OncoTherapy Science (Japan)

To select the most suitable chelate for 225 Ac radiolabeling of the anti-FZD10 antibody OTSA101, we directly compared three chelates: S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2,2',2″-(10-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (p-SCN-Bn-DOTAGA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DO3A-NHS-ester). We evaluated the binding affinity of the chelate-conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225 Ac-labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate-conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO-1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA-OTSA101 and DO3A-OTSA101 were 1.8-fold higher than that of DOTA-OTSA101 (p < 0.01). The stabilities were similar between 225 Ac-labeled DOTA-OTSA101, DOTAGA-OTSA101, and DO3A-OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor-absorbed doses by 225 Ac-labeled DOTA-OTSA101 and DOTAGA-OTSA101 compared with 225 Ac-DO3A-OTSA101 (p < 0.05). 225 Ac-DOTAGA-OTSA101 exhibited the highest tumor-to-bone marrow ratio, with bone marrow being the dose-limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225 Ac-labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Stromal alterations are observed following preoperative systemic therapy in breast cancer. The aim of the present study was to analyze the qualitative and quantitative changes of representative tumor stroma proteins in the context of neoadjuvant therapy and the response of patients undergoing preoperative systemic therapy.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Fifty women receiving preoperative systemic therapy were evaluated for clinical and pathologic parameters. Clinical response was defined according to International Union against Cancer (UICC) criteria, whereas pathologic responses to preoperative systemic therapy were defined according to the Chevallier and Sataloff classifications. The expression of tenascin-C, syndecan-1, collagen IV, and smooth muscle actin proteins was investigated using morphometric analysis of immunohistochemical reactions. Quantitative reverse transcription-PCR was done to evaluate the mRNA expression level of syndecan-1 and tenascin-C. The data were compared with 20 breast cancer samples of patients not treated with preoperative systemic therapy.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; According to UICC criteria, the expression levels of collagen IV were up-regulated in all preoperative systemic therapy–treated patients (&lt;i&gt;P&lt;/i&gt; = 0.002). Collagen IV was up-regulated in the preoperative systemic therapy group in both Chevallier and Sataloff classifications compared with the control cases (&lt;i&gt;P&lt;/i&gt; = 0.025 and &lt;i&gt;P&lt;/i&gt; = 001, respectively). There were no significant differences in the expression of smooth muscle actin between the treated and nontreated groups. The syndecan-1 proteoglycan level was significantly down-regulated in the preoperative systemic therapy group (Chevallier classes &lt;i&gt;P&lt;/i&gt; = 0.015, Sataloff classes &lt;i&gt;P&lt;/i&gt; = 0.015). Tenascin-C was up-regulated in women with progressive disease (&lt;i&gt;P&lt;/i&gt; = 0.005).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusion:&lt;/b&gt; We have observed that the stromal component of breast carcinomas following preoperative systemic therapy differs from the nontreated tumors, which can be evaluated with the analysis of the above mentioned proteins.&lt;/p&gt;&lt;/div&gt;

As the prognosis of biliary tract cancer (BTC) is extremely poor and treatment options are limited, new treatment modalities are urgently needed. We designed a phase II clinical trial to investigate the immune responses and clinical benefits of OCV-C01, an HLA-A*24:02-restricted three-peptide cancer vaccine targeting VEGFR1, VEGFR2, and KIF20A. Participants were patients with advanced BTC who had unresectable tumours and were refractory to standard chemotherapy. OCV-C01 was injected weekly until the discontinuance criteria were met. Six participants, including four patients positive for HLA-A*24:02, were enrolled in this study for assessment of efficacy. Four out of six patients exhibited vaccine-specific T-cell responses to one or more of three antigens. Log-rank tests revealed that vaccine-specific T cell responses contributed significantly to overall survival. The cancer vaccine had positive effects on survival, indicating that this approach warrants further clinical studies.

The effect of posttreatment of photoelectrochemical etched GaN trench structures was examined. A $5.8- \mu\mathrm{m}$ -thick n-type GaN epitaxial layer with a nominal Si concentration of $1.5\times {10}^{16}\mathrm{cm}^{-3}$ , grown on an n-GaN substrate, was etched by photoelectrochemical reaction through a Ti etching mask. A 25 wt% aqueous solution of tetramethylammonium hydroxide (TMAH) was used for posttreatment at 85 °C for 30 minutes. A cross-section of the TMAH-treated GaN trenches showed fine vertical sidewalls along the $m$ -axis. These results suggest that TMAH posttreatment is useful for realizing GaN vertical trench structures.

221 Background: The impact of the distance from the root of the splenic artery to the tumor (DST) on prognosis and selection of operative procedures in patients with pancreatic body/tail cancer remains to be unclear. Methods: Between 2008 and 2018, 98 and 17 patients who underwent distal pancreatectomy (DP) and DP with celiac axis resection (DP-CAR) for conventional pancreatic ductal carcinoma were retrospectively analyzed. DST (mm) was measured by preoperative CT scan images. The indications for DP-CAR are the following: tumor involvement of the common hepatic artery and/or the celiac artery or difficulty in keeping surgical margin at the stump of the splenic artery. Results: Patients with DST = 0 had longer operation time ( p = 0.005), greater amount of blood loss ( p= 0.002), and higher morbidity rate ( p= 0.010) than those with DST &gt; 0. The rate of introducing adjuvant chemotherapy in the DST = 0 group was significantly lower than that in the DST &gt; 0 group (50% vs. 82%, p= 0.012). The median survival time (MST) of the DST = 0 group was significantly worse than that of the DST &gt; 0 group (20 vs. 56 months, p&lt; 0.001). In contrast, there was no significant difference of MST between the groups of 0 &lt; DST≤10 and DST &gt; 10 ( p= 0.499). Multivariate analyses revealed that DST = 0 (HR 4.51, p= 0.001), preoperative CA19-9 ≥40 U/mL (HR 2.91, p= 0.032) and preoperative neutrophil-to-lymphocyte ratio ≥2.3 (HR 2.49, p= 0.001) were independent prognostic factors. Regarding to the operative procedures, DP-CAR was performed 12 out of 14 patients with DST = 0, and 5 out of 16 patients with 0 &lt; DST≤10. In the DST = 0 group, DP-CAR presented greater amount of dissected lymph nodes, higher rate of R0 resection, and lower rate of recurrence despite they were not identified statistically significant. In the 0 &lt; DST≤10 group, DP-CAR tended to need longer operative time and higher rate of blood transfusion compared to DP, while there was no difference of prognosis. Conclusions: Multidisciplinary treatment including DP-CAR should be warranted for patients with DST = 0, which was a prognostic indicator. If surgical margin at the root of the splenic artery is secured in patients with DST &gt; 0, DP should be an acceptable procedure.

This paper presents electroluminescence intensity mapping on a p–n junction plane of vertical GaN diodes under forward‐biased conditions for the first time. By this mapping, it has been discovered that current crowding existed, corresponding to the naturally formed surface stripes on epitaxial layers grown on freestanding GaN substrates. Detailed analyses by AFM and TOF‐SIMS clarified that the concentration of doped Mg acceptors on one slope of the stripe was higher than that on the other slope. The higher Mg‐concentration region should have lower electric resistance, which would cause the current crowding. By improving the surface flatness, the current crowding was suppressed and a low specific on‐resistance was obtained.

In this study, we demonstrated a very large freestanding GaN crystal with a diameter of 175 mm developed by the “tiling technique”. The technique merges small multiple seed wafers with a thick GaN layer grown by hydride vapor phase epitaxy. To the best of our knowledge, it is the largest GaN crystal ever reported. Its orientation deviation could be the same as those of applied individual seeds by using the starting substrate, which was prepared by binding all the seeds on a base plate with a high temperature adhesive. Scrupulous attention was required to select the materials. Furthermore, we were able to grow GaN with hydride vapor phase epitaxy on a high‐quality GaN substrate, which was prepared by an Na‐flux method, with no crystal deteriorations. Through the fusion of the above results, the ideal GaN substrates can be realized.Example of a freestanding GaN crystal with a diameter of 175 mm developed by the “tiling technique”.

While multiple post-translational modifications have been reported to regulate the function of epidermal growth factor receptor (EGFR), the effect of protein methylation on its function has not been well characterized. In this study, we show that WHSC1L1 mono-methylates lysine 721 in the tyrosine kinase domain of EGFR, and that this methylation leads to enhanced activation of its downstream ERK cascade without EGF stimulation. We also show that EGFR K721 mono-methylation not only affects the function of cytoplasmic EGFR, but also that of nuclear EGFR. WHSC1L1-mediated methylation of EGFR in the nucleus enhanced its interaction with PCNA in squamous cell carcinoma of the head and neck (SCCHN) cells and resulted in enhanced DNA synthesis and cell cycle progression. Overall, our study demonstrates the multifaceted oncogenic function of the protein lysine methyltransferase WHSC1L1 in SCCHN, which is mediated through direct non-histone methylation of the EGFR protein with effects both in its cytoplasmic and nuclear functions.