Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology

A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Time-related change evaluation of the cerebrospinal fluid using postmortem CT

Purpose: We retrospectively evaluated the cerebro-spinal fluid (CSF) CT density at the lateral ventricle to compare the postmortem intervals in cadavers. Materials and methods: The number of cadavers enrolled in this study was 189 (male 120, female 69). According to the estimated postmortem time, the cadavers were divided into 13 groups (postmortem day 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 7, 10, 14, 21, 30), and were also re-grouped into 3 groups according to the postmortem time-width: group A (postmortem day 0.5-2.5), group B (day 3-7), and group C (day 10-30). Comparisons between the CSF density and estimated postmortem time were also analyzed. Results: The CSF density was around 20 HU up to day 2.5, and it increased gradually after day 3. Day 3 and 4 presented higher CSF density than day 1 and 1.5 (p < 0.05). Day 7 presented higher CSF density than day 3 (p < 0.05). According to the postmortem time-width, the CSF density increased with postmortem time (p < 0.05). The simple linear regression equations presented negative correlation between CSF density and estimated postmortem time, and R2 was 0.119. Conclusion: The CSF density increased, but not linearly, according to the postmortem time, and the 3rd postmortem day was the earliest time allowing the difference to be detected. The CSF density needs further evaluation to enable estimation of the postmortem time

Unmanned Aerial Vehicle-Based Techniques for Monitoring and Prevention of Invasive Apple Snails (<i>Pomacea canaliculata</i>) in Rice Paddy Fields

The destructive impact of invasive apple snail (Pomacea canaliculata) on young rice seedlings has garnered global attention, particularly in warm regions where rice production occurs. The preventative application of insecticide, particularly in areas with young rice seedlings and water depths exceeding 4 cm, has proven effective in mitigating this damage. In line with this recommendation, our study investigates the efficacy of site-specific drone-based insecticide applications to mitigate snail damage in rice paddies. These site-specific drone applications were strategically executed as directed by a highly accurate prescription map indicating the required insecticide quantity at specific locations. The prescription map was automatically generated through an advanced data processing program that used the aerial images acquired by a Real-Time Kinematic (RTK)-Unmanned Aerial Vehicle (UAV) as the input. Criteria were established to select the treatment locations; a value of below 4 cm from the top 95% percentile in the histogram of ground elevation data was used as a threshold to identify areas with a high-density of snail damage. The results demonstrated reductions in both the rates of rice damage and chemical usage following site-specific drone applications compared with the control fields. The findings in this study contribute to the advancement of effective site-specific pest control in precision agriculture

Design and Synthesis of Far‐Red to Near‐Infrared Chromophores with Pyrazine‐Based Boron Complexes

We synthesized new binuclear boron complexes based on pyrazine with ortho and para substitution patterns. It was demonstrated that the para-linked complexes possess a significantly narrow energy gap between highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), leading to their far-red to near-infrared emission properties. Meanwhile, the ortho-substituted complex showed orange emission. Considering the HOMO and LUMO distributions of pyrazine, the boron complexation to the nitrogen atoms would stabilize its LUMO more efficiently than its HOMO because a nodal plane in the HOMO passes through the two nitrogen atoms. The theoretical study suggests that the para-substitution would not significantly perturb such a characteristic HOMO distribution originating from pyrazine in stark contrast to the ortho-substituted one. As a result, the HOMO-LUMO gap of the para-linked complex is dramatically narrower than that of the ortho-linked one

Stature estimation from anatomical landmarks in femur using postmortem CT

Objective: The present study aims to assess the correlation between stature and partial femur measurements in Japanese population, using three-dimensional (3D) computed tomographic (CT) images. Method: A total of 195 cadavers (105 males, 90 females) underwent postmortem CT scanning and subsequent forensic autopsy between April 2013 and June 2014. Five femur length measurements were taken from 3D CT volume rendering (VR) images according to three anatomical landmarks: the greater trochanter, the lesser trochanter, and the adductor tubercle. The correlations between stature and each of the femur length measurements were assessed with Spearman's rank correlation test, and showed significant correlations between stature and femur length measurements. Results: Using a mixed-sex regression formula, the R2 was from 0.644 to 0.766 and actual difference was less than 4.6 cm. Conclusion: Present study showed that femur length measurements, according to the anatomical landmarks obtained from 3DCT VR images, were useful for estimation of the stature, particularly in cases when a total femur bone was not available