Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial

Talimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB-IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB-IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB-IVM1a disease.The patients were randomized (2:1 ratio) to intralesional talimogene laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit-risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons.Among 249 evaluated patients with stage IIIB-IVM1a melanoma, DRR was higher with talimogene laherparepvec compared with GM-CSF (25.2% versus 1.2%; P<0.0001). ORR was also higher in the talimogene laherparepvec arm (40.5% versus 2.3%; P<0.0001), and 27 patients in the talimogene laherparepvec arm had a complete response, compared with none in GM-CSF-treated patients. The incidence rates of exposure-adjusted adverse events (AE) and serious AEs were similar with both treatments.The subgroup of patients with stage IIIB, IIIC and IVM1a melanoma (57.1% of the OPTiM intent-to-treat population) derived greater benefit in DRR and ORR from talimogene laherparepvec compared with GM-CSF. Talimogene laherparepvec was well tolerated

Absolute band-edge energies are over-emphasized in the design of photoelectrochemical materials

The absolute band-edge potentials of semiconductors and their positions relative to solution redox potentials are often invoked as design principles for photoelectrochemical devices and particulate photocatalysts. Here we show that these criteria are not necessary and limit the exploration of materials that may advance the fields of photoelectrochemistry, photochemistry and photocatalysis. We discuss how band-edge energies are not singular parameters and instead shift with pH, electrolyte type and surface chemistry. The free energies of electrons and holes, rather than those of solution redox couples, dictate overall reaction spontaneity and thus reactivity. Favourable charge-transfer kinetics can occur even when the relevant electrolyte redox potential(s) appear outside the bandgap, enabled by the inversion or accumulation of electronic charge at the semiconductor surface. This discussion informs design principles for photocatalytic systems engineering for both one-electron and multi-electron redox reactions (for example, H2 evolution, H2O oxidation and CO2 reduction). (Figure presented.

Amphiprion barberi, a new species of anemonefish (Pomacentridae) from Fiji, Tonga, and Samoa

Amphiprion barberi, a new species of anemonefish fish, is described from 46 specimens, 16.3-85.8 mm SL, collected at depths of 2-10 m from coral reefs of Fiji, Tonga, and Samoa. It is closely allied to A. melanopus, which is widely distributed in the western Pacific. The two species exhibit significant colour-pattern differences, including a mainly reddish orange body in A. barberi and dark brown or blackish body in A. melanopus. Adults of the new species also possess fewer spinules (11-19 versus 19-26) in the upper-opercular series than A. melanopus. Genetic data presented here confirms the separation of these species

Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial

Talimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial ({"type":"clinical-trial","attrs":{"text":"NCT00769704","term_id":"NCT00769704"}}NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB–IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB–IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB–IVM1a disease

Design of a Thermal Imaging Diagnostic Using 90-Degree, Off-Axis, Parabolic Mirrors

Thermal imaging is an important, though challenging, diagnostic for shockwave experiments. Shock-compressed materials undergo transient temperature changes that cannot be recorded with standard (greater than ms response time) infrared detectors. A further complication arises when optical elements near the experiment are destroyed. We have designed a thermal-imaging system for studying shock temperatures produced inside a gas gun at Sandia National Laboratories. Inexpensive, diamond-turned, parabolic mirrors relay an image of the shocked target to the exterior of the gas gun chamber through a sapphire vacuum port. The 3000–5000-nm portion of this image is directed to an infrared camera which acquires a snapshot of the target with a minimum exposure time of 150 ns. A special mask is inserted at the last intermediate image plane, to provide dynamic thermal background recording during the event. Other wavelength bands of this image are split into high-speed detectors operating at 900–1700 nm, and at 1700–3000 nm for timeresolved pyrometry measurements. This system incorporates 90-degree, off-axis parabolic mirrors, which can collect low f/# light over a broad spectral range, for high-speed imaging. Matched mirror pairs must be used so that aberrations cancel. To eliminate image plane tilt, proper tip-to-tip orientation of the parabolic mirrors is required. If one parabolic mirror is rotated 180 degrees about the optical axis connecting the pair of parabolic mirrors, the resulting image is tilted by 60 degrees. Different focal-length mirrors cannot be used to magnify the image without substantially sacrificing image quality. This paper analyzes performance and aberrations of this imaging diagnostic

High-Resolution UV Relay Lens for Particle Size Distribution Measurements Using Holography

Shock waves passing through a metal sample can produce ejecta particulates at a metal-vacuum interface. Holography records particle size distributions by using a high-power, short-pulse laser to freeze particle motion. The sizes of the ejecta particles are recorded using an in-line Fraunhofer holography technique. Because the holographic plate would be destroyed in an energetic environment, a high-resolution lens has been designed to relay the interference fringes to a safe environment. Particle sizes within a 12-mm-diameter, 5-mm-thick volume are recorded onto holographic film. To achieve resolution down to 0.5 μm, ultraviolet laser (UV) light is needed. The design and assembly of a nine-element lens that achieves &gt;2000 lp/mm resolution and operates at f/0.89 will be described. To set up this lens system, a doublet lens is temporarily attached that enables operation with 532-nm laser light and 1100 lp/mm resolution. Thus, the setup and alignment are performed with green light, but the dynamic recording is done with UV light. During setup, the 532-nm beam provides enough focus shift to accommodate the placement of a resolution target outside the ejecta volume; this resolution target does not interfere with the calibrated wires and pegs surrounding the ejecta volume. A television microscope archives images of resolution patterns that prove that the calibration wires, interference filter, holographic plate, and relay lenses are in their correct positions. Part of this lens is under vacuum, at the point where the laser illumination passes through a focus. Alignment and tolerancing of this high-resolution lens will be presented, and resolution variation through the 5-mm depth of field will be discussed

Yielded to Christ or conformed to this world? Postwar Mennonite responses to labour activism

This is the accepted version of the manuscript.The urbanization of North American Mennonites after the Second World War necessitated a reconsideration of Mennonite religious beliefs. Post-war concerns for social justice led to a greater emphasis on non-violence and agape at the expense of Gelassenheit. The tenor of Mennonite church conference resolutions regarding labour union membership changed; while skepticism remained regarding the wisdom of union involvement, the door was left open for participation in unions. The labour militancy of the 1970s led Manitoba Mennonites to re-examine their engagement with the labour movement, a process that has continued to the present day. Without further research on Mennonite workplaces, it cannot be known exactly how the change in religious emphases has affected Mennonite identity.https://journals.sagepub.com/doi/abs/10.1177/00084298070360020

Transcriptional activation by mitochondrial transcription factor A involves preferential distortion of promoter DNA

Mitochondrial transcription factor A (mtTFA/TFAM) is a nucleus-encoded, high-mobility-group-box (HMG-box) protein that regulates transcription of the mitochondrial genome by specifically recognizing light-strand and heavy-strand promoters (LSP, HSP1). TFAM also binds mitochondrial DNA in a non-sequence specific (NSS) fashion and facilitates its packaging into nucleoid structures. However, the requirement and contribution of DNA-bending for these two different binding modes has not been addressed in detail, which prompted this comparison of binding and bending properties of TFAM on promoter and non-promoter DNA. Promoter DNA increased the stability of TFAM to a greater degree than non-promoter DNA. However, the thermodynamic properties of DNA binding for TFAM with promoter and non-specific (NS) DNA were similar to each other and to other NSS HMG-box proteins. Fluorescence resonance energy transfer assays showed that TFAM bends promoter DNA to a greater degree than NS DNA. In contrast, TFAM lacking the C-terminal tail distorted both promoter and non-promoter DNA to a significantly reduced degree, corresponding with markedly decreased transcriptional activation capacity at LSP and HSP1 in vitro. Thus, the enhanced bending of promoter DNA imparted by the C-terminal tail is a critical component of the ability of TFAM to activate promoter-specific initiation by the core mitochondrial transcription machinery

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIM

BACKGROUND: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2). PATIENTS AND METHODS: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin RESULTS: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2. CONCLUSIONS: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients

The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 × 10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin