(5-Fluoro-2,6-dioxo-1,2,3,6-tetra-hydro-pyrimidin-1-ido-κN 1)(1,4,8,11-tetra-aza-cyclo-tetra-decane-κ4 N)zinc(II) perchlorate.

In the structure of the title complex, [Zn(C4H2FN2O2)(C10H24N4)]ClO4, the zinc(II) ion forms coordination bonds with the four nitro-gen atoms of cyclam (1,4,8,11-tetra-aza-cyclo-tetra-decane or [14]aneN4) as well as with the nitro-gen atom of a deprotonated 5-fluoro-uracil ion (FU-). Cyclam adopts a trans-I type conformation within this structure. The coordination structure of the zinc(II) ion is a square pyramid with a distorted base plane formed by the four nitro-gen atoms of the cyclam. FU- engages in inter-molecular hydrogen bonding with neighboring FU- mol-ecules and with the cyclam mol-ecule.

The Effects of Boron Neutron Capture Therapy on the Lungs in Recurrent Breast Cancer Treatment.

Boron neutron capture therapy (BNCT) has predominantly been performed for brain tumors or head and neck cancers. Although BNCT is known to be applicable to breast cancer, it has only been performed in a few cases involving thoracic region irradiation with reactor-based BNCT systems. Thus, there are very few reports on the effects of BNCT on the thoracic region and no reports of BNCT for breast cancer with accelerator-based BNCT systems. This paper introduces the world's first clinical study employing an accelerator-based BNCT system targeting recurrent breast cancer after radiation therapy. We aim to assess the efficacy and safety of BNCT, focusing on the dose response in the thoracic region, especially concerning the potential for radiation pneumonitis. Preliminary findings from the first three cases indicate no evidence of radiation pneumonitis within three months post treatment. This study not only establishes a foundation for novel breast cancer treatment options but also contributes significantly to the field of BNCT in the thoracic region.

An Evaluation of Renal Sinus Fat Accumulation Using the Anteroposterior Diameter of the Renal Sinus on a Computed Tomography Axial Image.

Backgrounds and objectives Renal sinus fat (RSF) is an indicator of obesity-related complications. However, the measurement and imaging process are complicated. For a simple measurement of RSF, we focused on the kidney's shape change caused by RSF accumulation. Thus, this study aimed to investigate whether the anteroposterior diameter of the renal sinus (APDRS) on a computed tomography (CT) axial image is useful for evaluating RSF accumulation. Materials and methods The correlation between APDRS and RSF was investigated in 98 outpatients who underwent abdominal CT. In addition, the correlation between APDRS or RSF and obesity indicators (estimated glomerular filtration rate from serum creatinine levels (eGFRcreat), body mass index (BMI), and visceral adipose tissue (VAT)) was also investigated. We classified patients based on the presence or absence of at least one underlying disease (chronic kidney disease (CKD), cardiovascular diseases (CVD), hypertension, and type 2 diabetes (T2D)) and investigated significant differences between the two groups at APDRS and RSF. The intraclass correlation coefficient (ICC) was also calculated for APDRS. Results There was a strong positive correlation between RSF and APDRS (r = 0.802, P < 0.01). The obesity indicators (eGFRcreat, BMI, and VAT) were correlated with RSF and APDRS (P < 0.01). Out of 98 outpatients, 48 had at least one underlying disease. There were statistically significant differences in APDRS and RSF between the patients with and without at least one of the underlying diseases caused by obesity (P < 0.01). The inter-reader ICC for the measurement of the APDRS was 0.98. Conclusions APDRS on a CT axial image may be useful for the evaluation of RSF accumulation.

Kamebakaurin Suppresses Antigen-Induced Mast Cell Activation by Inhibition of FcεRI Signaling Pathway.

INTRODUCTION: Kamebakaurin is an active constituent of both Rabdosia japonica and Rabdosia excisa, which are utilized in Chinese traditional medicine for improving symptoms in patients with allergies. We investigated the molecular mechanisms of the anti-allergic effects of kamebakaurin using BMMCs. METHODS: The degranulation ratio, histamine release, and the interleukin (IL)-4, leukotriene B4 (LTB4), and cysteinyl leukotriene productions on antigen-triggered BMMC were investigated. Additionally, the effects of kamebakaurin on signal transduction proteins were examined by Western blot and binding to the Syk and Lyn kinase domain was calculated. The effects of kamebakaurin on antigen-induced hyperpermeability were investigated using mouse model. RESULTS: At 10 µm, kamebakaurin partially inhibited degranulation, histamine release, and IL-4 production. At 30 µm, kamebakaurin partially reduced LTB4 and cysteinyl leukotriene productions and suppressed degranulation, histamine release, and IL-4 production. Phosphorylation of both Syk Y519/520 and its downstream protein, Gab2, was reduced by kamebakaurin, and complete inhibition was observed with 30 µm kamebakaurin. In contrast, phosphorylation of Erk was only partially inhibited, even in the presence of 30 µm kamebakaurin. Syk Y519/520 is known to be auto-phosphorylated via intramolecular ATP present in its own ATP-binding site, and this auto-phosphorylation triggers degranulation, histamine release, and IL-4 production. Docking simulation study indicated kamebakaurin blocked ATP binding to the ATP-binding site in Syk. Therefore, inhibition of Syk auto-phosphorylation by kamebakaurin binding to the Syk ATP-binding site appeared to cause a reduction of histamine release and IL-4 production. Kamebakaurin inhibited antigen-induced vascular hyperpermeability in a dose-dependent fashion but did not reduce histamine-induced vascular hyperpermeability. CONCLUSION: Kamebakaurin ameliorates allergic symptoms via inhibition of Syk phosphorylation; thus, kamebakaurin could be a lead compound for the new anti-allergic drug.

Hydroxyhexylitaconic acids as potent IMP-type metallo-ß-lactamase inhibitors for controlling carbapenem resistance in Enterobacterales.

Metallo-ß-lactamases (MBLs) represent one of the main causes of carbapenem resistance in the order Enterobacterales. To combat MBL-producing carbapenem-resistant Enterobacterales, the development of MBL inhibitors can restore carbapenem efficacy for such resistant bacteria. Microbial natural products are a promising source of attractive seed compounds for the development of antimicrobial agents. Here, we report that hydroxyhexylitaconic acids (HHIAs) produced by a member of the genus Aspergillus can suppress carbapenem resistance conferred by MBLs, particularly IMP (imipenemase)-type MBLs. HHIAs were found to be competitive inhibitors with micromolar orders of magnitude against IMP-1 and showed weak inhibitory activity toward VIM-2, while no inhibitory activity against NDM-1 was observed despite the high dosage. The elongated methylene chains of HHIAs seem to play a crucial role in exerting inhibitory activity because itaconic acid, a structural analog without long methylene chains, did not show inhibitory activity against IMP-1. The addition of HHIAs restored meropenem and imipenem efficacy to satisfactory clinical levels against IMP-type MBL-producing Escherichia coli and Klebsiella pneumoniae clinical isolates. Unlike EDTA and Aspergillomarasmine A, HHIAs did not cause the loss of zinc ions from the active site, resulting in the structural instability of MBLs. X-ray crystallography and in silico docking simulation analyses revealed that two neighboring carboxylates of HHIAs coordinated with two zinc ions in the active sites of VIM-2 and IMP-1, which formed a key interaction observed in MBL inhibitors. Our results indicated that HHIAs are promising for initiating the design of potent inhibitors of IMP-type MBLs.IMPORTANCEThe number and type of metallo-ß-lactamase (MΒL) are increasing over time. Carbapenem resistance conferred by MΒL is a significant threat to our antibiotic regimen, and the development of MΒL inhibitors is urgently required to restore carbapenem efficacy. Microbial natural products have served as important sources for developing antimicrobial agents targeting pathogenic bacteria since the discovery of antibiotics in the mid-20th century. MΒL inhibitors derived from microbial natural products are still rare compared to those derived from chemical compound libraries. Hydroxyhexylitaconic acids (HHIAs) produced by members of the genus Aspergillus have potent inhibitory activity against clinically relevant IMP-type MBL. HHIAs may be good lead compounds for the development of MBL inhibitors applicable for controlling carbapenem resistance in IMP-type MBL-producing Enterobacterales.

Aqua-{µ-1,4-bis-[(1,4,7,10-tetra-aza-cyclo-dodecan-1-yl)meth-yl]benzene}(nitrato-κO)dicopper(II) tris-(nitrate) trihydrate.

In the title dinuclear CuII complex, [Cu2(NO3)(C24H46N8)(H2O)](NO3)3·3H2O, the two CuII mol-ecules both have a square-pyramidal geometry, but the ligands in the axial positions are different: a water mol-ecule and a nitrate ion. All nitrate ions, water mol-ecules, and N-H groups are involved in an inter-molecular hydrogen-bond network.

Structural Characterization of Zinc(II)/Cobalt(II) Complexes of Chiral N-(Anthracen-9-yl)methyl-N,N-bis(2-picolyl)amine and Evaluation of DNA Photocleavage Activity.

We designed and synthesized a chiral ligand N-(anthracen-9-ylmethyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)ethanamine (APPE) DNA photocleavage agent to investigate the effects of chirality of bis(2-picolyl)amine on the DNA photocleavage activity of metal complexes. The structures of ZnII and CoII complexes in APPE were analyzed via X-ray crystallography and fluorometric titration. APPE formed metal complexes with a 1 : 1 stoichiometry in both the crystalline and solution states. Fluorometric titration was used to show that the ZnII and CoII association constants of these complexes (log Kas) were 4.95 and 5.39, respectively. The synthesized complexes were found to cleave pUC19 plasmid DNA when irradiated at 370 nm. The DNA photocleavage activity of the ZnII complex was higher than that of the CoII complex. The absolute configuration of the methyl-attached carbon did not affect DNA cleavage activity and, unfortunately, an achiral APPE derivative without the methyl group (ABPM) was found to perform DNA photocleavage more effectively than APPE. One reason for this may be that the methyl group suppressed the structural flexibility of the photosensitizer. These results will be useful for the design of new photoreactive reagents.

Difference in the Inhibitory Effect of Thiol Compounds and Demetallation Rates from the Zn(II) Active Site of Metallo-ß-lactamases (IMP-1 and IMP-6) Associated with a Single Amino Acid Substitution.

Gram-negative bacteria producing metallo-ß-lactamases (MBLs) have become a considerable threat to public health. MBLs including the IMP, VIM, and NDM types are Zn(II) enzymes that hydrolyze the ß-lactam ring present in a broad range of antibiotics, such as N-benzylpenicillin, meropenem, and imipenem. Among IMPs, IMP-1 and IMP-6 differ in a single amino acid substitution at position 262, where serine in IMP-1 is replaced by glycine in IMP-6, conferring a change in substrate specificity. To investigate how this mutation influences enzyme function, we examined lactamase inhibition by thiol compounds. Ethyl 3-mercaptopropionate acted as a competitive inhibitor of IMP-1, but a noncompetitive inhibitor of IMP-6. A comparison of the crystal structures previously reported for IMP-1 (PDB code: 5EV6) and IMP-6 (PDB code: 6LVJ) revealed a hydrogen bond between the side chain of Ser262 and Cys221 in IMP-1 but the absence of hydrogen bond in IMP-6, which affects the Zn2 coordination sphere in its active site. We investigated the demetallation rates of IMP-1 and IMP-6 in the presence of chelating agent ethylenediaminetetraacetic acid (EDTA) and found that the demetallation reactions had fast and slow phases with a first-order rate constant (kfast = 1.76 h-1, kslow = 0.108 h-1 for IMP-1, and kfast = 14.0 h-1 and kslow = 1.66 h-1 for IMP-6). The difference in the flexibility of the Zn2 coordination sphere between IMP-1 and IMP-6 may influence the demetallation rate, the catalytic efficiency against ß-lactam antibiotics, and the inhibitory effect of thiol compounds.

Tomotherapy: Comparison of Hi-ART, Tomo-HD, and Radixact.

Aim In this study, we compared three generations of tomotherapy (Hi-ART, Tomo-HD, and Radixact). This is to study the difference among tomotherapy systems in terms of dose distribution to planning target volume and organs at risk, and irradiation time.  Materials and methods The treatment planning CT and contour information used were seven cases of rectum cancer pre-operative irradiation. The contour information used was the planning target volume, and the organs at risk were set as the bladder and body. Optimization was conducted at each planning station using the parameters that were actually used in a clinical setting. The prescribed radiation dose was 25 Gy in five fractions and normalized at the isodose line, covering 95% of the planning target volume. Results There were no significant differences in planning target volume among the three models. Meanwhile, Hi-ART had a significantly higher dose than Tomo-HD and Radixact at body D50%. Radixact shortened the irradiation time by approximately 15% compared to Hi-ART/Tomo-HD. Conclusion Planning target volume dose distribution of tomotherapy devices was not different. Radixact required a significantly shorter time than Hi-ART and Tomo-HD.

Bis(nitrato-κO)(1,4,8,11-tetra-aza-cyclo-tetra-decane-κ4 N)zinc(II) methanol monosolvate.

The two ZnII atoms in the crystal structure of the title complex, [Zn(NO3)2(C10H24N4)]·CH3OH, have a distorted octa-hedral coordination sphere, defined by 1,4,8,11-tetra-aza-cyclo-tetra-decane (cyclam) N atoms in the equatorial plane and nitrate O atoms in the axial sites. The conformation of the cyclam is trans-III (R, R, S, S), which is typical for metal-cyclam complexes. Nitrate anions are involved in intra- and inter-molecular hydrogen bonding with the N-H groups of the ZnII-cyclam unit. Together with the methanol solvent mol-ecule, the hydrogen-bonding network connects the ZnII-cyclam units into ribbons running parallel to the a axis.

A Rapid and Sensitive Determination of Histamine in Mast Cells Using a Didansyl Derivatization Method.

BACKGROUND: Mast cells play a central role in allergic responses such as food allergy, asthma, allergic rhinitis, and allergic conjunctivitis. Symptoms in the early phase of these allergic diseases are primarily caused by histamine. However, due to the high histidine content in the cytosol and low histamine content in secretory granules, separating and quantifying histamine from histidine is often difficult. OBJECTIVES: We studied a method for rapid and sensitive quantitation of mast cell-derived histamine and evaluated its application to allergic disease research. METHODS: Bone marrow-derived mouse mast cells (BMMCs) were employed in this study. IgE-sensitized BMMCs were activated by FcεRI cross-linking. After activation, both the histamine released to the supernatant and histamine remaining in BMMCs were didansylated and then analyzed by high-performance liquid chromatography with fluorescence detection (HPLC-FD). Didansyl histamine was synthesized as a standard material. RESULTS: Synthetic didansyl histamine was detected by HPLC-FD with a peak retention time of 18.5 min. Very high linearity of the standard curve was maintained at concentrations of 10 pg/µL or less when the didansyl histamine method was used. This method enables detection of histamine released from 1 × 105 BMMCs. In addition, the histamine concentration in the supernatant due to spontaneous release was also determined. Finally, the ratio of histamine release was highly correlated with the degranulation ratio. CONCLUSION: These results indicate that the proposed method using didansylated histamine to determine mast cell-derived histamine is highly useful for allergy research applications.

Plan Quality Comparison Between Hippocampus-Sparing Whole-Brain Radiotherapy Treated With Halcyon and Tomotherapy Intensity-Modulated Radiotherapy.

Objective: Hippocampus-sparing whole-brain radiotherapy using Halcyon, an instrument dedicated to volumetric modulated arc therapy, has not been studied till date; hence, we aimed to examine whether it can meet the RTOG0933 criteria. Based on this, we compared Halcyon to Tomotherapy, which also uses an O-ring-type linear accelerator. Methods: This exploratory, experimental, and retrospective study used 5 sets of computed tomography images in the head area to investigate the planning target volume, hippocampal doses, and irradiation time. Calculations were performed from 1 to 4 arcs to determine the optimal number of arcs in the Halcyon plan, which were compared to those of Tomotherapy. Results: The Radiation Therapy Oncology Group 0933 criteria could not be satisfied in Halcyon with 1 arc. With 2 arcs, the condition Dmax<16 Gy was not satisfied for 1 case in the hippocampus. Since there were no significant differences between 3 and 4 arcs, including the irradiation time, 3 arcs were considered the best. We compared Halcyon at 3 arcs with tomotherapy and found that tomotherapy was inferior to Halcyon at D98%; however, it was superior to Halcyon in other dose parameters. In contrast, the irradiation time in Halcyon was overwhelmingly superior, with the irradiation time for Halcyon being 1/ninth the time for Tomotherapy. Conclusion: Halcyon was effective in handling hippocampus-sparing whole-brain radiotherapy. We believe that 3-arc radiation is best suited for this procedure. Although Halcyon was inferior to Tomotherapy in terms of dose distribution excluding D98%, it was overwhelmingly superior in terms of irradiation time.

Improvement of Metastatic Spinal Cord Compression After Decompression Surgery and Radiotherapy in a Patient Initially Treated for Rectal Cancer.

Many reports indicate that the prognosis of patients with rectal cancer who have thoracic spine metastases with spinal cord compression is poor. Here, we discuss a case of a patient who achieved an improvement of functional prognosis and long-term survival after undergoing surgery and radiotherapy. We report a case of a 64-year-old female who was found to have metastatic spinal cord compression (MSCC) in the second thoracic vertebra, 10 years after surgery for rectal cancer. She experienced numbness in both legs and had gait difficulties. She underwent posterior decompression surgery and radiotherapy. Her neurological symptoms improved after radiotherapy, and the patient could maintain a standing position without assistance within one week after irradiation. She has since received adjuvant chemotherapy and continues to survive five years six months since MSCC onset.

Potential Anti-allergic Effects of Bibenzyl Derivatives from Liverworts, Radula perrottetii.

The liverwort Radula perrottetii contains various bibenzyl derivatives which are known to possess various biological activities, such as anti-inflammatory effects. Mast cells (MC) play crucial roles in allergic and inflammatory diseases; thus, inhibition of MC activation is pivotal for the treatment of allergic and inflammatory disorders. We investigated the effects of perrottetin D (perD), isolated from Radula perrottetii, and perD diacetate (Ac-perD) on antigen-induced activation of MCs. Bone marrow-derived MCs (BMMCs) were generated from C57BL/6 mice. The degranulation ratio, histamine release, and the interleukin (IL)-4 and leukotriene B4 productions on antigen-triggered BMMC were investigated. Additionally, the effects of the bibenzyls on binding of IgE to FcεRI were observed by flow cytometry, and signal transduction proteins was examined by Western blot. Furthermore, binding of the bibenzyls to the Fyn kinase domain was calculated. At 10 µM, perD decreased the degranulation ratio (p < 0.01), whereas 10 µM Ac-perD down-regulated IL-4 production (p < 0.05) in addition to decreasing the degranulation ratio (p < 0.01). Both compounds tended to decrease histamine release at a concentration of 10 µM. Although 10 µM perD reduced only Syk phosphorylation, 10 µM Ac-perD diminished phosphorylation of Syk, Gab2, PLC-γ, and p38. PerD appeared to selectively bind Fyn, whereas Ac-perD appeared to act as a weak but broad-spectrum inhibitor of kinases, including Fyn. In conclusion, perD and Ac-perD suppressed the phosphorylation of signal transduction molecules downstream of the FcεRI and consequently inhibited degranulation, and/or IL-4 production. These may be beneficial potential lead compounds for the development of novel anti-allergic and anti-inflammatory drugs.

Influence of Modulation Factor on Treatment Plan Quality and Irradiation Time in Hippocampus-Sparing Whole-Brain Radiotherapy Using Tomotherapy.

Objectives: Hippocampus-sparing whole-brain radiotherapy (HS-WBRT) using tomotherapy is known to provide a better dose distribution than volumetric-modulated arc therapy but requires an extended irradiation time. The present study aimed to investigate whether irradiation time can be shortened by reducing the modulation factor (MF) without losing the target dose distribution. Methods: Using six tilted computed tomography images in the head area, the planning target volume (PTV) and hippocampal doses, and the irradiation time was investigated with a jaw width of 1 cm, a pitch of 0.200, and the MF changed from 3.0 to 2.6, 2.2, 1.8, and 1.4. Results: No significant changes in the PTV or hippocampus were found with MF in the range from 3.0 to 1.8, but marked deterioration was found with that of 1.4. The irradiation time showed a linear relationship with the MF within the range from 3.0 to 1.8, with 1334, 1158, 986, and 817 s at modulation factors of 3.0, 2.6, 2.2, and 1.8, respectively. However, when the MF was 1.4, the irradiation time was 808 s. Conclusions: When HS-WBRT is performed with a tilted body position and a jaw width of 1 cm, with a MF of 1.8, a favorable balance between dose parameters and irradiation time is achieved, whereas with a MF of 1.4, the quality of the radiotherapy plan deteriorates, and the irradiation time is approximately the same as that with a MF of 1.8.

Palliative radiation treatment used for multiple purposes in a single irradiation field.

In this case report, radiation therapy was performed for bilateral hydronephrosis developed during multiple bone metastases of breast cancer and ileus due to peritoneal dissemination. The patient's preirradiation creatinine level was 8.2 mg/dL, which decreased by the fourth day after starting irradiation therapy. Creatinine level ultimately decreased to 0.6 mg/dL. Pain due to lumbar spine metastasis alleviated and ileus was resolved, allowing the patient to live at home for approximately 5 weeks. The effect of radiotherapy for bilateral hydronephrosis and gastrointestinal obstruction was rapid and good. Palliative radiation treatment can be used for multiple purposes, and in the present patient, we were able to prolong the vital prognosis.

Crystal Structures of Metallo-ß-Lactamase (IMP-1) and Its D120E Mutant in Complexes with Citrate and the Inhibitory Effect of the Benzyl Group in Citrate Monobenzyl Ester.

The emergence and rapid spread of carbapenem-resistant pathogens producing metallo-ß-lactamases such as IMP-1 and NDM-1 have been of great concern in the global clinical setting. The X-ray crystal structures of IMP-1 from Serratia marcescens and its single mutant, D120E, in complexes with citrate were determined at resolutions of 2.00 and 1.85 Å, respectively. Two crystal structures indicate that a single mutation at position 120 caused a structural change around Zn1, where the geometry changes from a tetrahedron in the native IMP-1 to a square pyramid in D120E. Based on these two complex structures, the authors synthesized citrate monobenzyl ester 1 to evaluate the structural requirement for the inhibitory activity against IMP-1 and compared the inhibitory activities with nonsubstituted citrate. The introduction of a benzyl group into citrate enhanced the inhibitory activity in comparison to citrate (IC50 > 5 mM).

A Case of Suspected Radiation Recall Pneumonitis After a COVID-19 Infection.

We present the case of a 78-year-old woman who received definitive radiation therapy for small cell lung cancer three and a half years ago. She was asymptomatic when she tested positive for coronavirus disease 2019 (COVID-19). She then developed a rapid decline in respiratory status on day seven. Chest radiograph revealed a strong shadow at the prior irradiation site. Radiation recall reactions are usually caused by drug administration, but in this case, it was suspected to be caused by COVID-19.

Pretreatment PSA levels affects the completion rate of Ra-223 treatment.

The aim of this study was to review our initial experience of using radium 223 (Ra-223) for metastatic castration-resistant prostate cancer (CRPC) and to evaluate whether pretreatment PSA levels correlate with completion of Ra-223 treatment. In addition, we examined change ratios of PSA, ALP and BAP after the third administration to evaluate the correlation of these change ratios with completion of the subsequent Ra-223 treatment. Forty patients were enrolled in this retrospective study. Ra-223 treatment was considered completed in patients who received five or six administrations. Patient backgrounds and changes in biomarkers were compared between patient groups (complete vs. incomplete Ra-223 treatment). PSA levels before treatment were significantly lower in the complete compared with the incomplete group (cutoff value; 21.7). ALP and BAP levels had decreased after the third administration in the complete group, compared with baseline levels, while levels in the incomplete group had increased. Significant difference was seen in ALP levels, while was not seen in BAP levels between the two groups. Ra-223 treatment should be considered for CRPC with low PSA levels. Changes in PSA and ALP during Ra-223 treatment might provide markers to identify patients likely to complete Ra-223 treatment, with implications for prognosis.