Elotuzumab is a first in class humanized IgG1 monoclonal antibody for the treatment of multiple myeloma (MM). Elotuzumab targets the glycoprotein signaling lymphocyte activation molecule family 7 (SLAMF7, also described as CS1 or CRACC) which is expressed on the surface of myeloma cells and a subset of immune cells, including natural killer cells. A soluble version of SLAMF7 (sSLAMF7) has also been reported in MM patients but has not been evaluated as a potential biomarker following therapeutic intervention. In order to measure serum levels of sSLAMF7, two immunoassays were developed to monitor changes in circulating sSLAMF7 before and after elotuzumab treatment. Free (drug-unbound) and total (drug-bound and unbound) electrochemiluminescence (ECL) ELISA assays were developed and validated following a fit for purpose (FFP) methodology. Both assays met analytical acceptance criteria for precision, drug interference, dilution linearity, spike recovery, parallelism, and stability. Both exhibited the range and sensitivity necessary to measure clinical samples with an LLOQ of 51.2 pg/mL and ULOQs of 160 (free) and 800 ng/mL (total). Previously described assays were unable to detect sSLAMF7 in healthy individuals. However, due to the increased sensitivity of these new assays, low but measurable sSLAMF7 levels were detected in all normal healthy sera evaluated and were significantly elevated in MM patients. Cohort statistics revealed a significant increase of circulating sSLAMF7 in MM patients versus normal controls and both significant decreases in free and increases in total levels of protein post-elotuzumab treatment.

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On April 27, 2016 Varian Medical Systems (NYSE: VAR), reported that its 3D volumetric imaging technology is now being used at a California proton therapy center to enhance the precision and quality of its treatments for cancer patients (Press release, Varian Medical Systems, APR 27, 2016, View Source [SID:1234511483]). The treatments with image-guided intensity modulated proton therapy (IMPT) are being delivered on Varian’s ProBeam system at Scripps Proton Therapy Center in San Diego.

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3D volumetric image-guided IMPT is enabled by Varian’s cone beam computed tomography (CBCT) technology and supports adaptive treatment planning and delivery wherein clinicians can revise plans based on what they see in images during the course of treatment. Volumetric imaging is particularly important for proton radiosurgery, an ultra-precise form of treatment. ProBeam cone beam imaging is based on the same leading technology used in Varian’s radiation oncology systems including the TrueBeam platform.

The unique combination of 3D volumetric imaging with controlled pencil beam scanning makes it possible to conform dose to the size, shape and location of the tumor while potentially reducing side effects. With proton therapy, the risk of damage to healthy tissues and potential side effects are reduced because proton beams can be controlled so that they deposit their energy within the tumor site rather than passing all the way through the patient.

"Volumetric imaging is enormously beneficial, because IMPT is very sensitive to anatomic changes," said Dr. Lei Dong, chief of Medical Physics, Scripps Proton Therapy Center. "For the optimum treatment we need to know of any changes, not only to the target, but also the anatomy outside of the target. The cone beam imaging on the Varian ProBeam System is excellent and stays true to the same high quality that I’ve seen on their photon systems."

"This is an important milestone for Varian where we are bringing the most advanced 3D imaging capability to the ProBeam system for proton therapy patients," said Dr. Moataz Karmalawy, general manager of Varian’s Particle Therapy division. "This should enable clinicians to deliver proton radiosurgery that will allow precise treatments for cancer patients to be completed in fewer sessions. It should be a win for everybody."

For more information on Varian’s proton therapy solutions, visit View Source

The HIV-1-envelope (Env) trimer is covered by a glycan shield of ∼90 N-linked oligosaccharides, which comprises roughly half its mass and is a key component of HIV evasion from humoral immunity. To understand how antibodies can overcome the barriers imposed by the glycan shield, we crystallized fully glycosylated Env trimers from clades A, B, and G, visualizing the shield at 3.4-3.7 Å resolution. These structures reveal the HIV-1-glycan shield to comprise a network of interlocking oligosaccharides, substantially ordered by glycan crowding, that encase the protein component of Env and enable HIV-1 to avoid most antibody-mediated neutralization. The revealed features delineate a taxonomy of N-linked glycan-glycan interactions. Crowded and dispersed glycans are differently ordered, conserved, processed, and recognized by antibody. The structures, along with glycan-array binding and molecular dynamics, reveal a diversity in oligosaccharide affinity and a requirement for accommodating glycans among known broadly neutralizing antibodies that target the glycan-shielded trimer.
Copyright © 2016 Elsevier Inc. All rights reserved.

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On April 27, 2016 Varian Medical Systems (NYSE:VAR) reported non-GAAP net earnings of $1.09 per diluted share and GAAP net earnings of $1.01 per diluted share for the second quarter of fiscal year 2016 (Press release, Varian Medical Systems, APR 27, 2016, View Source [SID:1234511502]). Varian’s revenues totaled $759 million for the second quarter, equal to the year-ago quarter and up 2 percent in constant currency. The company ended the quarter with a $3.3 billion backlog, up 6 percent from the end of the second quarter of fiscal year 2015.

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"The company delivered solid results for the second quarter with strong gross order growth in our Oncology business and made promising progress in our Particle Therapy business," said Dow Wilson, CEO of Varian Medical Systems. "As expected, we continued to experience weakness in our Imaging Components business."

The company finished the second quarter of fiscal year 2016 with $961 million in cash and cash equivalents and $794 million of debt. Cash flow from operations was $32 million for the second quarter, bringing the total for the first half of the fiscal year to $109 million. During the quarter, the company spent $57 million to repurchase about 725,000 shares of common stock.

Oncology Systems

Oncology Systems’ second quarter revenues totaled $584 million, down 1 percent from the same quarter of fiscal year 2015 and up 1 percent in constant currency. Second-quarter Oncology gross orders were $618 million, up 6 percent from the year-ago quarter and up 8 percent in constant currency. In the Americas, Oncology gross orders increased by 2 percent in dollars and 3 percent in constant currency with 7 percent growth in North America offsetting a decline in Latin America. In EMEA, gross orders were up 19 percent in dollars and up 23 percent in constant currency. In APAC, gross orders rose 2 percent in dollars and 3 percent in constant currency, driven by robust growth in China.

"Oncology generated gross order growth with strategic wins in all three geographies," Wilson said. "Orders rose with the help of an expanding number of treatment rooms in China and India and demand for new products, including our VitalBeam accelerator, as well as our InSightive Analytics and RapidPlan software. Overall, we saw healthy global oncology demand during the quarter."

Imaging Components

Imaging Components revenues were $144 million for the second quarter, down 8 percent from the year-ago period. Gross orders were $138 million for the second quarter, down 12 percent from the year-ago period.

"The Imaging Components business continued to experience lower shipments of flat panels and tubes during the quarter," said Wilson. "Meanwhile, our new MeVis and Claymount businesses performed well in the quarter."

Other

The company’s Other category, including the Varian Particle Therapy business and the Ginzton Technology Center, recorded second quarter revenues of $31 million, up $16 million from the year-ago quarter. "We are continuing to build momentum in this business with growing interest in our single-room ProBeam Compact proton therapy system," Wilson said.

Outlook

"Including the results of the second quarter, we continue to believe that total company non-GAAP earnings will be in the range of $4.55 to $4.65 per diluted share for fiscal year 2016," said Wilson. "With expectations of a slower than anticipated recovery in our Imaging Components business due to high inventory levels at a major customer, we now believe revenues for fiscal year 2016 will increase by about 3 percent over fiscal year 2015.

"For the third quarter of fiscal year 2016, we expect non-GAAP earnings to be in the range of $1.16 to $1.20 per diluted share. We expect third quarter revenues to be about equal to the year-ago period with growth in our core businesses offset by a decline in our proton business versus the year-ago quarter when we booked the big University of Maryland project."

Please refer to "Discussion of Non-GAAP Financial Measures" below for a description of items excluded from expected non-GAAP earnings.

Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer’s disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1β), Tumor Necrosis Factor alpha (TNFα) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-α, IL-1β and iNOS induced by 10 μM β-amyloid1-42 (Aβ42). Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Aβ42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 μM or 500 μM) or R-flurbiprofen (3 μM or 100 μM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD.
Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

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