Evaluation of two high-throughput proteomic technologies for plasma biomarker discovery in immunotherapy-treated melanoma patients

Background: Selective kinase and immune checkpoint inhibitors, and their combinations, have significantly improved the survival of patients with advanced metastatic melanoma. Not all patients will respond to treatment however, and some patients will present with significant toxicities. Hence, the identification of biomarkers is critical for the selection and management of patients receiving treatment. Biomarker discovery often involves proteomic techniques that simultaneously profile multiple proteins but few studies have compared these platforms. Methods: In this study, we used the multiplex bead-based Eve Technologies Discovery assay and the aptamer-based SomaLogic SOMAscan assay to identify circulating proteins predictive of response to immunotherapy in melanoma patients treated with combination immune checkpoint inhibitors. Expression of four plasma proteins were further validated using the bead-based Millipore Milliplex assay. Results: Both the Discovery and the SOMAscan assays detected circulating plasma proteins in immunotherapy-treated melanoma patients. However, these widely used assays showed limited correlation in relative protein quantification, due to differences in specificity and the dynamic range of protein detection. Protein data derived from the Discovery and Milliplex bead-based assays were highly correlated. Conclusions: Our study highlights significant limitations imposed by inconsistent sensitivity and specificity due to differences in the detection antibodies or aptamers of these widespread biomarker discovery approaches. Our findings emphasize the need to improve these technologies for the accurate identification of biomarkers

The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma

The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care

The Making of a Queen: TOR Pathway Is a Key Player in Diphenic Caste Development

Honey bees (Apis mellifera) provide a principal example of diphenic development. Excess feeding of female larvae results in queens (large reproductives). Moderate diet yields workers (small helpers). The signaling pathway that links provisioning to female developmental fate is not understood, yet we reasoned that it could include TOR (target of rapamycin), a nutrient- and energy-sensing kinase that controls organismal growth.Here, the role of Apis mellifera TOR (amTOR) in caste determination is examined by rapamycin/FK506 pharmacology and RNA interference (RNAi) gene knockdown. We show that in queen-destined larvae, the TOR inhibitor rapamycin induces the development of worker characters that are blocked by the antagonist FK506. Further, queen fate is associated with elevated activity of the Apis mellifera TOR encoding gene, amTOR, and amTOR gene knockdown blocks queen fate and results in individuals with worker morphology.A much-studied insect dimorphism, thereby, can be governed by the TOR pathway. Our results present the first evidence for a role of TOR in diphenic development, and suggest that adoption of this ancestral nutrient-sensing cascade is one evolutionary pathway for morphological caste differentiation in social insects

Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. © 2013 Jilaveanu et al

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma

Background Metastatic melanoma is an aggressive skin cancer with a poor prognosis. Current treatment strategies for high-stage melanoma are based around the use of immunotherapy with immune checkpoint inhibitors such as anti-PDL1 or anti-CTLA4 antibodies to stimulate anti-cancer T cell responses, yet a number of patients will relapse and die of disease. Here, we report the first sustained complete remission in a patient with metastatic melanoma who failed two immunotherapy strategies, by targeting tumour arginine metabolism. Case presentation A 65-year-old patient with metastatic melanoma who progressed through two immunotherapy strategies with immune checkpoint inhibitor antibodies was enrolled in a phase I study (NCT02285101) and treated with 2 mg/kg intravenously, weekly pegylated recombinant arginase (BCT-100). The patient experienced no toxicities > grade 2 and entered a complete remission which is sustained for over 30 months. RNA-sequencing identified a number of transcriptomic pathway alterations compared to control samples. The tumour had absent expression of the recycling enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC) indicating a state of arginine auxotrophy, which was reconfirmed by immunohistochemistry, and validation in a larger cohort of melanoma tumour samples. Conclusions Targeting arginine metabolism with therapeutic arginase in arginine auxotrophic melanoma can be an effective salvage for the treatment of patients who fail immunotherapy

Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma.

Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit

Disk-Magnetosphere Interaction and Outflows: Conical Winds and Axial Jets

We investigate outflows from the disk-magnetosphere boundary of rotating magnetized stars in cases where the magnetic field of a star is bunched into an X-type configuration using axisymmetric and full 3D MHD simulations. Such configuration appears if viscosity in the disk is larger than diffusivity, or if the accretion rate in the disk is enhanced. Conical outflows flow from the inner edge of the disk to a narrow shell with an opening angle 30-45 degrees. Outflows carry 0.1-0.3 of the disk mass and part of the disk's angular momentum outward. Conical outflows appear around stars of different periods, however in case of stars in the "propeller" regime, an additional - much faster component appears: an axial jet, where matter is accelerated up to very high velocities at small distances from the star by magnetic pressure force above the surface of the star. Exploratory 3D simulations show that conical outflows are symmetric about rotational axis of the disk even if magnetic dipole is significantly misaligned. Conical outflows and axial jets may appear in different types of young stars including Class I young stars, classical T Tauri stars, and EXors.Comment: Invited review, conference proceedings of the meeting "Protostellar Jets in Context", 7-12 July 2008, island of Rhodes, Greece; editors: profs. Tom Ray and Kanaris Tsinganos; 10 pages, 10 figures, see animations at http://www.astro.cornell.edu/~romanova/conical.htm and http://www.astro.cornell.edu/~romanova/propeller.ht

Six months of multiwavelength follow-up of the tidal disruption candidate ASASSN-14li and implied TDE rates from ASAS-SN

We present ground-based and Swift photometric and spectroscopic observations of the candidate tidal disruption event (TDE) ASASSN-14li, found at the center of PGC043234 (d ' 90 Mpc) by the All-Sky Automated Survey for SuperNovae (ASAS-SN). The source had a peak bolometric luminosity of L ' 1044 ergs

Hydrodynamics of fossil fishes

Fromtheir earliest origins, fishes have developed a suite of adaptations for locomotion in water, which determine performance and ultimately fitness. Even without data from behaviour, soft tissue and extant relatives, it is possible to infer a wealth of palaeobiological and palaeoecological information. As in extant species, aspects of gross morphology such as streamlining, fin position and tail type are optimized even in the earliest fishes, indicating similar life strategies have been present throughout their evolutionary history. As hydrodynamical studies become more sophisticated, increasingly complex fluid movement can be modelled, including vortex formation and boundary layer control. Drag-reducing riblets ornamenting the scales of fast-moving sharks have been subjected to particularly intense research, but this has not been extended to extinct forms. Riblets are a convergent adaptation seen in many Palaeozoic fishes, and probably served a similar hydrodynamic purpose. Conversely, structures which appear to increase skin friction may act as turbulisors, reducing overall dragwhile serving a protective function. Here,we examine the diverse adaptions that contribute to drag reduction in modern fishes and review the few attempts to elucidate the hydrodynamics of extinct forms