On Accelerating Substrate Optimization Using Computational Gibbs Energy Barriers: A Numerical Consideration Utilizing a Computational Data Set.

Substrate optimization is a time- and resource-consuming step in organic synthesis. Recent advances in chemo- and materials-informatics provide systematic and efficient procedures utilizing tools such as Bayesian optimization (BO). This study explores the possibility of reducing the required experiments further by utilizing computational Gibbs energy barriers. To thoroughly validate the impact of using computational Gibbs energy barriers in BO-assisted substrate optimization, this study employs a computational Gibbs energy barrier data set in the literature and performs an extensive numerical investigation virtually regarding the Gibbs energy barriers as virtual experimental results and those with systematic and random noises as virtual computational results. The present numerical investigation shows that even the computational reactivity affected by noises of as much as 20 kJ/mol helps reduce the number of required experiments.

Evaluation of virtual monochromatic imaging with dual-energy computed tomography of small liver metastases from malignant abdominal tumours: Quantitative and qualitative analyses.

Background: The assessment of small metastatic liver tumours using dual-energy computed tomography (DECT) has not been fully established. Purpose: To assess the effect of low-keV virtual monochromatic imaging (VMI) with non-contrast and contrast-enhanced DECT on the qualitative and quantitative image parameters of small liver metastases. Material and methods: Two radiologists retrospectively evaluated 92 metastatic liver tumours (5-20 mm) in 32 patients. Non-contrast and contrast-enhanced VMI were reconstructed at seven energy levels (40-100 keV) with 10-keV intervals. Lesion boundary, lesion delineation, image noise, and overall image quality were evaluated using the visual analogue scale. A high subjective score indicates good overall image quality, clear nodal boundaries and delineation, and less noticeable image noise. Subjective scores were compared using the Kruskal-Wallis test. A quantitative analysis involving the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) was performed. Results: The lesion boundary was highest at 40 keV and significantly improved during the non-contrast portal venous phase compared to that at higher keV (p < .005). The lesion delineation score was significantly higher at 40 keV and tended to decrease at higher keV. Image noise and overall image quality were rated low at low keV; however, those at 80, 90, and 100 keV were rated the highest (p < .005). The CNR and SNR were highest for non-contrast CT at 100 keV. During the portal venous phase, no significant differences were observed in CNR and SNR at each keV. Conclusion: Low-keV imaging using non-contrast and contrast-enhanced DECT is useful for delineating small hepatic metastatic tumours.

In Vitro Characterization of Drug-Loaded Superabsorbent Polymer Microspheres: Absorption and Release Capacity of Contrast Material, Antibiotics and Analgesics.

PURPOSE: To examine the characteristics of drug-loaded superabsorbent polymer microspheres (SAP-MS) such as drug absorption, drug release, diameter, and visibility. MATERIALS AND METHODS: SAP-MS (HepaSphere150-200 µm; Merit Medical, South Jordan, UT, USA) were suspended in drug solutions: (a) cefazolin, (b) lidocaine, (c) iopamidol and cefazolin, (d) iopamidol and lidocaine, and (e) iopamidol, cefazolin, and lidocaine. The concentrations of drugs were measured, and the amount of each drug absorbed was calculated. Filtered drug-loaded SAP-MS were mixed with saline, and the drug release rates were calculated. The diameter changes of SAP-MS during absorption were observed. Radiography of drug-loaded SAP-MS was evaluated as radiopacity by contrast-to-noise ratio (CNR). RESULTS: The drug concentration did not change during absorption. The release rates increased for 10 min and then came to an equilibrium. The mean amounts of drug absorbed at 180 min and mean release rates at 24 h were (a) cefazolin: 265.4 mg, 64.2%; (b) lidocaine: 19.6 mg, 75.6%; (c) iopamidol: 830.2 mg, 22.5%; cefazolin: 137.6 mg, 21.2%; (d) iopamidol: 1620.6 mg, 78.5%; lidocaine: 13.5 mg, 81.4%; and (e) iopamidol: 643.7 mg, 52.9%; cefazolin: 194.0 mg, 51.6%; lidocaine: 5.3 mg, 58.4%. The diameter of SAP-MS increased for approximately 15 min. Finally, the diameters of SAP-MS were (a) 3.9 times, (b) 5.0 times, (c) 2.2 times, (d) 5.5 times, and (e) 3.6 times larger than the original size. Drug-loaded SAP-MS containing iopamidol were visible under X-ray imaging, with CNRs of (c) 3.0, (d) 9.0, and (e) 4.5. CONCLUSION: SAP-MS can absorb and release iopamidol, cefazolin, and lidocaine.

Subpleural fibrotic interstitial lung abnormalities are implicated in non-small cell lung cancer radiotherapy outcomes.

BACKGROUND: The relationship between interstitial lung abnormalities (ILAs) and the outcomes of lung cancer radiotherapy is unclear. This study investigated whether specific ILA subtypes are risk factors for radiation pneumonitis (RP). PATIENTS AND METHODS: This retrospective study analysed patients with non-small cell lung cancer treated with radical-intent or salvage radiotherapy. Patients were categorised into normal (no abnormalities), ILA, and interstitial lung disease (ILD) groups. The ILA group was further subclassified into non-subpleural (NS), subpleural non-fibrotic (SNF), and subpleural fibrotic (SF) types. The Kaplan-Meier and Cox regression methods were used to determine RP and survival rates and compare these outcomes between groups, respectively. RESULTS: Overall, 175 patients (normal, n = 105; ILA-NS, n = 5; ILA-SNF, n = 28; ILA-SF, n = 31; ILD, n = 6) were enrolled. Grade ≥2 RP was observed in 71 (41%) patients. ILAs (hazard ratio [HR]: 2.33, p = 0.008), intensity-modulated radiotherapy (HR: 0.38, p = 0.03), and lung volume receiving 20 Gy (HR: 54.8, p = 0.03) contributed to the cumulative incidence of RP. Eight patients with grade 5 RP were in the ILA group, seven of whom had ILA-SF. Among radically treated patients, the ILA group had worse 2-year overall survival (OS) than the normal group (35.3% vs 54.6%, p = 0.005). Multivariate analysis revealed that the ILA-SF group contributed to poor OS (HR: 3.07, p =0.02). CONCLUSIONS: ILAs, particularly ILA-SF, may be important risk factors for RP, which can worsen prognosis. These findings may aid in making decisions regarding radiotherapy.

Automatic one-click planning for hippocampal-avoidance whole-brain irradiation in RayStation.

This study aimed to verify the accuracy of auto-contouring and auto-dose optimization for hippocampal-avoidance whole-brain radiation therapy (HA-WBRT). Head computed tomography (CT) images of 15 patients were selected. The regions of interest, containing the brain, hippocampus, eyes, and lacrimal glands, were contoured manually and automatically on CT images. They were compared and evaluated for concordance rates using the Simpson coefficient. To verify the performance of dose optimization, auto-dose planning was compared with manual planning for 15 cases. All optimization plans were performed using the volumetric modulated arc therapy technique. The automatically contoured brain showed a very high concordance rate with the manually contoured brain; the Simpson coefficient was 0.990 ± 0.01. Contrastingly, the concordance rate of the hippocampal contour was low at 0.642 ± 0.15 (right) and 0.500 ± 0.16 (left); however, the rate improved to 0.871 ± 0.09 (right) and 0.852 ± 0.11 (left) with an additional 3-mm margin. For 2% of each planning target volume with the prescribed dose (D2%) and Dmean, there was no significant difference between the automatic and manual plans (35.50 Gy vs 35.23 Gy; p = 0.233 and 33.09 Gy vs 32.84 Gy; p = 0.073, respectively). The D98% was significantly better for the manual plan than for the automatic plan (25.49 Gy vs 26.11 Gy; p < 0.01). Dmax and D100% for the hippocampus did not show any significant difference between the automatic and manual plans (15.65, 16.09 Gy (right, left) vs 15.51, 15.80 Gy; p = 0.804, 0.233 and 8.08, 8.03 Gy vs 8.13, 8.01 Gy; p = 0.495, 1 respectively). The accuracy of auto-contouring for HA-WBRT can be guaranteed by providing an appropriate margin, and the precision of the auto-dose optimization was comparable to that of the manual plan.

A Dataset of Computational Reaction Barriers for the Claisen Rearrangement: Chemical and Numerical Analysis.

Theoretical reaction screening based on Gibbs energy barriers would be promising to accelerate chemical reactions mining. The number of quantum chemical calculations can be reduced by using an optimization algorithm such as genetic algorithm (GA) and Bayesian optimization (BO). The focus of this study is to generate a dataset of reaction barriers of size ∼100000. Such a dataset would be useful to quickly evaluate various implementations of an optimization algorithm such as GA and BO. The dataset includes Gibbs energy barriers of the Claisen rearrangement for ∼100000 molecules computed on the basis of a semiempirical theory PM7. After evaluating its chemical and numerical features, it is found that the dataset well reflects chemical trends of various substitutions and is useful in testing various implementations of an optimization algorithm. The dataset is available in the supplementary material of this paper.

Electroporation-Based ex Vivo Gene Delivery into Dendritic Cells by Anionic Polymer-Coated Versatile Nuclear Localization Signal/pDNA Complex.

In this study, we focused on a nuclear localization signal (NLS)-based versatile peptide vector, designed by us, combined with electroporation (EP) to establish an efficient gene delivery system to non-dividing or slow growing dendritic cells. We determined the intranuclear transport, gene expression, and cell viability in JAWS II mouse dendritic cells transfected with the green fluorescent protein (GFP) expression plasmid DNA alone (naked pEGFP); positive charged complex of NLS derivative STR-CH2SV40H2C, and pEGFP (binary complex); or negative charged complex of the binary complex with a biocompatible polyanion, γ-polyglutamic acid (ternary complex) combined with or without EP application. Although the binary complex showed higher nuclear transport and GFP expression in the absence of EP than those for naked pEGFP, the combination of EP significantly decreased the cell viability and did not improve the efficiency of compared gene expression. However, in the ternary complex, the intranuclear transport and GFP expression efficiency were significantly higher than those of naked pEGFP and the binary complex when combined with EP, and there was no decrease in cell viability. The results suggest that polyanion-coated ternary complex with EP is useful for non-viral gene delivery system into non-dividing cells for ex vivo gene/cell therapy.

[A case of primary intramedullary spinal cord lymphoma diagnosed by spinal cord biopsy of long spinal cord lesions showing persistent gadolinium contrast enhancement].

An 82-year-old man presented with subacute bilateral lower limb paralysis, deep sensory disturbance, and vesico-rectal disturbance. MRI of the spinal cord revealed a large gray matter-dominant lesion extending from the medulla oblongata to the lower thoracic spinal cord. The patient was treated with steroid-pulse therapy for myelitis, but without symptomatic improvement. A spinal cord biopsy was performed for treatment-resistant myelopathy, and histopathology revealed a diffuse large B-cell lymphoma, that was diagnosed as a primary intramedullary spinal cord lymphoma because systemic examination didn't show any other findings suggestive of malignant lymphoma. A spinal cord biopsy is necessary for the definitive diagnosis of this disease, but in the case of poor response to treatment and a progressive course, intramedullary malignant lymphoma should be considered if there is a persistent elevation of CSF IL-10 or a prolonged contrast effect.

Development of a Liquid Crystal Formulation that Can Penetrate the Stratum Corneum for Intradermal Delivery of Small Interfering RNA.

Topical delivery of small interfering RNA (siRNA) can be an attractive method for the treatment of skin diseases and improving the quality of life of patients. However, it is difficult for siRNA to pass through the two major barriers of the skin: the stratum corneum (SC) and tight junctions. We have previously reported that atopic dermatitis of skin without the SC can be efficiently treated by the intradermal administration of trans-activator of transcription (Tat) peptide and AT1002 (tight junction opening peptide). However, novel drug delivery systems are needed for effective SC penetration. Therefore, in the present study, we aimed to develop a lyotropic liquid crystalline (LC) system containing Tat and AT1002 for effective siRNA penetration through the SC. An LC formulation was prepared using selachyl alcohol and purified water, and its skin penetration ability was evaluated. No fluorescence was observed in mouse skin treated with a siRNA solution, as there was no intradermal localization of siRNA from naked siRNA. However, intradermal delivery of siRNA was remarkable and extensive with the LC formulation containing both Tat and AT1002. Semiquantitative analysis by brightness measurement revealed that the LC formulation containing both Tat and AT1002 had significantly enhanced intact skin permeability than other formulations. These results show that the functional peptides in the LC formulation increased SC penetration and intradermal delivery in the healthy skin. Therefore, this novel LC system may be useful in the treatment of various skin diseases.

Transcatheter Arterial Embolization Using Cone-beam Computed Tomography during Angiography and Automated Vessel Detection Software for Obscure Colonic Diverticular Hemorrhage after Unsuccessful Endoscopic Clipping: A Report of Two Cases.

We report the usefulness of cone-beam computed tomography angiography (CBCTA) and automated vessel detection (AVD) software in transcatheter arterial embolization in two cases of obscure ascending colonic diverticular hemorrhage after unsuccessful endoscopic clipping. Arteriography of the superior mesenteric artery demonstrated no active bleeding. Considering the positional relationship of the clips, we could narrow the responsible vessel down to two candidates but could not definitively identify the responsible vessel. We performed CBCTA at the marginal artery of the right colic artery, and the responsible branch was identified using AVD. The responsible vessel could be embolized, and hemostasis was achieved with no ischemic complications. CBCTA and AVD software for colonic diverticular hemorrhage after endoscopic clipping were useful for identifying the responsible vessel and in performing selective embolization.

Potential role of Howell-Jolly bodies in identifying functional hyposplenism: a prospective single-institute study.

Although patients with cancer and immunosuppression are at a risk of functional hyposplenism, how to detect it promptly remains unclear. Since hyposplenism allows erythrocytes with nuclear remnants (Howell-Jolly bodies [HJBs]) to appear in the peripheral blood, HJB detection by a routine microscopic examination may help identify patients with functional hyposplenism. This prospective study was thus performed to determine the underlying diseases in patients who presented with HJBs. Of 100 consecutive patients presenting with HJBs, 73 had a history of splenectomy. The remaining 27 had hematologic cancer (n = 6, 22%), non-hematologic cancer (n = 8, 30%), hepatic disorders (n = 4, 15%), premature neonates (n = 3, 11%), hemolytic anemia (n = 2, 7%), autoimmune disorders (n = 2, 7%) and miscellaneous diseases (n = 2, 7%), and their prior treatments included chemotherapy (n = 8, 30%), steroids (n = 7, 26%) and molecular-targeted therapy (n = 3, 11%). Among the 27 patients, 22 had computed tomography scans available: 3 (14%) had underlying diseases in the spleen, and the remaining 19 (86%) were all found to have a decreased splenic volume, including 11 (50%) with more than 50% of the ideal value. The present findings suggest that HJB detection identifies patients with potentially functional hyposplenism who should receive appropriate interventional treatment, such as vaccination and prophylactic antibiotics.

Nose-to-brain drug delivery system with ligand/cell-penetrating peptide-modified polymeric nano-micelles for intracerebral gliomas.

We previously developed a nose-to-brain delivery system using poly(ethylene glycol)-polycaprolactone block polymeric micelles modified by a cell-penetrating peptide, Tat (PEG-PCL-Tat). This system showed excellent delivery of the anti-cancer drug camptothecin to the brain and improved therapeutic efficacy in a brain tumor model. However, improvements are necessary to selectively deliver drugs to tumor sites once they enter the brain, and avoid toxic side effects to normal brain tissue. In this study, to develop tumor-selective novel polymeric micelles, mixed micelles consisting of Tat-conjugated polymer micelles and stearoyl-modified bombesin (Bom/PEG-PCL-Tat) were designed. The GRPR selectivity, cellular uptake, and cytotoxicity in C6 glioma cells as well as the intracerebral drug distribution and therapeutic efficacy of Bom/PEG-PCL-Tat mixed micelles after intranasal administration in C6 glioma orthotropic grafted rats were evaluated. Selective cellular uptake and marked cytotoxic effects against GRPR-expressing C6 glioma cells were observed, as well as C6 tumor tissue-specific accumulation in vivo. Rats treated with camptothecin subsequent to a brain tumor graft survived longer when the drug was delivered by Bom/PEG-PCL-Tat mixed micelles than by PEG-PCL-Tat micelles.

A global database of soil nematode abundance and functional group composition.

As the most abundant animals on earth, nematodes are a dominant component of the soil community. They play critical roles in regulating biogeochemical cycles and vegetation dynamics within and across landscapes and are an indicator of soil biological activity. Here, we present a comprehensive global dataset of soil nematode abundance and functional group composition. This dataset includes 6,825 georeferenced soil samples from all continents and biomes. For geospatial mapping purposes these samples are aggregated into 1,933 unique 1-km pixels, each of which is linked to 73 global environmental covariate data layers. Altogether, this dataset can help to gain insight into the spatial distribution patterns of soil nematode abundance and community composition, and the environmental drivers shaping these patterns.

Soil nematode abundance and functional group composition at a global scale.

Soil organisms are a crucial part of the terrestrial biosphere. Despite their importance for ecosystem functioning, few quantitative, spatially explicit models of the active belowground community currently exist. In particular, nematodes are the most abundant animals on Earth, filling all trophic levels in the soil food web. Here we use 6,759 georeferenced samples to generate a mechanistic understanding of the patterns of the global abundance of nematodes in the soil and the composition of their functional groups. The resulting maps show that 4.4 ± 0.64 × 1020 nematodes (with a total biomass of approximately 0.3 gigatonnes) inhabit surface soils across the world, with higher abundances in sub-Arctic regions (38% of total) than in temperate (24%) or tropical (21%) regions. Regional variations in these global trends also provide insights into local patterns of soil fertility and functioning. These high-resolution models provide the first steps towards representing soil ecological processes in global biogeochemical models and will enable the prediction of elemental cycling under current and future climate scenarios.

[A case of spinal and bulbar muscular atrophy with improved walking ability following gait training using the hybrid assistive limb (HAL)].

A 64-year-old man was diagnosed with spinal and bulbar muscular atrophy (SBMA) in 2014, and began gait training with the hybrid assistive limb (HAL) in 2017. We conducted 2 courses of HAL-based gait training and temporary improvement was confirmed both before and after intervention based on evaluation of the 2-minute walking distance, walking speed, and the Timed Up and Go test. HAL-based gait training may be effective for improving and maintaining walking ability in SBMA. However, long-term observation of this patient will be performed.

Transdermal anti-nuclear kappaB siRNA therapy for atopic dermatitis using a combination of two kinds of functional oligopeptide.

Nucleic acid-based targeting of nuclear factor kappaB (NF-κB) is gaining attention as a treatment option for skin diseases like atopic dermatitis (AD). Transdermal administration improves patient quality of life because of non-invasive; however, siRNA delivery into the skin can be challenging owing to the barrier of tight junctions in the granular layer. Therefore, we aimed to develop a delivery system of siRNA for topical skin application using functional peptides. We previously reported that combined treatment with a cytoplasm-responsive stearylated-arginine-rich peptide (STR-CH2R4H2C) and a tight junction opening peptide (AT1002) showed high siRNA permeability in the skin of AD-induced and normal mice. Here, we used murine macrophage RAW264.7 cells to examine siRNA permeation and the therapeutic effect of anti-NF-κB (RelA) siRNA (siRelA) complexed with STR-CH2R4H2C and AT1002 for AD-induced mice. We showed that significantly higher siRNA cellular uptake occurs after this treatment as well as decreased TNF-α and IL-6 expression. Additionally, we showed that effective siRNA transdermal delivery occurs with the suppression of the tight junction protein ZO-1. Moreover, topical skin application of siRelA with STR-CH2R4H2C and AT1002 improved AD-like symptoms in model mice. Thus, the combined treatment of STR-CH2R4H2C and AT1002 could serve as an effective transdermal siRNA therapeutic system for AD.

Successful combination immunotherapy of anti-gamma aminobutyric acid (GABA)A receptor antibody-positive encephalitis with extensive multifocal brain lesions.

A 78-year old woman who presented with akinetic mutism was admitted to our hospital. Brain MRI showed multifocal increased T2/FLAIR signal with extensive cortical-subcortical involvement. We suspected autoimmune encephalitis and the patient received methylprednisolone pulse. Her conscious level gradually recovered, but later relapsed again and presented with refractory status epilepticus. We treated her with intravenous immunoglobulin, plasma exchange and pulsed cyclophosphamide, with satisfactory response. A brain biopsy showed perivascular lymphocytic infiltrates and reactive gliosis. Anti-gamma aminobutyric acid (GABA)A receptor antibodies test came back to be positive after her recovery, and the diagnosis of anti-GABAA receptor antibody-positive encephalitis was made. This is a very rare case where brain biopsies were performed in a patient with anti-GABAA receptor antibody-positive encephalitis.

Development of an Innovative Intradermal siRNA Delivery System Using a Combination of a Functional Stearylated Cytoplasm-Responsive Peptide and a Tight Junction-Opening Peptide.

As a new category of therapeutics for skin diseases including atopic dermatitis (AD), nucleic acids are gaining importance in the clinical setting. Intradermal administration is noninvasive and improves patients' quality of life. However, intradermal small interfering RNA (siRNA) delivery is difficult because of two barriers encountered in the skin: intercellular lipids in the stratum corneum and tight junctions in the stratum granulosum. Tight junctions are the major barrier in AD; therefore, we focused on functional peptides to devise an intradermal siRNA delivery system for topical skin application. In this study, we examined intradermal siRNA permeability in the tape-stripped (20 times) back skin of mice or AD-like skin of auricles treated with 6-carboxyfluorescein-aminohexyl phosphoramidite (FAM)-labeled siRNA, the tight junction modulator AT1002, and the functional cytoplasm-responsive stearylated peptide STR-CH2R4H2C by using confocal laser microscopy. We found that strong fluorescence was observed deep and wide in the epidermis and dermis of back skin and AD-like ears after siRNA with STR-CH2R4H2C and AT1002 treatment. After 10 h from administration, brightness of FAM-siRNA was significantly higher for STR-CH2R4H2C + AT1002, compared to other groups. In addition, we confirmed the nontoxicity of STR-CH2R4H2C as a siRNA carrier using PAM212 cells. Thus, our results demonstrate the applicability of the combination of STR-CH2R4H2C and AT1002 for effective intradermal siRNA delivery.

Inflammatory Pseudotumor of the Brain Parenchyma with IgG4 Hypergammaglobulinemia.

A 58-year-old woman with a 1-month history of right hand clumsiness and speaking difficulty was admitted to our hospital. A neurological examination revealed sensory aphasia and right hemiparesis. Her laboratory tests showed elevated serum levels of IgG and IgG4, pancytopenia, and liver dysfunction. The results of the imaging studies of her abdomen were compatible with sclerosing cholangitis. Brain MRI showed extensive signal abnormalities in the left hemisphere on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, extending from left internal capsule to the cerebral peduncle with an irregularly enhancing lesion in the left parietal lobe. A brain biopsy revealed lymphocyte and plasma cell infiltration and reactive gliosis. Most of the plasma cells were IgG positive; however, IgG4-positive plasma cells were sparsely observed. After the initiation of betamethasone treatment, her symptoms and the brain MRI abnormalities showed significant improvement. The brain biopsy results did not meet the current criteria of IgG4-related disease. This is the first reported case of a tumefactive lesion of the brain parenchyma with serum IgG4 elevation, which was responsive to steroid treatment. The accumulation of a greater number of reports on the pathological investigation of cases of possible IgG4-related disease may help to elucidate the exact role of IgG4 in IgG4-related disorders.

Topical Anti-Nuclear Factor-Kappa B Small Interfering RNA with Functional Peptides Containing Sericin-Based Hydrogel for Atopic Dermatitis.

The small interfering RNA (siRNA) is suggested to offer a novel means of treating atopic dermatitis (AD) because it allows the specific silencing of genes related to AD pathogenesis. In our previous study, we found that siRNA targeted against RelA, an important nuclear factor-kappa B (NF-κB) subdomain, with functional peptides, showed therapeutic effects in a mouse model of AD. In the present study, to develop a topical skin application against AD, we prepared a hydrogel containing anti-RelA siRNA and functional peptides and determined the intradermal permeation and the anti-AD effects in an AD mouse model. We selected the silk protein, sericin (SC), which is a versatile biocompatible biomaterial to prepare hydrogel as an aqueous gel base. We found that the siRNA was more widely delivered to the site of application in AD-induced ear skin of mice after topical application via the hydrogel containing functional peptides than via the preparation without functional peptides. In addition, the ear thickness and clinical skin severity of the AD-induced mice treated with hydrogel containing anti-RelA siRNA with functional peptides improved more than that of mice treated with the preparation formulated with negative siRNA.