and withdrawal tendencies, respectively. By adding sadomasochistic (SM) scenes to the design and examining 12 subjects with and 12 subjects without sadomasochistic preferences, we introduced a picture category that induced erotic pleasure in one sample and disgust in the other sample. Since we also presented neutral pictures, all subjects viewed pictures of four different categories: neutral, disgust-inducing, erotic, and SM erotic pictures. The analysis indicated that several brain structures are commonly involved in the processing of disgust-inducing and erotic pictures (occipital cortex, hippocampus, thalamus, and the amygdala). The ventral striatum was specifically activated when subjects saw highly sexually arousing pictures. This indicates the involvement of the human reward system during the processing of visual erotica.