Fatigue in patients with cancer receiving outpatient chemotherapy: a prospective two-center study.

BACKGROUND: Cancer-related fatigue (CRF) is one of the most common symptoms in patients with cancer. However, CRF has not been sufficiently evaluated as it involves various factors. In this study, we evaluated fatigue in patients with cancer receiving chemotherapy in an outpatient setting. METHODS: Patients with cancer receiving chemotherapy at the outpatient treatment center of Fukui University Hospital and Saitama Medical University Medical Center Outpatient Chemotherapy Center were included. The survey period was from March 2020 to June 2020. The frequency of occurrence, time, degree, and related factors were examined. All patients were asked to fill out the Edmonton Symptom Assessment System Revised Japanese version (ESAS-r-J) questionnaire, which is a self-administered rating scale, and patients with ESAS-r-J "Tiredness" scores of ≥ 3 were evaluated for factors related to tiredness, such as age, sex, weight, and laboratory parameters. RESULTS: A total of 608 patients were enrolled in this study. Fatigue after chemotherapy occurred in 71.0% of patients. ESAS-r-J "Tiredness" scores of ≥ 3 were observed in 20.4% of patients. The factors related to CRF were low hemoglobin level and high C-reactive protein level. CONCLUSIONS: Twenty percent of patients receiving cancer chemotherapy on an outpatient basis had moderate or severe CRF. Patients with anemia and inflammation are at increased risk of developing fatigue after cancer chemotherapy.

Association of methicillin resistance with mortality of hospital-acquired Staphylococcus aureus bacteremia.

OBJECTIVE: Methicillin-resistant (MR) Staphylococcus aureus bacteremia (SAB) is associated with higher mortality rates than methicillin-susceptible (MS) SAB. This study assessed potential predictors of mortality and evaluated the association of methicillin resistance with mortality in patients with SAB. METHODS: We conducted a retrospective cohort study in patients with hospital-acquired SAB, from 2009 to 2018. Clinical features of patients with MR-SAB were compared with those of patients with MS-SAB and predictors of 30-day mortality were determined using Cox regression analysis. RESULTS: Among 162 patients, 56.8% had MR-SAB. Overall 30-day mortality was 19.1%; MR-SAB had higher mortality (25.0%) than MS-SAB (11.4%). Univariate analysis highlighted long-term hospitalization, prior antibiotics use, and delayed initiation of appropriate antibiotics as risk factors. Cox regression analysis showed that respiratory tract source, Pitt bacteremia score, Charlson comorbidity index, and appropriate antibiotic therapy within 24 hours were independently and significantly associated with 30-day mortality outcome. CONCLUSIONS: Methicillin resistance was not an independent risk factor for mortality in patients with SAB. Early, appropriate antibiotic treatment is an important prognostic factor.

Corrigendum: Loss-of-Function of a Tomato Receptor-Like Kinase Impairs Male Fertility and Induces Parthenocarpic Fruit Set.

[This corrects the article DOI: 10.3389/fpls.2019.00403.].

Population pharmacokinetic model development and exposure-response analysis of vincristine in patients with malignant lymphoma.

PURPOSE: Vincristine (VCR) is a key drug for treating various malignancies. However, few data are available on the pharmacokinetics of VCR, especially in adult patients. The objective of this study was to clarify the population pharmacokinetics and exposure-response relationships of VCR in adult malignant lymphoma patients. METHODS: Blood samples were collected from patients who were administered R-CHOP-like regimens, and the VCR plasma concentration was determined using liquid chromatography-mass spectrometry. Using NONMEM software, population pharmacokinetic parameters were estimated, and covariates were evaluated. The relationships between the individual parameters and adverse events or therapeutic effects were also investigated. RESULTS: Plasma concentrations were measured in 30 patients. In the final population pharmacokinetics model, body surface area and age were incorporated into clearance as significant covariates. The inter-individual variations in clearance and volume of distribution in the central and third compartments were 17.0, 26.6, and 66.3%, respectively, and the residual variability in the plasma concentration was 23.8%. Although the variability observed in the volume of distribution was large, good predictability was obtained in the individual estimation. The severity of anemia and peripheral neuropathy was correlated with clearance and peak concentration, respectively (adjusted P = 0.040 and 0.024, respectively). In diffuse large B cell lymphoma patients, those with higher area under the curve and dose experienced longer progression-free survival (P = 0.023 and 0.013, respectively). CONCLUSION: The population pharmacokinetics of VCR were evaluated in adult malignant lymphoma patients. VCR pharmacokinetic data could explain in part the adverse events and prognosis of these patients.

Comparative genomics of muskmelon reveals a potential role for retrotransposons in the modification of gene expression.

Melon exhibits substantial natural variation especially in fruit ripening physiology, including both climacteric (ethylene-producing) and non-climacteric types. However, genomic mechanisms underlying such variation are not yet fully understood. Here, we report an Oxford Nanopore-based high-grade genome reference in the semi-climacteric cultivar Harukei-3 (378 Mb + 33,829 protein-coding genes), with an update of tissue-wide RNA-seq atlas in the Melonet-DB database. Comparison between Harukei-3 and DHL92, the first published melon genome, enabled identification of 24,758 one-to-one orthologue gene pairs, whereas others were candidates of copy number variation or presence/absence polymorphisms (PAPs). Further comparison based on 10 melon genome assemblies identified genome-wide PAPs of 415 retrotransposon Gag-like sequences. Of these, 160 showed fruit ripening-inducible expression, with 59.4% of the neighboring genes showing similar expression patterns (r > 0.8). Our results suggest that retrotransposons contributed to the modification of gene expression during diversification of melon genomes, and may affect fruit ripening-inducible gene expression.

Loss-of-Function of a Tomato Receptor-Like Kinase Impairs Male Fertility and Induces Parthenocarpic Fruit Set.

Parthenocarpy arises when an ovary develops into fruit without pollination/fertilization. The mechanisms involved in genetic parthenocarpy have attracted attention because of their potential application in plant breeding and also for their elucidation of the mechanisms involved in early fruit development. We have isolated and characterized a novel small parthenocarpic fruit and flower (spff) mutant in the tomato (Solanum lycopersicum) cultivar Micro-Tom. This plant showed both vegetative and reproductive phenotypes including dwarfism of floral organs, male sterility, delayed flowering, altered axillary shoot development, and parthenocarpic production of small fruits. Genome-wide single nucleotide polymorphism array analysis coupled with mapping-by-sequencing using next generation sequencing-based high-throughput approaches resulted in the identification of a candidate locus responsible for the spff mutant phenotype. Subsequent linkage analysis and RNA interference-based silencing indicated that these phenotypes were caused by a loss-of-function mutation of a single gene (Solyc04g077010), which encodes a receptor-like protein kinase that was expressed in vascular bundles in young buds. Cytological and transcriptomic analyses suggested that parthenocarpy in the spff mutant was associated with enlarged ovarian cells and with elevated expression of the gibberellin metabolism gene, GA20ox1. Taken together, our results suggest a role for Solyc04g077010 in male organ development and indicate that loss of this receptor-like protein kinase activity could result in parthenocarpy.

Multiplex exome sequencing reveals genome-wide frequency and distribution of mutations in the 'Micro-Tom' Targeting Induced Local Lesions in Genomes (TILLING) mutant library.

While the 'Micro-Tom' TILLING mutant library is used for a wide range of purposes, including both basic research of gene function and breeding of commercial cultivars, genome-wide distribution and frequency of mutations have not yet been thoroughly elucidated on a population scale. In this study, we developed a 96-plex exome sequencing method to identify and analyze mutations within the TILLING mutants that were developed in the University of Tsukuba. First, an Illumina paired-end sequencing coupled with 96-plex exome capture resulted in the acquisition of an exome sequence dataset with an average read count of 5.6 million for the 95 mutants. Over 98% of the capture target region could be covered by the short reads with an averaged read depth of 12.8, which enabled us to identify single nucleotide polymorphisms and Indels in a genome-wide manner. By subtracting intra-cultivar DNA variations that are present between wild-type 'Micro-Tom' lines, we identified 241,391 mutation candidates in 95 mutant individuals. Of these, 64,319 and 6,480 mutations were expected to cause protein amino acid substitutions or premature stop codon, respectively. Based on the exome mutation dataset, a mutant line designated 'TOMJPW601' was found to carry a premature stop codon mutation (W261*) in a putative auxin influx carrier gene SlLAX1 (Solyc09G014380), consistent with our previous report of its curly leaf phenotype. Our results suggested that a population-scale mutation database developed by multiplexed exome sequencing could be used for in silico mutant screening, which in turn could contribute to both gene function research and breeding programs.

Influence of UGT1A1 polymorphism on etoposide plus platinum-induced neutropenia in Japanese patients with small-cell lung cancer.

BACKGROUND: The association between UGT1A1 polymorphism and etoposide-induced toxicities is still not clear. The aim of this study was to assess the association between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and severe hematologic toxicities in Japanese patients receiving etoposide plus platinum chemotherapy for small-cell lung cancer. METHODS: This retrospective analysis included patients with small-cell lung cancer who had received their first-line chemotherapy with etoposide plus cisplatin or carboplatin, between October 2008 and April 2018, at the University of Fukui Hospital. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia as well as thrombocytopenia was evaluated. RESULTS: A total of 55 patients were enrolled. The incidence of grade 4 neutropenia during the first cycle of etoposide-based chemotherapy was higher in patients with homozygous (hmz) polymorphisms for UGT1A1*28 and *6 (*28/*28, *6/*6, and *6/*28) than in patients with wild-type (wt) (*1/*1) and heterozygous (htz) (*1/*28 and *1/*6) polymorphisms (88% vs 43% P = 0.03). The incidence of febrile neutropenia and grade 4 thrombocytopenia, however, was not significantly different. Multivariate analysis suggested that grade 4 neutropenia associated significantly with an hmz UGT1A1 genotype [odds ratio (OR) 11.3; P = 0.04] and administration of granulocyte colony-stimulating factor (G-CSF) before the neutrophil counts dropped to < 500 cells/µL (OR; P = 0.01). CONCLUSIONS: UGT1A1*28 and UGT1A1*6 mutations might be regarded as predictors for etoposide-induced grade 4 neutropenia.

Evidence of the functional role of the ethylene receptor genes SlETR4 and SlETR5 in ethylene signal transduction in tomato.

Ethylene receptors are key factors for ethylene signal transduction. In tomato, six ethylene receptor genes (SlETR1-SlETR6) have been identified. Mutations in different ethylene receptor genes result in different phenotypes that are useful for elucidating the roles of each gene. In this study, we screened mutants of two ethylene receptor genes, SLETR4 and SLETR5, from a Micro-Tom mutant library generated by TILLING. We identified two ethylene receptor mutants with altered phenotypes and named them Sletr4-1 and Sletr5-1. Sletr4-1 has a mutation between the transmembrane and GAF domains, while Sletr5-1 has a mutation within the GAF domain. Sletr4-1 showed increased hypocotyl and root lengths, compared to those of wild type plants, under ethylene exposure. Moreover, the fruit shelf life of this mutant was extended, titratable acidity was increased and total soluble solids were decreased, suggesting a reduced ethylene sensitivity. In contrast, in the absence of exogenous ethylene, the hypocotyl and root lengths of Sletr5-1 were shorter than those of the wild type, and the fruit shelf life was shorter, suggesting that these mutants have increased ethylene sensitivity. Gene expression analysis showed that SlNR was up-regulated in the Sletr5-1 mutant line, in contrast to the down-regulation observed in the Sletr4-1 mutant line, while the down-regulation of SlCTR1, SlEIN2, SlEIL1, SlEIL3, and SlERF.E4 was observed in Sletr4-1 mutant allele, suggesting that these two ethylene receptors have functional roles in ethylene signalling and demonstrating, for the first time, a function of the GAF domain of ethylene receptors. These results suggest that the Sletr4-1 and Sletr5-1 mutants are useful for elucidating the complex mechanisms of ethylene signalling through the analysis of ethylene receptors in tomato.

Genetic and functional characterization of Sg-4 glycosyltransferase involved in the formation of sugar chain structure at the C-3 position of soybean saponins.

Triterpenoid saponins are specialized metabolites, which are abundant in soybean seeds. They have a wide variety of effects on human health and physiology. The composition of sugar chain attached to the aglycone moiety of saponins can be controlled by genetic loci, such as Sg-1, 3, and 4. Among these, the homozygous recessive sg-4 impairs the accumulation of saponins that have an arabinose moiety at the second position of the C-3 sugar chain (i.e., saponins Ad and ßa) in the hypocotyls. In this study, we found that sg-4 cultivars are disabled in Glyma.01G046300 expression in hypocotyls. This gene encodes a putative glycosyltransferase (UGT73P10) and is a homolog of GmSGT2 (UGT73P2) whose recombinant protein has been previously shown, in vitro, to conjugate the second galactose moiety at the C-3 position of soyasapogenol B monoglucuronide (SBMG). The sg-4 phenotype (absence of saponins Ad and ßa in hypocotyls) was restored by introducing the Glyma.01G046300 genomic DNA fragment that was obtained from the Sg-4 cultivar 'Ibarakimame 7'. Although Glyma.01G046300 is expressed in the cotyledons even in the sg-4 cultivars such as 'Enrei', the induced premature stop codon mutation (W244*) resulted in impaired accumulation of saponin ßa in this tissue also in the 'Enrei' genetic background. Furthermore, the recombinant Glyma.01G046300 protein was shown to conjugate the second Ara moiety at the C-3 position of SBMG using UDP-Ara as a sugar donor. These results demonstrate that Sg-4 is responsible for conjugation of the second Ara moiety at the C-3 position of soybean saponins.

An improved assembly and annotation of the melon (Cucumis melo L.) reference genome.

We report an improved assembly (v3.6.1) of the melon (Cucumis melo L.) genome and a new genome annotation (v4.0). The optical mapping approach allowed correcting the order and the orientation of 21 previous scaffolds and permitted to correctly define the gap-size extension along the 12 pseudomolecules. A new comprehensive annotation was also built in order to update the previous annotation v3.5.1, released more than six years ago. Using an integrative annotation pipeline, based on exhaustive RNA-Seq collections and ad-hoc transposable element annotation, we identified 29,980 protein-coding loci. Compared to the previous version, the v4.0 annotation improved gene models in terms of completeness of gene structure, UTR regions definition, intron-exon junctions and reduction of fragmented genes. More than 8,000 new genes were identified, one third of them being well supported by RNA-Seq data. To make all the new resources easily exploitable and completely available for the scientific community, a redesigned Melonomics genomic platform was released at http://melonomics.net . The resources produced in this work considerably increase the reliability of the melon genome assembly and resolution of the gene models paving the way for further studies in melon and related species.

SlLAX1 is Required for Normal Leaf Development Mediated by Balanced Adaxial and Abaxial Pavement Cell Growth in Tomato.

Leaves are the major plant organs with a primary function for photosynthesis. Auxin controls various aspects of plant growth and development, including leaf initiation, expansion and differentiation. Unique and intriguing auxin features include its polar transport, which is mainly controlled by the AUX1/LAX and PIN gene families as influx and efflux carriers, respectively. The role of AUX1/LAX genes in root development is well documented, but the role of these genes in leaf morphogenesis remains unclear. Moreover, most studies have been conducted in the plant model Arabidopsis thaliana, while studies in tomato are still scarce. In this study, we isolated six lines of the allelic curly leaf phenotype 'curl' mutants from a γ-ray and EMS (ethyl methanesulfonate) mutagenized population. Using a map-based cloning strategy combined with exome sequencing, we observed that a mutation occurred in the SlLAX1 gene (Solyc09g014380), which is homologous to an Arabidopsis auxin influx carrier gene, AUX1 (AtAUX1). Characterization of six alleles of single curl mutants revealed the pivotal role of SlLAX1 in controlling tomato leaf flatness by balancing adaxial and abaxial pavement cell growth, which has not been reported in tomato. Using TILLING (Targeting Induced Local Lesions IN Genome) technology, we isolated an additional mutant allele of the SlLAX1 gene and this mutant showed a curled leaf phenotype similar to other curl mutants, suggesting that Solyc09g014380 is responsible for the curl phenotype. These results showed that SlLAX1 is required for normal leaf development mediated by balanced adaxial and abaxial pavement cell growth in tomato.

Isolation and Characterization of the Soybean Sg-3 Gene that is Involved in Genetic Variation in Sugar Chain Composition at the C-3 Position in Soyasaponins.

Soyasaponins are specialized metabolites present in soybean seeds that affect the taste and quality of soy-based foods. The composition of the sugar chains attached to the aglycone moiety of soyasaponins is regulated by genetic loci such as sg-1, sg-3 and sg-4. Here, we report the cloning and characterization of the Sg-3 gene, which is responsible for conjugating the terminal (third) glucose (Glc) at the C-3 sugar chain of soyasaponins. The gene Glyma.10G104700 is disabled in the sg-3 cultivar, 'Mikuriya-ao', due to the deletion of genomic DNA that results in the absence of a terminal Glc residue on the C-3 sugar chain. Sg-3 encodes a putative glycosyltransferase (UGT91H9), and its predicted protein sequence has a high homology with that of the product of GmSGT3 (Glyma.08G181000; UGT91H4), which conjugates rhamnose (Rha) to the third position of the C-3 sugar chain in vitro. A recombinant Glyma.10G104700 protein could utilize UDP-Glc as a substrate to conjugate the third Glc to the C-3 sugar chain, and introducing a functional Glyma.10G104700 transgene into the mutant complemented the sg-3 phenotype. Conversely, induction of a premature stop codon mutation in Glyma.10G104700 (W270*) resulted in the sg-3 phenotype, suggesting that Glyma.10G104700 was Sg-3. The gmsgt3 (R339H) mutant failed to accumulate soyasaponins with the third Rha at the C-3 sugar chain, and the third Glc and Rha conjugations were both disabled in the sg-3 gmsgt3 double mutant. These results demonstrated that Sg-3 and GmSGT3 are non-redundantly involved in conjugation of the third Glc and Rha at the C-3 sugar chain of soyasaponins, respectively.

Melonet-DB, a Grand RNA-Seq Gene Expression Atlas in Melon (Cucumis melo L.).

Melon (Cucumis melo L.) is an important Cucurbitaceae crop produced worldwide, exhibiting wide genetic variations and comprising both climacteric and non-climacteric fruit types. The muskmelon cultivar "'Earl's favorite Harukei-3 (Harukei-3)"' known for its sweetness and rich aroma is used for breeding of high-grade muskmelon in Japan. We conducted RNA sequencing (RNA-seq) transcriptome studies in 30 different tissues of the 'Harukei-3' melon. These included root, stems, leaves, flowers, regenerating callus and ovaries, in addition to the flesh and peel sampled at seven stages of fruit development. The expression patterns of 20,752 genes were determined with fragments per kilobase of transcript per million fragments sequenced (FPKM) >1 in at least one tissue. Principal component analysis distinguished 30 melon tissues based on the global gene expression profile and, further, the weighted gene correlation network analysis classified melon genes into 45 distinct coexpression groups. Some coexpression groups exhibited tissue-specific gene expression. Furthermore, we developed and published web application tools designated "'Gene expression map viewer"' and "'Coexpression viewer"' on our website Melonet-DB (http://melonet-db.agbi.tsukuba.ac.jp/) to promote functional genomics research in melon. By using both tools, we analyzed melon homologs of tomato fruit ripening regulators such as E8, RIPENING-INHIBITOR (RIN) and NON-RIPENING (NOR). The "'Coexpression viewer"' clearly distinguished fruit ripening-associated melon RIN/NOR/CNR homologs from those expressed in other tissues. In addition, several other MADS-box, NAM/ATAF/CUC (NAC) and homeobox transcription factor genes were identified as fruit ripening-associated genes. Our tools provide useful information for research not only on melon but also on other fleshy fruit plants.

Metabolic switching of astringent and beneficial triterpenoid saponins in soybean is achieved by a loss-of-function mutation in cytochrome P450 72A69.

Triterpenoid saponins are major components of secondary metabolites in soybean seeds and are divided into two groups: group A saponins, and 2,3-dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP) saponins. The aglycone moiety of group A saponins consists of soyasapogenol A (SA), which is an oxidized ß-amyrin product, and the aglycone moiety of the DDMP saponins consists of soyasapogenol B (SB). Group A saponins produce a bitter and astringent aftertaste in soy products, whereas DDMP saponins have known health benefits for humans. We completed map-based cloning and characterization of the gene Sg-5, which is responsible for SA biosynthesis. The naturally occurring sg-5 mutant lacks group A saponins and has a loss-of-function mutation (L164*) in Glyma15g39090, which encodes the cytochrome P450 enzyme, CYP72A69. An enzyme assay indicated the hydroxylase activity of recombinant CYP72A69 against SB, which also suggested the production of SA. Additionally, induced Glyma15g39090 mutants (R44* or S348P) lacked group A saponins similar to the sg-5 mutant, indicating that Glyma15g39090 corresponds to Sg-5. Endogenous levels of DDMP saponins were higher in the sg-5 mutant than in the wild-type lines due to the loss of the enzyme activity that converts SB to SA. Interestingly, the genomes of palaeopolyploid soybean and the closely related common bean carry multiple Sg-5 paralogs in a genomic region syntenic to the soybean Sg-5 region. However, SA did not accumulate in common bean samples, suggesting that Sg-5 activity evolved after gene duplication event(s). Our results demonstrate that metabolic switching of undesirable saponins with beneficial saponins can be achieved in soybean by disabling Sg-5.

NIN-like protein 8 is a master regulator of nitrate-promoted seed germination in Arabidopsis.

Seeds respond to multiple different environmental stimuli that regulate germination. Nitrate stimulates germination in many plants but how it does so remains unclear. Here we show that the Arabidopsis NIN-like protein 8 (NLP8) is essential for nitrate-promoted seed germination. Seed germination in nlp8 loss-of-function mutants does not respond to nitrate. NLP8 functions even in a nitrate reductase-deficient mutant background, and the requirement for NLP8 is conserved among Arabidopsis accessions. NLP8 reduces abscisic acid levels in a nitrate-dependent manner and directly binds to the promoter of CYP707A2, encoding an abscisic acid catabolic enzyme. Genetic analysis shows that NLP8-mediated promotion of seed germination by nitrate requires CYP707A2. Finally, we show that NLP8 localizes to nuclei and unlike NLP7, does not appear to be activated by nitrate-dependent nuclear retention of NLP7, suggesting that seeds have a unique mechanism for nitrate signalling.

The Inhibitory Effect of Ciprofloxacin on the ß-Glucuronidase-mediated Deconjugation of the Irinotecan Metabolite SN-38-G.

The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. ß-Glucuronidase, an intestinal bacteria-produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide-conjugated drugs. In this study, we established an in vitro system to evaluate the ß-glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G to its active SN-38 form and the effect of ciprofloxacin thereon. SN-38 formation increased in a time-dependent manner from 5 to 30 min. in the presence of ß-glucuronidase. Ciprofloxacin and phenolphthalein-ß-D-glucuronide (PhePG), a typical ß-glucuronidase substrate, significantly decreased SN-38-G deconjugation and, hence SN-38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN-38-G to SN-38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose-dependent inhibitory effect on the ß-glucuronidase-mediated conversion of SN-38-G to SN-38 with a half-maximal inhibitory concentration (IC50 ) value of 83.8 µM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non-competitive manner, respectively. These findings suggest that the reduction in the serum SN-38 concentration following co-administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN-38 through the non-competitive inhibition of intestinal ß-glucuronidase-mediated SN-38-G deconjugation.

The Glycine max cv. Enrei Genome for Improvement of Japanese Soybean Cultivars.

We elucidated the genome sequence of Glycine max cv. Enrei to provide a reference for characterization of Japanese domestic soybean cultivars. The whole genome sequence obtained using a next-generation sequencer was used for reference mapping into the current genome assembly of G. max cv. Williams 82 obtained by the Soybean Genome Sequencing Consortium in the USA. After sequencing and assembling the whole genome shotgun reads, we obtained a data set with about 928 Mbs total bases and 60,838 gene models. Phylogenetic analysis provided glimpses into the ancestral relationships of both cultivars and their divergence from the complex that include the wild relatives of soybean. The gene models were analyzed in relation to traits associated with anthocyanin and flavonoid biosynthesis and an overall profile of the proteome. The sequence data are made available in DAIZUbase in order to provide a comprehensive informatics resource for comparative genomics of a wide range of soybean cultivars in Japan and a reference tool for improvement of soybean cultivars worldwide.

Clinical effect of a multidisciplinary team approach to the initial treatment of patients with hospital-acquired bloodstream infections at a Japanese university hospital.

BACKGROUND: Hospital-acquired bloodstream infections (BSIs) are significant causes of mortality, and strategies to improve outcomes are needed. We aimed to evaluate the clinical efficacy of a multidisciplinary infection control team (ICT) approach to the initial treatment of patients with hospital-acquired BSI. METHODS: A before-after quasiexperimental study of patients with hospital-acquired BSI was performed in a Japanese university hospital. The ICT provided immediate recommendations to the attending physician about appropriate antimicrobial therapy and management after reviewing blood cultures, Gram's stain, final organism, and antimicrobial susceptibility results. RESULTS: The sample included 469 patients with hospital-acquired BSI (n = 210, preintervention group; n = 259, postintervention group). There were no significant differences between the groups in background or microbiologic characteristics. The 30-day mortality was significantly lower and significantly more patients received appropriate antimicrobial therapy in the postintervention group (22.9% vs 14.3%; P = .02 and 86.5% vs 69.0%; P < .001, respectively). Multivariate analysis confirmed that the ICT intervention was significantly associated with appropriate antimicrobial therapy (odds ratio, 2.22; 95% confidence interval, 1.27-3.89) and 30-day mortality (odds ratio, 0.49; 95% confidence interval, 0.25-0.95). CONCLUSIONS: A timely multidisciplinary team approach decreases the delay of appropriate antimicrobial treatment and may improve HABSI patient outcomes.

Variations in the Blood Phenytoin Levels during Long-Term Combined Treatment with S-1 and Phenytoin.

Although combination therapy with the oral fluoropyrimidine anticancer drug S-1 and the anticonvulsant phenytoin (PHT) is known to increase blood levels of PHT and the risk of intoxication, reports on long-term monitoring of blood levels of PHT during combined S-1 and PHT treatment and a thorough understanding of their interaction are lacking. This report aims to describe interactive effects of S-1 and PHT through long-term therapeutic drug monitoring of PHT. A 72-year-old male had been prescribed oral PHT (130 mg/day) for over 20 years and started receiving S-1 therapy (80 mg/day for 4 weeks, followed by a 2-week rest) as postoperative adjuvant chemotherapy for gastric cancer. The blood PHT level was continuously monitored. Prior to receiving S-1, the patient's blood PHT concentration was 6.0 µg/ml, but it increased during S-1 therapy, reaching 22.9 µg/ml on day 84 (during a rest period of second cycle S-1 therapy). After reducing his PHT dosage to 100 mg/day, it never reached toxic levels (4.0-10.4 µg/ml). It was difficult to keep blood PHT concentrations constant because of the time lag between the period of combined use of S-1 and PHT and the timing of manifestation and disappearance of the drug interaction. The DIPS probability scale indicated a highly probable interaction between S-1 and PHT. We conclude that, when S-1 and PHT are used concurrently, occurrence and disappearance time of their interaction need to be predicted to maintain an effective and safe PHT concentration.