Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development

Introduction: Biologics drugs have succeeded in achieving a commercial dominance in the global market for new therapies and large pharmaceutical companies' interest remains strong through a continued commitment to pipeline development. It is not surprising, therefore, that next-generation biologics, particularly antibody-like scaffolds that offer many of the advantages of the original biologic drugs but in simplified formats, have entered the clinic as competing substitute therapeutic products, to capture market share.

Areas covered: Specifically, this paper will position shark-derived variable new antigen receptors (VNARs) within an overview of the existing biologics landscape including the growth, diversity and success to date of alternative scaffolds. The intention is not to provide a comprehensive review of biologics as a whole but to discuss the main competing single-domain technologies and the exciting therapeutic potential of VNAR domains as clinical candidates within this context.

Expert opinion: The inherent ability to specifically bind target and intervene in disease-related biological processes, while reducing off-site toxicity, makes mAbs an effective, potent and now proven class of therapeutics. There are, however, limitations to these ‘magic bullets’. Their size and complexity can restrict their utility in certain diseases types and disease locations. In contrast, a number of so-called alternative scaffolds, derived from both immunoglobulin- and non-immunoglobulin-based sources have been developed with real potential to overcome many of the shortcomings documented for mAb treatments. Unlike competing approaches such as Darpins and Affibodies, we now know that shark VNAR domains (like camel VHH nanobody domains), are an integral part of the adaptive immune system of these animals and have evolved naturally (but from very different starting molecules) to exhibit high affinity and selectivity for target. In addition, and again influenced by the environment in which they have evolved naturally, their small size, simple architecture, high solubility and stability, deliver additional flexibility compared to classical antibodies (and many non-natural alternative scaffolds), thereby providing an attractive basis for particular clinical indications where these attributes may offer advantages.     

Investigation of mtDNA control region sequences in an Egyptian population sample

The sequences of mitochondrial DNA (mtDNA) control region were investigated in 101 unrelated individuals living in the northern region of Nile delta (Gharbia, N = 55 and Kafrelsheikh, N = 46). DNA was extracted from blood stained filter papers or buccal swabs. HV1, HV2 and HV3 were PCR amplified and sequenced; the resulted sequences were aligned and compared with revised Cambridge sequence (rCRS). The results revealed presence of total 93 different haplotypes, 86 of them are unique and 7 are shared haplotypes, the most common haplotype, was observed with a frequency, 2.97% of population sample. High mtDNA diversity was observed with genetic diversity and power of discrimination, 0.9982 and 0.9883, respectively. In this dataset the west Eurasian haplogroups predominated over the African haplogroups. The results would be useful for forensic examinations and human genetic studies.     

Variable-density adaptive imaging for high-resolution coronary artery MRI.

Variable-density (VD) spiral k-space acquisitions are used to acquire high-resolution (0.78 mm), motion-compensated images of the coronary arteries. Unlike conventional methods, information for motion compensation is obtained directly from the coronary anatomy itself. Specifically, periods of minimal coronary distortion are identified by applying the correlation coefficient template matching algorithm to real-time images generated from the inner, high-density portions of the VD spirals. Combining the data associated with these images together, high-resolution, motion-compensated coronary images are generated. Because coronary motion is visualized directly, the need for cardiac-triggering, breath-holding, and navigator echoes is eliminated. The motion compensation capability of the technique is determined by the inner-spiral spatial and temporal resolution. Results indicate that the best performance is achieved using inner-spiral images with high spatial resolution (1.6-2.9 mm), even though temporal resolution (four to six independent frames per second) suffers as a result. Image quality within the template region in healthy volunteers was found to be comparable to that achieved with cardiac-triggered breath-hold scans, although extended acquisition times of around 5 min were needed to overcome reduced SNR efficiency.     

Reduction of flow-related signal loss in flow-compensated 3D TOF MR angiography, using variable echo time (3D TOF-VTE).

High-resolution MRA with phase/frequency flow compensation may require very long echo times (TEs). Variable TE (VTE) was implemented into flow-compensated 3D TOF to minimize the effective TE and reduce the flow-related signal void. The k-space of the 3D TOF was divided into segment groups ranging from two to 32 segments with different TEs. The TEs were minimized and the flow-compensation gradient lobes were calculated to null the total first moment at the peak of the echo for each segment. Possible artifacts and off-resonance effects were evaluated, with respect to the number of TE segments, using the point spread function (PSF) and corresponding experiments. The optimal number of TE segments for the least artifact was determined to be one-half of the number of slices. Two types of artifacts caused by VTE were predicted and subsequently observed. The developed pulse sequence 3D TOF-VTE was tested on clinical MRI systems, by performing scans of the cervical carotid artery and intracranial carotid artery at the carotid siphon. The signal distribution near the bifurcation and the siphon was much more uniform with VTE, and the flow-related signal loss was greatly reduced. The resultant MR angiograms provided improved vessel detail. The results show that VTE improved the quality of flow-compensated 3D TOF MRA.     

Head‐locking durability of fixed and variable angle locking screws under repetitive loading

Polyaxial locking screws are increasingly applied in fracture fixation. To investigate the durability of the head‐locking mechanism, the removal torque of variable angle (VA) and fixed angle (FA) stainless steel and titanium locking screws was investigated without and after a cyclic loading test. Stainless steel (St) and titanium (Ti) 2.4 mm orthogonally inserted FA screws and 2.4 mm VA screws inserted in different inclinations (0°–15°) (n = 6 per group) were locked at 0.8 Nm. Removal torque was determined without (W) and after (A) cyclic loading (sinusoidal load, 5 Hz, constant amplitude of 25 N, up to 10′000 cycles, or failure). Significant differences in‐between the groups were detected by Student's t‐test (p < 0.05). Except VA Ti in 0deg and FA, all groups exhibited a drop in removal torque below the insertion torque without and after cyclic testing. The removal torque was (St: FA W:0.81 Nm ± 0.04 A:0.72Nm ± 0.04; VA0deg W:0.73 Nm ± 0.04 A:0.65 Nm ± 0.05; VA15deg W:0.51 Nm ± 0.05 A:0.50 Nm ± 0.08; Ti: FA W:0.82 Nm ± 0.03 A:0.70 Nm ± 0.04; VA0deg W:0.80 Nm ± 0.02 A:0.72 Nm ± 0.05; VA15deg W:0.55 Nm ± 0.03 A:0.54 Nm ± 0.06). In all groups, the removal torque after cyclic testing did not drop below 16% of the removal torque without cyclic testing. No head loosening was observed after cyclic testing. Stainless steel and titanium 2.4 mm fixed and variable angle locking screws provide a stable and lasting head‐locking mechanism. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:949–952, 2016.     

A ph mesh refinement method for optimal control

A mesh refinement method is described for solving a continuous‐time optimal control problem using collocation at Legendre–Gauss–Radau points. The method allows for changes in both the number of mesh intervals and the degree of the approximating polynomial within a mesh interval. First, a relative error estimate is derived based on the difference between the Lagrange polynomial approximation of the state and a Legendre–Gauss–Radau quadrature integration of the dynamics within a mesh interval. The derived relative error estimate is then used to decide if the degree of the approximating polynomial within a mesh should be increased or if the mesh interval should be divided into subintervals. The degree of the approximating polynomial within a mesh interval is increased if the polynomial degree estimated by the method remains below a maximum allowable degree. Otherwise, the mesh interval is divided into subintervals. The process of refining the mesh is repeated until a specified relative error tolerance is met. Three examples highlight various features of the method and show that the approach is more computationally efficient and produces significantly smaller mesh sizes for a given accuracy tolerance when compared with fixed‐order methods. Copyright © 2014 John Wiley & Sons, Ltd.     

The need for a revival of psychoanalytic investigations into premature ejaculation

Although psychoanalysis was the first-choice treatment for premature ejaculation (PE) between 1920 and 1960, hardly any reports on its efficacy have been published. Moreover, a scientific debate about its findings has never been fully developed. The recent progress that has been made in the classification of three different PE syndromes creates a new opportunity for psychoanalytic investigations of men with complaints of PE, distinguished by the actual duration of their intravaginal ejaculation latency time (IELT). The term premature-like ejaculatory dysfunction has been introduced to distinguish men with self-perceived PE at normal and long IELT durations from those men with lifelong, acquired and normal variable PE. Psychoanalytic research may contribute to a better understanding of the consequences of objective early ejaculations on the unconscious mental life of men with the four forms of PE. By integrating neurobiological, clinical and epidemiological data of ejaculatory performance, a revival of psychoanalytic research of PE in the four distinct, classified PE groups, will probably contribute to a deeper insight in to the unconscious mental life of men affected by PE.     

类风湿关节炎发病运气分析

<正>类风湿关节炎(rheumatoid arthritis,RA)是一种发病机制不明的以侵蚀性、对称性多关炎为主要临床表现的慢性、全身性自身免疫性疾病~[1]。RA归属中医"痹证"范畴。《素问·痹论》云:"风寒湿三气杂至,合而为痹也。"风湿病的发病与"乘年之虚,失时之和"有着密切的关系~[2]。年运的太过不及、司天在泉、运气同化、主客气以及客主加临等因素对风湿病的发病起着一定的影响。本文将通过回顾性病例研究