Antibody–drug conjugates (ADCs), which consist of three components, antibody, linker, and payload, can function as “magic bullets”. These conjugates offer the ability to target drug delivery to ...specific cells, based on cell‐specific recognition and the binding of an antigen by a monoclonal antibody (mAb). In particular, by delivering a cytotoxic payload to cancer cells, ADCs are expected to provide a breakthrough in oncology treatments by providing a way to increase efficacy and decrease toxicity, in comparison with traditional chemotherapeutic treatments. The development of ADC therapeutics has dramatically progressed in the past decade and two ADCs have been approved and used as anticancer drugs in the clinic. However, several critical issues regarding the performance of ADCs are still being discussed and investigated. Indeed, in the past few years, several groups have reported that, changing the number and position of the drug payloads in the ADCs, affects the pharmacokinetics, drug release rates, and biological activity. The use of conventional heterogeneous conjugation methods for ADC preparation results in the drug/antibody ratio and connecting position of the payload having stochastic distributions. Therefore, it is important to investigate how these potential problems can be circumvented through site‐specific conjugation. Herein, various site‐specific chemical conjugation strategies with native mAbs that are currently used for the production of ADCs, including residue‐selective labeling for generating ADCs, disulfide rebridging, and affinity‐peptide‐mediated site‐specific chemical conjugation technologies, are reviewed and described.
On target: Antibody–drug conjugates offer the ability to target drug delivery to specific cells. Recent progress in chemistry‐based, site‐specific modification of native antibodies, including residue‐selective labeling, disulfide rebridging, and affinity‐peptide‐mediated labeling strategies, is reviewed.
In the recent 5 years (2014–2018), there has been growing interest in the use of machine learning (ML) techniques to explore image diagnosis and prognosis of therapeutic lesion changes within the ...area of neuroradiology. However, to date, the majority of research trend and current status have not been clearly illuminated in the neuroradiology field. More than 1000 papers have been published during the past 5 years on subject classification and prediction focused on multiple brain disorders. We provide a survey of 209 papers in this field with a focus on top ten active areas of research; i.e., Alzheimer’s disease/mild cognitive impairment, brain tumor; schizophrenia, depressive disorders, Parkinson’s disease, attention-deficit hyperactivity disorder, autism spectrum disease, epilepsy, multiple sclerosis, stroke, and traumatic brain injury. Detailed information of these studies, such as ML methods, sample size, type of inputted features and reported accuracy, are summarized. This paper reviews the evidences, current limitations and status of studies using ML to assess brain disorders in neuroimaging data. The main bottleneck of this research field is still the limited sample size, which could be potentially addressed by modern data sharing models, such as ADNI.
The need for atom‐precise biomolecule modification, and particularly the irreversible formation of covalent bonds to specific amino acids in proteins, has become an essential issue in the fields of ...pharmaceuticals and chemical biology. For example, antibody–drug conjugates (ADCs) are increasingly common entries into the clinical oncology pipeline. Herein, we report a new method of affinity peptide mediated regiodivergent functionalization (AJICAP™) that enables the synthesis of ADCs from native IgG antibodies. We succeeded in introducing thiol functional groups onto three lysine residues in IgGs using Fc affinity peptide reagents without antibody engineering. A cytotoxic molecule was then connected to the newly introduced thiol group, and both a surface plasmon resonance binding assay and in vivo xenograft mouse model results showed that the resulting ADC could selectively target and kill HER2‐positive cells. Our strategy provides a new approach for constructing complex antibody‐derived biomolecules.
AJICAP™, a method for the affinity‐peptide mediated‐regiodivergent functionalization of proteins that enables the synthesis of antibody–drug conjugates (ADCs) from native IgG antibodies is reported.
Abstract
Parity-violating (PV) gravity has recently attracted interest in several aspects. One of them is the axion–graviton coupling to test the axion–dark matter model. Moreover, by extending ...Chern–Simons (CS) gravity to include derivatives of a scalar field up to the second order, a more general class of PV gravity theory, which we call the CNCL model, has been proposed M. Crisostomi et al., Phys. Rev. D, 97, 044034 (2018). The model can be further extended by including even higher derivatives of the scalar field and/or higher curvature terms.
In this paper, we discuss the effect of parity violation in the gravitational sector on the propagation of gravitational waves from binary coalescence by introducing a model-independent parametrization of modification. Our parametrization includes the CNCL model as well as CS gravity. The effect of parity violation on the gravitational waveform is maximum when the source binary orientation to our line of sight is edge-on, while the modified waveform reduces to the parity-symmetric one when the source is face-on. We perform a search for the signature of such modification by using the LIGO/Virgo O1/O2 catalog. We find that the catalog data is consistent with general relativity and obtain constraints on parity violation in gravity for various post-Newtonian order modifications for the first time. The obtained constraint on CS gravity is consistent with the results in previous works. On the other hand, the constraint on the CNCL model that we obtain is tighter than the previous results by roughly 7 orders of magnitude.
To examine the variability in the qualitative and quantitative results of computed tomographic (CT) perfusion imaging generated from identical source data of stroke patients by using commercially ...available software programs provided by various CT manufacturers.
Institutional review board approval and informed consent were obtained. CT perfusion imaging data of 10 stroke patients were postprocessed by using five commercial software packages, each of which had a different algorithm: singular-value decomposition (SVD), maximum slope (MS), inverse filter (IF), box modulation transfer function (bMTF), and by using custom-made original software with standard (sSVD) and block-circulant (bSVD) SVD methods. Areas showing abnormalities in cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) were compared with each other and with the final infarct areas. Differences among the ratios of quantitative values in the final infarct areas and those in the unaffected side were also examined.
The areas with CBF or MTT abnormalities and the ratios of these values significantly varied among software, while those of CBV were stable. The areas with CBF or MTT abnormalities analyzed by using SVD or bMTF corresponded to those obtained with delay-sensitive sSVD, but overestimated the final infarct area. The values obtained from software by using MS or IF corresponded well with those obtained from the delay-insensitive bSVD and the final infarct area. Given the similarities between CBF and MTT, all software were separated in two groups (ie, sSVD and bSVD). The ratios of CBF or MTTs correlated well within both groups, but not across them.
CT perfusion imaging maps were significantly different among commercial software even when using identical source data, presumably because of differences in tracer-delay sensitivity.
Continuing work initiated in an earlier publication H. Asada, Phys. Rev. D 80, 064021 (2009), the gravitational radiation reaction to Lagrange's equilateral triangular solution of the three-body ...problem is investigated in an analytic method. The previous work is based on the energy balance argument, which is sufficient for a two-body system because the number of degrees of freedom (the semimajor axis and the eccentricity in quasi-Keplerian cases, for instance) equals that of the constants of motion such as the total energy and the orbital angular momentum. In a system with three (or more) bodies, however, the number of degrees of freedom is more than that of the constants of motion. Therefore, the present paper discusses the evolution of the triangular system by directly treating the gravitational radiation reaction force to each body. The perturbed equations of motion are solved by using the Laplace transform technique. It is found that the triangular configuration is adiabatically shrinking and is kept in equilibrium by increasing the orbital frequency due to the radiation reaction if the mass ratios satisfy the Newtonian stability condition. Long-term stability involving the first post-Newtonian corrections is also discussed.
Abstract
Although favourable surgical outcomes for myelopathy caused by cervical ossification of the posterior longitudinal ligament (OPLL) have been reported, factors significantly associated with ...post-operative neck pain attenuation still remain unclear. The primary aim of the present study was to determine factors significantly associated with post-operative neck pain attenuation in patients with cervical OPLL using a prospective multi-centre registry of surgically treated cervical OPLL. Significant postoperative neck pain reduction (50% reduction of neck pain) was achieved in 31.3% of patients. There was no significant difference in neck pain attenuation between surgical procedures. Statistical analyses with univariate analyses followed by stepwise logistic regression revealed neurological recovery as a factor having a significant positive association with post-operative neck pain attenuation (
p
= 0.04, odds ratio 5.68 (95% confidence interval: 1.27–22.2)). In conclusion, neurological recovery was an independent factor having a significant positive association with post-operative neck pain attenuation in patients with cervical myelopathy caused by OPLL who underwent cervical spine surgery.
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