On Demand Bioorthogonal Switching of an Antibody-Conjugated SPECT Probe to a Cytotoxic Payload: from Imaging to Therapy.

Antibody-drug conjugates (ADCs) for the treatment of cancer aim to achieve selective delivery of a cytotoxic payload to tumor cells while sparing normal tissue. In vivo, multiple tumor-dependent and -independent processes act on ADCs and their released payloads to impact tumor-versus-normal delivery, often resulting in a poor therapeutic window. An ADC with a labeled payload would make synchronous correlations between distribution and tissue-specific pharmacological effects possible, empowering preclinical and clinical efforts to improve tumor-selective delivery; however, few methods to label small molecules without destroying their pharmacological activity exist.

Underwater biomimetic orientation method using imaging polarization sensor based on direct sunlight compensation.

This paper addresses the challenge of significant interference caused by direct sunlight, which adversely affects the orientation accuracy of underwater imaging polarization sensors (IPS). A novel underwater polarization orientation method is proposed based on direct sunlight compensation. Firstly, based on the polarization transmission model at the water-air interface, the interference mechanism of the underwater direct sunlight polarization detection model was analyzed.

An Improved Bio-Orientation Method Based on Direct Sunlight Compensation for Imaging Polarization Sensor.

Direct sunlight in complex environmental conditions severely interferes with the light intensity response for imaging Polarization Sensor (PS), leading to a reduction in polarization orientation accuracy. Addressing this issue, this article analyzes the impact mechanism of direct sunlight on polarization sensor detection in a complex environment. The direct sunlight interference factor is introduced into the intensity response model of imaging polarization detection, enhancing the accuracy of the polarization detection model.

Attitude and heading measurement based on adaptive complementary Kalman filter for PS/MIMU integrated system.

The bionic polarization sensor (PS)/MEMS inertial measurement unit (MIMU) integrated system can provide reliable attitude and heading information for unmanned vehicles in the case of GNSS rejection. However, the existing measurement methods have poor adaptability to inclining, sheltering, and other harsh environments, and do not make full use of the complementary characteristics of the gyroscopes, accelerometers, and PS, which seriously affects the system performance. Therefore, this paper proposes an attitude and heading measurement method based on an adaptive complementary Kalman filter (ACKF), which corrects the gyroscopes according to the gravity measured by the accelerometers to improve the attitude accuracy and fuses the IMU heading and tilt-compensated polarization heading by Kalman optimal estimation.

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results.

Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA.

Analysis of sleep for the American population: Result from NHANES database.

Objectives: To assess the contemporary prevalence and decade-long trends of sleep duration, sleep disorders and trouble sleeping among adults in the United States, as well as their risk factors, from 2005 to 2018.

Materials And Methods: We used National Health and Nutrition Examination Survey data to calculate the sleep duration and weighted prevalence of sleep disorders and trouble sleeping in adults aged 20 years or older. Sleep duration, sleep disorders and trouble sleeping were assessed by questionnaire.

A high-sensitivity fiber Bragg grating sensor for displacement measurement in structural health monitoring.

Displacement measurement is of great significance to monitor the crack variation and ensure the health of building structures. Aiming at the problems of low sensitivity and high temperature error of fiber Bragg grating (FBG) displacement sensors in displacement monitoring, this paper presents an adjustable cantilever beam displacement sensor with the FBGs as the sensing element. The sensor adds double FBGs on the relative surfaces of the equal-strength cantilever beam, which increases the bending deformation on the FBG of the beam surface to improve the sensitivity and realize the temperature compensation of the sensor.

High-Accuracy Relative Pose Measurement of Noncooperative Objects Based on Double-Constrained Intersurface Mutual Projections.

Relative pose measurement for noncooperative objects is an important part of 3D shape recognition and motion tracking. The methods based on scanning point clouds have better environmental adaptability and stability than image-based methods. However, the discrete points obtained from a continuous surface are sparse, which leads to point-to-point dislocations in the overlapping area and seriously reduces the accuracy.

Chiral FA Conjugated CdTe/CdS Quantum Dots for Selective Cancer Ablation.

Inducing apoptosis in cancer cells is considered a potential therapeutic mechanism underlying cancers. Here, chiral folic acid (FA) conjugated Cys-CdTe/CdS quantum dots (QDs) conjugated with a cancer-targeting ligand were fabricated to induce apoptosis in vivo. Ligand-induced chirality mechanism for FA-Cys-CdTe/CdS QDs was discussed, which is verified by density functional theory (DFT) simulation.

A homogeneous high-DAR antibody-drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides.

The antibody-drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their originally-intended purpose of treating cancer. However, antibody-mediated delivery (AMD) remains inefficient, limiting its applicability to targeting highly potent payloads to cells with high antigen expression. Maximizing the number of payloads delivered per antibody is one key way in which delivery efficiency can be improved, although this has been challenging to carry out; with few exceptions, increasing the drug-to-antibody ratio (DAR) above ∼4 typically destroys the biophysical properties and efficacy for ADCs.

Identification and elimination of cancer cells by folate-conjugated CdTe/CdS Quantum Dots Chiral Nano-Sensors.

The specific identification and elimination of cancer cells has been a great challenge in the past few decades. In this study, the circular dichroism (CD) of cells was measured by a self-designed special system through the folate-conjugated chiral nano-sensor. A novel method was established to recognize cancer cells from normal cells according to the chirality of cells based on their CD signals.

Systematic Variation of Pyrrolobenzodiazepine (PBD)-Dimer Payload Physicochemical Properties Impacts Efficacy and Tolerability of the Corresponding Antibody-Drug Conjugates.

Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody-drug conjugates (ADCs), and many examples are currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines.

Fluorescence and Optical Activity of Chiral CdTe Quantum Dots in Their Interaction with Amino Acids.

Ligand-induced chirality in semiconducting nanocrystals has been the subject of extensive study in the past few years and shows potential applications in optics and biology. Yet, the origin of the chiroptical effect in semiconductor nanoparticles is still not fully understood. Here, we examine the effect of the interaction with amino acids on both the fluorescence and the optical activity of chiral semiconductor quantum dots (QDs).

Development, Optimization, and Structural Characterization of an Efficient Peptide-Based Photoaffinity Cross-Linking Reaction for Generation of Homogeneous Conjugates from Wild-Type Antibodies.

Site-specific conjugation of small molecules to antibodies represents an attractive goal for the development of more homogeneous targeted therapies and diagnostics. Most site-specific conjugation strategies require modification or removal of antibody glycans or interchain disulfide bonds or engineering of an antibody mutant that bears a reactive handle. While such methods are effective, they complicate the process of preparing antibody conjugates and can negatively impact biological activity.

Exploration of Pyrrolobenzodiazepine (PBD)-Dimers Containing Disulfide-Based Prodrugs as Payloads for Antibody-Drug Conjugates.

A number of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing various disulfide-based prodrugs were evaluated for their ability to undergo activation (disulfide cleavage) in vitro in the presence of either glutathione (GSH) or cysteine (Cys). A good correlation was observed between in vitro GSH stability and in vitro cytotoxicity toward tumor cell lines. The prodrug-containing compounds were typically more potent against cells with relatively high intracellular GSH levels (e.

Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells.

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane.

Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity.

Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells.

Attachment Site Cysteine Thiol pK Is a Key Driver for Site-Dependent Stability of THIOMAB Antibody-Drug Conjugates.

The incorporation of cysteines into antibodies by mutagenesis allows for the direct conjugation of small molecules to specific sites on the antibody via disulfide bonds. The stability of the disulfide bond linkage between the small molecule and the antibody is highly dependent on the location of the engineered cysteine in either the heavy chain (HC) or the light chain (LC) of the antibody. Here, we explore the basis for this site-dependent stability.

Development of Efficient Chemistry to Generate Site-Specific Disulfide-Linked Protein- and Peptide-Payload Conjugates: Application to THIOMAB Antibody-Drug Conjugates.

Conjugation of small molecule payloads to cysteine residues on proteins via a disulfide bond represents an attractive strategy to generate redox-sensitive bioconjugates, which have value as potential diagnostic reagents or therapeutics. Advancement of such "direct-disulfide" bioconjugates to the clinic necessitates chemical methods to form disulfide connections efficiently, without byproducts. The disulfide connection must also be resistant to premature cleavage by thiols prior to arrival at the targeted tissue.

JS-K, a nitric oxide prodrug, induces DNA damage and apoptosis in HBV-positive hepatocellular carcinoma HepG2.2.15 cell.

Hepatocellular carcinoma (HCC) is the most important cause of cancer-related death, and 85% of HCC is caused by chronic HBV infection, the prognosis of patients and the reduction of HBV DNA levels remain unsatisfactory. JS-K, a nitric oxide-releasing diazeniumdiolates, is effective against various tumors, but little is known on its effects on HBV positive HCC. We found that JS-K reduced the expression of HBsAg and HBeAg in HBV-positive HepG2.

[Clinical features of mild encephalitis/encephalopathy with a reversible splenial lesion in children].

Objective: To investigate the clinical features of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) in children.

Methods: The clinical data of 8 children with MERS were retrospectively analyzed.

Results: The mean age of onset was 5 years and 2 months (range 10 months to 12 years).

The cryptophycins as potent payloads for antibody drug conjugates.

The cryptophycins are a potent class of cytotoxic agents that were evaluated as antibody drug conjugate (ADC) payloads. Free cryptophycin analog 1 displayed cell activity an order of magnitude more potent than approved ADC payloads MMAE and DM1. This potency increase was also reflected in the activity of the cryptophycin ADCs, attached via a either cleavable or non-cleavable linker.

Buckwheat Rutin Inhibits AngII-induced Cardiomyocyte Hypertrophy via Blockade of CaN-dependent Signal Pathway.

Buckwheat rutin has been found to be able to inhibit angiotensin II (AngII) - induced hypertrophy in cultured neonatal rat cardiomyocytes, but the mechanism remains uncertain. In this study, myocardial hypertrophy model was made by adding AngII to the medium of cardiac myocytes of neonatal rats; meanwhile, different concentrations of buckwheat rutin were applied to observe their effects. Intracellular Ca(2+) level was detected by Hitachi - 850 fluorospectrophotometer, calcineurin (CaN) activity was measured by colorimetric method, the expression of CaN protein was observed with immunocytochemistry, and the proto - oncogene c - fos mRNA expression was assessed with reverse transcription polymerase chain reaction (RT - PCR).

Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells.

Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations.