A challenge in the structure-based design of specificity is modeling the negative states, i.e., the complexes that you do not want to form. This is a difficult problem because mutations predicted to destabilize the negative state might be accommodated by small conformational rearrangements. To overcome this challenge, we employ an iterative strategy that cycles between sequence design and protein docking in order to build up an ensemble of alternative negative state conformations for use in specificity prediction. We have applied our technique to the design of heterodimeric CH3 interfaces in the Fc region of antibodies. Combining computationally and rationally designed mutations produced unique designs with heterodimer purities greater than 90%. Asymmetric Fc crystallization was able to resolve the interface mutations; the heterodimer structures confirmed that the interfaces formed as designed. With these CH3 mutations, and those made at the heavy-/light-chain interface, we demonstrate one-step synthesis of four fully IgG-bispecific antibodies.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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On March 22, 2016 Varian Medical Systems (NYSE: VAR) reported a new Calypso 17G soft tissue Beacon transponder that is 50 percent smaller than the previous version (Press release, Varian Medical Systems, MAR 22, 2016, View Source [SID:1234509820]). The 17G device can help enhance the precision of radiotherapy and radiosurgery treatments for cancer by providing real-time, continuous tumor position information, based on the implanted transponders, and has received FDA 510(k) clearance and CE mark.

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The size of a grain of rice, the new Varian Calypso 17G soft tissue Beacon transponder, can help enhance the precision of radiotherapy and radiosurgery treatments for cancer by providing real-time, continuous tumor position information, based on the implanted transponders, and has received FDA 510(k) clearance and CE mark.
The size of a grain of rice, each Beacon transponder emits a non-ionizing electromagnetic signal that is tracked in real-time by the Calypso system, guiding treatment beams to precisely target tumors during treatment with medical linear accelerators, such as the Varian’s Edge radiosurgery system. The 17G Beacon transponders are commercially available, and for more information, visit View Source

The smaller Calypso technology benefits a broader range of patients during the implantation of the transponders, which is typically an outpatient procedure. "The new 17G implantation device has half the cross-sectional area as the prior 14G technology, increasing patient comfort and improving access to tumors," said Zachary S. Collins, M.D., section head of interventional radiology, Kansas University Medical Center. "The smaller technology may make the use of Calypso viable in a broader population of liver patients and may make it possible for interventional radiologists to implant Beacon transponders in the pancreas without an open surgical procedure."

The new transponders can be implanted within the soft tissue throughout the body, with the exception of the lung. Based on the transponder signals, the Calypso System uses "GPS for the body" technology to track even the slightest movement of the tumor without using ionizing radiation. Even tumors exhibiting respiratory motion can be precisely targeted through Calypso’s innovative technology, which allows the beam to be gated on only when the tumor is in the planned position.

The Calypso System is the only device on the market that delivers real-time, continuous (25 Hz update rate), 3D tumor position information, improving confidence that the prescribed dose has been delivered to the tumor. This increased precision can enable treatment margin reduction, which can protect healthy tissue and reduce certain side effects1. The Calypso system, when used with the new 17G transponders, delivers equivalent accuracy and precision as compared to the established 14G devices.

"With the precise targeting provided by Calypso technology, we are able to reduce treatment margins and liver toxicity compared to conventional radiotherapy without Calypso beacons," remarked Neal Dunlap, MD, Radiation Oncologist, University of Louisville, Kentucky.

Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy.
Copyright © 2016 Elsevier Inc. All rights reserved.

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Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).
Copyright© Ferrata Storti Foundation.

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Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.
Copyright © 2015 Elsevier Inc. All rights reserved.

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