Cross study analyses of SEND data: toxicity profile classification.

A SEND toxicology data transformation, harmonization and analysis platform was created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories. This work describes methods to analyze data and automate cross study analysis of toxicology studies. Cross study analysis can be used to understand a single compound's toxicity profile across all studies performed and/or to evaluate on-target versus off-target toxicity for multiple compounds intended for the same pharmacological target. This work involved development of data harmonization/transformation strategies to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND data sets from the BioCelerate database were used for the analyses. Toxicity profiles for key organ systems were developed for liver, kidney, male reproductive tract, endocrine system, and hematopoietic system using SEND domains. A Cross-Study Analysis dashboard with a built-in user-defined scoring system was created for custom analyses, including visualizations to evaluate data at the organ system level and drill down into individual animal data. This data analysis provides the tools for scientists to compare toxicity profiles across multiple studies using SEND. A cross-study analysis of two different compounds intended for the same pharmacological target is described and the analyses indicate potential on-target effects to liver, kidney, and hematopoietic systems.

Petroclival meningiomas: update of current treatment and consensus by the EANS skull base section.

BACKGROUND: The optimal management of petroclival meningiomas (PCMs) continues to be debated along with several controversies that persist. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the management of these tumors. To achieve this, the task force reviewed in detail the literature in this field and had formal discussions within the group. RESULTS: The constituted task force dealt with the existing definitions and classifications, pre-operative radiological investigations, management of small and asymptomatic PCMs, radiosurgery, optimal surgical strategies, multimodal treatment, decision-making, and patient's counselling. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the management of PCMs.

Evaluation of vascular anatomy for colon cancer located in the splenic flexure using the preoperative three-dimensional computed tomography angiography with colonography.

PURPOSE: The aim of this study is to reveal the vascular branching variation in SFC (splenic flexure cancer) patients using the preoperative three-dimensional computed tomography angiography with colonography (3D-CTAC). METHODS: We retrospectively analyzed patients with SFC who underwent preoperative 3D-CTAC between January 2014 and December 2019. RESULTS: Among 1256 colorectal cancer (CRC) patients, 96 (7.6%) manifested SFC. The arterial branching from the superior mesenteric artery (SMA) was classified into five patterns, as follows: (type 1A) the left branch of middle colic artery (LMCA) diverged from middle colic artery (MCA) (N = 47, 49.0%); (2A) the LMCA diverged from the MCA and the accessory middle colic artery (AMCA) (N = 26, 27.1%); (3A) the LMCA independently diverged from the SMA (N = 16, 16.7%); (4A) the LMCA independently diverged from the SMA and AMCA (N = 3, 3.1%); (5A) only the AMCA and the LMCA was absent (N = 4, 4.1%). Venous drainage was classified into four patterns, as follows: (type 1V) the SFV flows into the inferior mesenteric vein (IMV) then back to the splenic vein (N = 50, 52.1%); (2V) the SFV flows into the IMV then back to the superior mesenteric vein (SMV) (N = 19, 19.8%); (type 3V) the SFV independently flows into the splenic vein (N = 3, 3.1%); (type 4V) the SFV is absent (N = 24, 25.0%). CONCLUSION: 3D-CTAC could reveal accurate preoperative tumor localization and vascular branching. These classifications should be helpful in performing accurate complete mesocolic excision and central vessel ligation for SFC.

Factors associated with possession of accurate knowledge regarding occupational health management among operations leaders of radiation decontamination workers in Fukushima, Japan: a cross-sectional study.

OBJECTIVES: An operations leader (OL) takes an important role in occupational health management for radiation decontamination workers in Japan, and candidates for the position must participate in a training session to acquire the necessary knowledge as required by law. However, it has not been clarified whether the candidates for the OL position actually possess accurate knowledge regarding occupational health management for such work after the training session. We, therefore, aimed at examining the current occupational health management knowledge among the candidates and investigating factors related to the knowledge, with hypothesis that possession of accurate knowledge is associated with prior experience of having worked in radiation decontamination. DESIGN: A cross-sectional study. SETTING: The training sessions held by Fukushima Prefecture Labor Standard Associations in Fukushima, Japan, in 2017. PARTICIPANTS: Eighty male candidates participated in the training sessions. OUTCOME: The number/proportion of correct answers to the questions regarding occupational health management, such as those on working environment management, control of operations and health management. RESULTS: The proportion of those who possessed accurate knowledge regarding working environment management, control of operations and health management was 68.8%, 55.0% and 51.2%, respectively. Experience of radiation decontamination work was associated with the possession of inaccurate knowledge regarding working environment management (OR 0.140 (95% CI 0.042 to 0.464)), and the uncertainty of future radiation decontamination work schedules in difficult-to-return zones was associated with the possession of accurate knowledge regarding health management (OR 4.344 (95% CI 1.509 to 12.50)). CONCLUSIONS: Previous experience in radiation decontamination work may hinder the ability to acquire accurate information regarding working environment management among candidates for an OL position. To promote adequate occupational health management for radiation decontamination workers, it is required to establish an effective instructional method for the OL candidate training sessions with consideration of previous relevant experience.

High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis.

Both proto-oncogenic and tumor-suppressive functions have been reported for enhancer of zeste homolog 2 (EZH2). To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2-dSET). In a mouse bone marrow transplant model, EZH2-dSET expression in bone marrow cells induced a myelodysplastic syndrome (MDS)-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched. Interestingly, ABCG2 expression is specifically high in MDS patients. The present results indicate that ABCG2 de-repression induced by EZH2 mutations have crucial roles in MDS pathogenesis.

Chapter Seven - When Phosphorylation Encounters Ubiquitination: A Balanced Perspective on IGF-1R Signaling.

Cell-surface receptors govern the critical information passage from outside to inside the cell and hence control important cellular decisions such as survival, growth, and differentiation. These receptors, structurally grouped into different families, utilize common intracellular signaling-proteins and pathways, yet promote divergent biological consequences. In rapid processing of extracellular signals to biological outcomes, posttranslational modifications offer a repertoire of protein processing options. Protein ubiquitination was originally identified as a signal for protein degradation through the proteasome system. It is now becoming increasingly recognized that both ubiquitin and ubiquitin-like proteins, all evolved from a common ubiquitin structural superfold, are used extensively by the cell and encompass signal tags for many different cellular fates. In this chapter we examine the current understanding of the ubiquitin regulation surrounding the insulin-like growth factor and insulin signaling systems, major members of the larger family of receptor tyrosine kinases (RTKs) and key regulators of fundamental physiological and pathological states.

Successful treatment of toxoplasmic encephalitis diagnosed early by polymerase chain reaction after allogeneic hematopoietic stem cell transplantation: two case reports and review of the literature.

Toxoplasmic encephalitis represents a rare, but often fatal infection after allogeneic hematopoietic stem cell transplantation. Polymerase chain reaction (PCR)-based preemptive therapy is considered promising for this disease, but is not routinely applied, especially in low seroprevalence countries including Japan. We encountered 2 cases of toxoplasmic encephalitis after transplantation that were successfully treated. The diagnosis of toxoplasmic encephalitis in these cases was confirmed by PCR testing when neurological symptoms were observed. Both patients received pyrimethamine and sulfadiazine treatments within 2 weeks of the development of neurological symptoms, and remained free of recurrence for 32 and 12 months. These results emphasized the importance of the PCR test and immediate treatment after diagnosis for the management of toxoplasmic encephalitis.

Characteristic patterns of relapse after allogeneic hematopoietic SCT for adult T-cell leukemia-lymphoma: a comparative study of recurrent lesions after transplantation and chemotherapy by the Nagasaki Transplant Group.

Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (P<0.001). Furthermore, relapse with a new lesion only in the absence of the primary lesion was more frequent in allo-SCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.

First principles studies of GeTe based dilute magnetic semiconductors.

The electronic structure and magnetic properties of GeTe-based dilute magnetic semiconductors (DMS) are investigated by the Korringa-Kohn-Rostoker Green's function method and the projector augmented wave method. Our calculations for the formation energies of transition metal impurities (TM) in GeTe indicate that the solubilities of TM are quite high compared to typical III-V and II-VI based DMS and that the TM doped GeTe has a possibility of room temperature ferromagnetism with high impurity concentrations. The high solubilities originate from the fact that the top of the valence bands of GeTe consists of the Te-5p anti-bonding states which are favorable to acceptor doping. (Ge, Cr)Te system shows strong ferromagnetic interaction by the double exchange mechanism and is a good candidate for DMS with high Curie temperature. Additionally, in the case of (Ge, Mn)Te with the d(5) configuration, by introducing the Ge vacancies the p-d exchange interaction is activated and it dominates the antiferromagnetic superexchange, resulting in ferromagnetic exchange interactions between Mn. This explains recent experimental results reasonably. Based on the accurate estimation of the Curie temperatures by Monte Carlo simulation for the classical Heisenberg model with the calculated exchange coupling constants, we discuss the relevance of the TM doped GeTe for semiconductor spintronics.

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia.

Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30-50 mg m(-2) in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m(-2), P=0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

Computational materials design of negative effective U system in hole-doped chalcopyrite CuFeS2.

A general rule of negative effective U(U(eff)) system caused by (i) exchange correlation and (ii) charge excitation mechanisms is proposed. Based on the general rule, we perform ab initio electronic structure calculations by generalized gradient approximation (GGA) + U method for hole-doped chalcopyrite CuFeS2 [Cu(+)(d(10))Fe(3+)(d(5))S(2-)(s(2)p(6))2]. It is found from our calculations that the hole-doped CuFeS2 has the negative U(eff) = -0.44 eV, where U(eff) ≡ E(N + 1) + E(N - 1) - 2E(N) < 0 and E(N) is the total energy of the hole-doped CuFeS2. The negative U(eff) is caused by the charge-excitation in the hole-doped Cu(2+)(d(9)) and S(-)(s(2)p(5)), and also caused by the exchange-correlation in the hole-doped Fe(4+)(d(4)). The strong attractive electron-electron interaction (U(eff) = -0.44 eV ∼ -5000 K) originates from the purely electronic mechanism. The closed shell of the d(10) electronic configuration is more stable than the d(9) electronic configuration, since the first excited state with the d(9)s(1) electronic configuration and the ground state with the d(10) electronic configuration are very close, then these two states repel very strongly through the second order perturbation. Therefore, the spin-polarized total energy curve for the hole-doped CuFeS2 shows the strong upward convexity with N - 1, N and N + 1 electronic configurations leading to the negative U(eff). The hole-doped paramagnetic and metallic CuFeS2 with the negative U(eff) may cause a possible high-Tc superconductor (Tc ∼ 1000 K, if 2Δ/kBTc ≈ 10 by assuming a strong coupling regime) because of the strong attractive electron-electron interactions (superconducting gap Δ ≈ |U(eff|) ∼ 5000 K). Finally, we propose a new computational materials design methodology to design ultra high-Tc superconductors by using three steps starting from the atomic number only.

Hubbard U calculations for gap states in dilute magnetic semiconductors.

On the basis of constrained density functional theory, we present ab initio calculations for the Hubbard U parameter of transition metal impurities in dilute magnetic semiconductors, choosing Mn in GaN as an example. The calculations are performed by two methods: (i) the Korringa-Kohn-Rostoker (KKR) Green function method for a single Mn impurity in GaN and (ii) the full-potential linearized augmented plane-wave (FLAPW) method for a large supercell of GaN with a single Mn impurity in each cell. By changing the occupancy of the majority t2 gap state of Mn, we determine the U parameter either from the total energy differences E(N + 1) and E(N - 1) of the (N ± 1)-electron excited states with respect to the ground state energy E(N), or by using the single-particle energies for n(0) ± 1/2 occupancies around the charge-neutral occupancy n0 (Janak's transition state model). The two methods give nearly identical results. Moreover the values calculated by the supercell method agree quite well with the Green function values. We point out an important difference between the 'global' U parameter calculated using Janak's theorem and the 'local' U of the Hubbard model.

Expression of myeloperoxidase in acute myeloid leukemia blasts mirrors the distinct DNA methylation pattern involving the downregulation of DNA methyltransferase DNMT3B.

Myeloperoxidase (MPO) has been associated with both a myeloid lineage commitment and favorable prognosis in patients with acute myeloid leukemia (AML). DNA methyltransferase inhibitors (decitabine and zeburaline) induced MPO gene promoter demethylation and MPO gene transcription in AML cells with low MPO activity. Therefore, MPO gene transcription was directly and indirectly regulated by DNA methylation. A DNA methylation microarray subsequently revealed a distinct methylation pattern in 33 genes, including DNA methyltransferase 3 beta (DNMT3B), in CD34-positive cells obtained from AML patients with a high percentage of MPO-positive blasts. Based on the inverse relationship between the methylation status of DNMT3B and MPO, we found an inverse relationship between DNMT3B and MPO transcription levels in CD34-positive AML cells (P=0.0283). In addition, a distinct methylation pattern was observed in five genes related to myeloid differentiation or therapeutic sensitivity in CD34-positive cells from AML patients with a high percentage of MPO-positive blasts. Taken together, the results of the present study indicate that MPO may serve as an informative marker for identifying a distinct and crucial DNA methylation profile in CD34-positive AML cells.

The fallopian canal: a comprehensive review and proposal of a new classification.

INTRODUCTION: The facial nerve follows a complex course through the skull base. Understanding its anatomy is crucial during standard skull base approaches and resection of certain skull base tumors closely related to the nerve, especially, tumors at the cerebellopontine angle. METHODS: Herein, we review the fallopian canal and its implications in surgical approaches to the skull base. Furthermore, we suggest a new classification. CONCLUSIONS: Based on the anatomy and literature, we propose that the meatal segment of the facial nerve be included as a component of the fallopian canal. A comprehensive knowledge of the course of the facial nerve is important to those who treat patients with pathology of or near this cranial nerve.

Effects of green tea extract and (-)-epigallocatechin-3-gallate on pharmacokinetics of nadolol in rats.

Green tea catechins have been shown to affect the activities of drug transporters in vitro, including P-glycoprotein and organic anion transporting polypeptides. However, it remains unclear whether catechins influence the in vivo disposition of substrate drugs for these transporters. In the present study, we investigated effects of green tea extract (GTE) and (-)-epigallocatechin-3-gallate (EGCG) on pharmacokinetics of a non-selective hydrophilic ß-blocker nadolol, which is reported to be a substrate for several drug transporters and is not metabolized by cytochrome P450 enzymes. Male Sprague-Dawley rats received GTE (400 mg/kg), EGCG (150 mg/kg) or saline (control) by oral gavage, 30 min before a single intragastric administration of 10 mg/kg nadolol. Plasma and urinary concentrations of nadolol were determined using high performance liquid chromatography. Pharmacokinetic parameters were estimated by a noncompartmental analysis. Pretreatment with GTE resulted in marked reductions in the maximum concentration (Cmax) and area under the time-plasma concentration curve (AUC) of nadolol by 85% and 74%, respectively, as compared with control. In addition, EGCG alone significantly reduced Cmax and AUC of nadolol. Amounts of nadolol excreted into the urine were decreased by pretreatments with GTE and EGCG, while the terminal half-life of nadolol was not different among groups. These results suggest that the coadministration with green tea catechins, particularly EGCG, causes a significant alteration in the pharmacokinetics of nadolol, possibly through the inhibition of its intestinal absorption mediated by uptake transporters.

Gabriele Fallopio (1523-1562) and his contributions to the development of medicine and anatomy.

INTRODUCTION: Gabriele Fallopio was one of the greatest anatomists of the sixteenth century. He discovered and named numerous parts of the human body. His name survives to this day as it is associated with several anatomical structures including the Fallopian canal, Fallopian hiatus, Fallopian valve, Fallopian muscle, and the Fallopian tube. CONCLUSIONS: Our current knowledge of human anatomy is based on giants such as Fallopio. His contributions to neuroanatomy laid the foundations for the development of this discipline.

The influence of salinity and ammonium levels on amoA mRNA expression of ammonia-oxidizing prokaryotes.

This study investigated the influence of salinity and ammonium levels on ammonia-oxidizing bacteria (AOB) and archaea (AOA) by monitoring their amo subunit A (amoA) messenger RNA (mRNA) expression. The aerobic mini-continuous stirred-tank reactors (mini-CSTRs) were operated for 48 h under different salinity or ammonium levels. Quantification of archaeal and bacterial amoA mRNA levels using real-time reverse transcription polymerase chain reaction, combined with terminal restriction fragment length polymorphism (T-RFLP) analysis, was applied to investigate the differential transcriptional responses among AOA species. High salinity levels repressed both archaeal and bacterial amoA mRNA expressions. On the other hand, high ammonium levels repressed only archaeal mRNA expression, suggesting that ammonium is a significant environmental factor shaping abundance of AOA and AOB. T-RFLP results indicated that the impacts of salinity and ammonium levels were different among AOA species. Although further study is necessary to add significance to our findings, the combination of the short-term mini-CSTR operations and amoA mRNA-based analyses allow a preliminary study on the influences of environmental factors on competition between the AOA and AOB communities.