Anti-HER2/CD3, a T-cell-dependent bispecific antibody (TDB) construct, induces T-cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, ...thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. Although therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen-binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T-cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution, and noninvasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3ε expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short-term pharmacokinetics, tissue distribution, and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors, and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T-cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T-cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy.
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Diabetes related distress (DRD) is usual for patients with type 2 diabetes (T2D), which worsens glycemic control through negative effects on well-being and self-care behaviors. Diabetes Distress ...Scale (DDS) is a globally-used instrument to measure DRD. The aim of this study was to validate the Japanese version of the DDS (DDS-J) and to identify the characteristics of individuals at high risk for DRD.
DDS-J was developed conceptually equivalent to the original version through an appropriate process. A cross-sectional study was conducted in 206 T2D patients (mean age 64.1 years, 62.1% male, mean duration 13.2 years, mean HbA1c 7.6%) at outpatient department of 2 hospitals in Aichi, Japan from February to May 2018. Cronbach's α and test-retest method were used to assess reliability, and factor analysis to analyze validity. The 5-item WHO Well-Being Index (WHO-5) and Patient Health Questionnaire-9 (PHQ-9) scale were adopted to evaluate the criteria-related validity.
Four factors of regimen-related distress (RD), emotional burden (EB), physician-related distress (PD), and interpersonal distress (ID) were extracted by factor analysis. This factor structure was the same as the original. The overall Cronbach's α was 0.92, while ones for RD, EB, PD, and ID were 0.86, 0.89, 0.75 and 0.82, respectively. Test-retest correlation score was 0.63. The DDS-J score showed a moderate and significant correlation with WHO-5 (r=-0.43, p<0.01) and PHQ-9 (r=0.49, p<0.01). To analyze the variables associated with the DDS-J score, a multiple regression analysis was performed with age, BMI, gender, HbA1c, and injection use as independent variables. HbA1c (slope 3.62, p<0.01) and age (slope -0.28, p<0.01) remained significantly associated with DDS-J score with an R2 of 0.22.
DDS-J showed good validity and reliability, and can be used as an effective tool to assess DRD of Japanese adult T2D patients. Those with higher HbA1c and younger age should be paid attention in terms of DRD.
Disclosure
N. Takami: None. K. Okazaki: Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Abbott, Mitsubishi Tanabe Pharma Corporation, Sanofi. N. Takahashi: None. M. Suematsu: None. W. Ohashi: None.
The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. As mutation of
in ...HNSCC occurs in 60% to 80% of non-HPV-associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations.
Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the
and
sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA sequencing, and apoptosis analyses were performed to dissect molecular mechanisms.
We found that vorinostat synergizes with AZD1775
to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated HR through activation of CDK1, and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis
in an orthotopic mouse model of oral cancer and prolongs animal survival.
Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53
and
A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC.
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Magnetite (Fe3O4) nanoparticles were successfully synthesized by ascorbic acid mediated reduction of Fe (acac)3, without using any intentionally added capping agent. Fine tuning of synthesis ...parameters such as dropping rate of ascorbic acid solution, addition temperature, reflux temperature and time, and concentration of reactants have yielded nanoparticles of size 15±4 nm. Synthesis is observed to be highly reproducible. Possible mechanism for growth of Fe3O4 nanoparticles is suggested. Nanoparticles are characterized for their size, crystallinity and crystal structure, elemental analysis for impurities (if any), and presence of any additional oxide phases – by SEM and TEM, XRD, EDAX and XPS spectroscopy, respectively.
Synthesis of Fe3O4 nanoparticles was carried out by ascorbic acid mediated reduction of Fe(acac)3. In order to achieve control over size, synthesis was carried out at different synthesis conditions. ...Small (8 nm, 9 nm and 15 nm), medium (22 nm, 29 nm, 33 nm and 42 nm) and large (76 nm, 108 nm) sized Fe3O4 nanoparticles have been synthesized by varying and controlling the experimental conditions. Mechanism for the formation of Fe3O4 nanoparticles is proposed. Our method is observed to yield reproducible results, confirmed by doing the repeated synthesis several times.
Synthesis of Fe3O4 nanoparticles was carried out by ascorbic acid mediated reduction of Fe(acac)3. In order to achieve control over size, synthesis was carried out at different synthesis conditions. ...Small (8 nm, 9 nm and 15 nm), medium (22 nm, 29 nm, 33 nm and 42 nm) and large (76 nm, 108 nm) sized Fe3O4 nanoparticles have been synthesized by varying and controlling the experimental conditions. Mechanism for the formation of Fe3O4 nanoparticles is proposed. Our method is observed to yield reproducible results, confirmed by doing the repeated synthesis several times.
Novel method to synthesize graphene-Fe3O4 nanocomposite is disclosed. Graphene functionalized with carboxylic group was added during the chemical synthesis of Fe3O4 nanoparticles by reduction of ...Fe(acac)3 using ascorbic acid to get graphene-Fe3O4 nanocomposite, wherein the monodisperse spherical nanoparticles of Fe3O4 of 10 nm diameter remains attached to graphene surface. Physico-chemical characterization of the synthesized nanocomposite is done using scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, Raman and Fourier Transform Infra-red spectroscopy in order to understand different physico-chemical parameters and properties of the synthesized material.
A large silicon chip or interposer is mounted onto a large package substrate using flip-chip for high performance computing (HPC) such as artificial intelligence (AI) and fifth generation mobile ...communication systems (5G). Not only the flip-chip joint of the large silicon onto the large substrate but also the ball grid array (BGA) joint of the large package onto the motherboard is important to design board level systems. In fabricating BGA joints, a solder bridge or a non-wet may occur when the warpage of the package is too large. To keep excellent board level reliability (BLR) in temperature cycling (TC) test, reducing stress in BGA joint is important. Therefore, it is a crucial problem to optimize the coefficient of thermal expansion (CTE) of the package substrate between the CTE of silicon and the motherboard. An alternative option would be reducing the stress in BGA by decreasing Young's modulus of the package substrate. Based on the idea, four core materials made of glass fiber reinforced plastic (GFRP) with different CTE and Young's modulus, which are (A) conventional resin with E-glass cloth, (B) conventional resin with S-glass cloth, (C) low CTE and high modulus resin with S-glass cloth, and (D) low CTE and low modulus resin with S-glass cloth, were evaluated. A test vehicle with 50-mm-square silicon chip, 100-mm-square package substrate, and 160-mm-square motherboard was designed. The pitch of the flip-chip joint is 0.2 mm and that of the BGA is 1.0 mm. The dimension for the copper stiffener was set at 2.5-mm-thick and 16-mm-width and for the adhesive was set at 0.15-mm-thick to minimize the package warpage. As the result, for the package using the core material (D), the 0.43-mm-warpage at room temperature after flip-chip joint was about two third of the core material (B) and it was reduced to 0.25-mm-warpage by attaching the stiffener. Then, the package was assembled onto the motherboard using a 0.6-mm-diameter solder ball and surface mount technology (SMT) process. Finally, TC test was performed to demonstrate the design concept of the core material (D), which are low CTE and low Young's modulus. The lifetime of the BLR for the package made of core material (D) is almost the same as that of core material (B).
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