Purpose
Hand–foot syndrome (HFS) is a typical skin disorder caused by the use of cytotoxic anticancer drugs and molecular targets. Similarly, various anticancer drugs have been used as a conditioning ...regimen for hematopoietic stem cell transplantation (HSCT), and skin disorders such as HFS have been reported. The aim of this study was to determine retrospectively the frequency of HFS in recipients who have received a first allogeneic HSCT and the risk factors for HFS occurrence.
Methods
We retrospectively investigated the medical records of recipients who received their first allogeneic HSCT and neutrophil engraftment at Shizuoka Cancer Center from January 1, 2011, to December 31, 2019.
Results
The occurrence of HFS was confirmed in 78 cases (48.1%), and no grade 3 HFS was confirmed. The median occurrence of HFS was 8 (− 3 to 19) days. In recipients with and without confirmed HFS, the median neutrophil engraftment day was 16.5 (10–33) and 15.0 (11–26) days, respectively (
p
= 0.013). Multivariate analysis indicated that the frequency of HFS was statistically significantly higher in women (
p
= 0.032), recipients administered busulfan (Bu) four times daily (
p
= 0.011), and recipients previously treated with anthracycline (
p
= 0.002).
Conclusion
Attention should be paid to HFS that occurs due to the conditioning regimen for HSCT in women, recipients who received 0.8 mg/kg of Bu four times a day, and recipients with a history of anthracycline administration, as HFS may affect the duration to neutrophil engraftment.
Target organ toxicity is often a reason for attritions in nonclinical and clinical drug development. Leveraging emerging safety biomarkers in nonclinical studies provides an opportunity to monitor ...such toxicities early and efficiently, potentially translating to early clinical trials. As a part of the European Union's Innovative Medicines Initiative (IMI), two projects have focused on evaluating safety biomarkers of nervous system (NS) toxicity: Translational Safety Biomarker Pipeline (TransBioLine) and Neurotoxicity De-Risking in Preclinical Drug Discovery (NeuroDeRisk).
Performance of fluid-based NS injury biomarker candidates neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE) and total Tau in plasma and cerebrospinal fluid (CSF) was evaluated in 15 rat
studies. Model nervous system toxicants as well as other compounds were used to evaluate sensitivity and specificity. Histopathologic assessments of nervous tissues and behavioral observations were conducted to detect and characterize NS injuries. Receiver operator characteristic (ROC) curves were generated to compare the relative performance of the biomarkers in their ability to detect NS injury.
NF-L was the best performer in detecting both peripheral nervous system (PNS) and CNS injury in plasma, (AUC of 0.97-0.99; respectively). In CSF, Tau correlated the best with CNS (AUC 0.97), but not PNS injury. NSE and GFAP were suitable for monitoring CNS injury, but with lesser sensitivity. In summary, NF-L is a sensitive and specific biomarker in rats for detecting compound-induced central and peripheral NS injuries. While NF-L measurement alone cannot inform the site of the injury, addition of biomarkers like Tau and NSE and analysis in both blood and CSF can provide additional information about the origin of the NS injury.
These results demonstrate the utility of emerging safety biomarkers of drug-induced NS injury in rats and provide additional supporting evidence for biomarker translation across species and potential use in clinical settings to monitor drug-induced NS injury in patients.
The effect on hydraulic conductivity in porous media of CaCO3 precipitation induced by Sporosarcina pasteurii (ATCC 11859) was investigated using continuous-flow columns containing glass beads ...between 0.01 mm and 3 mm in diameter. Resting S. pasteurii cells and a precipitation solution composed of 0.5 M CaCl2 and 0.5 M urea were introduced into the columns, and it was shown that the subsequent formation of CaCO3 precipitation reduced hydraulic conductivity from between 8.38 × 10−1 and 3.27 × 10−4 cm/s to between 3.70 × 10−1 and 3.07 × 10−5 cm/s. The bacterial cells themselves did not decrease the hydraulic conductivity. The amount of precipitation was proportional with the bacterial number in the column. The specific CaCO3 precipitation rate of the resting cells was estimated as 4.0 ± 0.1 × 10−3 μg CaCO3/cell. Larger amounts of CaCO3 precipitation were deposited in columns packed with small glass beads than in those packed with large glass beads, resulting in a greater reduction in the hydraulic conductivity of the columns containing small glass beads. Analysis using the Kozeny–Carman equation suggested that the effect of microbially induced CaCO3 precipitation on hydraulic conductivity was not due to the formation of individual CaCO3 crystals but instead that the precipitate aggregated with the glass beads, thus increasing their diameter and consequently decreasing the pore size in the column.
To assess whether ovarian histopathological examination in repeated-dose rodent toxicity study could reliably anticipate toxic effects on female reproductive function and to assess whether ovarian ...change could be detected in a 2-week repeated-dose toxicity study, tamoxifen was administrated orally to female rats at 0.005, 0.03, or 0.2 mg/kg/day for 2 and 4 weeks in the repeated-dose toxicity studies, and for 2 weeks prior to cohabitation, during cohabitation, and through Gestation Day 7 in a female fertility study. The relationship between ovarian histopathological findings and fertility results was investigated. Findings at 0.03 and 0.2 mg/kg/day included decreases in body weight gains associated with decreases in food consumption, in 2- and 4-week repeated-dose toxicity studies and fertility study. The ovarian histopathological findings included increases in large atretic follicles, increases in interstitium cells and absence of newly-formed corpus lutea at 0.2 mg/kg/day in the 2-week study and at 0.03 and 0.2 mg/kg/day in the 4-week study. The treatment induced estrogenic and antiestrogenic reactions in the uterus, while mucinous degeneration was detected in the vagina. Effects on female fertility consisted primarily of disturbance of estrus cycle and decreases in numbers of pregnant rats which were considered to be related to ovarian histopathological changes. Based on these findings, ovarian histopathological evaluation in the repeated-dose toxicity study could anticipate the effects of tamoxifen on female fertility via ovarian dysfunction at slightly toxic doses, and 2-week treatment of tamoxifen at appropriate dose could be sufficient to detect ovarian toxicity by microscopic examination.
Toxicology studies in nonhuman primates were conducted to evaluate selective, brain penetrant inhibitors of LRRK2. GNE 7915 was limited to 7-day administration in cynomolgus monkeys at 65 mg/kg/day ...or limited to 14 days in rhesus at 22.5 mg/kg b.i.d. due to physical signs. Compound 25 demonstrated acceptable tolerability at 50 and 225 mg/kg b.i.d. for 7 days in rhesus monkeys. MK-1468 was tolerated during 7-day administration at 100, 200 or 800 mg/kg/day or for 30-day administration at 30, 100, or 500 mg/kg b.i.d. in rhesus monkeys. The lungs revealed hypertrophy of type 2 pneumocytes, with accumulation of intra-alveolar macrophages. Transmission electron microscopy confirmed increased lamellar structures within hypertrophic type 2 pneumocytes. Hypertrophy and hyperplasia of type 2 pneumocytes with accumulation of intra-alveolar macrophages admixed with neutrophils were prominent at peripheral lungs of animals receiving compound 25 or MK-1468. Affected type 2 pneumocytes were immuno-positive for pro-surfactant C, but negative for CD11c, a marker for intra-alveolar macrophages. Accumulation of collagen within alveolar walls, confirmed by histochemical trichrome stain, accompanied changes described for compound 25 and MK-1468. Following a 12-week treatment-free interval, animals previously receiving MK-1468 for 30 days exhibited remodeling of alveolar structure and interstitial components that did not demonstrate reversibility.
Alternative formulations of entecavir, a once daily oral hepatitis B antiretroviral, may improve treatment adherence by patients. We explored the use of biocompatible polymers to control entecavir ...dissolution in two formats suitable for subcutaneous implantation. Hot melt extrudates were prepared by extruding entecavir-polymer blends at specified weight ratios. Dip-coated tablets were prepared by compressing entecavir in a multi-tip tooling. Tablets were dip-coated in solutions of polymer and dried. In rodents, entecavir-poly(caprolactone) extrudates demonstrated >180 days of continuous drug release, although below the estimated efficacious target input rate. Drug pharmacokinetic profiles were tunable by varying the polymer employed and implant format. The rank order trends of drug input rates observed in vitro were observed in vivo in the detected plasma concentrations of entecavir. In all dose groups entecavir was not tolerated locally at the site of administration where adverse event severity correlated with drug input rate. These polymer-based implantable formats have applicability to long-acting formulations of high solubility compounds beyond entecavir.
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The hybrid commercial vehicles, which have been introducing into the market, still remains some of issues in practicality especially in Medium and Heavy duty category. The most practical solution for ...a while is to use the efficient diesel engine more effectively. In that case, the optimal basic vehicle architecture ' and its efficient on-board energy management of the vehicle are the most important technical issues to be improved. The future possibility of more electrification of the vehicle is strongly depending on the drastic improvement of the Energy Storage System performance. In this report, the basic theory of the diesel engine based hybrid commercial vehicle and the remained issues to be cleared for the next generation are mainly shown.
Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the ...clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.
The hydraulic conductivity of a paddy field (Anthraquic Dystrustept), a silty clay soil containing more than 29% (w/w) of gravel, in Nagoya University Farm was reduced by in situ treatment of ...subsurface soil using bentonite and biocalcification (microbial calcium carbonate precipitation) through the addition of CaCl
2
, urea, and corn steep liquor (CSL). The treatment decreased the hydraulic conductivity of the field from an average of 10
−3
cm/s to a range of 10
−5
to 10
−7
cm/s during 69 days, with reducing the proportion of pores of subsurface soil larger than 75 µm in diameter. The biocalcification effect was observed at 10-cm thickness from the treated subsurface. Laboratory soil core experiments demonstrated that the decrease in the hydraulic conductivity was not attributed to the effect of bentonite but mainly to the effect of biocalcification. The addition of CSL enhanced the urease activity of soil required for biocalcification, even at 4°C, as indicated by a decrease in urease activation energy temperature sensitivity. These experimental results agreed with the gradual decrease in hydraulic conductivity observed in the field when the average daily temperature was 7°C (days 24-69). It was suggested that the biocalcification is a potential technique to reduce the hydraulic conductivity of paddy field.
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