Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma.

BACKGROUND: Lenvatinib, a multiple receptor tyrosine kinase inhibitor, might exert antitumor effects via tumor immune modulation. However, changes in the tumor immune microenvironment induced by lenvatinib are poorly understood. We investigated the effect of lenvatinib on immune features in clinical samples from patients with hepatocellular carcinoma. METHODS: Fifty-one patients with advanced hepatocellular carcinoma who received lenvatinib monotherapy as first-line treatment were enrolled. We collected blood sample (n = 51) and tumor tissue (n, baseline/four weeks after treatment initiation/post-progression = 50/8/12). DNA, RNA, and proteins extracted from the tissues were subjected to multi-omics analysis, and patients were classified into two groups according to baseline immune status. Each group was investigated in terms of the dynamics of tumor signaling. We also longitudinally analyzed circulating immune proteins and chemokines in peripheral blood. RESULTS: Here we show that lenvatinib has similar anti-tumor efficacy with objective response rate and progression-free survival in both Immune-Hot and Immune-Cold subtypes. Immune signatures associated with T-cell functions and interferon responses are enriched in the early phase of treatment, while signatures associated with immunoinhibitory cells are downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings are supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. We also identify interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies. CONCLUSIONS: Our findings show the ability of lenvatinib to modulate tumor immunity in clinical samples of hepatocellular carcinoma.

Two types of therapy for liver cancer are immunotherapy and anti-angiogenic therapy. Immunotherapy helps the patient's immune system to attack the tumor. Anti-angiogenic therapy blocks the formation of new blood vessels (angiogenesis) in the tumor, and this type of therapy might also impact the immune system. We analyzed changes in the immune characteristics of human liver cancer samples induced by lenvatinib, an anti-angiogenic therapy. Patient outcomes on lenvatinib did not depend on the immune features of the tumor before treatment. However, immune characteristics of the tumors did change after treatment, and this may mean these tumors become easier to treat with immunotherapies. These findings help us to understand the effects of lenvatinib in liver cancer and whether, for example, it might be useful to combine this drug with immunotherapy.

Development of a microwave-discharge light-emitting diode (MDLED): a novel UV source for the UV-driven microwave-assisted TiO2 photocatalytic treatment of contaminated wastewaters.

This brief article reports on the fabrication of a prototype novel semiconductor digital device, a microwave-discharge light-emitting diode (MDLED), consisting of an LED and a Schottky barrier diode encapsulated in a quartz ampoule. Coating the surface of this ampoule with TiO2 yielded a new photocatalytic TiO2 unit (MDLED-TiO2) for use in treating contaminated wastewaters. To the extent that this MDLED-TiO2 is driven only by microwave energy, there is no need for electric wires or electrical AC power. As much of the activity of TiO2 photocatalyst is enhanced and ultraviolet light emission is generated only by irradiating with microwaves, the MDLED-TiO2 affords a simple water treatment device as demonstrated in the present study. The digital device consisted of 14 pieces of MDLED-TiO2  units immersed into a model contaminated wastewater toward the decomposition of organic pollutants and sterilization of natural bacteria-contaminated wastewaters performed in an energy-saving manner simply by irradiating the wastewaters with microwaves.

Can Deep Learning-Based Volumetric Analysis Predict Oxygen Demand Increase in Patients with COVID-19 Pneumonia?

Background and Objectives: This study aimed to investigate whether predictive indicators for the deterioration of respiratory status can be derived from the deep learning data analysis of initial chest computed tomography (CT) scans of patients with coronavirus disease 2019 (COVID-19). Materials and Methods: Out of 117 CT scans of 75 patients with COVID-19 admitted to our hospital between April and June 2020, we retrospectively analyzed 79 CT scans that had a definite time of onset and were performed prior to any medication intervention. Patients were grouped according to the presence or absence of increased oxygen demand after CT scan. Quantitative volume data of lung opacity were measured automatically using a deep learning-based image analysis system. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of the opacity volume data were calculated to evaluate the accuracy of the system in predicting the deterioration of respiratory status. Results: All 79 CT scans were included (median age, 62 years (interquartile range, 46-77 years); 56 (70.9%) were male. The volume of opacity was significantly higher for the increased oxygen demand group than for the nonincreased oxygen demand group (585.3 vs. 132.8 mL, p < 0.001). The sensitivity, specificity, and AUC were 76.5%, 68.2%, and 0.737, respectively, in the prediction of increased oxygen demand. Conclusion: Deep learning-based quantitative analysis of the affected lung volume in the initial CT scans of patients with COVID-19 can predict the deterioration of respiratory status to improve treatment and resource management.

Case report: Postoperative abdominal recurrence of pulmonary pleomorphic carcinoma showed a dramatic response to S-1 after pembrolizumab.

The patient was an 80-year-old woman with combined pulmonary fibrosis and emphysema. She was diagnosed with pulmonary pleomorphic carcinoma in the right upper lobe, which relapsed 18 months after the operation. Computed tomography showed a mass in contact with the posterior wall of the lower part of the stomach. The patient was treated with two cycles of pembrolizumab, but the disease progressed. She was treated with S-1 as second-line therapy, resulting in tumor-shrinking after two cycles. Progression was not observed over the next twelve months. We report a rare case involving S-1 after immune checkpoint inhibitor treatment.

Case Report: Takotsubo Cardiomyopathy in Bickerstaff Brainstem Encephalitis Triggered by COVID-19.

Takotsubo cardiomyopathy (TCM) is a stress-induced cardiomyopathy triggered by critical illness including severe neurological disorders. However, an association between TCM and Bickerstaff brainstem encephalitis (BBE) has rarely been described. During the current coronavirus disease 2019 (COVID-19) pandemic, growing evidence indicates that COVID-19 often leads to various neurological disorders, but there are few reports of an association between COVID-19 and BBE. Here we report a case of TCM associated with BBE triggered by COVID-19, which subsided with immunotherapy for BBE. Both transthoracic echocardiography and electrocardiography led to early and accurate diagnosis of TCM. Sustained hemodynamic instability due to TCM was immediately lessened with immunotherapy whereas additional plasmapheresis and immunotherapy were required to treat BBE. This case indicates that BBE might follow COVID-19 and TCM should be considered when hemodynamic status remains unstable in a patient with BBE.

Virtual Interpolation Images of Tumor Development and Growth on Breast Ultrasound Image Synthesis With Deep Convolutional Generative Adversarial Networks.

OBJECTIVES: We sought to generate realistic synthetic breast ultrasound images and express virtual interpolation images of tumors using a deep convolutional generative adversarial network (DCGAN). METHODS: After retrospective selection of breast ultrasound images of 528 benign masses, 529 malignant masses, and 583 normal breasts, 20 synthesized images of each were generated by the DCGAN. Fifteen virtual interpolation images of tumors were generated by changing the value of the input vector. A total of 60 synthesized images and 20 virtual interpolation images were evaluated by 2 readers, who scored them on a 5-point scale (1, very good; to 5, very poor) and then answered whether the synthesized image was benign, malignant, or normal. RESULTS: The mean score of overall quality for synthesized images was 3.05, and that of the reality of virtual interpolation images was 2.53. The readers classified the generated images with a correct answer rate of 92.5%. CONCLUSIONS: A DCGAN can generate high-quality synthetic breast ultrasound images of each pathologic tissue and has the potential to create realistic virtual interpolation images of tumor development.

Late-onset pneumothorax in a COVID-19 patient treated with ventilation and ECMO: A case report and literature review.

Coronavirus disease 2019 (COVID-19) has become a major threat to public health since the outbreak in Wuhan in 2019. Chest computed tomography is recommended for COVID-19 cases for evaluation and follow up of pneumonia and related complication. We report the case of a 66-year-old man with underlying hypertension and a history of smoking 76 packs a year; he was frequently monitored by computed tomography for pulmonary changes during the period from early symptom onset to death. Furthermore, he developed a pneumothorax during the course. The occurrence of pneumothorax in COVID-19 patients is not common, and there have been only a few previous reports. This is a valuable case of pneumothorax in a patient with COVID-19 treated with a ventilator and extracorporeal membrane oxygenation. This case and previous reports suggest that pneumothorax occurs in COVID-19 with a relatively late onset (3-8 weeks). Long-term pneumonia morbidity, steroid therapy, positive pressure ventilation, and extracorporeal membrane oxygenation can cause pneumothorax, leading to capillary and alveolar damage.

Evaluation of the Usefulness of CO-RADS for Chest CT in Patients Suspected of Having COVID-19.

The purpose of this study was to use the Coronavirus Disease 2019 (COVID-19) Reporting and Data System (CO-RADS) to evaluate the chest computed tomography (CT) images of patients suspected of having COVID-19, and to investigate its diagnostic performance and interobserver agreement. The Dutch Radiological Society developed CO-RADS as a diagnostic indicator for assessing suspicion of lung involvement of COVID-19 on a scale of 1 (very low) to 5 (very high). We investigated retrospectively 154 adult patients with clinically suspected COVID-19, between April and June 2020, who underwent chest CT and reverse transcription-polymerase chain reaction (RT-PCR). The patients' average age was 61.3 years (range, 21-93), 101 were male, and 76 were RT-PCR positive. Using CO-RADS, four radiologists evaluated the chest CT images. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated. Interobserver agreement was calculated using the intraclass correlation coefficient (ICC) by comparing the individual reader's score to the median of the remaining three radiologists. The average sensitivity was 87.8% (range, 80.2-93.4%), specificity was 66.4% (range, 51.3-84.5%), and AUC was 0.859 (range, 0.847-0.881); there was no significant difference between the readers (p > 0.200). In 325 (52.8%) of 616 observations, there was absolute agreement among observers. The average ICC of readers was 0.840 (range, 0.800-0.874; p < 0.001). CO-RADS is a categorical taxonomic evaluation scheme for COVID-19 pneumonia, using chest CT images, that provides outstanding performance and from substantial to almost perfect interobserver agreement for predicting COVID-19.

Efficient Anomaly Detection with Generative Adversarial Network for Breast Ultrasound Imaging.

We aimed to use generative adversarial network (GAN)-based anomaly detection to diagnose images of normal tissue, benign masses, or malignant masses on breast ultrasound. We retrospectively collected 531 normal breast ultrasound images from 69 patients. Data augmentation was performed and 6372 (531 × 12) images were available for training. Efficient GAN-based anomaly detection was used to construct a computational model to detect anomalous lesions in images and calculate abnormalities as an anomaly score. Images of 51 normal tissues, 48 benign masses, and 72 malignant masses were analyzed for the test data. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of this anomaly detection model were calculated. Malignant masses had significantly higher anomaly scores than benign masses (p < 0.001), and benign masses had significantly higher scores than normal tissues (p < 0.001). Our anomaly detection model had high sensitivities, specificities, and AUC values for distinguishing normal tissues from benign and malignant masses, with even greater values for distinguishing normal tissues from malignant masses. GAN-based anomaly detection shows high performance for the detection and diagnosis of anomalous lesions in breast ultrasound images.

Regioselective Functionalization of 9,9-Dimethyl-9-silafluorenes by Borylation, Bromination, and Nitration.

Despite the utility of 9-silafluorenes as functional materials and as building blocks, methods for efficient functionalization of their backbone are rare, probably because of the presence of easily cleavable C-Si bonds. Although controlling the regioselectivity of iridium-catalyzed direct borylation of C-H bonds is difficult, we found that bromination and nitration of 2-methoxy-9-silafluorene under mild conditions occurred predominantly at the electron-rich position. The resulting product having methoxy and bromo groups can be utilized as a building block for the synthesis of unsymmetrically substituted 9-silafluorene-containing π-conjugated molecules.

Transient Expression of WNT2 Promotes Somatic Cell Reprogramming by Inducing ß-Catenin Nuclear Accumulation.

Treatment with several Wnt/ß-catenin signaling pathway regulators can change the cellular reprogramming efficiency; however, the dynamics and role of endogenous Wnt/ß-catenin signaling in reprogramming remain largely unanswered. Here we identify the upregulation of WNT2 and subsequent ß-catenin nuclear accumulation as key events in reprogramming. Transient nuclear accumulation of ß-catenin occurs early in MEF reprogramming. Wnt2 is strongly expressed in the early stage of reprogramming. Wnt2 knockdown suppresses the nuclear accumulation of ß-catenin and reduces the reprogramming efficiency. WNT2 overexpression promotes ß-catenin nuclear accumulation and enhances the reprogramming efficiency. WNT2 contributes to the promotion of cell proliferation. Experiments with several drugs that control the Wnt pathway also indicate the importance of ß-catenin nuclear accumulation in reprogramming. Our findings reveal the role of WNT2/ß-catenin signaling in reprogramming.

Total Synthesis of (+)-Cytosporolide A via a Biomimetic Hetero-Diels-Alder Reaction.

The first total synthesis of (+)-cytosporolide A was achieved by a biomimetic hetero-Diels-Alder reaction of (-)-fuscoatrol A with o-quinone methide generated from (+)-CJ-12,373. The dienophile, highly oxygenated caryophyllene sesquiterpenoid (-)-fuscoatrol A, was synthesized from the synthetic intermediate in our previous total synthesis of (+)-pestalotiopsin A. The o-quinone methide precursor, isochroman carboxylic acid (+)-CJ-12,373, was synthesized through a Kolbe-Schmitt reaction and an oxa-Pictet-Spengler reaction. The hetero-Diels-Alder reaction of these two compounds proceeded with complete chemo-, regio-, and stereoselectivity to produce the complicated pentacyclic ring system of the cytosporolide skeleton. This total synthesis unambiguously demonstrates that natural cytosporolide A has the structure previously suggested.

Incorporation of cationic electron donor of Ni-pyridyltetrathiafulvalene with anionic electron acceptor of polyoxometalate.

A new salt-[Ni(II)(DMSO)(5)(TTFPy)](2)[α-SiW(12)O(40)] (1)-based on polyoxometalates was prepared by coordinating a cationic electron donor of pyridyltetrathiafulvalene (TTFPy) with Ni(II). Although the TTFPy molecule did not form a salt with the anionic α-[SiW(VI)(12)O(40)](4-) because of the weak charge-transfer (CT) interaction, the coordination of Ni with the pyridyl moiety permitted salt formation driven by electrostatic interaction, giving a single crystal of 1. Crystallographic analysis, UV-vis and IR spectroscopy and electrochemical characterization revealed that the fully oxidized α-[SiW(VI)(12)O(40)](4-) was crystallized with the neutral TTFPy moiety from the acetonitrile solution because of the low electron-withdrawing ability of α-[SiW(VI)(12)O(40)](4-), forming a brown-orange crystal. The crystal colour quickly turned to black by immersing in methanol, due to CT from TTF moiety to α-[SiW(VI)(12)O(40)](4-), which was caused by the solvent effect. Increase in the solvent acceptor number from 18.9 for acetonitrile to 41.3 for methanol resulted in the enhancement of the electron withdrawing ability of α-[SiW(VI)(12)O(40)](4-) by 0.317 V in methanol.

Changes in esculeoside A content in different regions of the tomato fruit during maturation and heat processing.

We previously demonstrated that esculeogenin A, a new aglycone of the tomato sapogenol esculeoside A, inhibits both acyl coenzyme A:cholesterol acyl-transferase (ACAT)-1 and -2 and ameliorates the pathogenesis of atherosclerosis in apoE deficient mice. Although we believe that daily intake of esculeoside A from tomato products can play a beneficial role in preventing the pathogenesis of atherosclerosis, the compound is not being used for preventive medicine due to the lack of information on methods for quantitative analysis and the content and stability of the compound in tomato products. In the present study, we report the development of a high-performance liquid chromatography (HPLC) method using an instrument equipped with a refractive index (RI) detector for esculeoside A quantification. We used this method to measure the changes in esculeoside A content during maturation, its distribution in the fruit body, and its stability during the heating process. The contents of esculeoside A in cherry tomatoes and Momotaro tomatoes were 21- and 9-fold, respectively, higher than that of lycopene, which is the most well-known compound in tomatoes. Furthermore, the esculeoside A content in pericarp wall was higher than in the whole tomato fruit and increased in a time-dependent manner during maturation. Although the melting point of purified esculeoside A was 225 °C, the esculeoside A in crude tomato extract decreased in a temperature-dependent manner. Degradation due to the heating process was inhibited under a pH of 9. These results demonstrated that the esculeoside A content differs in the various types of tomatoes, during maturation, and during the heating process used for preservation.