Effectiveness of Anti-PD-1 Antibody Monotherapy for the Primary Malignant Melanoma of the Esophagus： A Case Report

Primary malignant melanoma of the esophagus（PMME）is extraordinarily rare with a high degree of malignancy and poor prognosis, and a standard therapy remains to be established. The anti-PD-1 antibody nivolumab is a promising agent for various cancers. To our knowledge, this is the first case report of PMME where a complete response was achieved using nivolumab. We report an 80-year-old woman who was diagnosed with PMME with bone metastasis and lymph node metastases. Although dacarbazine combined chemotherapy was performed and continued for six cycles, the primary tumor progressed and liver metastases appeared. The patient then received nivolumab monotherapy. After three cycles, nivolumab monotherapy for PMME resulted in a complete response as shown by positron emission tomography, computed tomography, and esophagogastroduodenoscopy. In our case, nivolumab exerted a curative effect on PMME, thus suggesting that nivolumab can be effective in the treatment of this rare disease

Large-scale analysis of full-length cDNAs from the tomato (Solanum lycopersicum) cultivar Micro-Tom, a reference system for the Solanaceae genomics

<p>Abstract</p> <p>Background</p> <p>The Solanaceae family includes several economically important vegetable crops. The tomato (<it>Solanum lycopersicum</it>) is regarded as a model plant of the Solanaceae family. Recently, a number of tomato resources have been developed in parallel with the ongoing tomato genome sequencing project. In particular, a miniature cultivar, Micro-Tom, is regarded as a model system in tomato genomics, and a number of genomics resources in the Micro-Tom-background, such as ESTs and mutagenized lines, have been established by an international alliance.</p> <p>Results</p> <p>To accelerate the progress in tomato genomics, we developed a collection of fully-sequenced 13,227 Micro-Tom full-length cDNAs. By checking redundant sequences, coding sequences, and chimeric sequences, a set of 11,502 non-redundant full-length cDNAs (nrFLcDNAs) was generated. Analysis of untranslated regions demonstrated that tomato has longer 5'- and 3'-untranslated regions than most other plants but rice. Classification of functions of proteins predicted from the coding sequences demonstrated that nrFLcDNAs covered a broad range of functions. A comparison of nrFLcDNAs with genes of sixteen plants facilitated the identification of tomato genes that are not found in other plants, most of which did not have known protein domains. Mapping of the nrFLcDNAs onto currently available tomato genome sequences facilitated prediction of exon-intron structure. Introns of tomato genes were longer than those of Arabidopsis and rice. According to a comparison of exon sequences between the nrFLcDNAs and the tomato genome sequences, the frequency of nucleotide mismatch in exons between Micro-Tom and the genome-sequencing cultivar (Heinz 1706) was estimated to be 0.061%.</p> <p>Conclusion</p> <p>The collection of Micro-Tom nrFLcDNAs generated in this study will serve as a valuable genomic tool for plant biologists to bridge the gap between basic and applied studies. The nrFLcDNA sequences will help annotation of the tomato whole-genome sequence and aid in tomato functional genomics and molecular breeding. Full-length cDNA sequences and their annotations are provided in the database KaFTom <url>http://www.pgb.kazusa.or.jp/kaftom/</url> via the website of the National Bioresource Project Tomato <url>http://tomato.nbrp.jp</url>.</p

COVID-19 vaccine effectiveness against severe COVID-19 requiring oxygen therapy, invasive mechanical ventilation, and death in Japan: A multicenter case-control study (MOTIVATE study).

INTRODUCTION: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation. METHODS: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients. RESULTS: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes. CONCLUSION: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron

Determination of the Chemical Structures of Tandyukisins B–D, Isolated from a Marine Sponge-Derived Fungus

Tandyukisins B–D (1–3), novel decalin derivatives, have been isolated from a strain of Trichoderma harzianum OUPS-111D-4 originally derived from the marine sponge Halichondria okadai, and their structures have been elucidated on the basis of spectroscopic analyses using 1D and 2D NMR techniques. In addition, their chemical structures were established by chemical transformation. They exhibited weak cytotoxicity, but selective growth inhibition on panel screening using 39 human cancer cell lines

Aldehyde dehydrogenase, Ald4p, is a major component of mitochondrial fluorescent inclusion bodies in the yeast Saccharomyces cerevisiae

When Saccharomyces cerevisiae strain 3626 was cultured to the stationary phase in a medium that contained glucose, needle-like structures that emitted autofluorescence were observed in almost all cells by fluorescence microscopy under UV excitation. The needle-like structures completely overlapped with the profile of straight elongated mitochondria. Therefore, these structures were designated as mitochondrial fluorescent inclusion bodies (MFIBs). The MFIB-enriched mitochondrial fractions were successfully isolated and 2D-gel electrophoresis revealed that a protein of 54 kDa was only highly concentrated in the fractions. Determination of the N-terminal amino acid sequence of the 54-kDa protein identified it as a mitochondrial aldehyde dehydrogenase, Ald4p. Immunofluorescence microscopy showed that anti-Ald4p antibody specifically stained MFIBs. Freeze-substitution electron microscopy demonstrated that cells that retained MFIBs had electron-dense filamentous structures with a diameter of 10 nm in straight elongated mitochondria. Immunoelectron microscopy showed that Ald4p was localized to the electron-dense filamentous structures in mitochondria. These results together showed that a major component of MFIBs is Ald4p. In addition, we demonstrate that MFIBs are common features that appear in mitochondria of many species of yeast

Determination of Serum 25-Hydroxyvitamin D-3 by LC/MS/MS and Its Monthly Variation in Sapporo Indoor Workers

25-Hydroxyvitamin D-3 (25(OH)D-3) as the metabolite of vitamin D, is connected with various of diseases, and important to people with limited sunshine. Thus, the investigation of serum 25-hydroxyvitamin D and its variation in these people is necessary. In this study, a simple, precise, and accurate method for serum 25(OH)D-3 determination by LC/MS/MS was developed. Serum samples were obtained monthly for one year from 11 male and 11 female indoor workers in Sapporo, Japan, and the overall 25(OH)D-3 concentration was 12.9 +/- 4.7 ng/mL. The 25(OH)D-3 in females was significantly lower than that in males (14.0 +/- 5.0 vs. 11.9 +/- 4.3 ng/mL). The serum 25(OH)D-3 concentration in males and females were both strongly correlated to UV-B radiation (r(2) = 0.8477 and 0.7384, respectively), with a two-month's lag. Also the monthly change in 25(OH)D-3 in males was more significant than that in females

Sulfate conjugation of [11C]PBB3, a Tau imaging agent, in the brain

Introduction[11C]PBB3, a Tau imaging agent, is rapidly metabolized to form a sulfate conjugate ([11C]PBB3-sulfate) in peripheral tissues by sulfotransferase (SULT).1 After the administration of [11C]PBB3 to mice, [11C]PBB3-sulfate was observed also in the brain. The previous report concluded that it was due to the influx of [11C]PBB3-sulfate from blood to brain. However, it is known that SULT is expressed in the brain and [11C]PIB which possesses 6-hydroxybenzothiazole as a fundamental structure (Fig 1) is sulfated in the rat brain.2 It was therefore expected that [11C]PBB3, a [11C]PIB derivative, would be sulfated in the brain. In this study, the sulfate conjugation of [11C]PBB3 in the brain was investigated because the conjugation might affect the kinetic analysis of Tau imaging with [11C]PBB3. In addition, the hydrolysis of [11C]PBB3-sulfate to form parent [11C]PBB3 in the brain was investigated as sulfate conjugates can be hydrolyzed by sulfatase which is expressed in the brain.Materials & MethodsSulfate conjugation of [11C]PBB3 in the brain was evaluated by adding [11C]PBB3 and a sulfate donor, 3\u27-phosphoadenosine-5\u27-phosphosulfate (PAPS) to the brain homogenate sample. In mice samples (cerebrum, C57BL/6, 8 wo, n=3), reactions were carried out at 37°C for 30 min. In samples of a rhesus monkey (frontal cortex, Macacca mulatta, male, 23 yo), reactions were carried out at 37°C and the conjugates generated were analyzed at 5, 15, 30 min after starting reaction. In addition to the crude homogenate (around 0.2 g/mL for mice, 0.16 g/mL for monkey), the sulfate conjugation in the supernatant of homogenate was investigated. The conjugation was analyzed using radio-TLC. Similarly, [11C]PBB3-sulfate, which was prepared by O-sulfation of [11C]PBB3 using sulfur trioxide pyridine complex, was incubated in the mice brain homogenate at 37°C for 30 min to evaluate its hydrolysis.ResultsThe sulfate conjugation of [11C]PBB3 was observed in the mice brain samples with 30 min reaction time, and only 7.7±0.44% and 9.2±0.30% of [11C]PBB3 was conjugated in the crude homogenate and supernatant, respectively (Fig 2A). Meanwhile, [11C]PBB3-sulfate was slowly hydrolyzed to form [11C]PBB3 in the brain sample (3.1±0.13% in the crude homogenate and 3.7±0.20% in the supernatant, Fig 2B).The conjugation rates of [11C]PBB3 in the monkey brain samples were much faster than that in the mice brain samples. The conjugation in the crude homogenate of monkey brain followed first order manner (r2=1.0) up to 91% decrease of [11C]PBB3 and the rate was estimated to be 0.49 min–1(g/mL)–1. The first order kinetics suggested that the hydrolysis rate of [11C]PBB3-sulfate in the monkey brain was much slower than the conjugation rate. Indeed, the conjugation rate and the hydrolysis rate in the supernatant prepared from 0.16 g/mL of monkey brain homogenate were estimated to be 0.35 min-1 and 0.013 min-1, respectively (Fig 3).DiscussionIn mice, [11C]PBB3 slowly but significantly underwent sulfate conjugation in the brain. Therefore, a part of [11C]PBB3-sulfate observed in the mouse brain after [11C]PBB3 administration would be the metabolite generated in the brain. On the other hand, the sulfate conjugation of [11C]PBB3 was quite rapid and apparently irreversible in the monkey brain samples. In this study, large Interspecies differences regarding the sulfate conjugation of [11C]PBB3 in the brain was observed. Therefore, further investigation about the conjugation of [11C]PBB3 in the human brain would be required.References1.Hashimoto H, Kawamura K, Takei M et al. [2015] Nucl. Med. Biol. 42: 905–9102.Cole GB, Keum G, Liu J et al. [2010] Proc. Natl. Acad. Sci. USA 107: 6222–6227The XII International Symposium of Functional Neuroreceptor Mapping of the Living Brai