Accuracy of patient dose estimation in cone beam computed tomography in breast irradiation by size-specific dose estimates with position correction.

This study aims to investigate the effects of the position correction of size-specific dose estimates (SSDE) on patient dose estimation in cone beam computed tomography (CBCT). The relationship between the phantom position and absorbed dose in the right breast was studied using optically stimulated luminescence dosimeters and a simulated human body phantom. The effect of position correction for CT dose index (CTDI) on SSDE was investigated in 51 patients who underwent right breast irradiation by comparing the SSDE with position correction and SSDE without position correction. The absorbed dose in the right breast tended to decrease by 10.2% as the phantom was placed away from the center of CBCT. The mean and standard deviation of SSDE were 2.54 ± 0.29 and 2.92 ± 0.30 mGy with and without position correction, respectively. The SSDE with position correction was 13.1% lower than that without position correction (p < 0.05). SSDE was different when the patient's torso center was located at the isocenter of CBCT, and when it was not. The same tendency was seen in the case of the breast. Therefore, if the center of the patient is not at the acquisition center of the CT scanner, position correction is required when estimating SSDE.

dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells.

Deficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5-Fluorouracil (5-FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5-FU and uracil misincorporation, we examined cancer cells treated with 2'-deoxy-5-fluorouridine (FdUrd) in the presence of TAS-114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS-114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5-FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5-FU incorporation into RNA. TAS-114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short-term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5-FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA-treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5-FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR.

Evaluation of the relationship between phantom position and computed tomography dose index in cone beam computed tomography when assuming breast irradiation.

This study aims to investigate the influence of the phantom position on weighted computed tomography dose index (CTDIw ) in cone beam computed tomography (CBCT) when assuming breast irradiation. Computed tomography dose index (CTDI) was measured by the x-ray volume imaging of CBCT using parameters for image-guided radiation therapy (IGRT) in right breast irradiation. The measurement points of CTDI ranged from 0 (center) to 16 cm in the right-left (RL) direction, and from 0 (center) to 7.5 cm in the anterior-posterior (AP) direction, which assumed right breast irradiation. A nonuniform change exists in the relative value of CTDIw when the phantom deviated from the isocenter of CBCT. The CTDIw was ~30% lower compared with the value at the isocenter of CBCT when the phantom deviated 7.5 and 16 cm at the AP and RL directions, respectively. This study confirmed the influence of the phantom position on the CTDI values of CBCT. The CTDI measured at the isocenter of CBCT overestimates that measured at the irradiation center of the breast.

[Evaluation of Dose Reduction of the Active Collimator in Multi Detector Row CT].

The purpose of this study was to evaluate the performance of active collimator by changing acquisition parameters and obtaining dose profiles in z-axis direction. Dose profiles along z-axis were obtained using XRQA2 Gafchromic film. As a result, the active collimator reduced overranging about 55% compared to that without the active collimator. In addition, by changing the combination of X-ray beam width (32 mm, 40 mm), pitch factor (1.4, 0.6), and the X-ray tube rotation time (0.5 s/rot, 1.0 s/rot), the overranging changed from 19.4 to 34.9 mm. Although the active collimator is effective for reducing overranging, it is necessary to adjust acquisition parameters by taking the properties of the active collimator for acquisition parameters, especially setting beam width, into consideration.

Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors-Part 2.

Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood-brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H(3))methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner.

Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors - Part 3.

Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pKa value of the acidic moiety. The resulting compound 9 exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound 9, 1-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner.

[Influence of Stx2 Subtype on Bacteriological Identification of Outbreaks of EHEC O157: H- Infections in Saitama City].

In 2013, two outbreaks of enterohemorrhagic Escherichia coli (EHEC) occurred in Saitama city. According to reports from each of the medical institutions that detected the EHEC isolates, the isolates seemed to differ in their production of Vero Toxin (VT / Shiga Toxin: Stx) since one isolate produced only Stx1 and the other produced both Stx1 and Stx2. However, a patient survey conducted by a public health center revealed that common foodstuffs had been consumed in both outbreaks. Because, the two EHEC isolates were newly detected from two people in one patient's family, we analyzed the phenotypic and genetic relationships among four isolates in total. All the isolates were serotyped as O157: H-, and both stx1 and stx2 were detected. Subsequently, all four isolates were shown to have the same pulsed-field gel electrophoresis (PFGE) banding pattern. The findings suggested that these isolates belonged to the same strain group. Among these cases, the isolates had stx2c which is one of the stx2 subtypes. Reportedly, some cases with the Stx2 subtype can not be detected using conventional tests for toxin. In addition, Stx2 can be overlooked as a result of this limitation of Stx-production tests. Both epidemiological research by public health centers and genetic analysis by prefectural and municipal public health institutes (PHIs) are very important for clarifying possible relationships among outbreaks, as in the present cases. Moreover, collaborations and networks among medical institutions, PHIs and public health centers should be further strengthened to prevent the spread of infections.

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor.

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.

[Identification of resistance and susceptibility to cefotaxime in EHEC O121 strains isolated from an outbreak at two nurseries].

A Shiga toxin 2 producing enterohemorrhagic Escherichia coli (EHEC) O121: H19 was isolated from a 2-year-old child who attending a nursery. An EHEC O121 outbreak in two nurseries (A, B), involving a total of 17 infected persons including 12 children, was revealed through contact investigation. The symptoms of all infected persons were almost all mild, and no one developed the hemolytic uremic syndrome. The combination use of desoxycholate-hydrogen sulfide-lactose (DHL) and CHROMagar STEC as selective isolation media was employed for efficient fecal examination. Nursery A and nursery B were combined as one group after the outbreak in nursery A was confirmed. As a result, EHEC O121 infected persons were also detected in children from nursery B. The 17 strains of EHEC O121 obtained from the total population showed almost the same pulsed-gel electrophoresis (PFGE) pattern, suggesting that these strains were very closely related. However, 13 of these 17 strains obtained from nursery A were susceptible to cefotaxime, whereas the remaining 4 strains obtained from nursery B showed cefotaxime resistance. A cefotaxime resistant Escherichia coli (E. coli) O86 strain was isolated in the stool specimen from a child who had been infected with the cefotaxime resistant EHEC O121. Both the cefotaxime resistant EHEC O121 and E. coli O86 had the same drug resistant gene (bla(CTX-M-1) group). The child was the index case of these 4 later cases and had received no antibiotics therapy prior to the laboratory examination. These findings suggested the possibility that an EHEC O121 strain had acquired a drug resistant gene from E. coli O86 in the digestive tract of the child.

[Effect of oral dexamethasone given 24 hours previously on docetaxel-induced edema: a retrospective study].

In Europe and the United States, beginning steroid treatment on the day before docetaxel(DTX)administration is recommended to reduce edema and/or hypersensitivity symptoms. In this study, we investigated the usefulness of starting steroid treatment on the day before DTX administration. Patients with breast cancer who received 4 or more cycles of DTX with or without trastuzumab or DTX and cyclophosphamide(TC)with or without trastuzumab as pre- or post-operative chemotherapy in our hospital between January 2010 and May 2012 were analyzed in this retrospective study. Patients were classified as those who started taking steroids on the day of DTX administration(GroupA: 62 patients)and those who started taking steroids on the day before DTX administration(GroupB: 47 patients). The incidence of edema and/or hypersensitivity was retrospectively compared between these groups after the completion of 4 cycles of chemotherapy. The incidence of edema was significantly lower in GroupB (n=12, 25.5%)than in GroupA (n=28, 45.2%; p=0.04). The onset of edema also tended to be later in GroupB. The incidence of hypersensitivity tended to be lower in GroupB(n=3, 6.4%)than in GroupA (n=8, 12.9%), although this difference was not statistically significant. These results suggest the benefit of steroid treatment started on the day before DTX administration in preventing the development of edema. Results also suggest that the onset of edema could be delayed by this administration method. We recommend that steroid premedication, which can lead to a reduction in adverse drug reactions to DTX, be used to help maintain patients' quality of life(QOL)and to support treatment continuation.

[Evaluation of over ranging in 64-slice multidetector-row computed tomography examinations for upper abdomen].

64-slice multidetector-row computed tomography (MDCT) have become widely used in recent years, but there is a possibility that a large volume of dose is radiated at the outside of the scope of scanning due to the effect of over ranging (OR). In this research, the dose volume change at the outside of the scope of scanning in the case of X-ray beam width (BW) and pitch factor (PF) is measured, and the effect of BW and PF on OR is considered. We scanned the upper abdomen of an acrylic human phantom using 64-slice multidetector-row CT in 4 conditions while changing BW and PF. We then measured the dose volume absorbed in the breasts, ovary, uterus, and the dose profile on the surface of phantom. As a result, when BW and PF are increased, the dose volume radiated at the outside of the scope of scanning increased, and the effect of OR appeared. Therefore, when BW and PF are set, X-ray radiated at the outside of the scope of scanning should also be considered.

[Efficacy of L-shaped Shielding in Interventional Radiology by Transradial Approach and Consideration of Methods for Appropriate Use].

The present study investigated how effective an L-shaped shield was, depending on its position, in reducing a doctor's exposure to radiation during catheterization to access the transradial approach (TRA). The shield's effectiveness was evaluated by measuring the air kerma where the doctor stood under four conditions: with and without the shield, and with and without the shield in conjunction with conventional protection. To enable the shield to be positioned correctly in clinical practice, an illustrated instruction decal affixable to the shield's doctor-facing surface was produced, and the effectiveness of the decal was verified by means of a crossover test in which, as subjects of the study, different nurses set up the shield with and without the decal affixed to it. In the test, in which a human body phantom was used, the C-arm set at the PA angle, and the shield positioned 10 cm from the axilla of the phantom, the shield's effectiveness at 100 cm, 130 cm, and 160 cm above the floor where the doctor stood was 55%, 77%, and 47%, respectively. The effectiveness increased when the shield was positioned closer to the axilla. A significant difference in the positioning of the shield by the subjects was observed depending on whether or not the decal was affixed ( p<0.05, Wilcoxon signed-rank test), indicating that the use of the decal improved the positioning. It was concluded that, positioned correctly, the shield could effectively reduce the doctor's exposure to radiation during TRA.

Single-stranded DNA catenation mediated by human EVL and a type I topoisomerase.

The human Ena/Vasp-like (EVL) protein is considered to be a bifunctional protein, involved in both actin remodeling and homologous recombination. In the present study, we found that human EVL forms heat-stable multimers of circular single-stranded DNA (ssDNA) molecules in the presence of a type I topoisomerase in vitro. An electron microscopic analysis revealed that the heat-stable ssDNA multimers formed by EVL and topoisomerase were ssDNA catemers. The ssDNA catenation did not occur when either EVL or topoisomerase was omitted from the reaction mixture. A deletion analysis revealed that the ssDNA catenation completely depended on the annealing activity of EVL. Human EVL was captured from a human cell extract by TOPO IIIα-conjugated beads, and the interaction between EVL and TOPO IIIα was confirmed by a surface plasmon resonance analysis. Purified TOPO IIIα catalyzed the ssDNA catenation with EVL as efficiently as the Escherichia coli topoisomerase I. Since the ssDNA cutting and rejoining reactions, which are the sub-steps of ssDNA catenation, may be an essential process in homologous recombination, EVL and TOPO IIIα may function in the processing of DNA intermediates formed during homologous recombination.

Establishment of a Prediction Model for Overall Survival after Stereotactic Body Radiation Therapy for Primary Non-Small Cell Lung Cancer Using Radiomics Analysis.

Stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) leads to recurrence in approximately 18% of patients. We aimed to extract the radiomic features, with which we predicted clinical outcomes and to establish predictive models. Patients with primary non-metastatic NSCLC who were treated with SBRT between 2002 and 2022 were retrospectively reviewed. The 358 primary tumors were randomly divided into a training cohort of 250 tumors and a validation cohort of 108 tumors. Clinical features and 744 radiomic features derived from primary tumor delineation on pre-treatment computed tomography were examined as prognostic factors of survival outcomes by univariate and multivariate analyses in the training cohort. Predictive models of survival outcomes were established from the results of the multivariate analysis in the training cohort. The selected radiomic features and prediction models were tested in a validation cohort. We found that one radiomic feature showed a significant difference in overall survival (OS) in the validation cohort (p = 0.044) and one predicting model could estimate OS time (mean: 37.8 months) similar to the real OS time (33.7 months). In this study, we identified one radiomic factor and one prediction model that can be widely used.

TAS1553, a small molecule subunit interaction inhibitor of ribonucleotide reductase, exhibits antitumor activity by causing DNA replication stress.

Ribonucleotide reductase (RNR) is composed of two non-identical subunits, R1 and R2, and plays a crucial role in balancing the cellular dNTP pool, establishing it as an attractive cancer target. Herein, we report the discovery of a highly potent and selective small-molecule inhibitor, TAS1553, targeting protein-protein interaction between R1 and R2. TAS1553 is also expected to demonstrate superior selectivity because it does not directly target free radical or a substrate binding site. TAS1553 has shown antiproliferative activity in human cancer cell lines, dramatically reducing the intracellular dATP pool and causing DNA replication stress. Furthermore, we identified SLFN11 as a biomarker that predicts the cytotoxic effect of TAS1553. Oral administration of TAS1553 demonstrated robust antitumor efficacy against both hematological and solid cancer xenograft tumors and also provided a significant survival benefit in an acute myelogenous leukemia model. Our findings strongly support the evaluation of TAS1553 in clinical trials.

Role of vasopressin V(1A) receptor in the urethral closure reflex in rats.

An enhanced urethral closure reflex via the spinal cord is related to urethral resistance elevation during increased abdominal pressure. However, with the exception of monoamines, neurotransmitters modulating this reflex are not understood. We investigated whether the vasopressin V(1A) receptor (V(1A)R) is involved in the urethral closure reflex in urethane-anesthetized female rats. V(1A)R mRNA was highly expressed among the vasopressin receptor family in the total RNA purified from lamina IX in the spinal cord L6-S1 segment. In situ hybridization analysis of the spinal L6-S1 segment confirmed that these positive signals from the V(1A)Rs were only detected in lamina IX. Intrathecally injected Arg8-vasopressin (AVP), an endogenous ligand, significantly increased urethral resistance during an intravesical pressure rise, and its effect was blocked by the V(1A)R antagonist. AVP did not increase urethral resistance in rats in which the pelvic nerves were transected bilaterally. Urethral closure reflex responses to the intravesical pressure rise increased by up to threefold compared with the baseline response after AVP administration in contrast to no increase by vehicle. In addition, intravenously and intrathecally injected V(1A)R antagonists decreased urethral resistance. These results suggest that V(1A)R stimulation in the spinal cord enhances the urethral closure reflex response, thereby increasing urethral resistance during an abdominal pressure rise and that V(1A)R plays a physiological role in preventing urine leakage.

Synthesis of 6-F-ergosterol and its influence on membrane-permeabilization of amphotericin B and amphidinol 3.

Two well-known antifungals, amphotericin B (AmB) and amphodinol 3 (AM3), are thought to exert antifungal activity by forming ion-permeable channels or pores together with sterol molecules. However, detailed molecular recognitions for AmB-sterol and AM3-sterol in lipid bilayers have yet to be determined. Toward (19)F NMR-based investigation of the molecular recognition underlying their potent antifungal activity, we synthesized 6-fluoro-ergosterol in five steps via ring opening of (5α,6α)-epoxide of ergosterol acetate with using novel combination of TiF(4) and n-Bu(4)N(+)Ph(3)SiF(2)(-). Then we evaluated its activity of promoting pore formation of AmB and AM3, and found that pore formation of AmB was barely promoted by 6-F-ergosterol in clear contrast to the dramatic promotion effect of unmodified ergosterol, whereas AM3 activity was markedly enhanced in the presence of 6-F-ergosterol, which was comparable to that of unmodified ergosterol. These results indicate that the introduction of an F atom at C6 position of ergosterol plays an inhibitory role in interacting with AmB, but it is not the case with AM3.

[Etiology and management of venous pain during intravenous administration of oxaliplatin].

In Japan, XELOX (capecitabine plus oxaliplatin) was approved for the treatment of advanced/recurrent colorectal cancer in September 2009. However, patients treated with XELOX sometimes experience intense, sporadic venous pain during administration of oxaliplatin through peripheral vein. To investigate the etiology and management of this event, we measured the titratable acidity, osmotic pressure, and pH of 5% dextrose in water (D5W) containing oxaliplatin with or without dexamethasone. The dexamethasone-containing solution was then tested for its efficacy in venous pain relief. D5W containing oxaliplatin had a pH of approximately 4. 8, whereas the titratable acidity and osmotic pressure were 0. 1 mEq/L and 300-320 mOsm/L, respectively, suggesting that the venous pain was partly attributable to the pH.When 1. 65-6. 6 mg of dexamethasone was added to this solution, the pH of the resulting solution was increased to 6. 5-7. 6. Moreover, pain was relieved in patients administered oxaliplatin with dexamethasone in D5W. When adjusted for pH by the addition of 1. 65-3. 3 mg of dexamethasone, oxaliplatin in D5W is associated with less venous pain without decreasing oxaliplatin content although it is not generally recommended to dissolve oxaliplatin in a basic solution since it is unstable under alkaline conditions.

[Examination about the influence for daily life that nail and skin disorders induced by docetaxel in patients with breast cancer].

Docetaxel is one of the most important chemotherapeutic agents for the breast cancer patients. However, it has also experienced as toxicities causing nail diformation and skin trouble, and is considered as adverse elements other than edema and neurotoxicity. It is expected to have tremendous influence on women's daily life-decrease in quality of life. Nail and skin toxicity might occur among patients treated with docetaxel more frequently than evidence in the clinical medical records. Therefore, we have conducted a questionnaire investigation, targeting the patients who had been treated with docetaxel. Between March, 2004 and February, 2006, 52 patients, who had been prescribed docetaxel at the time of the surgery, or for their relapse, became subject to the evaluation. Skin impediments have found most during the second and the third courses; the contents include discomfort towards their beauty and housework. Influence to their daily life that the patients feel do not necessarily match the contents that doctors have recognized. In conclusion, this investigation evidenced that the troubles on quality of life such as nail and skin troubles, should be paid more attention, as well as major side effects such as edema, neutropenia, and neurotoxicity.

[A case of unresectable advanced pancreatic cancer treated by gemcitabine-based chemotherapy following cancer pain alleviation by low-dose matrix-type transdermal fentanyl].

Cancer pain often makes patient's performance status worsen and is one of the difficulties in anti-cancer therapy. We report a case of unresectable advanced pancreatic cancer with cancer pain, which was treated by matrix-type transdermal fentanyl following slow-releasing oxycodone, which caused severe constipation. Rotation to matrix-type transdermal fentanyl (Durotep MT 2.1 mg) releaved severe constipation as well as cancer pain. The patient could take gemcitabine-based chemotherapy. Low-dose matrix-type transdermal fentanyl (Durotep MT 2.1 mg) is useful for opioid rotation from low-dose morphine or oxycodone with uncontrolled side effects, and it contributes to continuation of anti-cancer therapy.