Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors.

BACKGROUND: Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors. METHODS: Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed. RESULTS: No DLTs occurred in parts A (n=18) or B (n=85). Grade 3-5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35). CONCLUSIONS: Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02043665.

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma.

Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM.

NOX4 is a major regulator of cord blood-derived endothelial colony-forming cells which promotes post-ischaemic revascularization.

AIMS: Cord blood-derived endothelial colony-forming cells (CB-ECFCs) are a defined progenitor population with established roles in vascular homeostasis and angiogenesis, which possess low immunogenicity and high potential for allogeneic therapy and are highly sensitive to regulation by reactive oxygen species (ROS). The aim of this study was to define the precise role of the major ROS-producing enzyme, NOX4 NADPH oxidase, in CB-ECFC vasoreparative function. METHODS AND RESULTS: In vitro CB-ECFC migration (scratch-wound assay) and tubulogenesis (tube length, branch number) was enhanced by phorbol 12-myristate 13-acetate (PMA)-induced superoxide in a NOX-dependent manner. CB-ECFCs highly-expressed NOX4, which was further induced by PMA, whilst NOX4 siRNA and plasmid overexpression reduced and potentiated in vitro function, respectively. Increased ROS generation in NOX4-overexpressing CB-ECFCs (DCF fluorescence, flow cytometry) was specifically reduced by superoxide dismutase, highlighting induction of ROS-specific signalling. Laser Doppler imaging of mouse ischaemic hindlimbs at 7 days indicated that NOX4-knockdown CB-ECFCs inhibited blood flow recovery, which was enhanced by NOX4-overexpressing CB-ECFCs. Tissue analysis at 14 days revealed consistent alterations in vascular density (lectin expression) and eNOS protein despite clearance of injected CB-ECFCs, suggesting NOX4-mediated modulation of host tissue. Indeed, proteome array analysis indicated that NOX4-knockdown CB-ECFCs largely suppressed tissue angiogenesis, whilst NOX4-overexpressing CB-ECFCs up-regulated a number of pro-angiogenic factors specifically-linked with eNOS signalling, in parallel with equivalent modulation of NOX-dependent ROS generation, suggesting that CB-ECFC NOX4 signalling may promote host vascular repair. CONCLUSION: Taken together, these findings indicate a key role for NOX4 in CB-ECFCs, thereby highlighting its potential as a target for enhancing their reparative function through therapeutic priming to support creation of a pro-reparative microenvironment and effective post-ischaemic revascularization.

Phylogenetic analysis of the Lancinae (Gastropoda, Lymnaeidae) with a description of the U.S. federally endangered Banbury Springs lanx.

We examined the patelliform snails of the subfamily Lancinae, endemic to northwestern North America, to test whether morphological variation correlated with genetic and anatomical differences. Molecular analyses using cox1, 16S, calmodulin intron, and 28S rDNA partial sequences and anatomical data supported recognition of four species in three genera. The relationships of lancines within Lymnaeidae are not yet well-resolved. The federally endangered Banbury Springs lanx is described as a new genus and species, Idaholanx fresti, confirming its distinctiveness and narrow endemicity.

Androgens and estrogens stimulate ribosome biogenesis in prostate and breast cancer cells in receptor dependent manner.

Ribosome biogenesis is a fundamental cellular process intimately linked to cell growth and proliferation, which is upregulated in most of cancers especially in aggressive cancers. In breast and prostate cancers steroid hormone receptor signalling is the principal stimulus for cancer growth and progression. Here we investigated the link between estrogen and androgen receptor signalling and the initial stage of ribosome biogenesis - transcription of rRNA genes. We have discovered that oestrogen or androgen treatment can positively regulate rRNA synthesis in breast and prostate cancer cells respectively and that this effect is receptor dependent. This novel and interesting finding suggests a previously unidentified link between steroid hormone receptor signalling pathways and the regulation of ribosome biogenesis.

Conversion of epidural labour analgesia to epidural anesthesia for intrapartum Cesarean delivery.

PURPOSE: To determine the rate of successful conversion of epidural labour analgesia (ELA) to epidural surgical anesthesia (ESA) for intrapartum Cesarean delivery (CD) with identification of potential risk factors for inadequate ESA. Secondary outcomes include a comparison of the management by subspecialist obstetric anesthesiologists (OB) vs. generalist anesthesiologists (GEN), when inadequate ESA was encountered, with an intention of identifying potential interventional strategies to reduce the need for general anesthesia (GA). METHODS: Health records of all parturients who received ELA and who underwent intrapartum CD during the 3-year period from April 01, 2001 to March 31, 2004 were manually reviewed. Data were analyzed using t test, Chi-square, Fisher's exact test, and analysis of variance where appropriate. A P < 0.05 was considered significant. RESULTS: Eight hundred ninety-nine cases were identified. Four were excluded, as two received continuous spinal labour analgesia and two underwent emergency CD with insufficient time for conversion to ESA. Initially, 86.6% (775/895) of the 895 cases were successfully converted to ESA leaving 120 cases of inadequate ESA, 36 of these were managed by OB and 84 by GEN. Ineffective ELA was identified as a risk factor for unsuccessful conversion. Pulling the epidural catheter back 1 cm was identified as an effective intervention that resulted in the successful conversion in >80% of the 120 cases of inadequate ESA. Spinal anesthesia proved effective in 75% of cases. Both interventions reduced the need for GA to 1.2% for OB and 5.6% for GEN. CONCLUSIONS: This investigation provides anesthesiologists with strategies to manage inadequate ESA for intrapartum CD that may reduce the need for GA.

Identification of 'extinct' freshwater mussel species using DNA barcoding.

Freshwater mollusks are highly imperiled, with 70% of the North American species extinct, endangered, or at risk of extinction. Impoundments and other human impacts on the Coosa River of Alabama, Georgia and Tennessee of the southeastern USA alone are believed to have caused 50 mollusk species extinctions, but uncertainty over boundaries among several putatively closely related species makes this number preliminary. Our examination of freshwater mussels collected during an extensive survey of the upper-drainage basin, DNA barcoding and molecular phylogenetic analyses confirm the rediscovery of four morphospecies in the genus Pleurobema (Unionidae) previously thought to be extinct from the upper Coosa basin. A fifth 'extinct' form was found in an adjoining basin. Molecular data show that the Coosa morphologies represent at least three species-level taxa: Pleurobema decisum, P. hanleyianum and P. stabile. Endemism is higher than currently recognized, both at the species level and for multispecies clades. Prompt conservation efforts may preserve some of these taxa and their ecosystem.

Epidural labour analgesia in a parturient with Noonan syndrome: a case report.

PURPOSE: Noonan syndrome is a relatively uncommon genetic disorder with implications for anesthesia due to multiple organ system involvement. Pregnancy presents additional concerns and there are only four reported cases of anesthesia for Cesarean delivery in parturients with Noonan syndrome. We describe the first reported management of labour analgesia in a parturient with Noonan syndrome culminating in vaginal delivery. CLINICAL FEATURES: A 21-yr-old parturient with Noonan syndrome received patient-controlled epidural analgesia for labour at 39 weeks gestation. Meticulous attention to the anesthetic technique resulted in good analgesia, and a successful outcome for mother and child. The different approaches to labour analgesia in parturients, with particular attention to combined spinal epidural vs epidural analgesia in this setting are discussed. CONCLUSION: Parturients with Noonan syndrome can present with an array of anomalies that may present difficulties to the anesthesiologist including a difficult airway, cardiopulmonary abnormalities, exaggerated lumbar lordosis and short stature. Careful preoperative consultation and determination of the degree of associated anomalies will help to prepare the anesthesiologist for potential problems.

A multicenter randomized controlled trial comparing patient-controlled epidural with intravenous analgesia for pain relief in labor.

In this multicenter, randomized, controlled trial, we sought to determine whether patient-controlled epidural analgesia (PCEA) for labor affected the incidence of cesarean delivery when compared with patient-controlled IV opioid analgesia (PCIA). Healthy, term nulliparous patients in 4 Canadian institutions were randomly assigned to receive PCIA with fentanyl (n = 118) or PCEA with 0.08% bupivacaine and fentanyl 1.6 microg/mL (n = 124). There was no difference in the incidence of cesarean delivery-10.2% (12 of 118) versus 9.7% (12 of 124)-or instrumental vaginal delivery-21.2% (25 of 118) versus 29% (36 of 124)-between groups. The duration of the second stage of labor was increased in the PCEA group by a median of 23 min (P = 0.02). Fifty-one patients (43%) in the PCIA group received epidural analgesia: 39 (33%) because of inadequate pain relief and 12 (10%) to facilitate operative delivery. Patients in the PCIA group required more antiemetic therapy (17% versus 6.4%; P = 0.01) and had more sedation (39% versus 5%; P < 0.001). Maternal mean pain and satisfaction with analgesia scores were better in the PCEA group (P < 0.001 and P = 0.02, respectively). More neonates in the PCIA group required active resuscitation (52% versus 31%; P = 0.001) and naloxone (17% versus 3%; P < 0.001). These observations support the hypothesis that PCEA does not result in an increased incidence of obstetrical intervention compared with PCIA. PCEA provides superior analgesia and less maternal and neonatal sedation compared with PCIA.

Parenteral opioids for labor analgesia.

Labor pain relief is an important aspect of women's health that has historically been neglected. Epidural analgesia is the only consistently effective method of labor pain relief and has recently undergone substantial improvements to address the concerns of both parturients and obstetric care providers. With increased physician awareness, these recent advances are becoming more widely accepted and routinely available for all laboring parturients. Unfortunately, an increasing number of women are presenting to maternity wards with an absolute contraindication to epidural labor analgesia. The present review will provide an outline of the recent developments in parenteral analgesic options which complement modern epidural analgesic techniques. Protocols for the initiation of "state-of-the-art" parenteral analgesic techniques are provided as a guide to facilitate effective, modern, parenteral labor analgesia.

A multicenter, randomized, controlled trial comparing bupivacaine with ropivacaine for labor analgesia.

BACKGROUND: A meta-analysis of studies comparing high doses of bupivacaine with ropivacaine for labor pain found a higher incidence of forceps deliveries, motor block, and poorer neonatal outcome with bupivacaine. The purpose of this study was to determine if there is a difference in these outcomes when a low concentration of patient-controlled epidural bupivacaine combined with fentanyl is compared with ropivacaine combined with fentanyl. METHODS: This was a multicenter, randomized, controlled trial, including term, nulliparous women undergoing induction of labor. For the initiation of analgesia, patients were randomized to receive either 15 ml bupivacaine, 0.1%, or 15 ml ropivacaine, 0.1%, each with 5 microg/ml fentanyl. Analgesia was maintained with patient-controlled analgesia with either local anesthetic, 0.08%, with 2 microg/ml fentanyl. The primary outcome was the incidence of operative delivery. We also examined other obstetric, neonatal, and analgesic outcomes. RESULTS: There was no difference in the incidence of operative delivery between the two groups (148 of 276 bupivacaine recipients vs. 135 of 279 ropivacaine recipients; P = 0.25) or any obstetric or neonatal outcome. The incidence of motor block was significantly increased in the bupivacaine group compared with the ropivacaine group at 6 h (47 of 93 vs. 29 of 93, respectively; P = 0.006) and 10 h (29 of 47 vs. 16 of 41, respectively; P = 0.03) after injection. Satisfaction with mobility was higher with ropivacaine than with bupivacaine (mean +/- SD: 76 +/- 23 vs. 72 +/- 23, respectively; P = 0.013). Satisfaction for analgesia at delivery was higher for bupivacaine than for ropivacaine (mean +/- SD: 71 +/- 25 vs. 66 +/- 26, respectively; P = 0.037). CONCLUSIONS: There was no difference in the incidence of operative delivery or neonatal outcome among nulliparous patients who received low concentrations of bupivacaine or ropivacaine for labor analgesia.