Predictive factors of acute skin reactions to carbon ion radiotherapy for the treatment of malignant bone and soft tissue tumors

学位記番号：医博甲166

A Unique Student Cohort’s Perceptions and Preferences about Gross Anatomy Education in the Medical Curriculum: JABSOM Student Survey 2020

Introduction: The SARS-CoV-2 (COVID) pandemic made it necessary for medical schools to integrate online learning into the delivery of curriculum involving cadaveric-based gross anatomy instruction and dissection, which may benefit post-COVID instruction. Objectives: The purpose of this study was to assess the perceptions of a unique student cohort arising from the COVID pandemic with respect to gross anatomy instruction. The hypothesis tested was that the medical student class of 2023’s perceptions concerning the delivery of gross anatomy education, as well as its educational significance, would differ between students that elected to dissect (D) compared with those who did not (N). Methods: A survey was conducted at the conclusion of the 2020 medical gross anatomy course at JABSOM, and 79 medical students responded to questions about the usefulness of anatomy, preference of lectures (slide decks without lectures, in-person lectures, live online lectures, and pre-recorded lectures) and dissection laboratories (no lab, live online labs, class in-person labs, and hybrid labs). The preference levels were assessed by Likert scale (highest, high, low, lowest), from which binary scale results (high or low) were also analyzed. Fisher’s exact tests were used to examine differences in survey responses between D (n=40) and N students (n=39). Open-ended questions were used to probe these perceptions. Results: D students rated gross anatomy’s usefulness more positively than N students (overall 87%; D 100%, N 74%, p<.001). More N students considered that anatomy dissection should be elective (overall 68%; D 38%, N 100%, p<.001). Overall, the students’ preference levels were high for live online lectures and pre-recorded lectures, and low for slide decks without lectures and in-person lectures. Pre-recorded lecture was rated the most valued, notably by D students (overall 80%; D 90%, N 68%, p=0.03), while slide decks without lecture was rated the lowest lecture-based modality (overall 80%; D 90%, N 68%, p=0.03). More than 90% of responses to open questions about the usefulness of pre-recorded lectures were positive. Hybrid lab was the most preferred laboratory type (high preference levels: overall 82%; D 72%, N 79%, p=0.02). No lab was least preferred and more disfavored by D students (overall 79%; D 90%, N 67%, p=0.01). Through open questions, most D students responded positively (95%) and had no regrets dissecting (86%). Discussion: Most students found dissection to be a useful educational activity. The benefits for students who elected to dissect included more opportunities to ask questions to instructors, better visibility of structures, and flexibility with dissection time. Students who did not elect to dissect felt safe during a pandemic, spent more time with loved ones, and had less financial burden commuting to school. The results show a strong contrast in that in-person lectures and slide decks without lectures were not preferred compared to live online lectures and pre-recorded lectures. Students expressed that watching lectures at their convenience benefited anatomy comprehension since more time was available to prepare rather than pursuing dissection immediately after a lecture traditionally. Among the methods for laboratory instruction experienced, the only significant preference was that no lab was the least preferred by the overall class. Although D was more extreme in opinion, N showed a similar trend with a large majority opting against no lab. A small minority of N did express regret not being to dissect during the unit, whether for academic or camaraderie-building benefit. Future work will be directed at assessing student perceptions concerning use of online technology as supplemental instruction for gross anatomy

MRマイクロイメージングとガドリニウム-デンドロン修飾ナノリポソーム造影剤を用いた3D微小血管およびナノ粒子分布の腫瘍内評価

The enhanced permeability and retention (EPR) effect is variable depending on nanoparticle properties and tumor/vessel conditions. Thus, intratumoral evaluations of the vasculature and nanoparticle distribution are important for predicting the therapeutic efficacy and the intractability of tumors. We aimed to develop a tumor vasculature evaluation method and high-resolution nanoparticle delivery imaging using magnetic resonance (MR) micro-imaging technology with a gadolinium (Gd)-dendron assembled liposomal contrast agent. Using the Gd-liposome and a cryogenic receiving coil, we achieved 50-μm isotropic MR angiography with clear visualization of tumor micro-vessel structure. The Gd-liposome-enhanced MR micro-imaging revealed differences in the vascular structures between Colon26- and SU-DHL6-grafted mice models. The vessel volumes and diameters measured for both tumors were significantly correlated with histological observations. The MR micro-imaging methods facilitate the evaluation of intratumoral vascularization patterns, the quantitative assessment of vascular-properties that alter tumor malignancy, particle retentivity, and the effects of treatment

Awake brain MRSI reveals anesthetic sensitivity and regional aging effects on [13C]bicarbonate metabolism in mice

Abnormalities and alterations in the glycolytic pathway in the pathology of neurodegenerative diseases and brain aging have received much attention, as clinical applications of proton-based magnetic resonance spectroscopy (MRS) have recently illuminated the elevation of lactate concentrations in the brains of patients with neurodegenerative diseases, including Alzheimer’s disease. Hyperpolarized [1-13C]pyruvate MRS has shown promise for neurological applications because it enables the real-time in vivo detection of glycolysis and oxidative phosphorylation flux. In studies of the mouse brain using hyperpolarized [1-13C]pyruvate, there are few reports that the signal of [13C]bicarbonate, a product of oxidative phosphorylation metabolized from [1-13C]pyruvate, was detected using MR spectroscopic imaging (MRSI) that allows spatial mapping of metabolism, although there have been reports of [13C]bicarbonate signals being detected by pulse-acquire sequences in the entire brain. In the present study, we compared hyperpolarized [1-13C]pyruvate metabolism between the brains of awake and isoflurane-anesthetized mice using a custom-made awake mouse restraint device with MRSI. Although the signal for [1-13C]lactate, a product of glycolysis metabolized from [1-13C]pyruvate, was detectable in multiple brain regions that include the orbitofrontal cortex and hippocampus in both awake and anesthetized mice, the signal for [13C]bicarbonate metabolized from [1-13C]pyruvate was only detectable in the brains of awake mice. Moreover, a comparison of hyperpolarized [1-13C]pyruvate metabolism in young and aged mouse brains using awake MRSI detected age-related decreases in oxidative phosphorylation flux in brain regions that include the hippocampus with variations in the extent of these changes across different brain regions. These results demonstrate that hyperpolarized [1-13C]pyruvate MRSI under awake conditions is useful for the spatial detection of abnormalities and alterations in glycolysis and oxidative phosphorylation flux in the brains of mice. Thus, the use of hyperpolarized [1-13C]pyruvate MRSI has potential in pathological and mechanistic studies of brain diseases and brain aging

Can combined intracavitary/interstitial approach be an alternative to interstitial brachytherapy with the Martinez Universal Perineal Interstitial Template (MUPIT) in computed tomography-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumors?

BACKGROUND: Interstitial brachytherapy (ISBT) is an optional treatment for locally advanced gynecological tumours for which conventional intracavitary brachytherapy (ICBT) would result in suboptimal dose coverage. However, ISBT with Martinez Universal Perineal Interstitial Template (MUPIT), in which ~10-20 needles are usually applied, is more time-consuming and labor-intensive than ICBT alone, making it a burden on both practitioners and patients. Therefore, here we investigated the applicability of a combined intracavitary/interstitial (IC/IS) approach in image-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumours for which interstitial brachytherapy (ISBT) was performed. METHODS: Twenty-one consecutive patients with gynecological malignancies treated with computed tomography-guided ISBT using MUPIT were analyzed as cases for this dosimetric study. For each patient, the IC/IS plan using a tandem and 1 or 2 interstitial needles, which was modeled after the combined IC/IS approach, was generated and compared with the IS plan based on the clinical ISBT plan, while the IC plan using only the tandem was applied as a simplified control. Maximal dose was prescribed to the high-risk clinical target volume (HR-CTV) while keeping the dose constraints of D(2cc) bladder < 7.0 Gy and D(2cc) rectum < 6.0 Gy. The plan with D90 HR-CTV exceeding 6.0 Gy was considered acceptable. RESULTS: The average D90 HR-CTV was 77%, 118% and 140% in the IC, IC/IS and IS plans, respectively, where 6 Gy corresponds to 100%. The average of the ratio of D90 HR-CTV to D(2cc) rectum (gain factor (GF) (rectum)) in the IC, IC/IS and IS plans was 0.8, 1.3 and 1.5 respectively, while GF(bladder) was 0.9, 1.4 and 1.6, respectively. In the IC/IS plan, D90 HR-CTV, GF(rectum) and GF(bladder) exceeded 100%, 1.0 and 1.0, respectively, in all patients. CONCLUSIONS: These data demonstrated that the combined IC/IS approach could be a viable alternative to ISBT for gynecological malignancies with bulky and/or irregularly shaped tumours. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13014-014-0222-6) contains supplementary material, which is available to authorized users

Adenosquamous Carcinoma of the Choledochus

The patient was an 86-year-old man who was admitted with obstructive jaundice. Computed tomography revealed a tumor in the hilar choledochus with peripheral hepatic duct dilatation. Endoscopic cholangiography (ERC) demonstrated the defect in the choledochus. Brushing cytology during ERC showed Orange-G-philic keratinized atypical cells, which led to a diagnosis of squamous cell carcinoma. Chemotherapy with tegafur-gimeracil-oteracil potassium was ineffective and was discontinued due to adverse effects. The patient died 5 months after the diagnosis and autopsy revealed tubular adenocarcinoma of the hilar bile duct with squamous cell carcinoma component. Progression of the disease might influence the distribution of adenosquamous carcinoma. The clinicopathological sequence of adenosquamous carcinoma of the choledochus was documented

Cyclosporin A Associated Helicase-Like Protein Facilitates the Association of Hepatitis C Virus RNA Polymerase with Its Cellular Cyclophilin B

BACKGROUND: Cyclosporin A (CsA) is well known as an immunosuppressive drug useful for allogeneic transplantation. It has been reported that CsA inhibits hepatitis C virus (HCV) genome replication, which indicates that cellular targets of CsA regulate the viral replication. However, the regulation mechanisms of HCV replication governed by CsA target proteins have not been fully understood. PRINCIPAL FINDINGS: Here we show a chemical biology approach that elucidates a novel mechanism of HCV replication. We developed a phage display screening to investigate compound-peptide interaction and identified a novel cellular target molecule of CsA. This protein, named CsA associated helicase-like protein (CAHL), possessed RNA-dependent ATPase activity that was negated by treatment with CsA. The downregulation of CAHL in the cells resulted in a decrease of HCV genome replication. CAHL formed a complex with HCV-derived RNA polymerase NS5B and host-derived cyclophilin B (CyPB), known as a cellular cofactor for HCV replication, to regulate NS5B-CyPB interaction. CONCLUSIONS: We found a cellular factor, CAHL, as CsA associated helicase-like protein, which would form trimer complex with CyPB and NS5B of HCV. The strategy using a chemical compound and identifying its target molecule by our phage display analysis is useful to reveal a novel mechanism underlying cellular and viral physiology

Heterogeneous Nucleation of Protein Crystals on Fluorinated Layered Silicate

Here, we describe an improved system for protein crystallization based on heterogeneous nucleation using fluorinated layered silicate. In addition, we also investigated the mechanism of nucleation on the silicate surface. Crystallization of lysozyme using silicates with different chemical compositions indicated that fluorosilicates promoted nucleation whereas the silicates without fluorine did not. The use of synthesized saponites for lysozyme crystallization confirmed that the substitution of hydroxyl groups contained in the lamellae structure for fluorine atoms is responsible for the nucleation-inducing property of the nucleant. Crystallization of twelve proteins with a wide range of pI values revealed that the nucleation promoting effect of the saponites tended to increase with increased substitution rate. Furthermore, the saponite with the highest fluorine content promoted nucleation in all the test proteins regardless of their overall net charge. Adsorption experiments of proteins on the saponites confirmed that the density of adsorbed molecules increased according to the substitution rate, thereby explaining the heterogeneous nucleation on the silicate surface

A comprehensive analysis of filamentous phage display vectors for cytoplasmic proteins: an analysis with different fluorescent proteins

Filamentous phage display has been extensively used to select proteins with binding properties of specific interest. Although many different display platforms using filamentous phage have been described, no comprehensive comparison of their abilities to display similar proteins has been conducted. This is particularly important for the display of cytoplasmic proteins, which are often poorly displayed with standard filamentous phage vectors. In this article, we have analyzed the ability of filamentous phage to display a stable form of green fluorescent protein and modified variants in nine different display vectors, a number of which have been previously proposed as being suitable for cytoplasmic protein display. Correct folding and display were assessed by phagemid particle fluorescence, and with anti-GFP antibodies. The poor correlation between phagemid particle fluorescence and recognition of GFP by antibodies, indicates that proteins may fold correctly without being accessible for display. The best vector used a twin arginine transporter leader to transport the displayed protein to the periplasm, and a coil-coil arrangement to link the displayed protein to g3p. This vector was able to display less robust forms of GFP, including ones with inserted epitopes, as well as fluorescent proteins of the Azami green series. It was also functional in mock selection experiments