Integrative network analysis identifies novel drivers of pathogenesis and progression in newly diagnosed multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide clinical and molecular heterogeneity. In this study we applied an integrative network biology approach to molecular and clinical data measured from 450 patients with newly diagnosed MM from the MMRF (Multiple Myeloma Research Foundation) CoMMpass study. A novel network model of myeloma (MMNet) was constructed, revealing complex molecular disease patterns and novel associations between clinical traits and genomic markers. Genomic alterations and groups of coexpressed genes correlate with disease stage, tumor clonality and early progression. We validated CDC42BPA and CLEC11A as novel regulators and candidate therapeutic targets of MMSET-related myeloma. We then used MMNet to discover novel genes associated with high-risk myeloma and identified a novel four-gene prognostic signature. We identified new patient classes defined by network features and enriched for clinically relevant genetic events, pathways and deregulated genes. Finally, we demonstrated the ability of deep sequencing techniques to detect relevant structural rearrangements, providing evidence that encourages wider use of such technologies in clinical practice. An integrative network analysis of CoMMpass data identified new insights into multiple myeloma disease biology and provided improved molecular features for diagnosing and stratifying patients, as well as additional molecular targets for therapeutic alternatives.

Routine screening for pain combined with a pain treatment protocol in head and neck cancer: a randomised controlled trial.

BACKGROUND: We compared the effectiveness and cost of a pain screening and treatment program, with usual care in head and neck cancer patients with significant pain. METHODS: Patients were screened for the presence of pain and then randomly assigned to either an intervention group, consisting of a pain treatment protocol and an education program, or to usual care. Primary outcome was change in the Pain Severity Index (PSI) over three months. RESULTS: We screened 1074 patients of whom 156 were randomized to either intervention or usual care. Mean PSI was reduced over three months in both groups, with no significant difference between the two groups. The Pain Management Index (PMI) at three months, was significantly improved in the intervention group compared with usual care (P<0.001), as was Patient Satisfaction (mean difference in scores was statistically significant: -0.30 [-0.60 to -0.15]). All subjects reported clinically significant levels of anxiety and depression throughout the study. Treatment costs were significantly higher for intervention (mean=£400) compared with usual care (£200), with a low likelihood of being cost-effective. CONCLUSIONS: There was no difference in the Pain Severity Index between the two groups. However there were significant improvements in the intervention group in patient satisfaction and PMI. The pain screening process itself was effective. Sufficient benefit was demonstrated as a result of the intervention to allow continued development of pain treatment pathways, rather than allowing pain treatment to be left to nonformalised ad hoc arrangements.

High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma.

Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.

The prevalence of pain in patients attending sarcoma outpatient clinics.

The prevalence of pain in patients with sarcoma is not well documented. We investigated this in outpatients at a tertiary cancer referral centre, assessing the adequacy of pain control and for risk factors leading to higher prevalence and severity of pain. 149 patients were surveyed. Patients with pain within the previous 7 days completed pain assessment tools (BPI, S-LANSS, PMI). 53% of patients had pain within the previous 7 days, and 25% had significant pain. Of those with pain, 63% was inadequately controlled and neuropathic pain was identified in 36%. Age, gender, tumour type, and the type of cancer treatment were not significant predictors of the prevalence or severity of the pain. Based on our results, patients with sarcoma should be actively screened for pain and have regular reviews of their analgesic requirements.

Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia.

Gastric absorption of oral paracetamol (acetaminophen) may be unreliable perioperatively in the starved and stressed patient. We compared plasma concentrations of parenteral paracetamol given preoperatively and oral paracetamol when given as premedication. Patients scheduled for elective ear; nose and throat surgery or orthopaedic surgery were randomised to receive either oral or intravenous paracetamol as preoperative medication. The oral dose was given 30 minutes before induction of anaesthesia and the intravenous dose given pre-induction. All patients were given a standardised anaesthetic by the same specialist anaesthetist who took blood for paracetamol concentrations 30 minutes after the first dose and then at 30 minute intervals for 240 minutes. Therapeutic concentrations of paracetamol were reached in 96% of patients who had received the drug parenterally, and 67% of patients who had received it orally. Maximum median plasma concentrations were 19 mg.l(-1) (interquartile range 15 to 23 mg.l(-1)) and 13 mg.l(-1) (interquartile range 0 to 18 mg.l(-1)) for the intravenous and oral group respectively. The difference between intravenous and oral groups was less marked after 150 minutes but the intravenous preparation gave higher plasma concentrations throughout the study period. It can be concluded that paracetamol gives more reliable therapeutic plasma concentrations when given intravenously.

Fetal protein loss in gastroschisis as an explanation of associated morbidity.

OBJECTIVE: Our purpose was to examine whether protein deficiency in utero develops in fetuses with gastroschisis. STUDY DESIGN: Twelve infants with prenatally diagnosed gastroschisis were compared with 29 control infants without gastroschisis and 2 infants with exomphalos who were delivered between 35 and 42 weeks of gestation. The groups were compared for birth weight, cord serum total protein and amniotic fluid total protein, and alpha-fetoprotein concentrations. The amniotic fluid samples were collected when the amniotic membranes were ruptured either during cesarean delivery or at artificial rupture of the membranes, and umbilical cord blood was obtained after delivery. RESULTS: In the 10 cases of gastroschisis in which cord serum total protein was measured, the median concentration was 51 g/L (range, 43-61 g/L) and was significantly lower than the median level of 62 g/L (range, 47-78 g/L) in the control group (P <.001). In the 8 cases of gastroschisis in which amniotic fluid total protein and alpha-fetoprotein concentrations were measured, the respective median levels were 5.1 g/L (range, 4.3-18.4 g/L) and 5.0 g/L (range, 2.4-13.2 g/L), which were significantly higher than the median levels of 2.0 g/L (range, 0.5-5.4 g/L) and 0.8 g/L (range, 0.5-1.7 g/L) in the control group (P <.0001). The ratio of amniotic fluid to cord serum total protein was significantly higher than that in the cases of exomphalos and in the control group (P <.001). The median birth weight in the neonates with gastroschisis was 2400 g (range, 1192-3155 g) and was significantly lower than the median value of 3535 g (range, 2520-4680 g) in the control group (P <.0001). CONCLUSIONS: Fetuses with gastroschisis have protein loss that could partly explain associated morbidity. However, whether this is a major contributor to poor fetal outcome remains to be shown.

Topical antibody delivery systems produce sustained levels in mucosal tissue and blood.

Immunity at mucosal surfaces, which are ports of entry for many pathogens, is essential in preventing infections. But most current strategies for passive immunization involve injection of antibodies for systemic, not mucosal, protection. We measured mucosal and systemic antibody levels after controlled topical delivery to the vagina. Poly(ethylene-co-vinyl acetate) disks containing 125I-labeled monoclonal IgG or anti-lactate dehydrogenase-C4 antibodies were placed in the vaginas of mice. High antibody levels (0.26-12 micrograms/ml) were maintained at the mucosal surface for 7 days after disk insertion. Antibody molecules also penetrated into the vaginal epithelium, presumably by diffusing through the extracellular space, and entered the circulation. Biologically active antibodies were detected in the blood. The antibody concentration in the blood was approximately 1% of the concentration in the vagina. Although the permeability of the epithelium to macro-molecules is low, high concentrations were maintained at the luminal surface for an extended period, permitting substantial systemic uptake of antibody.

Novel systems for controlled delivery of macromolecules.

Gene therapy promises new treatments for human disease by alterations in the DNA content of tissues. Methods for efficient and stable introduction of genes into target cells in the body are critically important in this effort. Researchers and physicians now have many years of experience with synthetic polymers for controlled drug delivery; many of these polymers can also be used to deliver macromolecules at controlled rates to tissues. This article reviews the use of polymers in controlled protein delivery and suggests ways that polymer delivery systems may be useful in the delivery of gene transfer agents.

Primary structure of an inactive mutant of phospholipase A2 in the venom of Bungarus fasciatus (banded krait).

From the acidic components of Bungarus fasciatus venom, a very small amount (0.16%) of a novel phospholipase A2 was obtained. Both neurotoxicity and enzyme activity were found to be lacking. Amino acid sequence study showed that it has a normal backbone of group I snake venom phospholipase A2 with 118 amino acid residues. The lack of enzyme activity was attributed to its mutation of the indispensable Asp residue to an Ala residue, i.e., the usual His-Asp47 turned out to be His-Ala47. This is the eighth isoform of phospholipase A2 found from the venom of Bungarus fasciatus. Examination of structural homology with three other isoforms revealed 66% similarity at most.